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Laymon JL, Whitten CJ, Radford AF, Brewer AR, Deo YS, Hooker MK, Geddati AA, Cooper MA. Distinguishing neural ensembles in the infralimbic cortex that regulate stress vulnerability and coping behavior. Neurobiol Stress 2025; 36:100720. [PMID: 40230624 PMCID: PMC11994976 DOI: 10.1016/j.ynstr.2025.100720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/19/2025] [Indexed: 04/16/2025] Open
Abstract
Neural ensembles in the medial prefrontal cortex regulate several types of responses to stress. We used a Syrian hamster model to investigate the role of infralimbic (IL) neurons in coping with social defeat stress and vulnerability to subsequent anxiety-like behavior. We created social dominance relationships in male and female hamsters, used a robust activity marker (RAM) approach to label IL neural ensembles activated during social defeat stress, and employed light-dark (LD), social avoidance (SA), and conditioned defeat (CD) tests to assess anxiety-like behavior. We found that dominant animals were less anxious in LD tests compared to subordinate animals after achieving their higher status. Also, status-dependent differences in anxiety-like behavior were maintained following social defeat in males, but not females. Subordinate males showed greater RAM-mKate2 expression in IL parvalbumin (PV) cells during social defeat exposure compared to dominant males, and submissive behavior during CD testing was correlated with RAM/PV co-expression. In contrast, greater RAM-mKate2 expression in IL neurons was correlated with a longer latency to submit during social defeat in dominant females, although the correlation of RAM/PV co-expression and defeat-induced anxiety in females was mixed. Overall, these findings suggest that activation of IL PV cells during social defeat predicts the development stress vulnerability in males, whereas activation of IL neurons is associated with a proactive response to social defeat exposure in females. Understanding how social dominance generates plasticity in IL PV cells should improve our understanding of the mechanisms by which behavioral treatments prior to stress might promote stress resilience.
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Affiliation(s)
- Jenna L. Laymon
- Translational Neuroscience Program, Wayne State University School of Medicine, USA
| | | | - Anna F. Radford
- Department of Psychology, University of Tennessee Knoxville, USA
| | | | - Yash S. Deo
- Department of Psychology, University of Tennessee Knoxville, USA
| | | | - Akhil A. Geddati
- Department of Psychology, University of Tennessee Knoxville, USA
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Zhao M, Xing L, Li Y, Zhang J, Liu Y, Ye F, Chen S. Multiomics-based analysis of key genes, metabolites and pathways unveils mechanism associated with social rank in Chickens. Poult Sci 2025; 104:105192. [PMID: 40319585 DOI: 10.1016/j.psj.2025.105192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/27/2025] [Accepted: 04/18/2025] [Indexed: 05/07/2025] Open
Abstract
Social rank plays a crucial role in shaping physiological, psychological and immune responses in animals. Our previous study found that gut microbes and short-chain fatty acids as well as brain neurotransmitters are involved with the mechanism of social hierarchy. Nevertheless, how these gut and brain metabolites interact to affect the mechanism of social hierarchy in chickens is not yet known. In this study, 40 hens were randomly divided into four groups at the age of 49 days, and social rank of each hen was determined by 6 times according to the feeding competition tests. Then hens ranked 1/2 were named High Social Rank (HSR, n = 8) and hens ranked 9/10 were named Low Social Rank (LSR, n = 8). We use multiomics to explore gut metabolites, neurotransmitters, and brain transcriptome, neurotransmitters and related gene expression in 91-day-old chickens, so as to better understand the underpinning mechanism that regulates the social hierarchy. We found that the pro-inflammatory genes were significantly lower while anti-inflammatory factor in spleen was higher in HSR chickens than in LSR chickens (P<0.05). Besides, seven immune-related genes were significantly different in the amygdala between HSR and LSR (P < 0.05). In addition, AVP, RXFP3, VIP and NKX2-1 were associated with the social rank through GABAergic neurons and neuroactive ligand-receptor pathways, with the up-regulation of 5-HT in the amygdala of LSR. Genes SLC11A2 and HMOX1 in ferroptosis pathway influenced the cecum metabolite l-glutamate and tyrosine. While fumaric, l-glutamic and 4-Oxoproline were found enriched in "alanine, aspartate and glutamate metabolism" and "arginine biosynthesis". In conclusion, social rank affects the immunity, in which higher ranking hens show better anti-inflammatory and lower pro-inflammatory than lower ranking hens. Genes TAP2, PLD4, P2RX7, ALDH9A1, SLC11A2, ADM, C3, AVP, RXFP3, VIP, NKX2-1, SLC11A2 and HMOX1 may play an important regulatory role on GABAergic neurons, neuroactive ligand-receptor and ferroptosis pathways related to neuron, immune, and stress behaviour, and in turn affects social rank. Fumaric, l-glutamic and 4-Oxoproline, may regulate social rank through the "alanine, aspartate and glutamate metabolism" and "arginine biosynthesis".
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Affiliation(s)
- Mengqiao Zhao
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, PR China
| | - Limin Xing
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, PR China
| | - Yushan Li
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, PR China
| | - Jiaxin Zhang
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, PR China
| | - Yinghui Liu
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, PR China
| | - Fei Ye
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, PR China
| | - Siyu Chen
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, PR China.
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Balasubramanian N, Wang R, Ismail S, Hartman B, Aboushaar Z, Marcinkiewcz CA. A New Insight into the Role of CART Peptide in Serotonergic Function and Anxiety. J Neurosci 2025; 45:e0467242024. [PMID: 39909575 PMCID: PMC11800755 DOI: 10.1523/jneurosci.0467-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 11/18/2024] [Accepted: 11/27/2024] [Indexed: 02/07/2025] Open
Abstract
Cocaine- and amphetamine-regulated transcript (CART) peptide has been implicated in stress-related behaviors that are regulated by central serotonergic (5-HT) systems in the dorsal raphe nucleus (DRN). Here, we aimed to investigate the interaction between CART and DRN 5-HTergic systems after initially observing CART axonal terminals in the DRN. We found that microinfusion of CART peptide (55-102) into the DRN-induced anxiogenic effects in male C57BL/6J mice, while central administration of CART reduced c-Fos in 5-HTDRN neurons. This inhibitory effect of exogenous CART on 5-HTDRN activity and local 5-HT release was also demonstrated via in vivo fiber photometry coupled with calcium and 5-HT biosensors. CART inputs to the DRN were observed in various subcortical nuclei, but only those in the centrally projecting Edinger-Westphal nucleus (EWcp) were highly responsive to stress. Chemogenetic activation of these DRN-projecting CARTEWcp neurons recapitulated the effects of intra-DRN CART infusion on anxiety-like behavior in males, but not in females, suggesting a sex-specific role for this pathway. Interestingly, CARTEWcp projections to the DRN made direct synaptic contact primarily with non-5-HT neurons, which were also found to express putative CART receptors. Furthermore, chemogenetic stimulation of this CARTEWcp→DRN pathway inhibited 5-HT neurons while increasing activity in local GABAergic neurons. In summary, this study establishes for the first time a neuromodulatory role for CARTEWcp neurons in 5-HTDRN neurotransmission and suggests that CART may drive anxiety-like behavior by promoting feedforward inhibition of 5-HT neurons.
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Affiliation(s)
- Nagalakshmi Balasubramanian
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa 52242
- Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242
| | - Ruixiang Wang
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa 52242
- Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242
| | - Shafa Ismail
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa 52242
| | - Benjamin Hartman
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa 52242
| | - Zeid Aboushaar
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa 52242
| | - Catherine A Marcinkiewcz
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa 52242
- Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242
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Conde KM, Wong H, Fang S, Li Y, Yu M, Deng Y, Liu Q, Fang X, Wang M, Shi Y, Ginnard OZ, Yang Y, Tu L, Liu H, Liu H, Yin N, Bean JC, Han J, Burt ME, Jossy SV, Yang Y, Tong Q, Arenkiel BR, Wang C, He Y, Xu Y. Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation. Metabolism 2025; 163:156099. [PMID: 39667432 PMCID: PMC11924950 DOI: 10.1016/j.metabol.2024.156099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/04/2024] [Accepted: 12/07/2024] [Indexed: 12/14/2024]
Abstract
Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HTDRN➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.
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Affiliation(s)
- Kristine M Conde
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - HueyZhong Wong
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Shuzheng Fang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yongxiang Li
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Meng Yu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yue Deng
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Qingzhuo Liu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Xing Fang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Mengjie Wang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yuhan Shi
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Olivia Z Ginnard
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yuxue Yang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Longlong Tu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Hesong Liu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Hailan Liu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Na Yin
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Jonathan C Bean
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Junying Han
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Megan E Burt
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Sanika V Jossy
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yongjie Yang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Qingchun Tong
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Benjamin R Arenkiel
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chunmei Wang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yang He
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yong Xu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
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5
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Koda M, Kawai H, Shirakawa H, Kaneko S, Nagayasu K. Effect of antidepressants and social defeat stress on the activity of dorsal raphe serotonin neurons in free-moving animals. J Pharmacol Sci 2025; 157:113-123. [PMID: 39828391 DOI: 10.1016/j.jphs.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/28/2024] [Accepted: 01/01/2025] [Indexed: 01/22/2025] Open
Abstract
Major depressive disorder (MDD) is among the most common mental disorders worldwide and is characterized by dysregulated reward processing associated with anhedonia. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for MDD; however, their onset of action is delayed. Recent reports have shown that serotonin neurons in the dorsal raphe nucleus (DRN) are activated by rewards and play a vital role in reward processing. However, whether antidepressant treatment affects the DRN serotonin neuronal response to rewards in awake animals remains unknown. In this study, we measured the activity of DRN serotonin neurons in awake mice and determined the effects of antidepressants and chronic stress on DRN serotonin neuronal activity. We found that acute treatment with citalopram, an SSRI, significantly decreased sucrose-induced activation of DRN serotonin neurons. The decrease in response to acute citalopram treatment was attenuated by chronic citalopram treatment. Acute treatment with (S)-WAY100135, a 5-HT1A receptor antagonist, dose-dependently inhibited the response to acute citalopram treatment. These results indicate that autoinhibition by activating 5-HT1A receptors via acute SSRI treatment may blunt the reward response, which can be recovered after chronic SSRI treatment.
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Affiliation(s)
- Masashi Koda
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Hiroyuki Kawai
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan; Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-cho, Abeno-ku, Osaka, 545-8585, Japan
| | - Hisashi Shirakawa
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Kazuki Nagayasu
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, 565-0871, Japan; Project for Neural Networks, Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, 565-0871, Japan.
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6
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Zhukovskaya A, Zimmerman CA, Willmore L, Pan-Vazquez A, Janarthanan SR, Lynch LA, Falkner AL, Witten IB. Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility. Neuron 2024; 112:3940-3956.e10. [PMID: 39393349 PMCID: PMC11624084 DOI: 10.1016/j.neuron.2024.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 07/04/2024] [Accepted: 09/08/2024] [Indexed: 10/13/2024]
Abstract
Some individuals are susceptible to chronic stress, and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After (but not before) chronic social defeat stress, the LHb is active when susceptible mice are in proximity of the aggressor strain. During stress, activity is higher in susceptible mice during aggressor interactions, and activation biases mice toward susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical vs. cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.
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Affiliation(s)
- Anna Zhukovskaya
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | | | - Lindsay Willmore
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | | | | | - Laura A Lynch
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | - Annegret L Falkner
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | - Ilana B Witten
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA; Howard Hughes Medical Institute, Princeton University, Princeton, NJ, USA.
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Cao W, Li H, Luo J. Prefrontal cortical circuits in social behaviors: an overview. J Zhejiang Univ Sci B 2024; 25:941-955. [PMID: 39626878 PMCID: PMC11634449 DOI: 10.1631/jzus.b2300743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 01/02/2024] [Indexed: 12/13/2024]
Abstract
Social behaviors are fundamental and intricate functions in both humans and animals, governed by the interplay of social cognition and emotions. A noteworthy feature of several neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ), is a pronounced deficit in social functioning. Despite a burgeoning body of research on social behaviors, the precise neural circuit mechanisms underpinning these phenomena remain to be elucidated. In this paper, we review the pivotal role of the prefrontal cortex (PFC) in modulating social behaviors, as well as its functional alteration in social disorders in ASD or SCZ. We posit that PFC dysfunction may represent a critical hub in the pathogenesis of psychiatric disorders characterized by shared social deficits. Furthermore, we delve into the intricate connectivity of the medial PFC (mPFC) with other cortical areas and subcortical brain regions in rodents, which exerts a profound influence on social behaviors. Notably, a substantial body of evidence underscores the role of N-methyl-D-aspartate receptors (NMDARs) and the proper functioning of parvalbumin-positive interneurons within the mPFC for social regulation. Our overarching goal is to furnish a comprehensive understanding of these intricate circuits and thereby contribute to the enhancement of both research endeavors and clinical practices concerning social behavior deficits.
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Affiliation(s)
- Wei Cao
- Institute of Brain Science and Department of Physiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
- Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
- Zhejiang Philosophy and Social Science Laboratory for Research in Early Development and Childcare, Hangzhou Normal University, Hangzhou 311121, China
| | - Huiyi Li
- Institute of Brain Science and Department of Physiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
- Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
| | - Jianhong Luo
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310013, China.
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China.
- NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
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Bremshey S, Groß J, Renken K, Masseck OA. The role of serotonin in depression-A historical roundup and future directions. J Neurochem 2024; 168:1751-1779. [PMID: 38477031 DOI: 10.1111/jnc.16097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024]
Abstract
Depression is one of the most common psychiatric disorders worldwide, affecting approximately 280 million people, with probably much higher unrecorded cases. Depression is associated with symptoms such as anhedonia, feelings of hopelessness, sleep disturbances, and even suicidal thoughts. Tragically, more than 700 000 people commit suicide each year. Although depression has been studied for many decades, the exact mechanisms that lead to depression are still unknown, and available treatments only help a fraction of patients. In the late 1960s, the serotonin hypothesis was published, suggesting that serotonin is the key player in depressive disorders. However, this hypothesis is being increasingly doubted as there is evidence for the influence of other neurotransmitters, such as noradrenaline, glutamate, and dopamine, as well as larger systemic causes such as altered activity in the limbic network or inflammatory processes. In this narrative review, we aim to contribute to the ongoing debate on the involvement of serotonin in depression. We will review the evolution of antidepressant treatments, systemic research on depression over the years, and future research applications that will help to bridge the gap between systemic research and neurotransmitter dynamics using biosensors. These new tools in combination with systemic applications, will in the future provide a deeper understanding of the serotonergic dynamics in depression.
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Affiliation(s)
- Svenja Bremshey
- Synthetic Biology, University of Bremen, Bremen, Germany
- Neuropharmacology, University of Bremen, Bremen, Germany
| | - Juliana Groß
- Synthetic Biology, University of Bremen, Bremen, Germany
| | - Kim Renken
- Synthetic Biology, University of Bremen, Bremen, Germany
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Henderson F, Dumas S, Gangarossa G, Bernard V, Pujol M, Poirel O, Pietrancosta N, El Mestikawy S, Daumas S, Fabre V. Regulation of stress-induced sleep perturbations by dorsal raphe VGLUT3 neurons in male mice. Cell Rep 2024; 43:114411. [PMID: 38944834 DOI: 10.1016/j.celrep.2024.114411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/07/2024] [Accepted: 06/12/2024] [Indexed: 07/02/2024] Open
Abstract
Exposure to stressors has profound effects on sleep that have been linked to serotonin (5-HT) neurons of the dorsal raphe nucleus (DR). However, the DR also comprises glutamatergic neurons expressing vesicular glutamate transporter type 3 (DRVGLUT3), leading us to examine their role. Cell-type-specific tracing revealed that DRVGLUT3 neurons project to brain areas regulating arousal and stress. We found that chemogenetic activation of DRVGLUT3 neurons mimics stress-induced sleep perturbations. Furthermore, deleting VGLUT3 in the DR attenuated stress-induced sleep perturbations, especially after social defeat stress. In the DR, VGLUT3 is found in subsets of 5-HT and non-5-HT neurons. We observed that both populations are activated by acute stress, including those projecting to the ventral tegmental area. However, deleting VGLUT3 in 5-HT neurons minimally affected sleep regulation. These findings suggest that VGLUT3 expression in the DR drives stress-induced sleep perturbations, possibly involving non-5-HT DRVGLUT3 neurons.
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Affiliation(s)
- Fiona Henderson
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France
| | | | - Giuseppe Gangarossa
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France; Institut Universitaire de France (IUF), Paris, France
| | - Véronique Bernard
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France
| | - Marine Pujol
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France
| | - Odile Poirel
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France
| | - Nicolas Pietrancosta
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France; Sorbonne Université, CNRS UMR 7203, Laboratoire des BioMolécules, 75005 Paris, France
| | - Salah El Mestikawy
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France; Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montréal, QC H4H 1R3, Canada
| | - Stéphanie Daumas
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France.
| | - Véronique Fabre
- Sorbonne Université, CNRS UMR 8246, INSERM U1130 - Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005 Paris, France.
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10
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Zhukovskaya A, Christopher Z, Willmore L, Pan Vazquez A, Janarthanan S, Falkner A, Witten I. Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.11.06.565681. [PMID: 39005438 PMCID: PMC11244933 DOI: 10.1101/2023.11.06.565681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Some individuals are susceptible to the experience of chronic stress and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After, but not before, chronic social defeat stress (CSDS), the LHb is active when susceptible mice are in the proximity of the aggressor strain. During stress itself, LHb activity is higher in susceptible mice during aggressor proximity, and activation of the LHb during stress biases mice towards susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical versus cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.
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11
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Feng YY, Bromberg-Martin ES, Monosov IE. Dorsal raphe neurons integrate the values of reward amount, delay, and uncertainty in multi-attribute decision-making. Cell Rep 2024; 43:114341. [PMID: 38878290 DOI: 10.1016/j.celrep.2024.114341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 03/27/2024] [Accepted: 05/23/2024] [Indexed: 06/25/2024] Open
Abstract
The dorsal raphe nucleus (DRN) is implicated in psychiatric disorders that feature impaired sensitivity to reward amount, impulsivity when facing reward delays, and risk-seeking when confronting reward uncertainty. However, it has been unclear whether and how DRN neurons signal reward amount, reward delay, and reward uncertainty during multi-attribute value-based decision-making, where subjects consider these attributes to make a choice. We recorded DRN neurons as monkeys chose between offers whose attributes, namely expected reward amount, reward delay, and reward uncertainty, varied independently. Many DRN neurons signaled offer attributes, and this population tended to integrate the attributes in a manner that reflected monkeys' preferences for amount, delay, and uncertainty. After decision-making, in response to post-decision feedback, these same neurons signaled signed reward prediction errors, suggesting a broader role in tracking value across task epochs and behavioral contexts. Our data illustrate how the DRN participates in value computations, guiding theories about the role of the DRN in decision-making and psychiatric disease.
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Affiliation(s)
- Yang-Yang Feng
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA
| | | | - Ilya E Monosov
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA; Washington University Pain Center, Washington University, St. Louis, MO, USA; Department of Neurosurgery, Washington University, St. Louis, MO, USA; Department of Electrical Engineering, Washington University, St. Louis, MO, USA.
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12
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Spreen A, Alkhoury D, Walter H, Müller S. Optogenetic behavioral studies in depression research: A systematic review. iScience 2024; 27:109776. [PMID: 38726370 PMCID: PMC11079475 DOI: 10.1016/j.isci.2024.109776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/21/2023] [Accepted: 04/15/2024] [Indexed: 05/12/2024] Open
Abstract
Optogenetics has made substantial contributions to our understanding of the mechanistic underpinnings of depression. This systematic review employs quantitative analysis to investigate the impact of optogenetic stimulation in mice and rats on behavioral alterations in social interaction, sucrose consumption, and mobility. The review analyses optogenetic behavioral studies using standardized behavioral tests to detect behavioral changes induced via optogenetic stimulation in stressed or stress-naive mice and rats. Behavioral changes were evaluated as either positive, negative, or not effective. The analysis comprises the outcomes of 248 behavioral tests of 168 studies described in 37 articles, including negative and null results. Test outcomes were compared for each behavior, depending on the animal cohort, applied type of stimulation and the stimulated neuronal circuit and cell type. The presented synthesis contributes toward a comprehensive picture of optogenetic behavioral research in the context of depression.
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Affiliation(s)
- Anika Spreen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Neurosciences, CCM, Berlin, Germany
- Experimental Biophysics, Institute for Biology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Dana Alkhoury
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Neurosciences, CCM, Berlin, Germany
| | - Henrik Walter
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Neurosciences, CCM, Berlin, Germany
| | - Sabine Müller
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Neurosciences, CCM, Berlin, Germany
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13
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Conde KM, Wong H, Fang S, Li Y, Yu M, Deng Y, Liu Q, Fang X, Wang M, Shi Y, Ginnard OZ, Yang Y, Tu L, Liu H, Liu H, Yin N, Bean JC, Han J, Burt ME, Jossy SV, Yang Y, Tong Q, Arenkiel BR, Wang C, He Y, Xu Y. 5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.26.591360. [PMID: 38746314 PMCID: PMC11092489 DOI: 10.1101/2024.04.26.591360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN→arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.
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Affiliation(s)
- Kristine M. Conde
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - HueyZhong Wong
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Shuzheng Fang
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yongxiang Li
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Meng Yu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yue Deng
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Qingzhuo Liu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Xing Fang
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Mengjie Wang
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yuhan Shi
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Olivia Z. Ginnard
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yuxue Yang
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Longlong Tu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Hesong Liu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Hailan Liu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Na Yin
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Jonathan C. Bean
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Junying Han
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Megan E. Burt
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Sanika V. Jossy
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yongjie Yang
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Qingchun Tong
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Benjamin R. Arenkiel
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chunmei Wang
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yang He
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yong Xu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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14
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Ren S, Zhang C, Yue F, Tang J, Zhang W, Zheng Y, Fang Y, Wang N, Song Z, Zhang Z, Zhang X, Qin H, Wang Y, Xia J, Jiang C, He C, Luo F, Hu Z. A midbrain GABAergic circuit constrains wakefulness in a mouse model of stress. Nat Commun 2024; 15:2722. [PMID: 38548744 PMCID: PMC10978901 DOI: 10.1038/s41467-024-46707-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 03/07/2024] [Indexed: 04/01/2024] Open
Abstract
Enhancement of wakefulness is a prerequisite for adaptive behaviors to cope with acute stress, but hyperarousal is associated with impaired behavioral performance. Although the neural circuitries promoting wakefulness in acute stress conditions have been extensively identified, less is known about the circuit mechanisms constraining wakefulness to prevent hyperarousal. Here, we found that chemogenetic or optogenetic activation of GAD2-positive GABAergic neurons in the midbrain dorsal raphe nucleus (DRNGAD2) decreased wakefulness, while inhibition or ablation of these neurons produced an increase in wakefulness along with hyperactivity. Surprisingly, DRNGAD2 neurons were paradoxically wakefulness-active and were further activated by acute stress. Bidirectional manipulations revealed that DRNGAD2 neurons constrained the increase of wakefulness and arousal level in a mouse model of stress. Circuit-specific investigations demonstrated that DRNGAD2 neurons constrained wakefulness via inhibition of the wakefulness-promoting paraventricular thalamus. Therefore, the present study identified a wakefulness-constraining role DRNGAD2 neurons in acute stress conditions.
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Affiliation(s)
- Shuancheng Ren
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China.
- No. 953 Army Hospital, Shigatse, Tibet Autonomous Region, 857000, China.
| | - Cai Zhang
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Faguo Yue
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
- Sleep and Psychology Center, Bishan Hospital of Chongqing Medical University, Chongqing, 402760, China
| | - Jinxiang Tang
- Sleep and Psychology Center, Bishan Hospital of Chongqing Medical University, Chongqing, 402760, China
| | - Wei Zhang
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Yue Zheng
- Department of Anesthesiology, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yuanyuan Fang
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China
| | - Na Wang
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
- College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Zhenbo Song
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Zehui Zhang
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Xiaolong Zhang
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Han Qin
- Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, 400064, China
| | - Yaling Wang
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Jianxia Xia
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Chenggang Jiang
- Psychology Department, Women and Children's Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, Chongqing, 401147, China
| | - Chao He
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China.
| | - Fenlan Luo
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China.
| | - Zhian Hu
- Department of Physiology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China.
- Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, 400064, China.
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15
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Nagayasu K. Integrative Research of Neuropharmacology and Informatics Pharmacology for Mental Disorder. Biol Pharm Bull 2024; 47:556-561. [PMID: 38432911 DOI: 10.1248/bpb.b23-00926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2024]
Abstract
Mental illness poses a huge social burden, accounting for approximately 14% of all deaths. Depression, a major component of mental illness, affects approximately 300 million people worldwide, mainly in developed countries, and is not only a major social burden but also a cause of suicide. The social burden of depression is estimated to increase further in developing countries, and overcoming it is a pressing issue for all countries, including Japan. Although clinical evidence has demonstrated the efficacy of serotonergic neurotransmission enhancers in the treatment of depression, the full picture of their therapeutic effects has not yet been fully elucidated. In this review, we show that the hyperactivity of serotonin neurons, especially those in the dorsal raphe nucleus, is commonly induced by various antidepressants within a period corresponding to the onset of their clinical efficacy. We established quantitative prediction methods for pharmacological activity using only chemical structures to translate the biological understanding of mental disorders, including major depressive disorders, into clinically effective therapeutics. Our method exhibited better performance than the previously reported methods of quantitative prediction, while targeting a larger number of proteins. Our article suggests the importance of integrative neuropharmacology and informatics-based pharmacology studies to understand the biological basis of mental disorders and facilitate drug development for these disorders.
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Affiliation(s)
- Kazuki Nagayasu
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
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16
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Li W, Shen Z, Yin X, Chang W, Chen X, Yu J, Xu S. Reduction of p11 in dorsal raphe nucleus serotonergic neurons mediates depression-like behaviors. Transl Psychiatry 2023; 13:359. [PMID: 37993435 PMCID: PMC10665321 DOI: 10.1038/s41398-023-02664-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/13/2023] [Accepted: 11/09/2023] [Indexed: 11/24/2023] Open
Abstract
The pathology of depression is related to the imbalance of various neurotransmitters. The dorsal raphe nucleus (DRN), the main brain region producing 5-HT, is crucially involved in the pathophysiology of depression. It contains several neuron types, in which GABAergic neurons are activated by stimuli associated with negative experiences and 5-HT neurons are activated by reward signals. However, little is known about its underlying molecular mechanisms. Here, we found that p11, a multifunctional protein associated with depression, was down-regulated by chronic social defeat stress in 5-HTDRN neurons. Knockdown of p11 in DRN induced depression-like behaviors, while its overexpression in 5-HTDRN neurons alleviated depression-like behavior caused by chronic social defeat stress. Further, p11 regulates membrane trafficking of glutamate receptors in 5-HTDRN neurons, suggesting a possible molecular mechanism underlying the participation of p11 in the pathological process of depression. This may facilitate the understanding of the molecular and cellular basis of depression.
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Affiliation(s)
- Wei Li
- Department of Acupuncture and Moxibustion, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, 200433, China
| | - Zuqi Shen
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, 200433, China
| | - Xuan Yin
- Department of Acupuncture and Moxibustion, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Weiqi Chang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, 200433, China
| | - Xiaorong Chen
- Department of Physiology, Laboratory of Neurodegenerative diseases, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Jin Yu
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, 200433, China.
| | - Shifen Xu
- Department of Acupuncture and Moxibustion, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
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17
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Chen T, Zhu SJ, Xu S, Wang YQ, Aji A, Zhang C, Wang H, Li FL, Chu YX. Resting-state fMRI reveals changes within the anxiety and social avoidance circuitry of the brain in mice with psoriasis-like skin lesions. Exp Dermatol 2023; 32:1900-1914. [PMID: 37622736 DOI: 10.1111/exd.14914] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 08/02/2023] [Accepted: 08/05/2023] [Indexed: 08/26/2023]
Abstract
Psoriasis is an autoimmune skin disease that often co-occurs with psychological morbidities such as anxiety and depression, and psychosocial issues also lead psoriasis patients to avoid other people. However, the precise mechanism underlying the comorbidity of psoriasis and anxiety is unknown. Also, whether the social avoidance phenomenon seen in human patients also exists in psoriasis-like animal models remains unknown. In the present study, anxiety-like behaviours and social avoidance-like behaviours were observed in an imiquimod-induced psoriasis-like C57-BL6 mouse model along with typical psoriasis-like dermatitis and itch-like behaviours. The 11.7T resting-state functional magnetic resonance imaging showed differences in brain regions between the model and control group, and voxel-based morphometry showed that the grey matter volume changed in the basal forebrain region, anterior commissure intrabulbar and striatum in the psoriasis-like mice. Seed-based resting state functional connectivity analysis revealed connectivity changes in the amygdala, periaqueductal gray, raphe nuclei and lateral septum. We conclude that the imiquimod-induced psoriasis-like C57-BL6 mouse model is well suited for mechanistic studies and for performing preclinical therapeutic trials for treating anxiety and pathological social avoidance in psoriasis patients.
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Affiliation(s)
- Teng Chen
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
| | - Sheng-Jie Zhu
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shuai Xu
- Department of Neurology, Institute of Science and Technology for Brain-Inspired Intelligence, Zhongshan Hospital, Human Phenome Institute, Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, Fudan University, Shanghai, China
| | - Yu-Quan Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
| | - Abudula Aji
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
| | - Chen Zhang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
| | - He Wang
- Department of Neurology, Institute of Science and Technology for Brain-Inspired Intelligence, Zhongshan Hospital, Human Phenome Institute, Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, Fudan University, Shanghai, China
| | - Fu-Lun Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu-Xia Chu
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
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18
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Giovanniello J, Bravo-Rivera C, Rosenkranz A, Matthew Lattal K. Stress, associative learning, and decision-making. Neurobiol Learn Mem 2023; 204:107812. [PMID: 37598745 DOI: 10.1016/j.nlm.2023.107812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/02/2023] [Accepted: 08/17/2023] [Indexed: 08/22/2023]
Abstract
Exposure to acute and chronic stress has significant effects on the basic mechanisms of associative learning and memory. Stress can both impair and enhance associative learning depending on type, intensity, and persistence of the stressor, the subject's sex, the context that the stress and behavior is experienced in, and the type of associative learning taking place. In some cases, stress can cause or exacerbate the maladaptive behavior that underlies numerous psychiatric conditions including anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, substance use disorder, and others. Therefore, it is critical to understand how the varied effects of stress, which may normally facilitate adaptive behavior, can also become maladaptive and even harmful. In this review, we highlight several findings of associative learning and decision-making processes that are affected by stress in both human and non-human subjects and how they are related to one another. An emerging theme from this work is that stress biases behavior towards less flexible strategies that may reflect a cautious insensitivity to changing contingencies. We consider how this inflexibility has been observed in different associative learning procedures and suggest that a goal for the field should be to clarify how factors such as sex and previous experience influence this inflexibility.
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Affiliation(s)
| | - Christian Bravo-Rivera
- Departments of Psychiatry and Anatomy & Neurobiology, University of Puerto Rico School of Medicine, San Juan, PR 00935, United States.
| | - Amiel Rosenkranz
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Chicago Medical School, Rosalind Franklin University of Medicine and Science, United States.
| | - K Matthew Lattal
- Department of Behavioral Neuroscience, Oregon Health & Science University, United States.
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19
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Feng YY, Bromberg-Martin ES, Monosov IE. Dorsal raphe neurons signal integrated value during multi-attribute decision-making. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.17.553745. [PMID: 37662243 PMCID: PMC10473596 DOI: 10.1101/2023.08.17.553745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
The dorsal raphe nucleus (DRN) is implicated in psychiatric disorders that feature impaired sensitivity to reward amount, impulsivity when facing reward delays, and risk-seeking when grappling with reward uncertainty. However, whether and how DRN neurons signal reward amount, reward delay, and reward uncertainty during multi-attribute value-based decision-making, where subjects consider all these attributes to make a choice, is unclear. We recorded DRN neurons as monkeys chose between offers whose attributes, namely expected reward amount, reward delay, and reward uncertainty, varied independently. Many DRN neurons signaled offer attributes. Remarkably, these neurons commonly integrated offer attributes in a manner that reflected monkeys' overall preferences for amount, delay, and uncertainty. After decision-making, in response to post-decision feedback, these same neurons signaled signed reward prediction errors, suggesting a broader role in tracking value across task epochs and behavioral contexts. Our data illustrate how DRN participates in integrated value computations, guiding theories of DRN in decision-making and psychiatric disease.
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Affiliation(s)
- Yang-Yang Feng
- Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | | | - Ilya E. Monosov
- Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Washington University Pain Center, Washington University, St. Louis, Missouri, USA
- Department of Neurosurgery, Washington University, St. Louis, Missouri, USA
- Department of Electrical Engineering, Washington University, St. Louis, Missouri, USA
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20
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Alvarez-Bagnarol Y, García R, Vendruscolo LF, Morales M. Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal. Neuropsychopharmacology 2023:10.1038/s41386-023-01620-5. [PMID: 37270620 DOI: 10.1038/s41386-023-01620-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/23/2023] [Accepted: 05/22/2023] [Indexed: 06/05/2023]
Abstract
Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified an association between dorsal raphe (DR) neurons and the expression of hyperalgesia during spontaneous heroin withdrawal. Here, we found that chemogenetic inhibition of DR neurons decreased hyperalgesia during spontaneous heroin withdrawal in male and female C57/B6 mice. By neuroanatomy, we identified three major subtypes of DR neurons expressing μ-opioid receptors (MOR) that were activated in hyperalgesia during spontaneous withdrawal, those expressing vesicular GABA transporter (VGaT), glutamate transporter 3 (VGluT3), or co-expressing VGluT3 and tryptophan hydroxylase (TPH). In contrast, we identified a small population of DR-MOR neurons expressing solely TPH, which were not activated in hyperalgesia during spontaneous withdrawal. Collectively, these findings indicate a role of the DR in hyperalgesia during spontaneous heroin withdrawal mediated, in part, by the activation of local MOR-GABAergic, MOR-glutamatergic and MOR-co-releasing glutamatergic-serotonergic neurons. We found that specific chemogenetic inhibition of DR-VGaT neurons blocked hyperalgesia during spontaneous heroin withdrawal in male and female mice. Collectively, these findings indicate that DR-GABAergic neurons play a role in the expression of hyperalgesia during spontaneous heroin withdrawal.
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Affiliation(s)
- Yocasta Alvarez-Bagnarol
- Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
- Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico
- Stress and Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Intramural Research Programs, Baltimore, MD, USA
| | - Raul García
- Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
| | - Leandro F Vendruscolo
- Stress and Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Intramural Research Programs, Baltimore, MD, USA
| | - Marisela Morales
- Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.
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21
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Lemes JA, Silva MSCF, Gonçalves BSM, Céspedes IC, Viana MB. Deep Brain Stimulation of the dorsal raphe induces anxiolytic and panicolytic-like effects and alters serotonin immunoreactivity. Behav Brain Res 2023; 449:114462. [PMID: 37121276 DOI: 10.1016/j.bbr.2023.114462] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/26/2023] [Accepted: 04/27/2023] [Indexed: 05/02/2023]
Abstract
Previously we showed that Deep Brain Stimulation (DBS) of the dorsal region (DRD) and of the lateral wings of the dorsal raphe (lwDR) respectively decreases anxiety and panic-like responses in the elevated T-maze (ETM). This study investigates neurobiological alterations which might respond for these behavioral effects. Male Wistar rats were submitted to high-frequency stimulation (100µA, 100Hz) of the DRD or of the lwDR for 1h, and subsequently tested in the avoidance or escape tasks of the ETM. Since serotonin (5-HT) reuptake inhibitors are first line pharmacological treatment for anxiety disorders, we also tested the effects of chronic fluoxetine administration (10mg/kg, IP, 21 days) on a separate group of rats. An open field was used for locomotor activity assessment. Additionally, we evaluated c-Fos immunoreactivity (Fos-ir) in serotonergic cells of the dorsal raphe (DR). Results showed that DBS of the DRD decreases avoidance reactions, an anxiolytic-like effect, without altering escape or locomotor activity. Both fluoxetine and DBS of the lwDR decreased escape responses in the ETM, a panicolytic-like effect, without altering avoidance measurements or locomotor activity. While DBS of the DRD decreased double immunostaining in the DRD, DBS of the lwDR increased Fos-ir and double immunostaining in the DRD and lwDR. Fluoxetine also increased double immunostaining in the lwDR and in the DRV but decreased it in the DRD. These results suggest that both the anxiolytic and panicolytic-like effects of DBS and fluoxetine are related to 5-HT modulation in different subnuclei of the DR.
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Affiliation(s)
- J A Lemes
- Departamento de Biociências, Federal University of São Paulo (UNIFESP), Santos, Brazil
| | - M S C F Silva
- Departamento de Biociências, Federal University of São Paulo (UNIFESP), Santos, Brazil
| | - B S M Gonçalves
- Departamento de Biociências, Federal University of São Paulo (UNIFESP), Santos, Brazil
| | - I C Céspedes
- Departamento de Morfologia e Genética, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - M B Viana
- Departamento de Biociências, Federal University of São Paulo (UNIFESP), Santos, Brazil.
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22
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Campos ACP, Pople C, Silk E, Surendrakumar S, Rabelo TK, Meng Y, Gouveia FV, Lipsman N, Giacobbe P, Hamani C. Neurochemical mechanisms of deep brain stimulation for depression in animal models. Eur Neuropsychopharmacol 2023; 68:11-26. [PMID: 36640729 DOI: 10.1016/j.euroneuro.2022.12.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 01/13/2023]
Abstract
Deep brain stimulation (DBS) has emerged as a neuromodulation therapy for treatment-resistant depression, but its actual efficacy and mechanisms of action are still unclear. Changes in neurochemical transmission are important mechanisms of antidepressant therapies. Here, we review the preclinical DBS literature reporting behavioural and neurochemical data associated with its antidepressant-like effects. The most commonly studied target in preclinical models was the ventromedial prefrontal cortex (vmPFC). In rodents, DBS delivered to this target induced serotonin (5-HT) release and increased 5-HT1B receptor expression. The antidepressant-like effects of vmPFC DBS seemed to be independent of the serotonin transporter and potentially mediated by the direct modulation of prefrontal projections to the raphe. Adenosinergic and glutamatergic transmission might have also play a role. Medial forebrain bundle (MFB) DBS increased dopamine levels and reduced D2 receptor expression, whereas nucleus accumbens (NAcc), and lateral habenula (LHb) stimulation increased catecholamine levels in different brain regions. In rodents, subthalamic nucleus (STN) DBS induced robust depression-like responses associated with a reduction in serotonergic transmission, as revealed by a decrease in serotonin release. Some of these effects seemed to be mediated by 5HT1A receptors. In conclusion, the antidepressant-like effects of DBS in preclinical models have been well documented in multiple targets. Though variable mechanisms have been proposed, DBS-induced acute and long-term changes in neurochemical substrates seem to play an important role in the antidepressant-like effects of this therapy.
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Affiliation(s)
- Ana Carolina P Campos
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Christopher Pople
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Esther Silk
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Shanan Surendrakumar
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Thallita K Rabelo
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Ying Meng
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Flavia Venetucci Gouveia
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Nir Lipsman
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Hurvitz Brain Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Division of Neurosurgery, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Peter Giacobbe
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Hurvitz Brain Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Neuropsychiatry Program, Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Clement Hamani
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Hurvitz Brain Sciences Centre, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Division of Neurosurgery, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada.
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23
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The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons. Mol Psychiatry 2023; 28:1027-1045. [PMID: 33990773 PMCID: PMC8590712 DOI: 10.1038/s41380-021-01137-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 04/08/2021] [Accepted: 04/19/2021] [Indexed: 01/07/2023]
Abstract
Dopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.
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24
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Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience. Cell Rep 2023; 42:112149. [PMID: 36821440 DOI: 10.1016/j.celrep.2023.112149] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 11/24/2022] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects.
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25
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Behera CK, Joshi A, Wang DH, Sharp T, Wong-Lin K. Degeneracy and stability in neural circuits of dopamine and serotonin neuromodulators: A theoretical consideration. Front Comput Neurosci 2023; 16:950489. [PMID: 36761394 PMCID: PMC9905743 DOI: 10.3389/fncom.2022.950489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 12/30/2022] [Indexed: 01/26/2023] Open
Abstract
Degenerate neural circuits perform the same function despite being structurally different. However, it is unclear whether neural circuits with interacting neuromodulator sources can themselves degenerate while maintaining the same neuromodulatory function. Here, we address this by computationally modeling the neural circuits of neuromodulators serotonin and dopamine, local glutamatergic and GABAergic interneurons, and their possible interactions, under reward/punishment-based conditioning tasks. The neural modeling is constrained by relevant experimental studies of the VTA or DRN system using, e.g., electrophysiology, optogenetics, and voltammetry. We first show that a single parsimonious, sparsely connected neural circuit model can recapitulate several separate experimental findings that indicated diverse, heterogeneous, distributed, and mixed DRNVTA neuronal signaling in reward and punishment tasks. The inability of this model to recapitulate all observed neuronal signaling suggests potentially multiple circuits acting in parallel. Then using computational simulations and dynamical systems analysis, we demonstrate that several different stable circuit architectures can produce the same observed network activity profile, hence demonstrating degeneracy. Due to the extensive D2-mediated connections in the investigated circuits, we simulate the D2 receptor agonist by increasing the connection strengths emanating from the VTA DA neurons. We found that the simulated D2 agonist can distinguish among sub-groups of the degenerate neural circuits based on substantial deviations in specific neural populations' activities in reward and punishment conditions. This forms a testable model prediction using pharmacological means. Overall, this theoretical work suggests the plausibility of degeneracy within neuromodulator circuitry and has important implications for the stable and robust maintenance of neuromodulatory functions.
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Affiliation(s)
- Chandan K. Behera
- Intelligent Systems Research Centre, School of Computing, Engineering and Intelligent Systems, Ulster University, Derry∼Londonderry, United Kingdom,*Correspondence: Chandan K. Behera,
| | - Alok Joshi
- Intelligent Systems Research Centre, School of Computing, Engineering and Intelligent Systems, Ulster University, Derry∼Londonderry, United Kingdom
| | - Da-Hui Wang
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China,School of Systems Science, Beijing Normal University, Beijing, China
| | - Trevor Sharp
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - KongFatt Wong-Lin
- Intelligent Systems Research Centre, School of Computing, Engineering and Intelligent Systems, Ulster University, Derry∼Londonderry, United Kingdom,KongFatt Wong-Lin,
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26
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Hon OJ, DiBerto JF, Mazzone CM, Sugam J, Bloodgood DW, Hardaway JA, Husain M, Kendra A, McCall NM, Lopez AJ, Kash TL, Lowery-Gionta EG. Serotonin modulates an inhibitory input to the central amygdala from the ventral periaqueductal gray. Neuropsychopharmacology 2022; 47:2194-2204. [PMID: 35999277 PMCID: PMC9630515 DOI: 10.1038/s41386-022-01392-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/21/2022] [Accepted: 07/11/2022] [Indexed: 11/08/2022]
Abstract
Fear is an adaptive state that drives defensive behavioral responses to specific and imminent threats. The central nucleus of the amygdala (CeA) is a critical site of adaptations that are required for the acquisition and expression of fear, in part due to alterations in the activity of inputs to the CeA. Here, we characterize a novel GABAergic input to the CeA from the ventral periaqueductal gray (vPAG) using fiber photometry and ex vivo whole-cell slice electrophysiology combined with optogenetics and pharmacology. GABA transmission from this ascending vPAG-CeA input was enhanced by serotonin via activation of serotonin type 2 C (5HT2C) receptors. Results suggest that these receptors are presynaptic. Interestingly, we found that GABA release from the vPAG-CeA input is enhanced following fear learning via activation of 5HT2C receptors and that this pathway is dynamically engaged in response to aversive stimuli. Additionally, we characterized serotonin release in the CeA during fear learning and recall for the first time using fiber photometry coupled to a serotonin biosensor. Together, these findings describe a mechanism by which serotonin modulates GABA release from ascending vPAG GABA inputs to the CeA and characterize a role for this pathway in fear.
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Affiliation(s)
- Olivia J Hon
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jeffrey F DiBerto
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Christopher M Mazzone
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jonathan Sugam
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Daniel W Bloodgood
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - J Andrew Hardaway
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mariya Husain
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alexis Kendra
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nora M McCall
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alberto J Lopez
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Thomas L Kash
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Emily G Lowery-Gionta
- Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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27
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Mendiguren A, Aostri E, Alberdi E, Pérez-Samartín A, Pineda J. Functional characterization of cannabidiol effect on the serotonergic neurons of the dorsal raphe nucleus in rat brain slices. Front Pharmacol 2022; 13:956886. [PMID: 36147343 PMCID: PMC9485894 DOI: 10.3389/fphar.2022.956886] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits several pharmacological effects via the 5-HT1A receptor. The dorsal raphe nucleus (DRN) is the main serotonergic cluster in the brain that expresses the 5-HT1A receptor. To date, the effect of CBD on the neuronal activity of DRN 5-HT cells and its interaction with somatodendritic 5-HT1A autoreceptors have not been characterized. Our aim was to study the effect of CBD on the firing activity of DRN 5-HT cells and the 5-HT1A autoreceptor activation by electrophysiological and calcium imaging techniques in male Sprague–Dawley rat brain slices. Perfusion with CBD (30 μM, 10 min) did not significantly change the firing rate of DRN 5-HT cells or the inhibitory effect of 5-HT (50–100 μM, 1 min). However, in the presence of CBD (30 μM, 10 min), the inhibitory effects of 8-OH-DPAT (10 nM) and ipsapirone (100 nM) were reduced by 66% and 53%, respectively. CBD failed to reverse ipsapirone-induced inhibition, whereas perfusion with the 5-HT1A receptor antagonist WAY100635 (30 nM) completely restored by 97.05 ± 14.63% the firing activity of 5-HT cells. Administration of AM251 (1 µM), MDL100907 (30 nM), or picrotoxin (20 μM) did not change the blockade produced by CBD (30 μM) on ipsapirone-induced inhibition. Our study also shows that CBD failed to modify the KCl (15 mM, 4 min)-evoked increase in [Ca2+]i or the inhibitory effect of ipsapirone (1 μM, 4 min) on KCl-evoked [Ca2+]i. In conclusion, CBD does not activate 5-HT1A autoreceptors, but it hindered the inhibitory effect produced by selective 5-HT1A receptor agonists on the firing activity of DRN 5-HT cells through a mechanism that does not involve CB1, 5-HT2A, or GABAA receptors. Our data support a negative allosteric modulation of DRN somatodendritic 5-HT1A receptor by CBD.
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Affiliation(s)
- Aitziber Mendiguren
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
- *Correspondence: Aitziber Mendiguren,
| | - Erik Aostri
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Elena Alberdi
- Achucarro Basque Center for Neuroscience, Department of Neuroscience, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Alberto Pérez-Samartín
- Achucarro Basque Center for Neuroscience, Department of Neuroscience, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Joseba Pineda
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
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28
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Bohne P, Volkmann A, Schwarz MK, Mark MD. Deletion of the P/Q-Type Calcium Channel from Serotonergic Neurons Drives Male Aggression in Mice. J Neurosci 2022; 42:6637-6653. [PMID: 35853721 PMCID: PMC9410759 DOI: 10.1523/jneurosci.0204-22.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/27/2022] [Accepted: 06/30/2022] [Indexed: 11/25/2022] Open
Abstract
Aggressive behavior is one of the most conserved social interactions in nature and serves as a crucial evolutionary trait. Serotonin (5-HT) plays a key role in the regulation of our emotions, such as anxiety and aggression, but which molecules and mechanisms in the serotonergic system are involved in violent behavior are still unknown. In this study, we show that deletion of the P/Q-type calcium channel selectively from serotonergic neurons in the dorsal raphe nuclei (DRN) augments aggressive behavior in male mice, while anxiety is not affected. These mice demonstrated increased induction of the immediate early gene c-fos and in vivo serotonergic firing activity in the DRN. The ventrolateral part of the ventromedial hypothalamus is also a prominent region of the brain mediating aggression. We confirmed a monosynaptic projection from the DRN to the ventrolateral part of the ventromedial hypothalamus, and silencing these projections with an inhibitory designer receptor exclusively activated by a designer drug effectively reduced aggressive behavior. Overall, our findings show that deletion of the P/Q-type calcium channel from DRN neurons is sufficient to induce male aggression in mice and regulating its activity may serve as a therapeutic approach to treat violent behavior.SIGNIFICANCE STATEMENT In this study, we show that P/Q-type calcium channel is mediating aggression in serotonergic neurons from the dorsal raphe nucleus via monosynaptic projections to the ventrolateral part of the ventromedial hypothalamus. More importantly, silencing these projections reduced aggressive behavior in mice and may serve as a therapeutic approach for treating aggression in humans.
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Affiliation(s)
- Pauline Bohne
- Behavioral Neuroscience, Ruhr-University Bochum, Bochum, D-44780, Germany
| | - Achim Volkmann
- Behavioral Neuroscience, Ruhr-University Bochum, Bochum, D-44780, Germany
| | - Martin K Schwarz
- Institute of Experimental Epileptology and Cognition Research, University of Bonn Medical School, Bonn, D-53127, Germany
| | - Melanie D Mark
- Behavioral Neuroscience, Ruhr-University Bochum, Bochum, D-44780, Germany
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29
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Petković A, Chaudhury D. Encore: Behavioural animal models of stress, depression and mood disorders. Front Behav Neurosci 2022; 16:931964. [PMID: 36004305 PMCID: PMC9395206 DOI: 10.3389/fnbeh.2022.931964] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/28/2022] [Indexed: 11/17/2022] Open
Abstract
Animal studies over the past two decades have led to extensive advances in our understanding of pathogenesis of depressive and mood disorders. Among these, rodent behavioural models proved to be of highest informative value. Here, we present a comprehensive overview of the most popular behavioural models with respect to physiological, circuit, and molecular biological correlates. Behavioural stress paradigms and behavioural tests are assessed in terms of outcomes, strengths, weaknesses, and translational value, especially in the domain of pharmacological studies.
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Affiliation(s)
| | - Dipesh Chaudhury
- Laboratory of Neural Systems and Behaviour, Department of Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
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30
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Brondi M, Bruzzone M, Lodovichi C, dal Maschio M. Optogenetic Methods to Investigate Brain Alterations in Preclinical Models. Cells 2022; 11:1848. [PMID: 35681542 PMCID: PMC9180859 DOI: 10.3390/cells11111848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/27/2022] [Accepted: 05/31/2022] [Indexed: 02/05/2023] Open
Abstract
Investigating the neuronal dynamics supporting brain functions and understanding how the alterations in these mechanisms result in pathological conditions represents a fundamental challenge. Preclinical research on model organisms allows for a multiscale and multiparametric analysis in vivo of the neuronal mechanisms and holds the potential for better linking the symptoms of a neurological disorder to the underlying cellular and circuit alterations, eventually leading to the identification of therapeutic/rescue strategies. In recent years, brain research in model organisms has taken advantage, along with other techniques, of the development and continuous refinement of methods that use light and optical approaches to reconstruct the activity of brain circuits at the cellular and system levels, and to probe the impact of the different neuronal components in the observed dynamics. These tools, combining low-invasiveness of optical approaches with the power of genetic engineering, are currently revolutionizing the way, the scale and the perspective of investigating brain diseases. The aim of this review is to describe how brain functions can be investigated with optical approaches currently available and to illustrate how these techniques have been adopted to study pathological alterations of brain physiology.
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Affiliation(s)
- Marco Brondi
- Institute of Neuroscience, National Research Council-CNR, Viale G. Colombo 3, 35121 Padova, Italy; (M.B.); (C.L.)
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy
| | - Matteo Bruzzone
- Department of Biomedical Sciences, Università degli Studi di Padova, Via U. Bassi 58B, 35121 Padova, Italy;
- Padova Neuroscience Center (PNC), Università degli Studi di Padova, Via Orus 2, 35129 Padova, Italy
| | - Claudia Lodovichi
- Institute of Neuroscience, National Research Council-CNR, Viale G. Colombo 3, 35121 Padova, Italy; (M.B.); (C.L.)
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy
- Department of Biomedical Sciences, Università degli Studi di Padova, Via U. Bassi 58B, 35121 Padova, Italy;
- Padova Neuroscience Center (PNC), Università degli Studi di Padova, Via Orus 2, 35129 Padova, Italy
| | - Marco dal Maschio
- Department of Biomedical Sciences, Università degli Studi di Padova, Via U. Bassi 58B, 35121 Padova, Italy;
- Padova Neuroscience Center (PNC), Università degli Studi di Padova, Via Orus 2, 35129 Padova, Italy
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Zhou L, Liu D, Xie Z, Deng D, Shi G, Zhao J, Bai S, Yang L, Zhang R, Shi Y. Electrophysiological Characteristics of Dorsal Raphe Nucleus in Tail Suspension Test. Front Behav Neurosci 2022; 16:893465. [PMID: 35711694 PMCID: PMC9194813 DOI: 10.3389/fnbeh.2022.893465] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/06/2022] [Indexed: 01/02/2023] Open
Abstract
The dorsal raphe nucleus (DRN) is a major source of serotonin in the central nervous system, which is closely related to depression-like behaviors and is modulated by local GABAergic interneurons. Although serotonin neurons are known to be activated by struggling behavior in tail suspension test (TST), the exact electrophysiological characteristics are still unclear. Here, we combined in vivo electrode recording and behavioral test to explore the mice neuron electrophysiology in DRN during TST and observed that gamma oscillation was related to despair-like behaviors whereas burst fraction was crucial for survival-like behaviors. We reported the identification of a subpopulation of DRN neurons which change their firing rates when mice get into and during TST immobile states. Both increase (putative despair units, D units for short) and decrease (putative survival units, S units for short) in firing rate were observed. Furthermore, using optogenetics to identify parvalbumin-positive (PV+) and serotonin transporter-positive (SERT+) neurons, we found that SERT+ neurons were almost S units. Interestingly, those that have been identified PV+ neurons include ~20% of D units and ~50% of S units. These results suggest that electrophysiological characteristics incorporated in despair-like behavior studies can provide new insight into the study of anti-depression targets, and GABAergic interneuron is a complex key hub to the coding and regulation of local neural network.
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Affiliation(s)
- Liuchang Zhou
- School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dan Liu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zedan Xie
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Di Deng
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Guoqi Shi
- School of Foreign Studies, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinlan Zhao
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shasha Bai
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Yang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rong Zhang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
- Rong Zhang
| | - Yafei Shi
- School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Yafei Shi
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32
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Rahaman SM, Chowdhury S, Mukai Y, Ono D, Yamaguchi H, Yamanaka A. Functional Interaction Between GABAergic Neurons in the Ventral Tegmental Area and Serotonergic Neurons in the Dorsal Raphe Nucleus. Front Neurosci 2022; 16:877054. [PMID: 35663550 PMCID: PMC9160575 DOI: 10.3389/fnins.2022.877054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/21/2022] [Indexed: 12/02/2022] Open
Abstract
GABAergic neurons in the ventral tegmental area (VTA) have brain-wide projections and are involved in multiple behavioral and physiological functions. Here, we revealed the responsiveness of Gad67+ neurons in VTA (VTAGad67+) to various neurotransmitters involved in the regulation of sleep/wakefulness by slice patch clamp recording. Among the substances tested, a cholinergic agonist activated, but serotonin, dopamine and histamine inhibited these neurons. Dense VTAGad67+ neuronal projections were observed in brain areas regulating sleep/wakefulness, including the central amygdala (CeA), dorsal raphe nucleus (DRN), and locus coeruleus (LC). Using a combination of electrophysiology and optogenetic studies, we showed that VTAGad67+ neurons inhibited all neurons recorded in the DRN, but did not inhibit randomly recorded neurons in the CeA and LC. Further examination revealed that the serotonergic neurons in the DRN (DRN5–HT) were monosynaptically innervated and inhibited by VTAGad67+ neurons. All recorded DRN5–HT neurons received inhibitory input from VTAGad67+ neurons, while only one quarter of them received inhibitory input from local GABAergic neurons. Gad67+ neurons in the DRN (DRNGad67+) also received monosynaptic inhibitory input from VTAGad67+ neurons. Taken together, we found that VTAGad67+ neurons were integrated in many inputs, and their output inhibits DRN5–HT neurons, which may regulate physiological functions including sleep/wakefulness.
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Affiliation(s)
- Sheikh Mizanur Rahaman
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Srikanta Chowdhury
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, United States
| | - Yasutaka Mukai
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Ono
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Yamaguchi
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akihiro Yamanaka
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
- *Correspondence: Akihiro Yamanaka,
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33
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Social interactions increase activation of vasopressin-responsive neurons in the dorsal raphe. Neuroscience 2022; 495:25-46. [DOI: 10.1016/j.neuroscience.2022.05.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/18/2022] [Accepted: 05/24/2022] [Indexed: 11/19/2022]
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34
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Dos Santos Guilherme M, Tsoutsouli T, Chongtham MC, Winter J, Gerber S, Müller MB, Endres K. Selective targeting of chronic social stress-induced activated neurons identifies neurogenesis-related genes to be associated with resilience in female mice. Psychoneuroendocrinology 2022; 139:105700. [PMID: 35220090 DOI: 10.1016/j.psyneuen.2022.105700] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/17/2022] [Accepted: 02/17/2022] [Indexed: 11/16/2022]
Abstract
Prolonged social stress is a major cause for depression in humans and is associated with a wide range of subsequent pathophysiological changes such as elevated blood pressure. A routinely used model for investigating this kind of stress in mice is the chronic social defeat paradigm where a smaller intruder is exposed to an aggressive inhabitant of a home cage. This model is restricted to males and includes a high proportion of physical stress that might e.g., interfere with immunological aspects of the stress. The prevalence of depression in humans is even higher in women than in men. Therefore, expanding models to female individuals is desirable. We here tested the social instability model as a tool for administering chronic social stress to female C57BL/6J mice and analyzed short-term as well as long-lasting effects. Animals were housed in groups of four and were shuffled two times a week, resulting in a permanent re-structuration of their social hierarchy. While directly after the stress exposure, serum corticosterone was elevated, increased body weight and fat deposits were observed in stressed mice even one year after discontinuation of the stress. At the behavioral level, animals could be stratified into resilient and susceptible animals directly post-stress, but those subgroups were not distinguishable any more in the long-term analysis. To identify molecular contributors to resilience in the here presented social instability induced stress model, Arc-activity dependent trapping of neurons was conducted in Arc-creERT2/sun1sfGFP mice. RNA samples derived from activated nuclei from the ventral hippocampus, a brain region involved in stress-regulation during attacks or explorative behavior of mice, were subjected to a neurogenesis pathway array. While several genes were differentially regulated by stress, in particular, artemin, a neurotrophic factor was upregulated in resilient versus susceptible individuals.
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Affiliation(s)
- Malena Dos Santos Guilherme
- Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Theodora Tsoutsouli
- Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Monika Chanu Chongtham
- Institute for Human Genetics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; Leibniz Institute for Resilience Research (LIR), Mainz, Germany
| | - Jennifer Winter
- Institute for Human Genetics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; Leibniz Institute for Resilience Research (LIR), Mainz, Germany
| | - Susanne Gerber
- Institute for Human Genetics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marianne B Müller
- Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany; Leibniz Institute for Resilience Research (LIR), Mainz, Germany
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
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35
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Stress-sensitive inference of task controllability. Nat Hum Behav 2022; 6:812-822. [PMID: 35273354 DOI: 10.1038/s41562-022-01306-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 01/17/2022] [Indexed: 11/08/2022]
Abstract
Estimating the controllability of the environment enables agents to better predict upcoming events and decide when to engage controlled action selection. How does the human brain estimate controllability? Trial-by-trial analysis of choices, decision times and neural activity in an explore-and-predict task demonstrate that humans solve this problem by comparing the predictions of an 'actor' model with those of a reduced 'spectator' model of their environment. Neural blood oxygen level-dependent responses within striatal and medial prefrontal areas tracked the instantaneous difference in the prediction errors generated by these two statistical learning models. Blood oxygen level-dependent activity in the posterior cingulate, temporoparietal and prefrontal cortices covaried with changes in estimated controllability. Exposure to inescapable stressors biased controllability estimates downward and increased reliance on the spectator model in an anxiety-dependent fashion. Taken together, these findings provide a mechanistic account of controllability inference and its distortion by stress exposure.
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36
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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37
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Hashimoto K, Yamawaki Y, Yamaoka K, Yoshida T, Okada K, Tan W, Yamasaki M, Matsumoto-Makidono Y, Kubo R, Nakayama H, Kataoka T, Kanematsu T, Watanabe M, Okamoto Y, Morinobu S, Aizawa H, Yamawaki S. Spike firing attenuation of serotonin neurons in learned helplessness rats is reversed by ketamine. Brain Commun 2021; 3:fcab285. [PMID: 34939032 PMCID: PMC8688795 DOI: 10.1093/braincomms/fcab285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/04/2021] [Accepted: 10/25/2021] [Indexed: 11/14/2022] Open
Abstract
Animals suffering from uncontrollable stress sometimes show low effort to escape stress (learned helplessness). Changes in serotonin (5-hydroxytryptamine) signalling are thought to underlie this behaviour. Although the release of 5-hydroxytryptamine is triggered by the action potential firing of dorsal raphe nuclei 5-hydroxytryptamine neurons, the electrophysiological changes induced by uncontrollable stress are largely unclear. Herein, we examined electrophysiological differences among 5-hydroxytryptamine neurons in naïve rats, learned helplessness rats and rats resistant to inescapable stress (non-learned helplessness). Five-week-old male Sprague Dawley rats were exposed to inescapable foot shocks. After an avoidance test session, rats were classified as learned helplessness or non-learned helplessness. Activity-dependent 5-hydroxytryptamine release induced by the administration of high-potassium solution was slower in free-moving learned helplessness rats. Subthreshold electrophysiological properties of 5-hydroxytryptamine neurons were identical among the three rat groups, but the depolarization-induced spike firing was significantly attenuated in learned helplessness rats. To clarify the underlying mechanisms, potassium (K+) channels regulating the spike firing were initially examined using naïve rats. K+ channels sensitive to 500 μM tetraethylammonium caused rapid repolarization of the action potential and the small conductance calcium-activated K+ channels produced afterhyperpolarization. Additionally, dendrotoxin-I, a blocker of Kv1.1 (encoded by Kcna1), Kv1.2 (encoded by Kcna2) and Kv1.6 (encoded by Kcna6) voltage-dependent K+ channels, weakly enhanced the spike firing frequency during depolarizing current injections without changes in individual spike waveforms in naïve rats. We found that dendrotoxin-I significantly enhanced the spike firing of 5-hydroxytryptamine neurons in learned helplessness rats. Consequently, the difference in spike firing among the three rat groups was abolished in the presence of dendrotoxin-I. These results suggest that the upregulation of dendrotoxin-I-sensitive Kv1 channels underlies the firing attenuation of 5-hydroxytryptamine neurons in learned helplessness rats. We also found that the antidepressant ketamine facilitated the spike firing of 5-hydroxytryptamine neurons and abolished the firing difference between learned helplessness and non-learned helplessness by suppressing dendrotoxin-I-sensitive Kv1 channels. The dendrotoxin-I-sensitive Kv1 channel may be a potential target for developing drugs to control activity of 5-hydroxytryptamine neurons.
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Affiliation(s)
- Kouichi Hashimoto
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yosuke Yamawaki
- Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Kenji Yamaoka
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Takayuki Yoshida
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Kana Okada
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Wanqin Tan
- Department of Neurobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Miwako Yamasaki
- Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Yoshiko Matsumoto-Makidono
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Reika Kubo
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Hisako Nakayama
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Tsutomu Kataoka
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Takashi Kanematsu
- Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Masahiko Watanabe
- Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Yasumasa Okamoto
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shigeru Morinobu
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Hidenori Aizawa
- Department of Neurobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shigeto Yamawaki
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
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38
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Xu Z, Feng Z, Zhao M, Sun Q, Deng L, Jia X, Jiang T, Luo P, Chen W, Tudi A, Yuan J, Li X, Gong H, Luo Q, Li A. Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in the mouse dorsal and median raphe nuclei. eLife 2021; 10:65502. [PMID: 34792021 PMCID: PMC8626088 DOI: 10.7554/elife.65502] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 11/17/2021] [Indexed: 11/25/2022] Open
Abstract
The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons that regulate diverse behavioral functions. However, their whole-brain input-output circuits remain incompletely elucidated. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We found that these neurons received inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus had divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons projected to the lateral habenula through multiple pathways. Correlation and cluster analysis revealed that glutamatergic and GABAergic neurons in the same raphe nucleus received heterogeneous inputs and sent different collateral projections. This connectivity atlas further elucidates the anatomical architecture of the raphe nuclei, which could facilitate better understanding of their behavioral functions.
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Affiliation(s)
- Zhengchao Xu
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China
| | - Zhao Feng
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China.,HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China
| | - Mengting Zhao
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China
| | - Qingtao Sun
- HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China
| | - Lei Deng
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China
| | - Xueyan Jia
- HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China
| | - Tao Jiang
- HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China
| | - Pan Luo
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China
| | - Wu Chen
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China
| | - Ayizuohere Tudi
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Yuan
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China.,HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China
| | - Xiangning Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China.,HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China
| | - Hui Gong
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China.,HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Science, Shanghai, China
| | - Qingming Luo
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China.,HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China.,School of Biomedical Engineering, Hainan University, Haikou, China
| | - Anan Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, China.,HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Science, Shanghai, China
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39
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Watanabe N, Takeda M. Neurophysiological dynamics for psychological resilience: A view from the temporal axis. Neurosci Res 2021; 175:53-61. [PMID: 34801599 DOI: 10.1016/j.neures.2021.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 10/19/2022]
Abstract
When an individual is faced with adversity, the brain and body work cooperatively to adapt to it. This adaptive process is termed psychological resilience, and recent studies have identified several neurophysiological factors ("neurophysiological resilience"), such as monoamines, oscillatory brain activity, hemodynamics, autonomic activity, stress hormones, and immune systems. Each factor is activated in an interactive manner during specific time windows after exposure to stress. Thus, the differences in psychological resilience levels among individuals can be characterized by differences in the temporal dynamics of neurophysiological resilience. In this review, after briefly introducing the frequently used approaches in this research field and the well-known factors of neurophysiological resilience, we summarize the temporal dynamics of neurophysiological resilience. This viewpoint clarifies an important time window, the more-than-one-hour scale, but the neurophysiological dynamics during this window remain elusive. To address this issue, we propose exploring brain-wide oscillatory activities using concurrent functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) techniques.
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Affiliation(s)
- Noriya Watanabe
- Research Center for Brain Communication, Research Institute, Kochi University of Technology, Kochi, Japan; Center for Information and Neural Networks, National Institute of Information and Communications Technology, Osaka, Japan.
| | - Masaki Takeda
- Research Center for Brain Communication, Research Institute, Kochi University of Technology, Kochi, Japan
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40
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Bhave VM, Nectow AR. The dorsal raphe nucleus in the control of energy balance. Trends Neurosci 2021; 44:946-960. [PMID: 34663507 DOI: 10.1016/j.tins.2021.09.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/04/2021] [Accepted: 09/23/2021] [Indexed: 01/07/2023]
Abstract
Energy balance is orchestrated by an extended network of highly interconnected nuclei across the central nervous system. While much is known about the hypothalamic circuits regulating energy homeostasis, the 'extra-hypothalamic' circuits involved are relatively poorly understood. In this review, we focus on the brainstem's dorsal raphe nucleus (DRN), integrating decades of research linking this structure to the physiologic and behavioral responses that maintain proper energy stores. DRN neurons sense and respond to interoceptive and exteroceptive cues related to energy imbalance and in turn induce appropriate alterations in energy intake and expenditure. The DRN is also molecularly differentiable, with different populations playing distinct and often opposing roles in controlling energy balance. These populations are integrated into the extended circuit known to regulate energy balance. Overall, this review summarizes the key evidence demonstrating an important role for the DRN in regulating energy balance.
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Affiliation(s)
- Varun M Bhave
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Alexander R Nectow
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
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41
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Alexander C, Vasefi M. Cannabidiol and the corticoraphe circuit in post-traumatic stress disorder. IBRO Neurosci Rep 2021; 11:88-102. [PMID: 34485973 PMCID: PMC8408530 DOI: 10.1016/j.ibneur.2021.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/04/2021] [Accepted: 08/18/2021] [Indexed: 01/06/2023] Open
Abstract
Post-Traumatic Stress Disorder (PTSD), characterized by re-experiencing, avoidance, negative affect, and impaired memory processing, may develop after traumatic events. PTSD is complicated by impaired plasticity and medial prefrontal cortex (mPFC) activity, hyperactivity of the amygdala, and impaired fear extinction. Cannabidiol (CBD) is a promising candidate for treatment due to its multimodal action that enhances plasticity and calms hyperexcitability. CBD’s mechanism in the mPFC of PTSD patients has been explored extensively, but literature on the mechanism in the dorsal raphe nucleus (DRN) is lacking. Following the PRISMA guidelines, we examined current literature regarding CBD in PTSD and overlapping symptomologies to propose a mechanism by which CBD treats PTSD via corticoraphe circuit. Acute CBD inhibits excess 5-HT release from DRN to amygdala and releases anandamide (AEA) onto amygdala inputs. By first reducing amygdala and DRN hyperactivity, CBD begins to ameliorate activity disparity between mPFC and amygdala. Chronic CBD recruits the mPFC, creating harmonious corticoraphe signaling. DRN releases enough 5-HT to ameliorate mPFC hypoactivity, while the mPFC continuously excites DRN 5-HT neurons via glutamate. Meanwhile, AEA regulates corticoraphe activity to stabilize signaling. AEA prevents DRN GABAergic interneurons from inhibiting 5-HT release so the DRN can assist the mPFC in overcoming its hypoactivity. DRN-mediated restoration of mPFC activity underlies CBD’s mechanism on fear extinction and learning of stress coping.
CBD reduces PTSD symptoms via the DRN and corticoraphe circuit. Acute effects of CBD reduce DRN-amygdala excitatory signaling to lessen the activity disparity between amygdala and mPFC. Chronic CBD officially resolves mPFC hypoactivity by facilitating 5-HT release from DRN to mPFC. CBD-facilitated endocannabinoid signaling stabilizes DRN activity and restores mPFC inhibitory control. Chronically administered CBD acts via the corticoraphe circuit to favor fear extinction over fear memory reconsolidation.
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Key Words
- 2-AG, 2-arachidonoylglycerol
- 5-HT, Serotonin
- 5-HT1AR, 5-HT Receptor Type 1A
- 5-HT2AR, 5-HT Receptor Type 2 A
- AEA, Anandamide
- CB1R, Cannabinoid Receptor Type 1
- CB2R, Cannabinoid Receptor Type 2
- CBD, Cannabidiol
- COVID-19, SARS-CoV-2
- Cannabidiol
- DRN, Dorsal Raphe Nucleus
- ERK1/2, Extracellular Signal-Related Kinases Type 1 or Type 2
- FAAH, Fatty Acid Amide Hydrolase
- GABA, Gamma-Aminobutyric Acid
- GPCRs, G-Protein Coupled Receptors
- NMDAR, N-Methyl-D-aspartate Receptors
- PET, Positron Emission Tomography
- PFC, DRN and Raphe
- PFC, Prefrontal Cortex
- PTSD
- PTSD, Post-Traumatic Stress Disorder
- SSNRI, Selective Norepinephrine Reuptake Inhibitor
- SSRI, Selective Serotonin Reuptake Inhibitor
- Serotonin
- TRPV1, Transient Receptor Potential Vanilloid 1 Channels
- Traumatic Stress
- fMRI, Functional Magnetic Resonance Imaging
- mPFC, Medial Prefrontal Cortex
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Affiliation(s)
- Claire Alexander
- Department of Biology, Lamar University, Beaumont, TX 77710, USA
| | - Maryam Vasefi
- Department of Biology, Lamar University, Beaumont, TX 77710, USA
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mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse. Int J Mol Sci 2021; 22:ijms22168671. [PMID: 34445375 PMCID: PMC8395521 DOI: 10.3390/ijms22168671] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/08/2021] [Accepted: 08/09/2021] [Indexed: 12/21/2022] Open
Abstract
Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.
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Angiotensin II induces cognitive decline and anxiety-like behavior via disturbing pattern of theta-gamma oscillations. Brain Res Bull 2021; 174:84-91. [PMID: 34090935 DOI: 10.1016/j.brainresbull.2021.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/13/2021] [Accepted: 06/01/2021] [Indexed: 01/11/2023]
Abstract
Hypertension is the most common chronic disease accompanied by cognitive decline and anxiety-like behavior. Angiotensin II (Ang II) induces hypertension by activating angiotensin II receptor subtype 1 (AT1R). The purpose of the study was to examine the potential underlying mechanism of alterations in cognition and anxiety-like behavior induced by Ang II. Adult C57 mice were intraperitoneal injected with either 1 mg/kg/d Ang II or saline individually for 14 consecutive days. Ang II resulted in cognitive decline and anxious like behavior in C57 mice. Moreover, Ang II disturbed bidirectional synaptic plasticity and neural oscillation coupling between high theta and gamma on PP (perforant pathway)-DG (dentate gyrus) pathway. In addition, Ang II decreased the expression of N-methyl-d-aspartate receptor (NR) 2A and NR 2B and increased the expression of GABAAR α1. The data suggest that Ang II disturb neural oscillations via altering excitatory and inhibitory (E/I) balance and eventually damage cognition and anxiety-like behavior in mice.
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LeClair KB, Russo SJ. Using social rank as the lens to focus on the neural circuitry driving stress coping styles. Curr Opin Neurobiol 2021; 68:167-180. [PMID: 33930622 DOI: 10.1016/j.conb.2021.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/02/2021] [Accepted: 03/11/2021] [Indexed: 10/21/2022]
Abstract
Social hierarchy position in humans is negatively correlated with stress-related psychiatric disease risk. Animal models have largely corroborated human studies, showing that social rank can impact stress susceptibility and is considered to be a major risk factor in the development of psychiatric illness. Differences in stress coping style is one of several factors that mediate this relationship between social rank and stress susceptibility. Coping styles encompass correlated groupings of behaviors associated with differential physiological stress responses. Here, we discuss recent insights from animal models that highlight several neural circuits that can contribute to social rank-associated differences in coping style.
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Affiliation(s)
- Katherine B LeClair
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Scott J Russo
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Liu H, Rastogi A, Narain P, Xu Q, Sabanovic M, Alhammadi AD, Guo L, Cao JL, Zhang H, Aqel H, Mlambo V, Rezgui R, Radwan B, Chaudhury D. Blunted diurnal firing in lateral habenula projections to dorsal raphe nucleus and delayed photoentrainment in stress-susceptible mice. PLoS Biol 2021; 19:e3000709. [PMID: 33690628 PMCID: PMC7984642 DOI: 10.1371/journal.pbio.3000709] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/22/2021] [Accepted: 02/04/2021] [Indexed: 01/29/2023] Open
Abstract
Daily rhythms are disrupted in patients with mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the 15-day chronic social defeat stress (CSDS) paradigm and in vitro slice electrophysiology, we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb→DRN) and unlabeled DRN cells. We also performed optogenetic experiments to investigate if increased firing in cellsLHb→DRN during exposure to a weak 7-day social defeat stress (SDS) paradigm induces stress-susceptibility. Last, we investigated whether exposure to CSDS affected the ability of mice to photoentrain to a new light–dark (LD) cycle. The cellsLHb→DRN and unlabeled DRN cells of stress-susceptible mice express greater blunted diurnal firing compared to stress-näive (control) and stress-resilient mice. Daytime optogenetic activation of cellsLHb→DRN during SDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that exposure to strong stressors induces blunted daily rhythms in firing in cellsLHb→DRN, DRN cells and decreases the initial rate of photoentrainment in susceptible-mice. In contrast, resilient-mice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb→DRN and also show rapid photoentrainment to a new LD cycle. Daily rhythms are disrupted in patients suffering from mood disorders, and it is known that the lateral habenula and dorsal raphe nucleus contribute to circadian timekeeping and regulate mood. This study shows that stress-susceptible mice have blunted and inverted diurnal firing rhythms in lateral habenula cells that project to the dorsal raphe nucleus, and have a slow rate of photoentrainment to a new light cycle.
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Affiliation(s)
- He Liu
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
- Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Jiangsu Province Key Laboratory of Anesthesiology & Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, The Xuzhou Medical University, Xuzhou, China
| | - Ashutosh Rastogi
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Priyam Narain
- Center for Genomics and Systems Biology, New York University Abu Dhabi, United Arab Emirates
| | - Qing Xu
- Center for Genomics and Systems Biology, New York University Abu Dhabi, United Arab Emirates
| | - Merima Sabanovic
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | | | - Lihua Guo
- Center for Genomics and Systems Biology, New York University Abu Dhabi, United Arab Emirates
| | - Jun-Li Cao
- Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Center for Genomics and Systems Biology, New York University Abu Dhabi, United Arab Emirates
| | - Hongxing Zhang
- Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hala Aqel
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Vongai Mlambo
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Rachid Rezgui
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Basma Radwan
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Dipesh Chaudhury
- The Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
- * E-mail:
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Fakhoury M. Optogenetics: A revolutionary approach for the study of depression. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106:110094. [PMID: 32890694 DOI: 10.1016/j.pnpbp.2020.110094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/13/2020] [Accepted: 08/30/2020] [Indexed: 10/24/2022]
Abstract
Depression is a severe and chronic mental disorder that affects millions of individuals worldwide. Symptoms include depressed mood, loss of interest, reduced motivation and suicidal thoughts. Even though findings from genetic, molecular and imaging studies have helped provide some clues regarding the mechanisms underlying depression-like behaviors, there are still many unanswered questions that need to be addressed. Optogenetics, a technique developed in the early 2000s, has proved effective in the study and treatment of depression and depression-like behaviors and has revolutionized already known experimental techniques. This technique employs light and genetic tools to either inhibit or excite specific neurons or pathways within the brain. In this review paper, an up-to-date understanding of the use of optogenetics in the study of depression-like behaviors is provided, along with suggestions for future research directions.
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Affiliation(s)
- Marc Fakhoury
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut Campus, Lebanon.
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Yoo H, Yang SH, Kim JY, Yang E, Park HS, Lee SJ, Rhyu IJ, Turecki G, Lee HW, Kim H. Down-regulation of habenular calcium-dependent secretion activator 2 induces despair-like behavior. Sci Rep 2021; 11:3700. [PMID: 33580180 PMCID: PMC7881199 DOI: 10.1038/s41598-021-83310-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 01/29/2021] [Indexed: 01/07/2023] Open
Abstract
Calcium-dependent secretion activator 2 (CAPS2) regulates the trafficking and exocytosis of neuropeptide-containing dense-core vesicles (DCVs). CAPS2 is prominently expressed in the medial habenula (MHb), which is related to depressive behavior; however, how MHb neurons cause depressive symptoms and the role of CAPS2 remains unclear. We hypothesized that dysfunction of MHb CAPS neurons might cause defects in neuropeptide secretion and the activity of monoaminergic centers, resulting in depressive-like behaviors. In this study, we examined (1) CAPS2 expression in the habenula of depression animal models and major depressive disorder patients and (2) the effects of down-regulation of MHb CAPS2 on the animal behaviors, synaptic transmission in the interpeduncular nucleus (IPN), and neuronal activity of monoamine centers. Habenular CAPS2 expression was decreased in the rat chronic restraint stress model, mouse learned helplessness model, and showed tendency to decrease in depression patients who died by suicide. Knockdown of CAPS2 in the mouse habenula evoked despair-like behavior and a reduction of the release of DCVs in the IPN. Neuronal activity of IPN and monoaminergic centers was also reduced. These results implicate MHb CAPS2 as playing a pivotal role in depressive behavior through the regulation of neuropeptide secretion of the MHb-IPN pathway and the activity of monoaminergic centers.
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Affiliation(s)
- Hyeijung Yoo
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea
- Department of Biomedical Sciences, Brain Korea 21 FOUR, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Soo Hyun Yang
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea
- Department of Biomedical Sciences, Brain Korea 21 FOUR, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Jin Yong Kim
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Esther Yang
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea
- Department of Biomedical Sciences, Brain Korea 21 FOUR, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Hyung Sun Park
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Se Jeong Lee
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Im Joo Rhyu
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea
- Department of Biomedical Sciences, Brain Korea 21 FOUR, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Gustavo Turecki
- Department of Psychiatry, McGill University, Douglas, Mental Health University Institute, Montreal, QC, H4H 1R3, Canada
| | - Hyun Woo Lee
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea.
- Department of Biomedical Sciences, Brain Korea 21 FOUR, College of Medicine, Korea University, Seoul, 02841, Korea.
| | - Hyun Kim
- Department of Anatomy, College of Medicine, Korea University, Seoul, 02841, Korea.
- Department of Biomedical Sciences, Brain Korea 21 FOUR, College of Medicine, Korea University, Seoul, 02841, Korea.
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48
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Biselli T, Lange SS, Sablottny L, Steffen J, Walther A. Optogenetic and chemogenetic insights into the neurocircuitry of depression-like behaviour: A systematic review. Eur J Neurosci 2021; 53:9-38. [PMID: 31633833 DOI: 10.1111/ejn.14603] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 09/13/2019] [Accepted: 10/14/2019] [Indexed: 12/13/2022]
Abstract
Major depressive disorder (MDD) and its treatment are challenges for global health. Optogenetics and chemogenetics are driving MDD research forward by unveiling causal relations between cell-type-specific control of neurons and depressive-like behaviour in rodents. Using a systematic search process, in this review, a set of 43 original studies applying optogenetic or chemogenetic techniques in rodent models of depression was identified. Our aim was to provide an examination of all available studies elucidating central neuronal mechanisms leading to depressive-like behaviour in rodents and thereby unveiling the most promising routes for future research. A complex interacting network of relevant structures, in which central circuitries causally related to depressive-like behaviour are implicated, has been identified. As most relevant structures emerge: medial prefrontal cortex, anterior cingulate cortex, amygdala, nucleus accumbens, ventral tegmental area, hippocampus and raphe nuclei. Further evidence, though examined by only few studies, emerges for structures like the lateral habenula, or medial dorsal thalamus. Most of the identified brain areas have previously been associated with MDD neuropathology, but now evidence can be provided for causal pathological mechanisms within a complex cortico-limbic reward circuitry. However, the studies also show conflicting results concerning the mechanisms underlying the causal involvement of specific circuitries. Comparability of studies is partly limited since even small deviations in methodological approaches lead to different outcomes. Factors influencing study outcomes were identified and need to be considered in future studies (e.g. frequency used for stimulation, time and duration of stimulation, limitations of applied animal models of MDD).
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Affiliation(s)
- Tom Biselli
- Biological Psychology, TU Dresden, Dresden, Germany
| | | | | | | | - Andreas Walther
- Biological Psychology, TU Dresden, Dresden, Germany
- Clinical Psychology and Psychotherapy, University of Zurich, Zurich, Switzerland
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Zeng H, Yu Z, Huang Q, Xu H. Attachment Insecurity in Rats Subjected to Maternal Separation and Early Weaning: Sex Differences. Front Behav Neurosci 2021; 15:637678. [PMID: 33897386 PMCID: PMC8058211 DOI: 10.3389/fnbeh.2021.637678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/16/2021] [Indexed: 02/05/2023] Open
Abstract
Attachment insecurity in the forms of attachment anxiety and avoidance is associated with mental disorders in humans. In this research field, rodents, especially mice and rats, are commonly used to study social behaviors and underlying biological mechanisms due to their pronounced sociability. However, quantitative assessment of attachment security/insecurity in rodents has been a major challenge. The present study identified attachment insecurity behaviors in rats subjected to maternal separation (MS) during postnatal days (PD) 2-16 and early weaning (EW) during PD 17-21. This MSEW procedure has been used to mimic early life neglect in humans. After MSEW, rats continued to survive until early adulthood when they were subjected to open-field, social interaction, and elevated-plus maze tests. Compared to CNT rats in either gender, MSEW rats moved longer distances at higher velocities in the open-field. The MSEW rats also showed lower ratios of travel distance at central zone over that on whole arena of the open-field compared to CNT rats. In social interaction test, male CNT rats preferred to investigate an empty cage than females; whereas female CNT rats spent more time with a partner-containing cage as compared to males. This gender-specific difference was reversed in MSEW rats. On elevated-plus maze female CNT rats exhibited more risk-taking behaviors as compared to male counterparts. Moreover, female MSEW rats experienced a greater difficulty in making a decision on whether approaching to or averting from which arms of elevated-plus maze. Taken together, male MSEW rats behaved like attachment anxiety while females' phenotype is alike to attachment avoidance described in humans. These results shall prompt further application of MSEW rat in abnormal psychology and biological psychiatry research.
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Affiliation(s)
- Haiyan Zeng
- The Mental Health Center, Shantou University Medical College, Shantou, China
- Xianyue Hospital/Xiamen Mental Health Center, Xiamen, China
| | - Zijia Yu
- The Mental Health Center, Shantou University Medical College, Shantou, China
| | - Qingjun Huang
- The Mental Health Center, Shantou University Medical College, Shantou, China
| | - Haiyun Xu
- The Mental Health Center, Shantou University Medical College, Shantou, China
- The School of Psychiatry, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Haiyun Xu,
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50
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Fonseca R, Madeira N, Simoes C. Resilience to fear: The role of individual factors in amygdala response to stressors. Mol Cell Neurosci 2020; 110:103582. [PMID: 33346000 DOI: 10.1016/j.mcn.2020.103582] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/13/2020] [Accepted: 12/02/2020] [Indexed: 10/22/2022] Open
Abstract
Resilience to stress is an adaptive process that varies individually. Resilience refers to the adaptation, or the ability to maintain or regain mental health, despite being subject to adverse situation. Resilience is a dynamic concept that reflects a combination of internal individual factors, including age and gender interacting with external factors such as social, cultural and environmental factors. In the last decade, we have witnessed an increase in the prevalence of anxiety disorders, including post-traumatic stress disorder. Given that stress in unavoidable, it is of great interest to understand the neurophysiological mechanisms of resilience, the individual factors that may contribute to susceptibility and promote efficacious approaches to improve resilience. Here, we address this complex question, attempting at defining clear and operational definitions that may allow us to improve our analysis of behavior incorporating individuality. We examine how individual perception of the stressor can alter the outcome of an adverse situation using as an example, the fear-conditioning paradigm and discuss how individual differences in the reward system can contribute to resilience. Given the central role of the endocannabinoid system in regulating fear responses and anxiety, we discuss the evidence that polymorphisms in several molecules of this signaling system contribute to different anxiety phenotypes. The endocannabinoid system is highly interconnected with the serotoninergic and dopaminergic modulatory systems, contributing to individual differences in stress perception and coping mechanisms. We review how the individual variability in these modulatory systems can be used towards a multivariable assessment of stress risk. Incorporating individuality in our research will allow us to define biomarkers of anxiety disorders as well as assess prognosis, towards a personalized clinical approach to mental health.
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Affiliation(s)
- Rosalina Fonseca
- Cellular and Systems Neurobiology, Chronic Diseases Research Center (CEDOC), NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130 1169-056 Lisboa, Portugal.
| | - Natália Madeira
- Cellular and Systems Neurobiology, Chronic Diseases Research Center (CEDOC), NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130 1169-056 Lisboa, Portugal
| | - Carla Simoes
- Cellular and Systems Neurobiology, Chronic Diseases Research Center (CEDOC), NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130 1169-056 Lisboa, Portugal
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