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1
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Burdakov D, Peleg-Raibstein D. How may the hypothalamus control distinct types and stages of memory? Neuropharmacology 2025:110513. [PMID: 40381884 DOI: 10.1016/j.neuropharm.2025.110513] [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: 01/12/2025] [Revised: 05/13/2025] [Accepted: 05/14/2025] [Indexed: 05/20/2025]
Abstract
Memory is a complex and multifaceted cognitive function integral to all aspects of survival across species. It involves short-term and long-term components, which are supported by distinct yet interconnected brain systems, each specialized in processing distinct types of information. These systems interact in an integrated and dynamic manner, allowing for the encoding, consolidation, retrieval, and updating of memories. In this review, we explore the role of orexin and melanin-concentrating hormone (MCH) neurons, clustered primarily within lateral hypothalamus (LH), in orchestrating these memory processes. We consider its demonstrated and potential contributions across memory phases (e.g., short-term, long-term), transitional processes (e.g., consolidation, retrieval), and memory types (e.g., declarative, nondeclarative). Particular attention is given to its neuropeptides, orexin and MCH, which have been implicated in modulating arousal, sleep, and neural plasticity - key factors in memory formation and maintenance. While orexin and MCH neurons have direct (arousal-independent) synaptic effects relevant to memory, their overall influence on memory processes is likely to include their established roles in regulating arousal, vigilance, and sleep. We further link these roles to the LH's traditional view as a nutritional sensor and regulator of arousal states, highlighting its unique position at the intersection of homeostatic and cognitive functions. By providing a unified perspective on the LH's involvement in memory, this work aims to bridge gaps in our understanding of its broader cognitive significance.
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Affiliation(s)
- Denis Burdakov
- Laboratory of Neurobehavioural Dynamics, Institute for Neuroscience, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, Federal Institute of Technology Zurich, ETH Zurich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland; Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
| | - Daria Peleg-Raibstein
- Laboratory of Neurobehavioural Dynamics, Institute for Neuroscience, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, Federal Institute of Technology Zurich, ETH Zurich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland; Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
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2
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Kongstorp M, Karnani MM, McCutcheon JE. Does the lateral hypothalamus govern the transition between appetitive and consummatory feeding? Neuropharmacology 2025; 275:110438. [PMID: 40194590 DOI: 10.1016/j.neuropharm.2025.110438] [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: 12/05/2024] [Revised: 03/20/2025] [Accepted: 03/28/2025] [Indexed: 04/09/2025]
Abstract
Feeding is a cyclic behaviour that includes appetitive, consummatory and termination phases. Identifying the neural circuits controlling these phases and triggering specific transitions between phases would be a key advance in understanding feeding behaviour. The lateral hypothalamus (LH) has long been recognized for its central role in feeding. We review evidence suggesting that the LH acts as a regulator of the appetitive-consummatory transition using a switchboard-like circuit architecture. Within the LH, several neuronal subpopulations can be defined based on molecular markers, and - although these subpopulations are functionally diverse - they contribute to appetitive and consummatory behaviours to varying extents. We summarise the current evidence on whether these subpopulations have functional identities and speculate on the role of the LH as a controller of behavioural transitions.
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Affiliation(s)
- Mette Kongstorp
- Department of Psychology, UiT The Arctic University of Norway, Huginbakken 32, 9037, Tromsø, Norway
| | - Mahesh M Karnani
- Centre for Discovery Brain Sciences, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK
| | - James E McCutcheon
- Department of Psychology, UiT The Arctic University of Norway, Huginbakken 32, 9037, Tromsø, Norway.
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3
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King CP, Chitre AS, Leal‐Gutiérrez JD, Tripi JA, Netzley AH, Horvath AP, Lamparelli AC, George A, Martin C, St. Pierre CL, Missfeldt Sanches T, Bimschleger HV, Gao J, Cheng R, Nguyen K, Holl KL, Polesskaya O, Ishiwari K, Chen H, Robinson TE, Flagel SB, Solberg Woods LC, Palmer AA, Meyer PJ. Genetic Loci Influencing Cue-Reactivity in Heterogeneous Stock Rats. GENES, BRAIN, AND BEHAVIOR 2025; 24:e70018. [PMID: 40049657 PMCID: PMC11884905 DOI: 10.1111/gbb.70018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 01/23/2025] [Accepted: 02/12/2025] [Indexed: 03/10/2025]
Abstract
Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues. Both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1596 heterogeneous stock (HS) rats. Rats underwent a Pavlovian conditioned approach task that characterized the responses to food-associated stimuli ("cues"). Responses ranged from cue-directed "sign-tracking" behavior to food-cup directed "goal-tracking" behavior (12 measures, SNP heritability: 0.051-0.215). Next, rats performed novel operant responses for unrewarded presentations of the cue using the conditioned reinforcement procedure. GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits across both tasks. Interval sizes of these QTLs varied widely. Seven traits shared a QTL on chromosome 1 that contained a few genes (e.g., Tenm4, Mir708) that have been associated with substance use disorders and other psychiatric disorders in humans. Other candidate genes (e.g., Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on addiction-related behaviors in HS rats and found that the QTL on chromosome 1 was also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive motivational processes and provide further support for a relationship between the attribution of incentive salience and drug abuse-related traits.
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Affiliation(s)
- Christopher P. King
- Department of PsychologyUniversity at BuffaloBuffaloNew YorkUSA
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
| | - Apurva S. Chitre
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | | | - Jordan A. Tripi
- Department of PsychologyUniversity at BuffaloBuffaloNew YorkUSA
| | - Alesa H. Netzley
- Department of Emergency MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Aidan P. Horvath
- Department of PsychologyUniversity of MichiganAnn ArborMichiganUSA
| | | | - Anthony George
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
| | - Connor Martin
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
| | | | | | | | - Jianjun Gao
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Riyan Cheng
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Khai‐Minh Nguyen
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Katie L. Holl
- Department of PhysiologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Oksana Polesskaya
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Keita Ishiwari
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
- Department of Pharmacology and ToxicologyUniversity at BuffaloBuffaloNew YorkUSA
| | - Hao Chen
- Department of Pharmacology, Addiction Science and ToxicologyUniversity of Tennessee Health Science CenterMemphisTennesseeUSA
| | | | - Shelly B. Flagel
- Department of PsychiatryUniversity of MichiganAnn ArborMichiganUSA
- Michigan Neuroscience Institute, University of MichiganAnn ArborMichiganUSA
| | - Leah C. Solberg Woods
- Department of Internal Medicine, Molecular Medicine, Center on Diabetes, Obesity and MetabolismWake Forest School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Abraham A. Palmer
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
- Institute for Genomic Medicine, University of California San DiegoLa JollaCaliforniaUSA
| | - Paul J. Meyer
- Department of PsychologyUniversity at BuffaloBuffaloNew YorkUSA
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Izawa S, Fusca D, Jiang H, Heilinger C, Hausen AC, Wunderlich FT, Steuernagel L, Kloppenburg P, Brüning JC. Orexin/hypocretin receptor 2 signaling in MCH neurons regulates REM sleep and insulin sensitivity. Cell Rep 2025; 44:115277. [PMID: 39946231 DOI: 10.1016/j.celrep.2025.115277] [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: 09/24/2024] [Revised: 11/05/2024] [Accepted: 01/16/2025] [Indexed: 02/28/2025] Open
Abstract
Orexin/hypocretin receptor type 2 (Ox2R), which is widely expressed in the brain, receives orexin signals and modulates sleep and metabolism. Ox2R selective agonists are currently under clinical trials for narcolepsy treatment. Here, we focused on Ox2R expression and function in melanin-concentrating hormone (MCH) neurons, which have opposite roles to orexin neurons in sleep and metabolism regulation. Ox2R-expressing MCH neurons showed heterogeneity of RNA expression, and orexin B application in brain slices induced both excitatory and inhibitory responses in distinct MCH neuron populations. Ox2R inactivation in MCH neurons reduced transitions from non-rapid eye movement (NREM) to REM sleep and impaired insulin sensitivity with excessive feeding after a fasting period in female mice. In conclusion, Ox2R mediates excitatory and inhibitory responses in MCH neuron sub-populations in vivo, which regulate sleep and metabolism in female mice.
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Affiliation(s)
- Shuntaro Izawa
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Debora Fusca
- Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Institute of Zoology, Department of Biology, University of Cologne, Cologne, Germany
| | - Hong Jiang
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Neurobiology, School of Basic Medical Sciences, Neuroscience Research Institute, Peking University, No. 38, Xueyuan Rd., Haidian District, Beijing 100191, China
| | - Christian Heilinger
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - A Christine Hausen
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - F Thomas Wunderlich
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Lukas Steuernagel
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Peter Kloppenburg
- Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Institute of Zoology, Department of Biology, University of Cologne, Cologne, Germany
| | - Jens C Brüning
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany; National Center for Diabetes Research (DZD), Neuherberg, Germany.
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Li AH, Tsai WS, Tsai WH, Yang SB. Systemic Glucose Homeostasis Requires Pancreatic but Not Neuronal ATP-sensitive Potassium Channels. FUNCTION 2025; 6:zqaf002. [PMID: 39809576 PMCID: PMC11815579 DOI: 10.1093/function/zqaf002] [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: 11/07/2024] [Revised: 12/31/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025] Open
Abstract
The adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits, are essential for glucose homeostasis. While the role of pancreatic KATP channels in regulating insulin secretion is well-documented, the specific contributions of neuronal KATP channels remain unclear due to challenges in precisely targeting neuronal subpopulations. In this study, we utilized a Kir6.2 conditional knockout mouse model to distinguish the roles of KATP channels in different cell types. Our findings demonstrate that deletion of neuronal KATP channels does not impair glucose homeostasis, as glucose-sensing neurons retained their responsiveness despite the absence of functional KATP channels. In contrast, the deletion of KATP channels in pancreatic β cells led to significant hyperglycemia and glucose intolerance, indicating unstable blood glucose levels under varying physiological conditions. Importantly, we showed that restoring KATP channel function exclusively in pancreatic β cells within a global Kir6.2 knockout background effectively reversed glucose regulation defects. This underscores the critical role of pancreatic KATP channels in maintaining systemic glucose homeostasis. Our results challenge the previous hypothesis that neuronal KATP channels are essential for glucose regulation, suggesting that their primary function may be neuroprotective rather than homeostatic. These findings highlight pancreatic KATP channels as key regulators of glucose balance and potential therapeutic targets for correcting glucose dysregulation.
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Affiliation(s)
- Athena H Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 115, Taiwan
| | - Wen-Sheng Tsai
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Wen-Hao Tsai
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Shi-Bing Yang
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 115, Taiwan
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6
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Adekunle RD, Chowdhury MS, Fang LZ, Hirasawa M. Electrophysiological properties of melanin-concentrating hormone neuron subpopulations defined by anatomical localization and CART expression. Front Cell Neurosci 2025; 18:1439752. [PMID: 39911950 PMCID: PMC11794810 DOI: 10.3389/fncel.2024.1439752] [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: 05/28/2024] [Accepted: 12/24/2024] [Indexed: 02/07/2025] Open
Abstract
Introduction Melanin-concentrating hormone (MCH) neurons are essential regulators of energy and glucose homeostasis, sleep-wake behaviors, motivation, learning and memory. These neurons are anatomically distributed across the medial (MH) and lateral hypothalamus (LH), and the adjacent zona incerta (ZI), which may represent functional subgroups with distinct connectivity with different brain regions. Furthermore, MCH neurons can be classified according to co-expression of neuropeptides, such as cocaine and amphetamine- regulated transcript (CART). Methods To identify functional similarities and differences of MCH subpopulations, we characterized their intrinsic electrophysiological properties using whole cell current clamp recording on acute brain slices from male and female mice. Results MCH neurons were classified into subgroups according to their anatomical localization in three MCH-rich brain areas: MH, LH and ZI. Among the three brain regions, ZI MCH neurons were the least excitable while LH MCH neurons were the most excitable. Furthermore, grouping MCH neurons according to CART co-expression revealed that MCH/CART- cells are uniquely depolarized and excitable, and display H-currents. These MCH/CART- cells were mainly found in the LH, which may in part explain why LH MCH neurons are more excitable. While some sex differences were found, the majority of parameters investigated were not different. Discussion Our results suggest that MCH/CART- cells are electrophysiologically distinct, whereas MCH/CART+ cells are largely similar despite their diffuse distribution in the hypothalamus. It is therefore a combination of intrinsic electrophysiological properties and neurochemical identities, in addition to anatomy and connectivity that are likely to be critical in defining functional subpopulations of MCH neurons.
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Affiliation(s)
| | | | | | - Michiru Hirasawa
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
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7
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Thorens B. Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion. Physiol Rev 2024; 104:1461-1486. [PMID: 38661565 DOI: 10.1152/physrev.00038.2023] [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: 09/29/2023] [Revised: 04/16/2024] [Accepted: 04/20/2024] [Indexed: 04/26/2024] Open
Abstract
Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle and glucose production by the liver. The balance between the secretions of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet β-cells and α-cells can sense variations in glycemia and respond by an appropriate secretory response. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and thus a vital interest in ensuring that glycemic levels never fall below ∼5 mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cell secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we present the autonomic innervation of the pancreatic islets; the mechanisms of neuron activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow integration of specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function; and, finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.
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Affiliation(s)
- Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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8
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Pham XT, Abe Y, Mukai Y, Ono D, Tanaka KF, Ohmura Y, Wake H, Yamanaka A. Glutamatergic signaling from melanin-concentrating hormone-producing neurons: A requirement for memory regulation, but not for metabolism control. PNAS NEXUS 2024; 3:pgae275. [PMID: 39035036 PMCID: PMC11259978 DOI: 10.1093/pnasnexus/pgae275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 06/29/2024] [Indexed: 07/23/2024]
Abstract
Melanin-concentrating hormone-producing neurons (MCH neurons), found mainly in the lateral hypothalamus and surrounding areas, play essential roles in various brain functions, including sleep and wakefulness, reward, metabolism, learning, and memory. These neurons coexpress several neurotransmitters and act as glutamatergic neurons. The contribution of glutamate from MCH neurons to memory- and metabolism-related functions has not been fully investigated. In a mouse model, we conditionally knocked out Slc17a6 gene, which encodes for vesicular glutamate transporter 2 (vGlut2), in the MCH neurons exclusively by using two different methods: the Cre recombinase/loxP system and in vivo genome editing using CRISPR/Cas9. Then, we evaluated several aspects of memory and measured metabolic rates using indirect calorimetry. We found that mice with MCH neuron-exclusive vGlut2 ablation had higher discrimination ratios between novel and familiar stimuli for novel object recognition, object location, and three-chamber tests. In contrast, there was no significant change in body weight, food intake, oxygen consumption, respiratory quotient, or locomotor activity. These findings suggest that glutamatergic signaling from MCH neurons is required to regulate memory, but its role in regulating metabolic rate is negligible.
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Affiliation(s)
- Xuan Thang Pham
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Department of Psychiatry, Hanoi Medical University, Hanoi 100000, Vietnam
| | - Yoshifumi Abe
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yasutaka Mukai
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Japan Society for the Promotion of Science, Tokyo 102-0083, Japan
| | - Daisuke Ono
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Kenji F Tanaka
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yu Ohmura
- Chinese Institute for Brain Research, Beijing (CIBR), Beijing 102206, China
| | - Hiroaki Wake
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Akihiro Yamanaka
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
- Chinese Institute for Brain Research, Beijing (CIBR), Beijing 102206, China
- National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8585, Japan
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Concetti C, Viskaitis P, Grujic N, Duss SN, Privitera M, Bohacek J, Peleg-Raibstein D, Burdakov D. Exploratory Rearing Is Governed by Hypothalamic Melanin-Concentrating Hormone Neurons According to Locus Ceruleus. J Neurosci 2024; 44:e0015242024. [PMID: 38575343 PMCID: PMC11112542 DOI: 10.1523/jneurosci.0015-24.2024] [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: 01/03/2024] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/06/2024] Open
Abstract
Information seeking, such as standing on tiptoes to look around in humans, is observed across animals and helps survival. Its rodent analog-unsupported rearing on hind legs-was a classic model in deciphering neural signals of cognition and is of intense renewed interest in preclinical modeling of neuropsychiatric states. Neural signals and circuits controlling this dedicated decision to seek information remain largely unknown. While studying subsecond timing of spontaneous behavioral acts and activity of melanin-concentrating hormone (MCH) neurons (MNs) in behaving male and female mice, we observed large MN activity spikes that aligned to unsupported rears. Complementary causal, loss and gain of function, analyses revealed specific control of rear frequency and duration by MNs and MCHR1 receptors. Activity in a key stress center of the brain-the locus ceruleus noradrenaline cells-rapidly inhibited MNs and required functional MCH receptors for its endogenous modulation of rearing. By defining a neural module that both tracks and controls rearing, these findings may facilitate further insights into biology of information seeking.
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Affiliation(s)
- Cristina Concetti
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
| | - Paulius Viskaitis
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
| | - Nikola Grujic
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
| | - Sian N Duss
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
| | - Mattia Privitera
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
| | - Johannes Bohacek
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
| | - Daria Peleg-Raibstein
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
| | - Denis Burdakov
- Department of Health Sciences and Technology, Neuroscience Center Zürich (ZNZ), Swiss Federal Institute of Technology (ETH Zürich), Zürich 8092, Switzerland
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10
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Adhikary K, Sarkar R, Maity S, Banerjee I, Chatterjee P, Bhattacharya K, Ahuja D, Sinha NK, Maiti R. The underlying causes, treatment options of gut microbiota and food habits in type 2 diabetes mellitus: a narrative review. J Basic Clin Physiol Pharmacol 2024; 35:153-168. [PMID: 38748886 DOI: 10.1515/jbcpp-2024-0043] [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: 03/23/2024] [Accepted: 05/01/2024] [Indexed: 07/05/2024]
Abstract
Type 2 diabetes mellitus is a long-lasting endocrine disorder characterized by persistent hyperglycaemia, which is often triggered by an entire or relative inadequacy of insulin production or insulin resistance. As a result of resistance to insulin (IR) and an overall lack of insulin in the body, type 2 diabetes mellitus (T2DM) is a metabolic illness that is characterized by hyperglycaemia. Notably, the occurrence of vascular complications of diabetes and the advancement of IR in T2DM are accompanied by dysbiosis of the gut microbiota. Due to the difficulties in managing the disease and the dangers of multiple accompanying complications, diabetes is a chronic, progressive immune-mediated condition that plays a significant clinical and health burden on patients. The frequency and incidence of diabetes among young people have been rising worldwide. The relationship between the gut microbiota composition and the physio-pathological characteristics of T2DM proposes a novel way to monitor the condition and enhance the effectiveness of therapies. Our knowledge of the microbiota of the gut and how it affects health and illness has changed over the last 20 years. Species of the genus Eubacterium, which make up a significant portion of the core animal gut microbiome, are some of the recently discovered 'generation' of possibly helpful bacteria. In this article, we have focused on pathogenesis and therapeutic approaches towards T2DM, with a special reference to gut bacteria from ancient times to the present day.
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Affiliation(s)
- Krishnendu Adhikary
- Department of Interdisciplinary Science, Centurion University of Technology & Management, Bhubaneswar, Odisha, India
| | - Riya Sarkar
- Department of Medical Laboratory Technology, 231513 Dr. B. C. Roy Academy of Professional Courses , Durgapur, West Bengal, India
| | - Sriparna Maity
- Department of Medical Laboratory Technology, 231513 Dr. B. C. Roy Academy of Professional Courses , Durgapur, West Bengal, India
| | - Ipsita Banerjee
- Department of Nutrition, Paramedical College Durgapur, Durgapur, West Bengal, India
| | - Prity Chatterjee
- Department of Biotechnology, Paramedical College Durgapur, Durgapur, West Bengal, India
| | - Koushik Bhattacharya
- School of Paramedics and Allied Health Sciences, Centurion University of Technology & Management, Bhubaneswar, Odisha, India
| | - Deepika Ahuja
- School of Paramedics and Allied Health Sciences, Centurion University of Technology & Management, Bhubaneswar, Odisha, India
| | - Nirmalya Kumar Sinha
- Department of Nutrition and Department of NSS, Raja Narendra Lal Khan Women's College (Autonomous), Midnapore, West Bengal, India
| | - Rajkumar Maiti
- Department of Physiology, 326624 Bankura Christian College , Bankura, West Bengal, India
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11
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Kuebler IRK, Suárez M, Wakabayashi KT. Sex differences and sex-specific regulation of motivated behavior by Melanin-concentrating hormone: a short review. Biol Sex Differ 2024; 15:33. [PMID: 38570844 PMCID: PMC10993549 DOI: 10.1186/s13293-024-00608-0] [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: 11/11/2023] [Accepted: 03/23/2024] [Indexed: 04/05/2024] Open
Abstract
Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH's role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.
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Affiliation(s)
- Isabel R K Kuebler
- Neurocircuitry of Motivated Behavior Laboratory, Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, 68588-0308, USA
| | - Mauricio Suárez
- Neurocircuitry of Motivated Behavior Laboratory, Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, 68588-0308, USA
| | - Ken T Wakabayashi
- Neurocircuitry of Motivated Behavior Laboratory, Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, 68588-0308, USA.
- Rural Drug Addiction Research Center, University of Nebraska-Lincoln, 660 N 12th St., Lincoln, NE, 68588, USA.
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12
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King CP, Chitre AS, Leal-Gutiérrez JD, Tripi JA, Hughson AR, Horvath AP, Lamparelli AC, George A, Martin C, Pierre CLS, Sanches T, Bimschleger HV, Gao J, Cheng R, Nguyen KM, Holl KL, Polesskaya O, Ishiwari K, Chen H, Woods LCS, Palmer AA, Robinson TE, Flagel SB, Meyer PJ. Genomic Loci Influencing Cue-Reactivity in Heterogeneous Stock Rats. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.13.584852. [PMID: 38559127 PMCID: PMC10980002 DOI: 10.1101/2024.03.13.584852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues; both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1,645 genetically diverse heterogeneous stock (HS) rats. We tested HS rats in a Pavlovian conditioned approach task, in which we characterized the individual responses to food-associated stimuli ("cues"). Rats exhibited either cue-directed "sign-tracking" behavior or food-cup directed "goal-tracking" behavior. We then used the conditioned reinforcement procedure to determine whether rats would perform a novel operant response for unrewarded presentations of the cue. We found that these measures were moderately heritable (SNP heritability, h2 = .189-.215). GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits we examined. Interval sizes of these QTLs varied widely. 7 traits shared a QTL on chromosome 1 that contained a few genes (e.g. Tenm4, Mir708) that have been associated with substance use disorders and other mental health traits in humans. Other candidate genes (e.g. Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on other behavioral measures in HS rats and found that regions containing QTLs on chromosome 1 were also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive salience and provide further support for a relationship between attribution of incentive salience and drug abuse-related traits.
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Affiliation(s)
- Christopher P. King
- Department of Psychology, University at Buffalo, Buffalo, USA
- Clinical and Research Institute on Addictions, Buffalo, USA
| | - Apurva S. Chitre
- Department of Psychiatry, University of California San Diego, La Jolla, USA
| | | | - Jordan A. Tripi
- Department of Psychology, University at Buffalo, Buffalo, USA
| | - Alesa R. Hughson
- Department of Psychology, University of Michigan, Ann Arbor, USA
| | - Aidan P. Horvath
- Department of Psychology, University of Michigan, Ann Arbor, USA
| | | | - Anthony George
- Clinical and Research Institute on Addictions, Buffalo, USA
| | - Connor Martin
- Clinical and Research Institute on Addictions, Buffalo, USA
| | | | - Thiago Sanches
- Department of Psychiatry, University of California San Diego, La Jolla, USA
| | | | - Jianjun Gao
- Department of Psychiatry, University of California San Diego, La Jolla, USA
| | - Riyan Cheng
- Department of Psychiatry, University of California San Diego, La Jolla, USA
| | - Khai-Minh Nguyen
- Department of Psychiatry, University of California San Diego, La Jolla, USA
| | - Katie L. Holl
- Department of Physiology, Medical College of Wisconsin, Milwaukee, USA
| | - Oksana Polesskaya
- Department of Psychiatry, University of California San Diego, La Jolla, USA
| | - Keita Ishiwari
- Clinical and Research Institute on Addictions, Buffalo, USA
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo USA
| | - Hao Chen
- Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, USA
| | - Leah C. Solberg Woods
- Department of Internal Medicine, Molecular Medicine, Center on Diabetes, Obesity and Metabolism, Wake Forest School of Medicine, Winston-Salem, USA
| | - Abraham A. Palmer
- Department of Psychiatry, University of California San Diego, La Jolla, USA
- Institute for Genomic Medicine, University of California San Diego, La Jolla, USA
| | | | - Shelly B. Flagel
- Department of Psychiatry, University of Michigan, Ann Arbor, USA
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, USA
| | - Paul J. Meyer
- Department of Psychology, University at Buffalo, Buffalo, USA
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13
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Harris JJ, Burdakov D. A role for MCH neuron firing in modulating hippocampal plasticity threshold. Peptides 2024; 172:171128. [PMID: 38070684 DOI: 10.1016/j.peptides.2023.171128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/25/2023]
Abstract
It has been revealed that hypothalamic neurons containing the peptide, melanin-concentrating hormone (MCH) can influence learning [1] and memory formation [2], but the cellular mechanisms by which they perform this function are not well understood. Here, we examine the role of MCH neural input to the hippocampus, and show in vitro that optogenetically increasing MCH axon activity facilitates hippocampal plasticity by lowering the threshold for synaptic potentiation. These results align with increasing evidence that MCH neurons play a regulatory role in learning, and reveal that this could be achieved by modulating plasticity thresholds in the hippocampus.
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Affiliation(s)
- Julia J Harris
- Sensory Circuits and Neurotechnology Laboratory, Francis Crick Institute, London, UK; Department of Life Sciences, Imperial College London, London, UK; System Neuroscience and Energy Control Laboratory, Francis Crick Institute, London, UK.
| | - Denis Burdakov
- System Neuroscience and Energy Control Laboratory, Francis Crick Institute, London, UK; Department of Health Sciences and Technology, ETH Zürich, 8603 Schwerzenbach, Switzerland; Institute for Neuroscience, Department of Health Sciences and Technology, ETH Zürich, 8603 Schwerzenbach, Switzerland; Institute of Food Nutrition and Health, Department of Health Sciences and Technology, ETH Zürich, 8603 Schwerzenbach, Switzerland; Neuroscience Center Zürich, 8057 Zürich, Switzerland.
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14
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Miller PA, Williams-Ikhenoba JG, Sankhe AS, Hoffe BH, Chee MJ. Neuroanatomical, electrophysiological, and morphological characterization of melanin-concentrating hormone cells coexpressing cocaine- and amphetamine-regulated transcript. J Comp Neurol 2024; 532:e25588. [PMID: 38335050 DOI: 10.1002/cne.25588] [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: 05/01/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 02/12/2024]
Abstract
Melanin-concentrating hormone (MCH) cells in the hypothalamus regulate fundamental physiological functions like energy balance, sleep, and reproduction. This diversity may be ascribed to the neurochemical heterogeneity among MCH cells. One prominent subpopulation of MCH cells coexpresses cocaine- and amphetamine-regulated transcript (CART), and as MCH and CART can have opposing actions, MCH/CART+ and MCH/CART- cells may differentially modulate behavioral outcomes. However, it is not known if there are differences in the cellular properties underlying their functional differences; thus, we compared the neuroanatomical, electrophysiological, and morphological properties of MCH cells in male and female Mch-cre;L10-Egfp reporter mice. Half of MCH cells expressed CART and were most prominent in the medial hypothalamus. Whole-cell patch-clamp recordings revealed differences in their passive and active membrane properties in a sex-dependent manner. Female MCH/CART+ cells had lower input resistances, but male cells largely differed in their firing properties. All MCH cells increased firing when stimulated, but their firing frequency decreases with sustained stimulation. MCH/CART+ cells showed stronger spike rate adaptation than MCH/CART- cells. The kinetics of excitatory events at MCH cells also differed by cell type, as the rising rate of excitatory events was slower at MCH/CART+ cells. By reconstructing the dendritic arborization of our recorded cells, we found no sex differences, but male MCH/CART+ cells had less dendritic length and fewer branch points. Overall, distinctions in topographical division and cellular properties between MCH cells add to their heterogeneity and help elucidate their response to stimuli or effect on modulating their respective neural networks.
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Affiliation(s)
| | | | - Aditi S Sankhe
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Brendan H Hoffe
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Melissa J Chee
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
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15
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Meira E Cruz M. Modulatory mechanisms of cannabinoids as a window of hope to patients with sleep-related cardiometabolic risk. Biomed Pharmacother 2023; 168:115721. [PMID: 37852101 DOI: 10.1016/j.biopha.2023.115721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 10/08/2023] [Accepted: 10/11/2023] [Indexed: 10/20/2023] Open
Affiliation(s)
- Miguel Meira E Cruz
- Sleep Unit, Centro Cardiovascular da Universidade de Lisboa, Lisbon School of Medicine, Lisbon, Portugal; Centro Europeu do Sono, Lisbon, Portugal.
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16
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Concetti C, Peleg-Raibstein D, Burdakov D. Hypothalamic MCH Neurons: From Feeding to Cognitive Control. FUNCTION 2023; 5:zqad059. [PMID: 38020069 PMCID: PMC10667013 DOI: 10.1093/function/zqad059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 10/06/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Modern neuroscience is progressively elucidating that the classic view positing distinct brain regions responsible for survival, emotion, and cognitive functions is outdated. The hypothalamus demonstrates the interdependence of these roles, as it is traditionally known for fundamental survival functions like energy and electrolyte balance, but is now recognized to also play a crucial role in emotional and cognitive processes. This review focuses on lateral hypothalamic melanin-concentrating hormone (MCH) neurons, producing the neuropeptide MCH-a relatively understudied neuronal population with integrative functions related to homeostatic regulation and motivated behaviors, with widespread inputs and outputs throughout the entire central nervous system. Here, we review early findings and recent literature outlining their role in the regulation of energy balance, sleep, learning, and memory processes.
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Affiliation(s)
- Cristina Concetti
- Neurobehavioural Dynamics Laboratory, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland
| | - Daria Peleg-Raibstein
- Neurobehavioural Dynamics Laboratory, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland
| | - Denis Burdakov
- Neurobehavioural Dynamics Laboratory, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland
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17
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Maes ME, Colombo G, Schoot Uiterkamp FE, Sternberg F, Venturino A, Pohl EE, Siegert S. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout. iScience 2023; 26:107780. [PMID: 37731609 PMCID: PMC10507162 DOI: 10.1016/j.isci.2023.107780] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/10/2023] [Accepted: 08/28/2023] [Indexed: 09/22/2023] Open
Abstract
Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.
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Affiliation(s)
- Margaret E. Maes
- Institute of Science and Technology Austria (ISTA), Am Campus 1, 3400 Klosterneuburg, Austria
| | - Gloria Colombo
- Institute of Science and Technology Austria (ISTA), Am Campus 1, 3400 Klosterneuburg, Austria
| | | | - Felix Sternberg
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Veterinärplatz 1, 1210 Vienna, Austria
| | - Alessandro Venturino
- Institute of Science and Technology Austria (ISTA), Am Campus 1, 3400 Klosterneuburg, Austria
| | - Elena E. Pohl
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Veterinärplatz 1, 1210 Vienna, Austria
| | - Sandra Siegert
- Institute of Science and Technology Austria (ISTA), Am Campus 1, 3400 Klosterneuburg, Austria
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18
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Rossi MA. Control of energy homeostasis by the lateral hypothalamic area. Trends Neurosci 2023; 46:738-749. [PMID: 37353461 PMCID: PMC10524917 DOI: 10.1016/j.tins.2023.05.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 06/25/2023]
Abstract
The lateral hypothalamic area (LHA) is a subcortical brain region that exerts control over motivated behavior, feeding, and energy balance across species. Recent single-cell sequencing studies have defined at least 30 distinct LHA neuron types. Some of these influence specific aspects of energy homeostasis; however, the functions of many LHA cell types remain unclear. This review addresses the rapidly emerging evidence from cell-type-specific investigations that the LHA leverages distinct neuron populations to regulate energy balance through complex connections with other brain regions. It will highlight recent findings demonstrating that LHA control of energy balance extends beyond mere food intake and propose outstanding questions to be addressed by future research.
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Affiliation(s)
- Mark A Rossi
- Child Health Institute of New Jersey, New Brunswick, NJ, USA; Department of Psychiatry, Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Brain Health Institute, Rutgers University, New Brunswick, NJ, USA.
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19
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Emin MT, Lee MJ, Bhattacharya J, Hough RF. Mitochondria of lung venular capillaries mediate lung-liver cross talk in pneumonia. Am J Physiol Lung Cell Mol Physiol 2023; 325:L277-L287. [PMID: 37431588 PMCID: PMC10625830 DOI: 10.1152/ajplung.00209.2022] [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: 06/29/2022] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/12/2023] Open
Abstract
Failure of the lung's endothelial barrier underlies lung injury, which causes the high mortality acute respiratory distress syndrome (ARDS). Multiple organ failure predisposes to the mortality, but mechanisms are poorly understood. Here, we show that mitochondrial uncoupling protein 2 (UCP2), a component of the mitochondrial inner membrane, plays a role in the barrier failure. Subsequent lung-liver cross talk mediated by neutrophil activation causes liver congestion. We intranasally instilled lipopolysaccharide (LPS). Then, we viewed the lung endothelium by real-time confocal imaging of the isolated, blood-perfused mouse lung. LPS caused alveolar-capillary transfer of reactive oxygen species and mitochondrial depolarization in lung venular capillaries. The mitochondrial depolarization was inhibited by transfection of alveolar Catalase and vascular knockdown of UCP2. LPS instillation caused lung injury as indicated by increases in bronchoalveolar lavage (BAL) protein content and extravascular lung water. LPS or Pseudomonas aeruginosa instillation also caused liver congestion, quantified by liver hemoglobin and plasma aspartate aminotransferase (AST) increases. Genetic inhibition of vascular UCP2 prevented both lung injury and liver congestion. Antibody-mediated neutrophil depletion blocked the liver responses, but not lung injury. Knockdown of lung vascular UCP2 mitigated P. aeruginosa-induced mortality. Together, these data suggest a mechanism in which bacterial pneumonia induces oxidative signaling to lung venular capillaries, known sites of inflammatory signaling in the lung microvasculature, depolarizing venular mitochondria. Successive activation of neutrophils induces liver congestion. We conclude that oxidant-induced UCP2 expression in lung venular capillaries causes a mechanistic sequence leading to liver congestion and mortality. Lung vascular UCP2 may present a therapeutic target in ARDS.NEW & NOTEWORTHY We report that mitochondrial injury in lung venular capillaries underlies barrier failure in pneumonia, and venular capillary uncoupling protein 2 (UCP2) causes neutrophil-mediated liver congestion. Using in situ imaging, we found that epithelial-endothelial transfer of H2O2 activates UCP2, depolarizing mitochondria in venular capillaries. The conceptual advance from our findings is that mitochondrial depolarization in lung capillaries mediates liver cross talk through circulating neutrophils. Pharmacologic blockade of UCP2 could be a therapeutic strategy for lung injury.
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Affiliation(s)
- Memet T Emin
- Department of Pediatrics, Pediatric Critical Care and Hospital Medicine, Columbia University Irving Medical Center, New York, New York, United States
| | - Michael J Lee
- Department of Pathology and Cell Biology, Columbia University, New York, New York, United States
| | - Jahar Bhattacharya
- Lung Biology Laboratory, Pulmonary Division, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, United States
| | - Rebecca F Hough
- Department of Pediatrics, Pediatric Critical Care and Hospital Medicine, Columbia University Irving Medical Center, New York, New York, United States
- Lung Biology Laboratory, Pulmonary Division, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, United States
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20
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Bouâouda H, Jha PK. Orexin and MCH neurons: regulators of sleep and metabolism. Front Neurosci 2023; 17:1230428. [PMID: 37674517 PMCID: PMC10478345 DOI: 10.3389/fnins.2023.1230428] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 08/07/2023] [Indexed: 09/08/2023] Open
Abstract
Sleep-wake and fasting-feeding are tightly coupled behavioral states that require coordination between several brain regions. The mammalian lateral hypothalamus (LH) is a functionally and anatomically complex brain region harboring heterogeneous cell populations that regulate sleep, feeding, and energy metabolism. Significant attempts were made to understand the cellular and circuit bases of LH actions. Rapid advancements in genetic and electrophysiological manipulation help to understand the role of discrete LH cell populations. The opposing action of LH orexin/hypocretin and melanin-concentrating hormone (MCH) neurons on metabolic sensing and sleep-wake regulation make them the candidate to explore in detail. This review surveys the molecular, genetic, and neuronal components of orexin and MCH signaling in the regulation of sleep and metabolism.
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Affiliation(s)
- Hanan Bouâouda
- Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Pawan Kumar Jha
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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21
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Fang LZ, Linehan V, Licursi M, Alberto CO, Power JL, Parsons MP, Hirasawa M. Prostaglandin E 2 activates melanin-concentrating hormone neurons to drive diet-induced obesity. Proc Natl Acad Sci U S A 2023; 120:e2302809120. [PMID: 37467285 PMCID: PMC10401019 DOI: 10.1073/pnas.2302809120] [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: 03/07/2023] [Accepted: 05/09/2023] [Indexed: 07/21/2023] Open
Abstract
Hypothalamic inflammation reduces appetite and body weight during inflammatory diseases, while promoting weight gain when induced by high-fat diet (HFD). How hypothalamic inflammation can induce opposite energy balance outcomes remains unclear. We found that prostaglandin E2 (PGE2), a key hypothalamic inflammatory mediator of sickness, also mediates diet-induced obesity (DIO) by activating appetite-promoting melanin-concentrating hormone (MCH) neurons in the hypothalamus in rats and mice. The effect of PGE2 on MCH neurons is excitatory at low concentrations while inhibitory at high concentrations, indicating that these neurons can bidirectionally respond to varying levels of inflammation. During prolonged HFD, endogenous PGE2 depolarizes MCH neurons through an EP2 receptor-mediated inhibition of the electrogenic Na+/K+-ATPase. Disrupting this mechanism by genetic deletion of EP2 receptors on MCH neurons is protective against DIO and liver steatosis in male and female mice. Thus, an inflammatory mediator can directly stimulate appetite-promoting neurons to exacerbate DIO and fatty liver.
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Affiliation(s)
- Lisa Z. Fang
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’sA1B 3V6, Canada
| | - Victoria Linehan
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’sA1B 3V6, Canada
| | - Maria Licursi
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’sA1B 3V6, Canada
| | - Christian O. Alberto
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’sA1B 3V6, Canada
| | - Jacob L. Power
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’sA1B 3V6, Canada
| | - Matthew P. Parsons
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’sA1B 3V6, Canada
| | - Michiru Hirasawa
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’sA1B 3V6, Canada
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22
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Beekly BG, Rupp A, Burgess CR, Elias CF. Fast neurotransmitter identity of MCH neurons: Do contents depend on context? Front Neuroendocrinol 2023; 70:101069. [PMID: 37149229 PMCID: PMC11190671 DOI: 10.1016/j.yfrne.2023.101069] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/07/2023] [Accepted: 04/29/2023] [Indexed: 05/08/2023]
Abstract
Hypothalamic melanin-concentrating hormone (MCH) neurons participate in many fundamental neuroendocrine processes. While some of their effects can be attributed to MCH itself, others appear to depend on co-released neurotransmitters. Historically, the subject of fast neurotransmitter co-release from MCH neurons has been contentious, with data to support MCH neurons releasing GABA, glutamate, both, and neither. Rather than assuming a position in that debate, this review considers the evidence for all sides and presents an alternative explanation: neurochemical identity, including classical neurotransmitter content, is subject to change. With an emphasis on the variability of experimental details, we posit that MCH neurons may release GABA and/or glutamate at different points according to environmental and contextual factors. Through the lens of the MCH system, we offer evidence that the field of neuroendocrinology would benefit from a more nuanced and dynamic interpretation of neurotransmitter identity.
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Affiliation(s)
- B G Beekly
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States; Elizabeth W. Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, United States.
| | - A Rupp
- Elizabeth W. Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, United States
| | - C R Burgess
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - C F Elias
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States; Elizabeth W. Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, United States
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23
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Subramanian KS, Lauer LT, Hayes AMR, Décarie-Spain L, McBurnett K, Nourbash AC, Donohue KN, Kao AE, Bashaw AG, Burdakov D, Noble EE, Schier LA, Kanoski SE. Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes in rats. Nat Commun 2023; 14:1755. [PMID: 36990984 PMCID: PMC10060386 DOI: 10.1038/s41467-023-37344-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 03/13/2023] [Indexed: 03/31/2023] Open
Abstract
The lateral hypothalamic area (LHA) integrates homeostatic processes and reward-motivated behaviors. Here we show that LHA neurons that produce melanin-concentrating hormone (MCH) are dynamically responsive to both food-directed appetitive and consummatory processes in male rats. Specifically, results reveal that MCH neuron Ca2+ activity increases in response to both discrete and contextual food-predictive cues and is correlated with food-motivated responses. MCH neuron activity also increases during eating, and this response is highly predictive of caloric consumption and declines throughout a meal, thus supporting a role for MCH neurons in the positive feedback consummatory process known as appetition. These physiological MCH neural responses are functionally relevant as chemogenetic MCH neuron activation promotes appetitive behavioral responses to food-predictive cues and increases meal size. Finally, MCH neuron activation enhances preference for a noncaloric flavor paired with intragastric glucose. Collectively, these data identify a hypothalamic neural population that orchestrates both food-motivated appetitive and intake-promoting consummatory processes.
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Affiliation(s)
- Keshav S Subramanian
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA
| | - Logan Tierno Lauer
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
| | - Anna M R Hayes
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
| | - Léa Décarie-Spain
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
| | - Kara McBurnett
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
| | - Anna C Nourbash
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
| | - Kristen N Donohue
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
| | - Alicia E Kao
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
| | - Alexander G Bashaw
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA
| | - Denis Burdakov
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Emily E Noble
- Department of Nutritional Sciences, University of Georgia, Athens, USA
| | - Lindsey A Schier
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA
| | - Scott E Kanoski
- Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA.
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA.
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24
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Sankhe AS, Bordeleau D, Alfonso DIM, Wittman G, Chee MJ. Loss of glutamatergic signalling from MCH neurons reduced anxiety-like behaviours in novel environments. J Neuroendocrinol 2023; 35:e13222. [PMID: 36529144 DOI: 10.1111/jne.13222] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/10/2022] [Accepted: 11/23/2022] [Indexed: 12/02/2022]
Abstract
Melanin-concentrating hormone (MCH) neurons within the hypothalamus are heterogeneous and can coexpress additional neuropeptides and transmitters. The majority of MCH neurons express vesicular transporters to package glutamate for synaptic release, and MCH neurons can directly innervate downstream neurons via glutamate release. Although glutamatergic signalling from MCH neurons may support physiological and behavioural roles that are independent of MCH (e.g., in glucose homeostasis and nutrient-sensing), it can also mediate similar roles to MCH in the regulation of energy balance. In addition to energy balance, the MCH system has also been implicated in mood disorders, as MCH receptor antagonists have anxiolytic and anti-depressive effects. However, the contribution of glutamatergic signalling from MCH neurons to mood-related functions have not been investigated. We crossed Mch-cre mice with floxed-Vglut2 mice to delete the expression of the vesicular glutamate transporter 2 (Vglut2) and disable glutamatergic signalling specifically from MCH neurons. The resulting Mch-Vglut2-KO mice showed Vglut2 deletion from over 75% of MCH neurons, and although we did not observe changes in depressive-like behaviours, we found that Mch-Vglut2-KO mice displayed anxiety-like behaviours. Mch-Vglut2-KO mice showed reduced exploratory activity when placed in a new cage and were quicker to consume food placed in the centre of a novel open arena. These findings showed that Vglut2 deletion from MCH neurons resulted in anxiolytic actions and suggested that the anxiogenic effects of glutamate are similar to those of the MCH peptide. Taken together, these findings suggest that glutamate and MCH may synergize to regulate and promote anxiety-like behaviour.
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Affiliation(s)
- Aditi S Sankhe
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - Dillon Bordeleau
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | | | - Gábor Wittman
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, MA, USA
| | - Melissa J Chee
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
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25
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Potter LE, Burgess CR. The melanin-concentrating hormone system as a target for the treatment of sleep disorders. Front Neurosci 2022; 16:952275. [PMID: 36177357 PMCID: PMC9513178 DOI: 10.3389/fnins.2022.952275] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/24/2022] [Indexed: 11/13/2022] Open
Abstract
Given the widespread prevalence of sleep disorders and their impacts on health, it is critical that researchers continue to identify and evaluate novel avenues of treatment. Recently the melanin-concentrating hormone (MCH) system has attracted commercial and scientific interest as a potential target of pharmacotherapy for sleep disorders. This interest emerges from basic scientific research demonstrating a role for MCH in regulating sleep, and particularly REM sleep. In addition to this role in sleep regulation, the MCH system and the MCH receptor 1 (MCHR1) have been implicated in a wide variety of other physiological functions and behaviors, including feeding/metabolism, reward, anxiety, depression, and learning. The basic research literature on sleep and the MCH system, and the history of MCH drug development, provide cause for both skepticism and cautious optimism about the prospects of MCH-targeting drugs in sleep disorders. Extensive efforts have focused on developing MCHR1 antagonists for use in obesity, however, few of these drugs have advanced to clinical trials, and none have gained regulatory approval. Additional basic research will be needed to fully characterize the MCH system’s role in sleep regulation, for example, to fully differentiate between MCH-neuron and peptide/receptor-mediated functions. Additionally, a number of issues relating to drug design will continue to pose a practical challenge for novel pharmacotherapies targeting the MCH system.
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Affiliation(s)
- Liam E. Potter
- Department of Molecular and Integrative Physiology, Michigan Medicine, Ann Arbor, MI, United States
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Liam E. Potter,
| | - Christian R. Burgess
- Department of Molecular and Integrative Physiology, Michigan Medicine, Ann Arbor, MI, United States
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
- Christian R. Burgess,
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26
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Sun Y, Bu LG, Wang B, Ren J, Li TY, Kong LL, Ni H. Expression and hormone regulation of UCP2 in goat uterus. Anim Reprod Sci 2022; 243:107015. [PMID: 35689907 DOI: 10.1016/j.anireprosci.2022.107015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/21/2022] [Accepted: 06/03/2022] [Indexed: 12/01/2022]
Abstract
Pregnancy success is closely related to the molecular mechanisms that control energy metabolism balance. However, the mechanisms have not been fully understood. Uncoupling protein 2 (UCP2) plays a physiological role by regulating energy metabolism in numerous tissues. In this study, we determined the expression and hormone regulation of UCP2 in goat uterus. UCP2 is expressed in the luminal and glandular epithelia of goat uterus during early pregnancy, as revealed by in situ hybridization and immunohistochemistry conducted on pregnant goats. The signals were detected from day 0 (D0) to D30 of pregnancy, though weak on D16 (the adhesion period). The low levels of UCP2 on D16 were confirmed by RT-qPCR and western blot. In goat uterus and endometrial epithelial cells (EECs), UCP2 was up-regulated by progesterone and estrogen. In addition, after goat EECs were treated with genipin (an inhibitor of UCP2), not only UCP2 expression but also cell proliferation was inhibited. Collectively, UCP2 is dynamically expressed in goat uterus and can affect EEC proliferation, suggesting that it may participate in regulating the energy metabolism balance of goat uterus during early pregnancy.
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Affiliation(s)
- Ya Sun
- The Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China
| | - Li-Ge Bu
- The Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China
| | - Bo Wang
- The Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China
| | - Jie Ren
- The Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China
| | - Ting-Yue Li
- The Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China
| | - Li-Li Kong
- The Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China
| | - Hua Ni
- The Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China.
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27
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Viskaitis P, Arnold M, Garau C, Jensen LT, Fugger L, Peleg-Raibstein D, Burdakov D. Ingested non-essential amino acids recruit brain orexin cells to suppress eating in mice. Curr Biol 2022; 32:1812-1821.e4. [PMID: 35316652 DOI: 10.1016/j.cub.2022.02.067] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 01/10/2022] [Accepted: 02/23/2022] [Indexed: 12/22/2022]
Abstract
Ingested nutrients are proposed to control mammalian behavior by modulating the activity of hypothalamic orexin/hypocretin neurons (HONs). Previous in vitro studies showed that nutrients ubiquitous in mammalian diets, such as non-essential amino acids (AAs) and glucose, modulate HONs in distinct ways. Glucose inhibits HONs, whereas non-essential (but not essential) AAs activate HONs. The latter effect is of particular interest because its purpose is unknown. Here, we show that ingestion of a dietary-relevant mix of non-essential AAs activates HONs and shifts behavior from eating to exploration. These effects persisted despite ablation of a key neural gut → brain communication pathway, the cholecystokinin-sensitive vagal afferents. The behavioral shift induced by the ingested non-essential AAs was recapitulated by targeted HON optostimulation and abolished in mice lacking HONs. Furthermore, lick microstructure analysis indicated that intragastric non-essential AAs and HON optostimulation each reduce the size, but not the frequency, of consumption bouts, thus implicating food palatability modulation as a mechanism for the eating suppression. Collectively, these results suggest that a key purpose of HON activation by ingested, non-essential AAs is to suppress eating and re-initiate food seeking. We propose and discuss possible evolutionary advantages of this, such as optimizing the limited stomach capacity for ingestion of essential nutrients.
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Affiliation(s)
- Paulius Viskaitis
- ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse, Schwerzenbach 8603, Switzerland
| | - Myrtha Arnold
- ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse, Schwerzenbach 8603, Switzerland
| | - Celia Garau
- University of Leicester, Department of Neuroscience, Psychology & Behaviour, University Road, Leicester LE1 9HN, UK
| | - Lise T Jensen
- Aarhus University, Department of Clinical Medicine - Department of Clinical Immunology, Palle Juul-Jensens Boulevard, Aarhus 8200, Denmark
| | - Lars Fugger
- Aarhus University, Department of Clinical Medicine - Department of Clinical Immunology, Palle Juul-Jensens Boulevard, Aarhus 8200, Denmark; University of Oxford, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, Oxford OX3 9DS, UK
| | - Daria Peleg-Raibstein
- ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse, Schwerzenbach 8603, Switzerland
| | - Denis Burdakov
- ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse, Schwerzenbach 8603, Switzerland.
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28
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Hypothalamic melanin-concentrating hormone regulates hippocampus-dorsolateral septum activity. Nat Neurosci 2022; 25:61-71. [PMID: 34980924 PMCID: PMC8741735 DOI: 10.1038/s41593-021-00984-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 11/10/2021] [Indexed: 12/15/2022]
Abstract
Hypothalamic melanin-concentrating hormone (MCH) polypeptide contributes to regulating energy homeostasis, sleep, and memory, though the mechanistic bases of its effects are unknown. Here, in mice, we uncover the physiological mechanism underlying the functional role of MCH signaling in projections to the dorsolateral septum (dLS), a region involved in routing hippocampal firing rhythms and encoding spatial memory based on such rhythms. Firing activity within the dLS in response to dorsal CA3 (dCA3) excitation is limited by strong feed-forward inhibition (FFI). We find that MCH synchronizes dLS neuronal firing with its dCA3 inputs by enhancing GABA release, which subsequently reduces the FFI and augments dCA3 excitatory input strength, both via presynaptic mechanisms. At the functional level, our data reveal a role for MCH signaling in the dLS in facilitating spatial memory. These findings support a model in which peptidergic signaling within the dLS modulates dorsal hippocampal output and supports memory encoding.
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29
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Yang D, Hou X, Yang G, Li M, Zhang J, Han M, Zhang Y, Liu Y. Effects of the POMC System on Glucose Homeostasis and Potential Therapeutic Targets for Obesity and Diabetes. Diabetes Metab Syndr Obes 2022; 15:2939-2950. [PMID: 36186941 PMCID: PMC9521683 DOI: 10.2147/dmso.s380577] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
The hypothalamus is indispensable in energy regulation and glucose homeostasis. Previous studies have shown that pro-opiomelanocortin neurons receive both central neuronal signals, such as α-melanocyte-stimulating hormone, β-endorphin, and adrenocorticotropic hormone, as well as sense peripheral signals such as leptin, insulin, adiponectin, glucagon-like peptide-1, and glucagon-like peptide-2, affecting glucose metabolism through their corresponding receptors and related signaling pathways. Abnormalities in these processes can lead to obesity, type 2 diabetes, and other metabolic diseases. However, the mechanisms by which these signal molecules fulfill their role remain unclear. Consequently, in this review, we explored the mechanisms of these hormones and signals on obesity and diabetes to suggest potential therapeutic targets for obesity-related metabolic diseases. Multi-drug combination therapy for obesity and diabetes is becoming a trend and requires further research to help patients to better control their blood glucose and improve their prognosis.
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Affiliation(s)
- Dan Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Xintong Hou
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Guimei Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Mengnan Li
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Jian Zhang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Minmin Han
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China
- Correspondence: Yi Zhang, Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China, Email
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- Yunfeng Liu, Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China, Tel +86 18703416196, Email
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30
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Wu J, Liu D, Li J, Sun J, Huang Y, Zhang S, Gao S, Mei W. Central Neural Circuits Orchestrating Thermogenesis, Sleep-Wakefulness States and General Anesthesia States. Curr Neuropharmacol 2022; 20:223-253. [PMID: 33632102 PMCID: PMC9199556 DOI: 10.2174/1570159x19666210225152728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/01/2021] [Accepted: 02/24/2021] [Indexed: 11/22/2022] Open
Abstract
Great progress has been made in specifically identifying the central neural circuits (CNCs) of the core body temperature (Tcore), sleep-wakefulness states (SWs), and general anesthesia states (GAs), mainly utilizing optogenetic or chemogenetic manipulations. We summarize the neuronal populations and neural pathways of these three CNCs, which gives evidence for the orchestration within these three CNCs, and the integrative regulation of these three CNCs by different environmental light signals. We also outline some transient receptor potential (TRP) channels that function in the CNCs-Tcore and are modulated by some general anesthetics, which makes TRP channels possible targets for addressing the general-anestheticsinduced- hypothermia (GAIH). We suggest this review will provide new orientations for further consummating these CNCs and elucidating the central mechanisms of GAIH.
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Affiliation(s)
- Jiayi Wu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Daiqiang Liu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jiayan Li
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jia Sun
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yujie Huang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shuang Zhang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shaojie Gao
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wei Mei
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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31
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Yang Y, He Y, Liu H, Zhou W, Wang C, Xu P, Cai X, Liu H, Yu K, Pei Z, Hyseni I, Fukuda M, Tong Q, Xu J, Sun Z, O'Malley BW, Xu Y. Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition. Cell Rep 2021; 37:110075. [PMID: 34879284 PMCID: PMC8715676 DOI: 10.1016/j.celrep.2021.110075] [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: 09/23/2020] [Revised: 08/09/2021] [Accepted: 11/09/2021] [Indexed: 01/09/2023] Open
Abstract
The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage.
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Affiliation(s)
- Yongjie Yang
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Yanlin He
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hailan Liu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Wenjun Zhou
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Chunmei Wang
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Pingwen Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xing Cai
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hesong Liu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kaifan Yu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhou Pei
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ilirjana Hyseni
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Makoto Fukuda
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Qingchun Tong
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Zheng Sun
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Bert W O'Malley
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yong Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
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32
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Al-Massadi O, Dieguez C, Schneeberger M, López M, Schwaninger M, Prevot V, Nogueiras R. Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis. Nat Rev Endocrinol 2021; 17:745-755. [PMID: 34608277 DOI: 10.1038/s41574-021-00559-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/16/2021] [Indexed: 12/12/2022]
Abstract
Melanin-concentrating hormone (MCH) is a small cyclic peptide expressed in all mammals, mainly in the hypothalamus. MCH acts as a robust integrator of several physiological functions and has crucial roles in the regulation of sleep-wake rhythms, feeding behaviour and metabolism. MCH signalling has a very broad endocrine context and is involved in physiological functions and emotional states associated with metabolism, such as reproduction, anxiety, depression, sleep and circadian rhythms. MCH mediates its functions through two receptors (MCHR1 and MCHR2), of which only MCHR1 is common to all mammals. Owing to the wide variety of MCH downstream signalling pathways, MCHR1 agonists and antagonists have great potential as tools for the directed management of energy balance disorders and associated metabolic complications, and translational strategies using these compounds hold promise for the development of novel treatments for obesity. This Review provides an overview of the numerous roles of MCH in energy and glucose homeostasis, as well as in regulation of the mesolimbic dopaminergic circuits that encode the hedonic component of food intake.
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Affiliation(s)
- Omar Al-Massadi
- Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
- CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
| | - Carlos Dieguez
- CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Marc Schneeberger
- Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA
| | - Miguel López
- CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Vincent Prevot
- Univ. Lille, Inserm, CHU Lille, Lille Neuroscience and Cognition, Laboratory of Development and Plasticity of the Neuroendocrine Brain, UMR-S1172, EGID, Lille, France
| | - Ruben Nogueiras
- CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
- Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain.
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Song N, Fang Y, Zhu H, Liu J, Jiang S, Sun S, Xu R, Ding J, Hu G, Lu M. Kir6.2 is essential to maintain neurite features by modulating PM20D1-reduced mitochondrial ATP generation. Redox Biol 2021; 47:102168. [PMID: 34673451 PMCID: PMC8577462 DOI: 10.1016/j.redox.2021.102168] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/28/2022] Open
Abstract
Kir6.2, a pore-forming subunit of the ATP-sensitive potassium (KATP) channels, regulates the functions of metabolically active tissues and acts as an ideal therapeutic target for multiple diseases. Previous studies have been conducted on peripheral kir6.2, but its precise physiological roles in the central nervous system (CNS) have rarely been revealed. In the current study, we evaluated the neurophenotypes and neuroethology of kir6.2 knockout (kir6.2-/-) mice. We demonstrated the beneficial effects of kir6.2 on maintaining the morphology of mesencephalic neurons and controlling the motor coordination of mice. The mechanisms underlying the abnormal neurological features of kir6.2 deficiency were analyzed by RNA sequencing (RNA-seq). Pm20d1, a gene encoding PM20D1 secretase that promotes the generation of endogenous mitochondria uncouplers in vivo, was dramatically upregulated in the midbrain of kir6.2-/- mice. Further investigations verified that PM20D1-induced increase of N-acyl amino acids (N-AAAs) from circulating fatty acids and amino acids promoted mitochondrial impairments and cut down the ATP generation, which mediated the morphological defects of the mesencephalic neurons and thus led to the behavioral impairments of kir6.2 knockout mice. This study is the first evidence to demonstrate the roles of kir6.2 in the morphological maintenance of neurite and motor coordination control of mice, which extends our understanding of kir6.2/KATP channels in regulating the neurophysiological function.
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Affiliation(s)
- Nanshan Song
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China
| | - Yinquan Fang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China
| | - Hong Zhu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China
| | - Jiaqi Liu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China
| | - Siyuan Jiang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China
| | - Sifan Sun
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Rong Xu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China
| | - Jianhua Ding
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China
| | - Gang Hu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China; Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Ming Lu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China; Neuroprotective Drug Discovery Key Laboratory, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China.
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Alhassen W, Kobayashi Y, Su J, Robbins B, Nguyen H, Myint T, Yu M, Nauli SM, Saito Y, Alachkar A. Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations. Mol Neurobiol 2021; 59:245-265. [PMID: 34665407 DOI: 10.1007/s12035-021-02511-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/29/2021] [Indexed: 12/23/2022]
Abstract
The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate-putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length.
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Affiliation(s)
- Wedad Alhassen
- Departments of Pharmaceutical Sciences, School of Pharmacy, University of California, Irvine, CA, 92697, USA
| | - Yuki Kobayashi
- Graduate School of Integrated Sciences for Life, Hiroshima University, 1-7-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8521, Japan
| | - Jessica Su
- Departments of Pharmaceutical Sciences, School of Pharmacy, University of California, Irvine, CA, 92697, USA
| | - Brianna Robbins
- Departments of Pharmaceutical Sciences, School of Pharmacy, University of California, Irvine, CA, 92697, USA
| | - Henry Nguyen
- Departments of Pharmaceutical Sciences, School of Pharmacy, University of California, Irvine, CA, 92697, USA
| | - Thant Myint
- Departments of Pharmaceutical Sciences, School of Pharmacy, University of California, Irvine, CA, 92697, USA
| | - Micah Yu
- Departments of Pharmaceutical Sciences, School of Pharmacy, University of California, Irvine, CA, 92697, USA
| | - Surya M Nauli
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Health Science Campus, Chapman University, Irvine, CA, 92618, USA
| | - Yumiko Saito
- Graduate School of Integrated Sciences for Life, Hiroshima University, 1-7-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8521, Japan
| | - Amal Alachkar
- Departments of Pharmaceutical Sciences, School of Pharmacy, University of California, Irvine, CA, 92697, USA. .,Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California, Irvine, CA, 92697, USA.
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35
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Chen Y, Zhang J. How Energy Supports Our Brain to Yield Consciousness: Insights From Neuroimaging Based on the Neuroenergetics Hypothesis. Front Syst Neurosci 2021; 15:648860. [PMID: 34295226 PMCID: PMC8291083 DOI: 10.3389/fnsys.2021.648860] [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: 01/02/2021] [Accepted: 05/26/2021] [Indexed: 11/13/2022] Open
Abstract
Consciousness is considered a result of specific neuronal processes and mechanisms in the brain. Various suggested neuronal mechanisms, including the information integration theory (IIT), global neuronal workspace theory (GNWS), and neuronal construction of time and space as in the context of the temporospatial theory of consciousness (TTC), have been laid forth. However, despite their focus on different neuronal mechanisms, these theories neglect the energetic-metabolic basis of the neuronal mechanisms that are supposed to yield consciousness. Based on the findings of physiology-induced (sleep), pharmacology-induced (general anesthesia), and pathology-induced [vegetative state/unresponsive wakeful syndrome (VS/UWS)] loss of consciousness in both human subjects and animals, we, in this study, suggest that the energetic-metabolic processes focusing on ATP, glucose, and γ-aminobutyrate/glutamate are indispensable for functional connectivity (FC) of normal brain networks that renders consciousness possible. Therefore, we describe the energetic-metabolic predispositions of consciousness (EPC) that complement the current theories focused on the neural correlates of consciousness (NCC).
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Affiliation(s)
- Yali Chen
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jun Zhang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical college, Fudan University, Shanghai, China
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36
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Cocaine-induced neural adaptations in the lateral hypothalamic melanin-concentrating hormone neurons and the role in regulating rapid eye movement sleep after withdrawal. Mol Psychiatry 2021; 26:3152-3168. [PMID: 33093653 PMCID: PMC8060355 DOI: 10.1038/s41380-020-00921-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/30/2020] [Accepted: 10/07/2020] [Indexed: 12/21/2022]
Abstract
Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic drug use. Notably, rapid eye movement (REM) sleep regulates emotional memory, and persistent REM sleep impairment after cocaine withdrawal negatively impacts relapse-like behaviors in rats. However, it is not understood how cocaine experience may alter REM sleep regulatory machinery, and what may serve to improve REM sleep after withdrawal. Here, we focus on the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH), which regulate REM sleep initiation and maintenance. Using adult male Sprague-Dawley rats trained to self-administer intravenous cocaine, we did transcriptome profiling of LH MCH neurons after long-term withdrawal using RNA-sequencing, and performed functional assessment using slice electrophysiology. We found that 3 weeks after withdrawal from cocaine, LH MCH neurons exhibit a wide range of gene expression changes tapping into cell membrane signaling, intracellular signaling, and transcriptional regulations. Functionally, they show reduced membrane excitability and decreased glutamatergic receptor activity, consistent with increased expression of voltage-gated potassium channel gene Kcna1 and decreased expression of metabotropic glutamate receptor gene Grm5. Finally, chemogenetic or optogenetic stimulations of LH MCH neural activity increase REM sleep after long-term withdrawal with important differences. Whereas chemogenetic stimulation promotes both wakefulness and REM sleep, optogenetic stimulation of these neurons in sleep selectively promotes REM sleep. In summary, cocaine exposure persistently alters gene expression profiles and electrophysiological properties of LH MCH neurons. Counteracting cocaine-induced hypoactivity of these neurons selectively in sleep enhances REM sleep quality and quantity after long-term withdrawal.
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Barbier M, González JA, Houdayer C, Burdakov D, Risold P, Croizier S. Projections from the dorsomedial division of the bed nucleus of the stria terminalis to hypothalamic nuclei in the mouse. J Comp Neurol 2021; 529:929-956. [PMID: 32678476 PMCID: PMC7891577 DOI: 10.1002/cne.24988] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/30/2020] [Accepted: 07/14/2020] [Indexed: 12/18/2022]
Abstract
As stressful environment is a potent modulator of feeding, we seek in the present work to decipher the neuroanatomical basis for an interplay between stress and feeding behaviors. For this, we combined anterograde and retrograde tracing with immunohistochemical approaches to investigate the patterns of projections between the dorsomedial division of the bed nucleus of the stria terminalis (BNST), well connected to the amygdala, and hypothalamic structures such as the paraventricular (PVH) and dorsomedial (DMH), the arcuate (ARH) nuclei and the lateral hypothalamic areas (LHA) known to control feeding and motivated behaviors. We particularly focused our study on afferences to proopiomelanocortin (POMC), agouti-related peptide (AgRP), melanin-concentrating-hormone (MCH) and orexin (ORX) neurons characteristics of the ARH and the LHA, respectively. We found light to intense innervation of all these hypothalamic nuclei. We particularly showed an innervation of POMC, AgRP, MCH and ORX neurons by the dorsomedial and dorsolateral divisions of the BNST. Therefore, these results lay the foundation for a better understanding of the neuroanatomical basis of the stress-related feeding behaviors.
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Affiliation(s)
- Marie Barbier
- EA481, Neurosciences Intégratives et Cliniques, UFR SantéUniversité Bourgogne Franche‐ComtéBesançonFrance
- Department of PsychiatrySeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - J. Antonio González
- The Francis Crick InstituteLondonUK
- The Rowett Institute, School of MedicineMedical Sciences and Nutrition, University of AberdeenAberdeenUK
| | - Christophe Houdayer
- EA481, Neurosciences Intégratives et Cliniques, UFR SantéUniversité Bourgogne Franche‐ComtéBesançonFrance
| | - Denis Burdakov
- The Francis Crick InstituteLondonUK
- Neurobehavioural Dynamics Lab, Institute for Neuroscience, D‐HESTSwiss Federal Institute of Technology / ETH ZürichZürichSwitzerland
| | - Pierre‐Yves Risold
- EA481, Neurosciences Intégratives et Cliniques, UFR SantéUniversité Bourgogne Franche‐ComtéBesançonFrance
| | - Sophie Croizier
- University of LausanneCenter for Integrative GenomicsLausanneSwitzerland
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38
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Vallejo FA, Vanni S, Graham RM. UCP2 as a Potential Biomarker for Adjunctive Metabolic Therapies in Tumor Management. Front Oncol 2021; 11:640720. [PMID: 33763373 PMCID: PMC7982524 DOI: 10.3389/fonc.2021.640720] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/01/2021] [Indexed: 12/16/2022] Open
Abstract
Glioblastoma (GBM) remains one of the most lethal primary brain tumors in both adult and pediatric patients. Targeting tumor metabolism has emerged as a promising-targeted therapeutic strategy for GBM and characteristically resistant GBM stem-like cells (GSCs). Neoplastic cells, especially those with high proliferative potential such as GSCs, have been shown to upregulate UCP2 as a cytoprotective mechanism in response to chronic increased reactive oxygen species (ROS) exposure. This upregulation plays a central role in the induction of the highly glycolytic phenotype associated with many tumors. In addition to shifting metabolism away from oxidative phosphorylation, UCP2 has also been implicated in increased mitochondrial Ca2+ sequestration, apoptotic evasion, dampened immune response, and chemotherapeutic resistance. A query of the CGGA RNA-seq and the TCGA GBMLGG database demonstrated that UCP2 expression increases with increased WHO tumor-grade and is associated with much poorer prognosis across a cohort of brain tumors. UCP2 expression could potentially serve as a biomarker to stratify patients for adjunctive anti-tumor metabolic therapies, such as glycolytic inhibition alongside current standard of care, particularly in adult and pediatric gliomas. Additionally, because UCP2 correlates with tumor grade, monitoring serum protein levels in the future may allow clinicians a relatively minimally invasive marker to correlate with disease progression. Further investigation of UCP2’s role in metabolic reprogramming is warranted to fully appreciate its clinical translatability and utility.
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Affiliation(s)
- Frederic A Vallejo
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States.,University of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Steven Vanni
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Regina M Graham
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States.,University of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
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39
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Lord MN, Subramanian K, Kanoski SE, Noble EE. Melanin-concentrating hormone and food intake control: Sites of action, peptide interactions, and appetition. Peptides 2021; 137:170476. [PMID: 33370567 PMCID: PMC8025943 DOI: 10.1016/j.peptides.2020.170476] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 12/10/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022]
Abstract
Given the increased prevalence of obesity and its associated comorbidities, understanding the mechanisms through which the brain regulates energy balance is of critical importance. The neuropeptide melanin-concentrating hormone (MCH) is produced in the lateral hypothalamic area and the adjacent incerto-hypothalamic area and promotes both food intake and energy conservation, overall contributing to body weight gain. Decades of research into this system has provided insight into the neural pathways and mechanisms (behavioral and neurobiological) through which MCH stimulates food intake. Recent technological advancements that allow for selective manipulation of MCH neuron activity have elucidated novel mechanisms of action for the hyperphagic effects of MCH, implicating neural "volume" transmission in the cerebrospinal fluid and sex-specific effects of MCH on food intake control as understudied areas for future investigation. Highlighted here are historical and recent findings that illuminate the neurobiological mechanisms through which MCH promotes food intake, including the identification of various specific neural signaling pathways and interactions with other peptide systems. We conclude with a framework that the hyperphagic effects of MCH signaling are predominantly mediated through enhancement of an "appetition" process in which early postoral prandial signals promote further caloric consumption.
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Affiliation(s)
- Magen N Lord
- Department of Foods and Nutrition, University of Georgia, Athens, GA 30606, USA
| | - Keshav Subramanian
- Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA
| | - Scott E Kanoski
- Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA; Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Emily E Noble
- Department of Foods and Nutrition, University of Georgia, Athens, GA 30606, USA.
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40
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Lee J, Raycraft L, Johnson AW. The dynamic regulation of appetitive behavior through lateral hypothalamic orexin and melanin concentrating hormone expressing cells. Physiol Behav 2020; 229:113234. [PMID: 33130035 DOI: 10.1016/j.physbeh.2020.113234] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023]
Abstract
The lateral hypothalamic area (LHA) is a heterogeneous brain structure extensively studied for its potent role in regulating energy balance. The anatomical and molecular diversity of the LHA permits the orchestration of responses to energy sensing cues from the brain and periphery. Two of the primary cell populations within the LHA associated with integration of this information are Orexin (ORX) and Melanin Concentrating Hormone (MCH). While both of these non-overlapping populations exhibit orexigenic properties, the activities of these two systems support feeding behavior through contrasting mechanisms. We describe the anatomical and functional properties as well as interaction with other neuropeptides and brain reward and hedonic systems. Specific outputs relating to arousal, food seeking, feeding, and metabolism are coordinated through these mechanisms. We then discuss how both the ORX and MCH systems harmonize in a divergent yet overall cooperative manner to orchestrate feeding behavior through transitions between various appetitive states, and thus offer novel insights into LHA allostatic control of appetite.
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Affiliation(s)
| | | | - Alexander W Johnson
- Department of Psychology; Neuroscience Program, Michigan State University, East Lansing.
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Bandaru SS, Khanday MA, Ibrahim N, Naganuma F, Vetrivelan R. Sleep-Wake Control by Melanin-Concentrating Hormone (MCH) Neurons: a Review of Recent Findings. Curr Neurol Neurosci Rep 2020; 20:55. [PMID: 33006677 PMCID: PMC11891936 DOI: 10.1007/s11910-020-01075-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE OF THE REVIEW Melanin-concentrating hormone (MCH)-expressing neurons located in the lateral hypothalamus are considered as an integral component of sleep-wake circuitry. However, the precise role of MCH neurons in sleep-wake regulation has remained unclear, despite several years of research employing a wide range of techniques. We review recent data on this aspect, which are mostly inconsistent, and propose a novel role for MCH neurons in sleep regulation. RECENT FINDINGS While almost all studies using "gain-of-function" approaches show an increase in rapid eye movement sleep (or paradoxical sleep; PS), loss-of-function approaches have not shown reductions in PS. Similarly, the reported changes in wakefulness or non-rapid eye movement sleep (slow-wave sleep; SWS) with manipulation of the MCH system using conditional genetic methods are inconsistent. Currently available data do not support a role for MCH neurons in spontaneous sleep-wake but imply a crucial role for them in orchestrating sleep-wake responses to changes in external and internal environments.
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Affiliation(s)
- Sathyajit S Bandaru
- Department of Neurology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Center for Life Science # 711, Boston, MA, USA
| | - Mudasir A Khanday
- Department of Neurology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Center for Life Science # 711, Boston, MA, USA
- Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA
| | - Nazifa Ibrahim
- Department of Neurology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Center for Life Science # 711, Boston, MA, USA
- Department of Public Health Sciences, University of Massachusetts, Amherst, MA, USA
| | - Fumito Naganuma
- Department of Neurology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Center for Life Science # 711, Boston, MA, USA
- Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Ramalingam Vetrivelan
- Department of Neurology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Center for Life Science # 711, Boston, MA, USA.
- Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
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Sohn JW, Ho WK. Cellular and systemic mechanisms for glucose sensing and homeostasis. Pflugers Arch 2020; 472:1547-1561. [PMID: 32960363 DOI: 10.1007/s00424-020-02466-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/14/2020] [Accepted: 09/14/2020] [Indexed: 12/25/2022]
Abstract
Glucose is a major source of energy in animals. Maintaining blood glucose levels within a physiological range is important for facilitating glucose uptake by cells, as required for optimal functioning. Glucose homeostasis relies on multiple glucose-sensing cells in the body that constantly monitor blood glucose levels and respond accordingly to adjust its glycemia. These include not only pancreatic β-cells and α-cells that secrete insulin and glucagon, but also central and peripheral neurons regulating pancreatic endocrine function. Different types of cells respond distinctively to changes in blood glucose levels, and the mechanisms involved in glucose sensing are diverse. Notably, recent studies have challenged the currently held views regarding glucose-sensing mechanisms. Furthermore, peripheral and central glucose-sensing cells appear to work in concert to control blood glucose level and maintain glucose and energy homeostasis in organisms. In this review, we summarize the established concepts and recent advances in the understanding of cellular and systemic mechanisms that regulate glucose sensing and its homeostasis.
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Affiliation(s)
- Jong-Woo Sohn
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
| | - Won-Kyung Ho
- Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 03080, South Korea.
- Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea.
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43
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Burdakov D, Peleg-Raibstein D. The hypothalamus as a primary coordinator of memory updating. Physiol Behav 2020; 223:112988. [DOI: 10.1016/j.physbeh.2020.112988] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/05/2020] [Accepted: 05/26/2020] [Indexed: 12/19/2022]
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44
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Control of fear extinction by hypothalamic melanin-concentrating hormone-expressing neurons. Proc Natl Acad Sci U S A 2020; 117:22514-22521. [PMID: 32848057 PMCID: PMC7486764 DOI: 10.1073/pnas.2007993117] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely identified. We studied fear suppression through a procedure in which, after acquiring fear of aversive events (fear learning), subjects were exposed to fear-eliciting cues without aversive events (safety learning), leading to suppression of fear behavior (fear extinction). Here we show that inappropriate, learning-resistant fear behavior results from disruption of brain components not previously implicated in this disorder: hypothalamic melanin-concentrating hormone-expressing neurons (MNs). Using real-time recordings of MNs across fear learning and extinction, we provide evidence that fear-inducing aversive events elevate MN activity. We find that optogenetic disruption of this MN activity profoundly impairs safety learning, abnormally slowing down fear extinction and exacerbating fear relapse. Importantly, we demonstrate that the MN disruption impairs neither fear learning nor related sensory responses, indicating that MNs differentially control safety and fear learning. Thus, we identify a neural substrate for inhibition of excessive fear behavior.
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45
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Beekly BG, Frankel WC, Berg T, Allen SJ, Garcia-Galiano D, Vanini G, Elias CF. Dissociated Pmch and Cre Expression in Lactating Pmch-Cre BAC Transgenic Mice. Front Neuroanat 2020; 14:60. [PMID: 32982701 PMCID: PMC7475711 DOI: 10.3389/fnana.2020.00060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 08/04/2020] [Indexed: 12/11/2022] Open
Abstract
The melanin-concentrating hormone (MCH) system plays a role in many physiological processes including reproduction and lactation. However, research regarding the function of MCH on different aspects of the reproductive function lags, due in part to a lack of validated genetic models with which to interrogate the system. This is particularly true in the case of female reproduction, as the anatomy and function of the MCH system is not well-characterized in the female mouse. We set out to determine whether the commercially available Pmch-Cre transgenic mouse line is a viable model to study the role of MCH neurons in distinct female reproductive states. We found that Pmch is transiently expressed in several nuclei of the rostral forebrain at the end of lactation. This includes the medial subdivision of the medial preoptic nucleus, the paraventricular nucleus of the hypothalamus, the ventral subdivision of the lateral septum, the anterodorsal preoptic nucleus and the anterodorsal nucleus of the thalamus. The Pmch expression in these sites, however, does not reliably induce Cre expression in the Pmch-Cre (BAC) transgenic mouse, making this line an inadequate model with which to study the role of MCH in behavioral and/or neuroendocrine adaptations of lactation. We also contribute to the general knowledge of the anatomy of the murine MCH system by showing that lactation-induced Pmch expression in the rostral forebrain is mostly observed in GABAergic (VGAT) neurons, in contrast to the typical MCH neurons of the tuberal and posterior hypothalamus which are glutamatergic (VGLUT2).
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Affiliation(s)
- Bethany G Beekly
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States.,Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States
| | - William C Frankel
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States.,Baylor College of Medicine, Houston, TX, United States
| | - Tova Berg
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Susan J Allen
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - David Garcia-Galiano
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Giancarlo Vanini
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States.,Department of Anesthesiology, School of Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Carol F Elias
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States.,Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States.,Department of Obstetrics and Gynecology, School of Medicine, University of Michigan, Ann Arbor, MI, United States
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Glucose transporters in brain in health and disease. Pflugers Arch 2020; 472:1299-1343. [PMID: 32789766 PMCID: PMC7462931 DOI: 10.1007/s00424-020-02441-x] [Citation(s) in RCA: 296] [Impact Index Per Article: 59.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/20/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters in capillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-d-glucose cotransporters SGLT1 are expressed. The glucose transporters mediate uptake of d-glucose across the blood-brain barrier and delivery of d-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demands in response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified and proposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based on experiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and their cerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, and SGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functional changes of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy deficiency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome.
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Yu K, He Y, Hyseni I, Pei Z, Yang Y, Xu P, Cai X, Liu H, Qu N, Liu H, He Y, Yu M, Liang C, Yang T, Wang J, Gourdy P, Arnal JF, Lenfant F, Xu Y, Wang C. 17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling. Mol Metab 2020; 42:101053. [PMID: 32712433 PMCID: PMC7484552 DOI: 10.1016/j.molmet.2020.101053] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/20/2022] Open
Abstract
Objective Estrogen protects animals from obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, the effects of estrogen on feeding behavior in hungry animals remain unclear. In this study, we examined the roles of 17β-estradiol (E2) and ERα in the regulation of feeding in hungry female animals and explored the underlying mechanisms. Methods Wild-type female mice with surgical depletion of endogenous estrogens were used to examine the effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF20 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying acute feeding triggered by either fasting or central glucopenia (induced by intracerebroventricular injections of 2-deoxy-D-glucose). We also used electrophysiology to explore the impact of these ERα mutations on the neural activities of ERα neurons in the hypothalamus. Results In the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF20 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERα-C451A mutation consistently impaired the neural responses of hypothalamic ERα neurons to hypoglycemia. Conclusion In addition to previous evidence that estrogen reduces deviations in energy balance by inhibiting eating at a satiated state, our findings demonstrate the unexpected role of E2 that promotes eating in hungry mice, also contributing to the stability of energy homeostasis. This latter effect specifically requires membrane-bound ERα activity.
Endogenous E2 is required to maintain acute refeeding in hungry female mice after starvation. Membrane-bound ERα activity in female mice is required for efficient refeeding after starvation. Membrane-bound ERα activity is required for hypothalamic ERα neurons to respond to hypoglycemia.
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Affiliation(s)
- Kaifan Yu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA; College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, China
| | - Yanlin He
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA; Pennington Biomedical Research Center, Brain Glycemic and Metabolism Control Department, Louisiana State University, Baton Rouge, LA, 70808, USA
| | - Ilirjana Hyseni
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Zhou Pei
- 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
| | - Pingwen Xu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Xing Cai
- 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
| | - Na Qu
- 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
| | - Yang He
- 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
| | - Chen Liang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Tingting Yang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Julia Wang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Pierre Gourdy
- I2MC, Inserm U1048, CHU de Toulouse and Université de Toulouse III, Toulouse, France
| | - Jean-Francois Arnal
- I2MC, Inserm U1048, CHU de Toulouse and Université de Toulouse III, Toulouse, France
| | - Francoise Lenfant
- I2MC, Inserm U1048, CHU de Toulouse and Université de Toulouse III, Toulouse, France
| | - 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, One Baylor Plaza, 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.
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Perez-Bonilla P, Santiago-Colon K, Leinninger GM. Lateral hypothalamic area neuropeptides modulate ventral tegmental area dopamine neurons and feeding. Physiol Behav 2020; 223:112986. [PMID: 32492498 DOI: 10.1016/j.physbeh.2020.112986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 05/19/2020] [Accepted: 05/26/2020] [Indexed: 01/26/2023]
Abstract
Understanding how the brain coordinates energy status with the motivation to eat is crucial to identify strategies to improve disordered body weight. The ventral tegmental area (VTA), known as the core of the mesolimbic system, is of particular interest in this regard because it controls the motivation to consume palatable, calorie-dense foods and to engage in volitional activity. The VTA is largely composed of dopamine (DA) neurons, but modulating these DA neurons has been alternately linked with promoting and suppressing feeding, suggesting heterogeneity in their function. Subsets of VTA DA neurons have recently been described based on their anatomical distribution, electrophysiological features, connectivity and molecular expression, but to date there are no signatures to categorize how DA neurons control feeding. Assessing the neuropeptide receptors expressed by VTA DA neurons may be useful in this regard, as many neuropeptides mediate anorexic or orexigenic responses. In particular, the lateral hypothalamic area (LHA) releases a wide variety of feeding-modulating neuropeptides to the VTA. Since VTA neurons intercept LHA neuropeptides known to either evoke or suppress feeding, expression of the cognate neuropeptide receptors within the VTA may point to VTA DA neuronal mechanisms to promote or suppress feeding, respectively. Here we review the role of the VTA in energy balance and the LHA neuropeptide signaling systems that act in the VTA, whose receptors might be used to classify how VTA DA neurons contribute to energy balance.
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Affiliation(s)
- Patricia Perez-Bonilla
- Neuroscience Graduate Program, USA; Pharmacology and Toxicology Graduate Program, USA; Michigan State University, East Lansing, MI 48114, USA
| | - Krystal Santiago-Colon
- Department of Biology, University of Puerto Rico - Cayey, USA; Bridge to the PhD in Neuroscience Program, USA
| | - Gina M Leinninger
- Department of Physiology, USA; Michigan State University, East Lansing, MI 48114, USA.
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MCH Neurons Regulate Permeability of the Median Eminence Barrier. Neuron 2020; 107:306-319.e9. [PMID: 32407670 PMCID: PMC7383232 DOI: 10.1016/j.neuron.2020.04.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 03/06/2020] [Accepted: 04/20/2020] [Indexed: 01/17/2023]
Abstract
Melanin-concentrating hormone (MCH)-expressing neurons are key regulators of energy and glucose homeostasis. Here, we demonstrate that they provide dense projections to the median eminence (ME) in close proximity to tanycytes and fenestrated vessels. Chemogenetic activation of MCH neurons as well as optogenetic stimulation of their projections in the ME enhance permeability of the ME by increasing fenestrated vascular loops and enhance leptin action in the arcuate nucleus of the hypothalamus (ARC). Unbiased phosphoRiboTrap-based assessment of cell activation upon chemogenetic MCH neuron activation reveals MCH-neuron-dependent regulation of endothelial cells. MCH neurons express the vascular endothelial growth factor A (VEGFA), and blocking VEGF-R signaling attenuates the leptin-sensitizing effect of MCH neuron activation. Our experiments reveal that MCH neurons directly regulate permeability of the ME barrier, linking the activity of energy state and sleep regulatory neurons to the regulation of hormone accessibility to the ARC.
MCH neurons provide dense projections to the median eminence MCH neuron activation promotes permeability of the median eminence barrier MCH neuron activation enhances microvessel fenestration in the ME MCH neuron activation enhances leptin action in the arcuate nucleus
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