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Lee R, Kim G, Black ER, Kim S. Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction, fear memory loss, and amyloid pathology in Alzheimer's disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.07.08.602576. [PMID: 39026693 PMCID: PMC11257460 DOI: 10.1101/2024.07.08.602576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Alzheimer's disease (AD) is the most common form of dementia with no known cause and cure. Research suggests that a reduction of GABAergic inhibitory interneurons' activity in the hippocampus by beta-amyloid peptide (Aβ) is a crucial trigger for amyloid pathology and cognitive impairment in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be protective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation in excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in hippocampal excitatory neurons. Here, we discover that α7- and α4β2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. Furthermore, we reveal that co-activation of these receptors is necessary to reverse hippocampal network dysfunction, amyloid pathology, and fear memory loss in the amyloid pathology model mice. This suggests that co-activation of PV+ and SST+ cells via stimulating α7- and α4β2-nAChRs together is a novel strategy for neuroprotection against AD.
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Aghjayan SL, Polk SE, Ripperger HS, Huang H, Wan L, Kamarck T, Marsland AL, Kang C, Voss MW, Sutton BP, Oberlin LE, Burns JM, Vidoni ED, McAuley E, Hillman CH, Kramer AF, Erickson KI. Associations Between Episodic Memory and Hippocampal Volume in Late Adulthood. Hippocampus 2025; 35:e70010. [PMID: 40129092 PMCID: PMC12001747 DOI: 10.1002/hipo.70010] [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: 06/26/2024] [Revised: 01/10/2025] [Accepted: 03/12/2025] [Indexed: 03/26/2025]
Abstract
Different tasks of episodic memory (EM) are only moderately correlated with each other. Furthermore, various EM tasks exhibit disproportional relationships with the hippocampus. This study examined the covariance structure of EM tasks and assessed whether this structure relates differently to hippocampal volume (HV) in a sample of 648 cognitively unimpaired older adults (mean age = 69.88). A confirmatory factor analysis (CFA) and linear regression models were used to test the associations between the observed factors of EM and HV. A model with three first-order subfactors (immediate verbal recall, delayed verbal recall, and visuospatial) derived from a second-order EM domain factor satisfied model fit (χ2 p value ≥ 0.05, CFI > 0.90, RMSEA < 0.08, SRMR < 0.08). Total, left, and right HV explained a similar amount of variance in all EM subfactors. CA1, CA3, subiculum, and entorhinal cortex volume were associated with all subfactors, while CA2 and dentate gyrus volume were not associated with EM. These results suggest that EM tasks are measuring the same construct, but different complex processes contribute to EM. Furthermore, HV accounted for a small portion of the variance in EM, suggesting that HV might not be a useful marker of EM in cognitively unimpaired older adults. Finally, this study provides evidence that various hippocampal subfield volumes may not be purely associated with any one aspect of EM processing.
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Affiliation(s)
- Sarah L. Aghjayan
- Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sarah E. Polk
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
| | - Hayley S. Ripperger
- Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Haiqing Huang
- AdventHealth Research Institute, Department of Neuroscience, AdventHealth, Orlando, Florida, USA
| | - Lu Wan
- AdventHealth Research Institute, Department of Neuroscience, AdventHealth, Orlando, Florida, USA
| | - Thomas Kamarck
- Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anna L. Marsland
- Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Chaeryon Kang
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Michelle W. Voss
- Department of Psychological and Brain Science, University of Iowa, Iowa, Iowa, USA
| | - Bradley P. Sutton
- Bioengineering Department, University of Illinois, Champaign, Illinois, USA
| | - Lauren E. Oberlin
- AdventHealth Research Institute, Department of Neuroscience, AdventHealth, Orlando, Florida, USA
- Department of Psychiatry, Weill Cornell Medicine, New York, New York, USA
| | - Jeffrey M. Burns
- Department of Neurology, University of Kansas Medical Center, Kansas, USA
| | - Eric D. Vidoni
- Department of Neurology, University of Kansas Medical Center, Kansas, USA
| | - Edward McAuley
- Department of Kinesiology, University of Illinois, Champaign, Illinois, USA
| | - Charles H. Hillman
- Department of Psychology, Northeastern University, Boston, Massachusetts, USA
| | - Arthur F. Kramer
- Department of Kinesiology, University of Illinois, Champaign, Illinois, USA
- Center for Cognitive & Brain Health, Northeastern University, Boston, Massachusetts, USA
- Beckman Institute, University of Illinois, Urbana, Illinois, USA
| | - Kirk I. Erickson
- Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- AdventHealth Research Institute, Department of Neuroscience, AdventHealth, Orlando, Florida, USA
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3
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Tang B, Wu Z, Wang Q, Tang J. Neuronal Network Activation Induced by Forniceal Deep Brain Stimulation in Mice. Genes (Basel) 2025; 16:210. [PMID: 40004540 PMCID: PMC11855867 DOI: 10.3390/genes16020210] [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: 12/28/2024] [Revised: 01/26/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry mechanisms remain unknown. This study we explored the neural network circuits involved in forniceal DBS treatment. Methods: We used acute forniceal DBS-induced expression of c-Fos, an activity-dependent neuronal marker, to map the brain structures functionally connected to the fornix. We also evaluated the mouse behavior of locomotion, anxiety, and fear memory after acute forniceal DBS treatment. Results: Acute forniceal DBS induces robust activation of multiple structures in the limbic system. DBS-induced neuronal activation extends beyond hippocampal formation and includes brain structures not directly innervated by the fornix. Conclusions: Acute forniceal DBS activates multiple limbic structures associated with emotion and memory. The neural circuits revealed here help elucidate the neural network effect and pave the way for further research on the mechanism by which forniceal DBS induces benefits on cognitive impairments.
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Affiliation(s)
- Bin Tang
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; (B.T.); (Z.W.); (Q.W.)
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhenyu Wu
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; (B.T.); (Z.W.); (Q.W.)
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Qi Wang
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; (B.T.); (Z.W.); (Q.W.)
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jianrong Tang
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; (B.T.); (Z.W.); (Q.W.)
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Yang M, Singh A, de Araujo A, McDougle M, Ellis H, Décarie-Spain L, Kanoski SE, de Lartigue G. Separate orexigenic hippocampal ensembles shape dietary choice by enhancing contextual memory and motivation. Nat Metab 2025; 7:276-296. [PMID: 39815079 PMCID: PMC11860247 DOI: 10.1038/s42255-024-01194-6] [Citation(s) in RCA: 1] [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: 10/23/2023] [Accepted: 11/28/2024] [Indexed: 01/18/2025]
Abstract
The hippocampus (HPC) has emerged as a critical player in the control of food intake, beyond its well-known role in memory. While previous studies have primarily associated the HPC with food intake inhibition, recent research suggests a role in appetitive processes. Here we identified spatially distinct neuronal populations within the dorsal HPC (dHPC) that respond to either fats or sugars, potent natural reinforcers that contribute to obesity development. Using activity-dependent genetic capture of nutrient-responsive dHPC neurons, we demonstrate a causal role of both populations in promoting nutrient-specific intake through different mechanisms. Sugar-responsive neurons encoded spatial memory for sugar location, whereas fat-responsive neurons selectively enhanced the preference and motivation for fat intake. Importantly, stimulation of either nutrient-responsive dHPC neurons increased food intake, while ablation differentially impacted obesogenic diet consumption and prevented diet-induced weight gain. Collectively, these findings uncover previously unknown orexigenic circuits underlying macronutrient-specific consumption and provide a foundation for developing potential obesity treatments.
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Affiliation(s)
- Mingxin Yang
- Monell Chemical Senses Center, Philadelphia, PA, USA
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Arashdeep Singh
- Monell Chemical Senses Center, Philadelphia, PA, USA
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alan de Araujo
- Monell Chemical Senses Center, Philadelphia, PA, USA
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Molly McDougle
- Monell Chemical Senses Center, Philadelphia, PA, USA
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hillary Ellis
- Monell Chemical Senses Center, Philadelphia, PA, USA
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Léa Décarie-Spain
- Human & Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - Scott E Kanoski
- Human & Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - Guillaume de Lartigue
- Monell Chemical Senses Center, Philadelphia, PA, USA.
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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5
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Nunes A, Singh S, Khayachi A, Stern S, Trappenberg T, Alda M. The Impact of Electrophysiological Diversity on Pattern Completion in Lithium Nonresponsive Bipolar Disorder: A Computational Modeling Approach. Brain Behav 2025; 15:e70209. [PMID: 39832133 PMCID: PMC11745123 DOI: 10.1002/brb3.70209] [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: 07/01/2024] [Revised: 10/28/2024] [Accepted: 12/01/2024] [Indexed: 01/22/2025] Open
Abstract
INTRODUCTION Patients with bipolar disorder (BD) demonstrate episodic memory deficits, which may be hippocampal-dependent and may be attenuated in lithium responders. Induced pluripotent stem cell-derived CA3 pyramidal cell-like neurons show significant hyperexcitability in lithium-responsive BD patients, while lithium nonresponders show marked variance in hyperexcitability. We hypothesize that this variable excitability will impair episodic memory recall, as assessed by cued retrieval (pattern completion) within a computational model of the hippocampal CA3. METHODS We simulated pattern completion tasks using a computational model of the CA3 with different degrees of pyramidal cell excitability variance. Since pyramidal cell excitability variance naturally leads to a mix of hyperexcitability and hypoexcitability, we also examined what fraction (hyper- vs. hypoexcitable) was predominantly responsible for pattern completion errors in our model. RESULTS Pyramidal cell excitability variance impaired pattern completion (linear model β = -2.00, SE = 0.03, p < 0.001). The effect was invariant to all other parameter settings in the model. Excitability variance, specifically hyperexcitability, increased the number of spuriously active neurons, increasing false alarm rates and producing pattern completion deficits. Excessive inhibition also induces pattern completion deficits by limiting the number of correctly active neurons during pattern retrieval. CONCLUSIONS Excitability variance in CA3 pyramidal cell-like neurons observed in lithium nonresponders may predict pattern completion deficits in these patients. These cognitive deficits may not be fully corrected by medications that minimize excitability. Future studies should test our predictions by examining behavioral correlates of pattern completion in lithium-responsive and -nonresponsive BD patients.
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Affiliation(s)
- Abraham Nunes
- Department of PsychiatryDalhousie UniversityHalifaxNova ScotiaCanada
- Faculty of Computer ScienceDalhousie UniversityHalifaxNova ScotiaCanada
| | - Selena Singh
- Department of Psychology, Neuroscience & BehaviourMcMaster UniversityHamiltonOntarioCanada
| | - Anouar Khayachi
- Montreal Neurological Institute, Department of Neurology & NeurosurgeryMcGill UniversityMontrealQuebecCanada
| | - Shani Stern
- Sagol Department of Neurobiology, Faculty of Natural SciencesUniversity of HaifaHaifaIsrael
| | | | - Martin Alda
- Department of PsychiatryDalhousie UniversityHalifaxNova ScotiaCanada
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Leana-Sandoval G, Kolli AV, Sandoval MA, Saavedra E, Li KH, Chen LY, Burlingame AL, Ramírez-Franco J, Díaz-Alonso J. The VGCC auxiliary subunit α2δ1 is an extracellular GluA1 interactor and regulates LTP, spatial memory, and seizure susceptibility. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.02.626379. [PMID: 39677598 PMCID: PMC11642997 DOI: 10.1101/2024.12.02.626379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Activity-dependent synaptic accumulation of AMPA receptors (AMPARs) and subsequent long-term synaptic strengthening underlie different forms of learning and memory. The AMPAR subunit GluA1 amino-terminal domain is essential for synaptic docking of AMPAR during LTP, but the precise mechanisms involved are not fully understood. Using unbiased proteomics, we identified the epilepsy and intellectual disability-associated VGCC auxiliary subunit α2δ1 as a candidate extracellular AMPAR slot. Presynaptic α2δ1 deletion in CA3 affects synaptic AMPAR incorporation during long-term potentiation, but not basal synaptic transmission, at CA1 synapses. Consistently, mice lacking α2δ1 in CA3 display a specific impairment in CA1-dependent spatial memory, but not in memory tests involving other cortical regions. Decreased seizure susceptibility in mice lacking α2δ1 in CA3 suggests a regulation of circuit excitability by α2δ1/AMPAR interactions. Our study sheds light on the regulation of activity-dependent AMPAR trafficking, and highlights the synaptic organizing roles of α2δ1.
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Affiliation(s)
- Gerardo Leana-Sandoval
- Department of Anatomy & Neurobiology, University of California at Irvine, CA, 92617, USA
- Center for the Neurobiology of Learning and Memory, University of California at Irvine, CA, USA
| | - Ananth V. Kolli
- Department of Anatomy & Neurobiology, University of California at Irvine, CA, 92617, USA
- Center for the Neurobiology of Learning and Memory, University of California at Irvine, CA, USA
| | - Matthew A. Sandoval
- Department of Anatomy & Neurobiology, University of California at Irvine, CA, 92617, USA
- Center for the Neurobiology of Learning and Memory, University of California at Irvine, CA, USA
| | - Emily Saavedra
- Department of Anatomy & Neurobiology, University of California at Irvine, CA, 92617, USA
- Center for the Neurobiology of Learning and Memory, University of California at Irvine, CA, USA
| | - Kathy H. Li
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Lulu Y. Chen
- Department of Anatomy & Neurobiology, University of California at Irvine, CA, 92617, USA
- Center for the Neurobiology of Learning and Memory, University of California at Irvine, CA, USA
| | - Alma L. Burlingame
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Jorge Ramírez-Franco
- Institut de Neurosciences de la Timone, Aix-Marseille Université (AMU) & CNRS, UMR7289, 13005, Marseille, France
| | - Javier Díaz-Alonso
- Department of Anatomy & Neurobiology, University of California at Irvine, CA, 92617, USA
- Center for the Neurobiology of Learning and Memory, University of California at Irvine, CA, USA
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Kong E, Zabeh E, Liao Z, Mihaila TS, Wilson C, Santhirasegaran C, Peterka DS, Losonczy A, Geiller T. Recurrent Connectivity Shapes Spatial Coding in Hippocampal CA3 Subregions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.07.622379. [PMID: 39574766 PMCID: PMC11581023 DOI: 10.1101/2024.11.07.622379] [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: 11/30/2024]
Abstract
Stable and flexible neural representations of space in the hippocampus are crucial for navigating complex environments. However, how these distinct representations emerge from the underlying local circuit architecture remains unknown. Using two-photon imaging of CA3 subareas during active behavior, we reveal opposing coding strategies within specific CA3 subregions, with proximal neurons demonstrating stable and generalized representations and distal neurons showing dynamic and context-specific activity. We show in artificial neural network models that varying the recurrence level causes these differences in coding properties to emerge. We confirmed the contribution of recurrent connectivity to functional heterogeneity by characterizing the representational geometry of neural recordings and comparing it with theoretical predictions of neural manifold dimensionality. Our results indicate that local circuit organization, particularly recurrent connectivity among excitatory neurons, plays a key role in shaping complementary spatial representations within the hippocampus.
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Affiliation(s)
- Eunji Kong
- Department of Neuroscience, Columbia University, New York, NY, United States
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
| | - Erfan Zabeh
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Zhenrui Liao
- Department of Neuroscience, Columbia University, New York, NY, United States
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
| | - Tiberiu S Mihaila
- Department of Neuroscience, Columbia University, New York, NY, United States
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
| | - Caroline Wilson
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
| | - Charan Santhirasegaran
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
| | - Darcy S Peterka
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
| | - Attila Losonczy
- Department of Neuroscience, Columbia University, New York, NY, United States
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States
| | - Tristan Geiller
- Department of Neuroscience, Yale University, New Haven, CT, USA
- Wu Tsai Institute, Yale University, New Haven, CT, USA
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8
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Chen S, Cheng N, Chen X, Wang C. Integration and competition between space and time in the hippocampus. Neuron 2024; 112:3651-3664.e8. [PMID: 39241779 DOI: 10.1016/j.neuron.2024.08.007] [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: 03/12/2024] [Revised: 07/11/2024] [Accepted: 08/09/2024] [Indexed: 09/09/2024]
Abstract
Episodic memory is organized in both spatial and temporal contexts. The hippocampus is crucial for episodic memory and has been demonstrated to encode spatial and temporal information. However, how the representations of space and time interact in the hippocampal memory system is still unclear. Here, we recorded the activity of hippocampal CA1 neurons in mice in a variety of one-dimensional navigation tasks while systematically varying the speed of the animals. For all tasks, we found neurons simultaneously represented space and elapsed time. There was a negative correlation between the preferred space and lap duration, e.g., the preferred spatial position shifted more toward the origin when the lap duration became longer. A similar relationship between the preferred time and traveled distance was also observed. The results strongly suggest a competitive and integrated representation of space-time by single hippocampal neurons, which may provide the neural basis for spatiotemporal contexts.
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Affiliation(s)
- Shijie Chen
- Brain Research Centre, Department of Neuroscience, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China
| | - Ning Cheng
- Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Xiaojing Chen
- Brain Research Centre, Department of Neuroscience, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Cheng Wang
- Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
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9
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Kopsick JD, Kilgore JA, Adam GC, Ascoli GA. Formation and retrieval of cell assemblies in a biologically realistic spiking neural network model of area CA3 in the mouse hippocampus. J Comput Neurosci 2024; 52:303-321. [PMID: 39285088 PMCID: PMC11470887 DOI: 10.1007/s10827-024-00881-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 08/05/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024]
Abstract
The hippocampal formation is critical for episodic memory, with area Cornu Ammonis 3 (CA3) a necessary substrate for auto-associative pattern completion. Recent theoretical and experimental evidence suggests that the formation and retrieval of cell assemblies enable these functions. Yet, how cell assemblies are formed and retrieved in a full-scale spiking neural network (SNN) of CA3 that incorporates the observed diversity of neurons and connections within this circuit is not well understood. Here, we demonstrate that a data-driven SNN model quantitatively reflecting the neuron type-specific population sizes, intrinsic electrophysiology, connectivity statistics, synaptic signaling, and long-term plasticity of the mouse CA3 is capable of robust auto-association and pattern completion via cell assemblies. Our results show that a broad range of assembly sizes could successfully and systematically retrieve patterns from heavily incomplete or corrupted cues after a limited number of presentations. Furthermore, performance was robust with respect to partial overlap of assemblies through shared cells, substantially enhancing memory capacity. These novel findings provide computational evidence that the specific biological properties of the CA3 circuit produce an effective neural substrate for associative learning in the mammalian brain.
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Affiliation(s)
- Jeffrey D Kopsick
- Center for Neural Informatics, Structures, & Plasticity, College of Engineering and Computing, George Mason University, Fairfax, VA, USA
- Interdisciplinary Program in Neuroscience, College of Science, George Mason University, Fairfax, VA, USA
| | - Joseph A Kilgore
- Department of Electrical and Computer Engineering, George Washington University, Washington, D.C., USA
| | - Gina C Adam
- Department of Electrical and Computer Engineering, George Washington University, Washington, D.C., USA
| | - Giorgio A Ascoli
- Center for Neural Informatics, Structures, & Plasticity, College of Engineering and Computing, George Mason University, Fairfax, VA, USA.
- Interdisciplinary Program in Neuroscience, College of Science, George Mason University, Fairfax, VA, USA.
- Bioengineering Department, College of Engineering and Computing, George Mason University, Fairfax, VA, USA.
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10
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Wanjia G, Han S, Kuhl BA. Repulsion of CA3 / dentate gyrus representations is driven by distinct internal beliefs in the face of ambiguous sensory input. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.23.619862. [PMID: 39484581 PMCID: PMC11527005 DOI: 10.1101/2024.10.23.619862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Recent human neuroimaging studies of episodic memory have revealed a counterintuitive phenomenon in the hippocampus: when events are highly similar, corresponding hippocampal activity patterns are sometimes less correlated than activity patterns associated with unrelated events. This phenomenon-repulsion-is not accounted for by most theories of the hippocampus, and the conditions that trigger repulsion remain poorly understood. Here, we used a spatial route-learning task and high-resolution fMRI in humans to test whether hippocampal repulsion is fundamentally driven by internal beliefs about the environment. By precisely measuring participants' internal beliefs and actively manipulating them, we show that repulsion selectively occurred in hippocampal subfields CA3 and dentate gyrus when visual input was ambiguous-or even identical-but internal beliefs were distinct. These findings firmly establish conditions that elicit repulsion and have broad relevance to theories of hippocampal function and to the fields of human episodic memory and rodent spatial navigation.
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Affiliation(s)
- Guo Wanjia
- University of Oregon, Department of Psychology & Institute of Neuroscience
| | - Subin Han
- University of Virginia, Department of Psychology
| | - Brice A Kuhl
- University of Oregon, Department of Psychology & Institute of Neuroscience
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11
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Carretero-Guillén A, Treviño M, Gómez-Climent MÁ, Dogbevia GK, Bertocchi I, Sprengel R, Larkum ME, Vlachos A, Gruart A, Delgado-García JM, Hasan MT. Dentate gyrus is needed for memory retrieval. Mol Psychiatry 2024; 29:2939-2950. [PMID: 38609585 PMCID: PMC11449802 DOI: 10.1038/s41380-024-02546-0] [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: 03/07/2023] [Revised: 03/03/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024]
Abstract
The hippocampus is crucial for acquiring and retrieving episodic and contextual memories. In previous studies, the inactivation of dentate gyrus (DG) neurons by chemogenetic- and optogenetic-mediated hyperpolarization led to opposing conclusions about DG's role in memory retrieval. One study used Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-mediated clozapine N-oxide (CNO)-induced hyperpolarization and reported that the previously formed memory was erased, thus concluding that denate gyrus is needed for memory maintenance. The other study used optogenetic with halorhodopsin induced hyperpolarization and reported and dentate gyrus is needed for memory retrieval. We hypothesized that this apparent discrepancy could be due to the length of hyperpolarization in previous studies; minutes by optogenetics and several hours by DREADD/CNO. Since hyperpolarization interferes with anterograde and retrograde neuronal signaling, it is possible that the memory engram in the dentate gyrus and the entorhinal to hippocampus trisynaptic circuit was erased by long-term, but not with short-term hyperpolarization. We developed and applied an advanced chemogenetic technology to selectively silence synaptic output by blocking neurotransmitter release without hyperpolarizing DG neurons to explore this apparent discrepancy. We performed in vivo electrophysiology during trace eyeblink in a rabbit model of associative learning. Our work shows that the DG output is required for memory retrieval. Based on previous and recent findings, we propose that the actively functional anterograde and retrograde neuronal signaling is necessary to preserve synaptic memory engrams along the entorhinal cortex to the hippocampal trisynaptic circuit.
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Affiliation(s)
- Alejandro Carretero-Guillén
- Division of Neuroscience, University Pablo de Olavide, Seville, Spain
- Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Mario Treviño
- Max Planck Institute for Medical Research, Heidelberg, Germany
- Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara, 44130, México
| | | | - Godwin K Dogbevia
- Max Planck Institute for Medical Research, Heidelberg, Germany
- Health Canada, Ottawa, ON, Canada
| | - Ilaria Bertocchi
- Max Planck Institute for Medical Research, Heidelberg, Germany
- Neuroscience Institute Cavalieri-Ottolenghi (NICO), University of Turin, Turin, Italy
| | - Rolf Sprengel
- Max Planck Institute for Medical Research, Heidelberg, Germany
| | | | | | - Agnès Gruart
- Division of Neuroscience, University Pablo de Olavide, Seville, Spain
| | | | - Mazahir T Hasan
- Achucarro Basque Center for Neuroscience, Leioa, Spain.
- Max Planck Institute for Medical Research, Heidelberg, Germany.
- NeuroCure, Charité - Universitätsmedizin, Berlin, Germany.
- Ikerbasque - Basque Foundation for Science, Bilbao, Spain.
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12
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Gava GP, Lefèvre L, Broadbelt T, McHugh SB, Lopes-Dos-Santos V, Brizee D, Hartwich K, Sjoberg H, Perestenko PV, Toth R, Sharott A, Dupret D. Organizing the coactivity structure of the hippocampus from robust to flexible memory. Science 2024; 385:1120-1127. [PMID: 39236189 PMCID: PMC7616439 DOI: 10.1126/science.adk9611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 07/01/2024] [Accepted: 08/05/2024] [Indexed: 09/07/2024]
Abstract
New memories are integrated into prior knowledge of the world. But what if consecutive memories exert opposing demands on the host brain network? We report that acquiring a robust (food-context) memory constrains the mouse hippocampus within a population activity space of highly correlated spike trains that prevents subsequent computation of a flexible (object-location) memory. This densely correlated firing structure developed over repeated mnemonic experience, gradually coupling neurons in the superficial sublayer of the CA1 stratum pyramidale to whole-population activity. Applying hippocampal theta-driven closed-loop optogenetic suppression to mitigate this neuronal recruitment during (food-context) memory formation relaxed the topological constraint on hippocampal coactivity and restored subsequent flexible (object-location) memory. These findings uncover an organizational principle for the peer-to-peer coactivity structure of the hippocampal cell population to meet memory demands.
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Affiliation(s)
- Giuseppe P Gava
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Laura Lefèvre
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Tabitha Broadbelt
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Stephen B McHugh
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Vítor Lopes-Dos-Santos
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Demi Brizee
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Katja Hartwich
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Hanna Sjoberg
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Pavel V Perestenko
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Robert Toth
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Andrew Sharott
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - David Dupret
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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13
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Li M, Jiang YQ, Lee DK, Wang H, Lu MC, Sun Q. Dorsoventral Heterogeneity of Synaptic Connectivity in Hippocampal CA3 Pyramidal Neurons. J Neurosci 2024; 44:e0370242024. [PMID: 39025678 PMCID: PMC11326861 DOI: 10.1523/jneurosci.0370-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 06/11/2024] [Accepted: 07/12/2024] [Indexed: 07/20/2024] Open
Abstract
The hippocampal CA3 region plays an important role in learning and memory. CA3 pyramidal neurons (PNs) receive two prominent excitatory inputs-mossy fibers (MFs) from dentate gyrus (DG) and recurrent collaterals (RCs) from CA3 PNs-that play opposing roles in pattern separation and pattern completion, respectively. Although the dorsoventral heterogeneity of the hippocampal anatomy, physiology, and behavior has been well established, nothing is known about the dorsoventral heterogeneity of synaptic connectivity in CA3 PNs. In this study, we performed Timm's sulfide silver staining, dendritic and spine morphological analyses, and ex vivo electrophysiology in mice of both sexes to investigate the heterogeneity of MF and RC pathways along the CA3 dorsoventral axis. Our morphological analyses demonstrate that ventral CA3 (vCA3) PNs possess greater dendritic lengths and more complex dendritic arborization, compared with dorsal CA3 (dCA3) PNs. Moreover, using ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording, we found that the ratio of the RC-to-MF excitatory drive onto CA3 PNs increases substantially from dCA3 to vCA3, with vCA3 PNs receiving significantly weaker MFs, but stronger RCs, excitation than dCA3 PNs. Given the distinct roles of MF versus RC inputs in pattern separation versus completion, our findings of the significant dorsoventral variations of MF and RC excitation in CA3 PNs may have important functional implications for the contribution of CA3 circuit to the dorsoventral difference in hippocampal function.
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Affiliation(s)
- Minghua Li
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Yu-Qiu Jiang
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Daniel K Lee
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Haoran Wang
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Melissa C Lu
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Qian Sun
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
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14
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Miranda M, Silva A, Morici JF, Coletti MA, Belluscio M, Bekinschtein P. Retrieval of contextual memory can be predicted by CA3 remapping and is differentially influenced by NMDAR activity in rat hippocampus subregions. PLoS Biol 2024; 22:e3002706. [PMID: 38950066 PMCID: PMC11244845 DOI: 10.1371/journal.pbio.3002706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 07/12/2024] [Accepted: 06/12/2024] [Indexed: 07/03/2024] Open
Abstract
Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.
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Affiliation(s)
- Magdalena Miranda
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, CONICET-Fundación INECO-Universidad Favaloro, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Azul Silva
- Laboratorio Bases neuronales del comportamiento, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Médicas, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- CONICET—Universidad de Buenos Aires, Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Juan Facundo Morici
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, CONICET-Fundación INECO-Universidad Favaloro, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Marcos Antonio Coletti
- Laboratorio Bases neuronales del comportamiento, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Médicas, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- CONICET—Universidad de Buenos Aires, Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Mariano Belluscio
- Laboratorio Bases neuronales del comportamiento, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Médicas, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- CONICET—Universidad de Buenos Aires, Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Pedro Bekinschtein
- Laboratorio de Memoria y Cognición Molecular, Instituto de Neurociencia Cognitiva y Traslacional, CONICET-Fundación INECO-Universidad Favaloro, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
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15
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Liu Y, Fan M, Yang J, Mihaljević L, Chen KH, Ye Y, Sun S, Qiu Z. KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3. SCIENCE ADVANCES 2024; 10:eadm9326. [PMID: 38758792 PMCID: PMC11100567 DOI: 10.1126/sciadv.adm9326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 04/15/2024] [Indexed: 05/19/2024]
Abstract
Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose mutations cause KAT6A syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown. Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice. We further identify a CA3-enriched gene Rspo2, encoding Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Deletion of Rspo2 in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 neurons rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A syndrome and related neurodevelopmental diseases.
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Affiliation(s)
- Yongqing Liu
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Minghua Fan
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Junhua Yang
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ljubica Mihaljević
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Kevin Hong Chen
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Yingzhi Ye
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shuying Sun
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Zhaozhu Qiu
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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16
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Miller TD, Kennard C, Gowland PA, Antoniades CA, Rosenthal CR. Differential effects of bilateral hippocampal CA3 damage on the implicit learning and recognition of complex event sequences. Cogn Neurosci 2024; 15:27-55. [PMID: 38384107 PMCID: PMC11147457 DOI: 10.1080/17588928.2024.2315818] [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: 09/12/2023] [Accepted: 01/25/2024] [Indexed: 02/23/2024]
Abstract
Learning regularities in the environment is a fundament of human cognition, which is supported by a network of brain regions that include the hippocampus. In two experiments, we assessed the effects of selective bilateral damage to human hippocampal subregion CA3, which was associated with autobiographical episodic amnesia extending ~50 years prior to the damage, on the ability to recognize complex, deterministic event sequences presented either in a spatial or a non-spatial configuration. In contrast to findings from related paradigms, modalities, and homologue species, hippocampal damage did not preclude recognition memory for an event sequence studied and tested at four spatial locations, whereas recognition memory for an event sequence presented at a single location was at chance. In two additional experiments, recognition memory for novel single-items was intact, whereas the ability to recognize novel single-items in a different location from that presented at study was at chance. The results are at variance with a general role of the hippocampus in the learning and recognition of complex event sequences based on non-adjacent spatial and temporal dependencies. We discuss the impact of the results on established theoretical accounts of the hippocampal contributions to implicit sequence learning and episodic memory.
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Affiliation(s)
- Thomas D. Miller
- Wellcome Centre for Human Neuroimaging, University College London, London, UK
- National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
| | - Christopher Kennard
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Penny A. Gowland
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, UK
| | | | - Clive R. Rosenthal
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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17
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Kopsick JD, Kilgore JA, Adam GC, Ascoli GA. Formation and Retrieval of Cell Assemblies in a Biologically Realistic Spiking Neural Network Model of Area CA3 in the Mouse Hippocampus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.27.586909. [PMID: 38585941 PMCID: PMC10996657 DOI: 10.1101/2024.03.27.586909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
The hippocampal formation is critical for episodic memory, with area Cornu Ammonis 3 (CA3) a necessary substrate for auto-associative pattern completion. Recent theoretical and experimental evidence suggests that the formation and retrieval of cell assemblies enable these functions. Yet, how cell assemblies are formed and retrieved in a full-scale spiking neural network (SNN) of CA3 that incorporates the observed diversity of neurons and connections within this circuit is not well understood. Here, we demonstrate that a data-driven SNN model quantitatively reflecting the neuron type-specific population sizes, intrinsic electrophysiology, connectivity statistics, synaptic signaling, and long-term plasticity of the mouse CA3 is capable of robust auto-association and pattern completion via cell assemblies. Our results show that a broad range of assembly sizes could successfully and systematically retrieve patterns from heavily incomplete or corrupted cues after a limited number of presentations. Furthermore, performance was robust with respect to partial overlap of assemblies through shared cells, substantially enhancing memory capacity. These novel findings provide computational evidence that the specific biological properties of the CA3 circuit produce an effective neural substrate for associative learning in the mammalian brain.
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Affiliation(s)
- Jeffrey D. Kopsick
- Center for Neural Informatics, Structures, & Plasticity, College of Engineering and Computing, George Mason University, Fairfax, VA, United States
- Interdisciplinary Program in Neuroscience, College of Science, George Mason University, Fairfax, VA, United States
| | - Joseph A. Kilgore
- Department of Electrical and Computer Engineering, George Washington University, Washington, D.C., United States
| | - Gina C. Adam
- Department of Electrical and Computer Engineering, George Washington University, Washington, D.C., United States
| | - Giorgio A. Ascoli
- Center for Neural Informatics, Structures, & Plasticity, College of Engineering and Computing, George Mason University, Fairfax, VA, United States
- Interdisciplinary Program in Neuroscience, College of Science, George Mason University, Fairfax, VA, United States
- Bioengineering Department, College of Engineering and Computing, George Mason University, Fairfax, VA, United States
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18
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Grob AM, Heinbockel H, Milivojevic B, Doeller CF, Schwabe L. Causal role of the angular gyrus in insight-driven memory reconfiguration. eLife 2024; 12:RP91033. [PMID: 38407185 PMCID: PMC10942625 DOI: 10.7554/elife.91033] [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] [Indexed: 02/27/2024] Open
Abstract
Maintaining an accurate model of the world relies on our ability to update memory representations in light of new information. Previous research on the integration of new information into memory mainly focused on the hippocampus. Here, we hypothesized that the angular gyrus, known to be involved in episodic memory and imagination, plays a pivotal role in the insight-driven reconfiguration of memory representations. To test this hypothesis, participants received continuous theta burst stimulation (cTBS) over the left angular gyrus or sham stimulation before gaining insight into the relationship between previously separate life-like animated events in a narrative-insight task. During this task, participants also underwent EEG recording and their memory for linked and non-linked events was assessed shortly thereafter. Our results show that cTBS to the angular gyrus decreased memory for the linking events and reduced the memory advantage for linked relative to non-linked events. At the neural level, cTBS targeting the angular gyrus reduced centro-temporal coupling with frontal regions and abolished insight-induced neural representational changes for events linked via imagination, indicating impaired memory reconfiguration. Further, the cTBS group showed representational changes for non-linked events that resembled the patterns observed in the sham group for the linked events, suggesting failed pruning of the narrative in memory. Together, our findings demonstrate a causal role of the left angular gyrus in insight-related memory reconfigurations.
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Affiliation(s)
- Anna-Maria Grob
- Department of Cognitive Psychology, Institute of Psychology, Universität HamburgHamburgGermany
| | - Hendrik Heinbockel
- Department of Cognitive Psychology, Institute of Psychology, Universität HamburgHamburgGermany
| | - Branka Milivojevic
- Radboud University, Donders Institute for Brain, Cognition and BehaviourNijmegenNetherlands
| | - Christian F Doeller
- Kavli Institute for Systems Neuroscience, Centre for Neural Computation, The Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Jebsen Centre for Alzheimer’s Disease, Norwegian University of Science and TechnologyTrondheimNorway
- Max-Planck-Insitute for Human Cognitive and Brain SciencesLeipzigGermany
- Wilhelm Wundt Institute of Psychology, Leipzig UniversityLeipzigGermany
| | - Lars Schwabe
- Department of Cognitive Psychology, Institute of Psychology, Universität HamburgHamburgGermany
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19
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Yokose J, Marks WD, Kitamura T. Visuotactile integration facilitates mirror-induced self-directed behavior through activation of hippocampal neuronal ensembles in mice. Neuron 2024; 112:306-318.e8. [PMID: 38056456 DOI: 10.1016/j.neuron.2023.10.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 08/28/2023] [Accepted: 10/17/2023] [Indexed: 12/08/2023]
Abstract
Remembering the visual features of oneself is critical for self-recognition. However, the neural mechanisms of how the visual self-image is developed remain unknown because of the limited availability of behavioral paradigms in experimental animals. Here, we demonstrate a mirror-induced self-directed behavior (MSB) in mice, resembling visual self-recognition. Mice displayed increased mark-directed grooming to remove ink placed on their heads when an ink-induced visual-tactile stimulus contingency occurred. MSB required mirror habituation and social experience. The chemogenetic inhibition of dorsal or ventral hippocampal CA1 (vCA1) neurons attenuated MSB. Especially, a subset of vCA1 neurons activated during the mirror exposure was significantly reactivated during re-exposure to the mirror and was necessary for MSB. The self-responding vCA1 neurons were also reactivated when mice were exposed to a conspecific of the same strain. These results suggest that visual self-image may be developed through social experience and mirror habituation and stored in a subset of vCA1 neurons.
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Affiliation(s)
- Jun Yokose
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - William D Marks
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Takashi Kitamura
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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20
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Viana da Silva S, Haberl MG, Gaur K, Patel R, Narayan G, Ledakis M, Fu ML, de Castro Vieira M, Koo EH, Leutgeb JK, Leutgeb S. Localized APP expression results in progressive network dysfunction by disorganizing spike timing. Neuron 2024; 112:124-140.e6. [PMID: 37909036 PMCID: PMC10877582 DOI: 10.1016/j.neuron.2023.10.001] [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: 12/26/2022] [Revised: 06/16/2023] [Accepted: 10/02/2023] [Indexed: 11/02/2023]
Abstract
Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.
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Affiliation(s)
- Silvia Viana da Silva
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA; NeuroCure Excellence Cluster and German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
| | - Matthias G Haberl
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Neuroscience Research Center, Charitéplatz 1, 10117 Berlin, Germany
| | - Kshitij Gaur
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Rina Patel
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Gautam Narayan
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Max Ledakis
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Maylin L Fu
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Miguel de Castro Vieira
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Neuroscience Research Center, Charitéplatz 1, 10117 Berlin, Germany
| | - Edward H Koo
- Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Jill K Leutgeb
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
| | - Stefan Leutgeb
- Neurobiology Department, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA; Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA, USA.
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21
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Bannerman DM, Barkus C, Eltokhi A. Behavioral Analysis of NMDAR Function in Rodents: Tests of Long-Term Spatial Memory. Methods Mol Biol 2024; 2799:107-138. [PMID: 38727905 DOI: 10.1007/978-1-0716-3830-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
NMDAR-dependent forms of synaptic plasticity in brain regions like the hippocampus are widely believed to provide the neural substrate for long-term associative memory formation. However, the experimental data are equivocal at best and may suggest a more nuanced role for NMDARs and synaptic plasticity in memory. Much of the experimental data available comes from studies in genetically modified mice in which NMDAR subunits have been deleted or mutated in order to disrupt NMDAR function. Behavioral assessment of long-term memory in these mice has involved tests like the Morris watermaze and the radial arm maze. Here we describe these behavioral tests and some of the different testing protocols that can be used to assess memory performance. We discuss the importance of distinguishing selective effects on learning and memory processes from nonspecific effects on sensorimotor or motivational aspects of performance.
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Affiliation(s)
- David M Bannerman
- Department of Experimental Psychology, University of Oxford, Oxford, UK.
| | - Chris Barkus
- Department of Experimental Psychology, University of Oxford, Oxford, UK
| | - Ahmed Eltokhi
- Department of Biomedical Sciences, School of Medicine, Mercer University, Columbus, GA, USA
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22
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Singh S, Becker S, Trappenberg T, Nunes A. Granule cells perform frequency-dependent pattern separation in a computational model of the dentate gyrus. Hippocampus 2024; 34:14-28. [PMID: 37950569 DOI: 10.1002/hipo.23585] [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: 05/14/2023] [Revised: 09/28/2023] [Accepted: 10/23/2023] [Indexed: 11/12/2023]
Abstract
Mnemonic discrimination (MD) may be dependent on oscillatory perforant path input frequencies to the hippocampus in a "U"-shaped fashion, where some studies show that slow and fast input frequencies support MD, while other studies show that intermediate frequencies disrupt MD. We hypothesize that pattern separation (PS) underlies frequency-dependent MD performance. We aim to study, in a computational model of the hippocampal dentate gyrus (DG), the network and cellular mechanisms governing this putative "U"-shaped PS relationship. We implemented a biophysical model of the DG that produces the hypothesized "U"-shaped input frequency-PS relationship, and its associated oscillatory electrophysiological signatures. We subsequently evaluated the network's PS ability using an adapted spatiotemporal task. We undertook systematic lesion studies to identify the network-level mechanisms driving the "U"-shaped input frequency-PS relationship. A minimal circuit of a single granule cell (GC) stimulated with oscillatory inputs was also used to study potential cellular-level mechanisms. Lesioning synapses onto GCs did not impact the "U"-shaped input frequency-PS relationship. Furthermore, GC inhibition limits PS performance for fast frequency inputs, while enhancing PS for slow frequency inputs. GC interspike interval was found to be input frequency dependent in a "U"-shaped fashion, paralleling frequency-dependent PS observed at the network level. Additionally, GCs showed an attenuated firing response for fast frequency inputs. We conclude that independent of network-level inhibition, GCs may intrinsically be capable of producing a "U"-shaped input frequency-PS relationship. GCs may preferentially decorrelate slow and fast inputs via spike timing reorganization and high frequency filtering.
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Affiliation(s)
- Selena Singh
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario, Canada
| | - Suzanna Becker
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario, Canada
| | - Thomas Trappenberg
- Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Abraham Nunes
- Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
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23
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Zhang XO, Zhang Y, Cho CE, Engelke DS, Smolen P, Byrne JH, Do-Monte FH. Enhancing Associative Learning in Rats With a Computationally Designed Training Protocol. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:165-181. [PMID: 38298784 PMCID: PMC10829654 DOI: 10.1016/j.bpsgos.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/30/2023] [Accepted: 07/20/2023] [Indexed: 02/02/2024] Open
Abstract
Background Learning requires the activation of protein kinases with distinct temporal dynamics. In Aplysia, nonassociative learning can be enhanced by a computationally designed learning protocol with intertrial intervals (ITIs) that maximize the interaction between fast-activated PKA (protein kinase A) and slow-activated ERK (extracellular signal-regulated kinase). Whether a similar strategy can enhance associative learning in mammals is unknown. Methods We simulated 1000 training protocols with varying ITIs to predict an optimal protocol based on empirical data for PKA and ERK dynamics in rat hippocampus. Adult male rats received the optimal protocol or control protocols in auditory fear conditioning and fear extinction experiments. Immunohistochemistry was performed to evaluate pCREB (phosphorylated cAMP response element binding)\protein levels in brain regions that have been implicated in fear acquisition. Results Rats exposed to the optimal conditioning protocol with irregular ITIs exhibited impaired extinction memory acquisition within the session using a standard footshock intensity, and stronger fear memory retrieval and spontaneous recovery with a weaker footshock intensity, compared with rats that received massed or spaced conditioning protocols with fixed ITIs. Rats exposed to the optimal extinction protocol displayed improved extinction of contextual fear memory and reduced spontaneous recovery compared with rats that received standard extinction protocols. Moreover, the optimal conditioning protocol increased pCREB levels in the dentate gyrus of the dorsal hippocampus, suggesting enhanced induction of long-term potentiation. Conclusions These findings demonstrate that a computational model-driven behavioral intervention can enhance associative learning in mammals and may provide insight into strategies to improve cognition in humans.
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Affiliation(s)
- Xu O. Zhang
- Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Yili Zhang
- Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Claire E. Cho
- Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Douglas S. Engelke
- Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Paul Smolen
- Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - John H. Byrne
- Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Fabricio H. Do-Monte
- Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
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24
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Yu Y, Wu K, Yang X, Long J, Chang C. Terahertz Photons Improve Cognitive Functions in Posttraumatic Stress Disorder. RESEARCH (WASHINGTON, D.C.) 2023; 6:0278. [PMID: 38111677 PMCID: PMC10726292 DOI: 10.34133/research.0278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/12/2023] [Indexed: 12/20/2023]
Abstract
Posttraumatic stress disorder (PTSD) is a serious psychosis leading to cognitive impairment. To restore cognitive functions for patients, the main treatments are based on medication or rehabilitation training but with limited effectiveness and strong side effects. Here, we demonstrate a new treatment approach for PTSD by using terahertz (THz) photons stimulating the hippocampal CA3 subregion. We verified that this method can nonthermally restore cognitive function in PTSD rats in vivo. After THz photon irradiation, the PTSD rats' recognitive index improved by about 10% in a novel object recognition test, the PTSD rats' accuracy improved by about 100% in a shuttler box test, the PTSD rats' numbers to identify target box was about 5 times lower in a Barnes maze test, and the rate of staying in new arm increased by approximately 40% in a Y-maze test. Further experimental studies found that THz photon (34.5 THz) irradiation could improve the expression of NR2B (increased by nearly 40%) and phosphorylated NR2B (increased by about 50%). In addition, molecular dynamics simulations showed that THz photons at a frequency of 34.5 THz are mainly absorbed by the pocket of glutamate receptors rather than by glutamate molecules. Moreover, the binding between glutamate receptors and glutamate molecules was increased by THz photons. This study offers a nondrug, nonthermal approach to regulate the binding between the excitatory neurotransmitter (glutamate) and NR2B. By increasing synaptic plasticity, it effectively improves the cognitive function of animals with PTSD, providing a promising treatment strategy for NR2B-related cognitive disorders.
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Affiliation(s)
- Yun Yu
- School of Life Science and Technology,
Xi’an Jiaotong University, Xi’an 710049, China
- Innovation Laboratory of Terahertz Biophysics,
National Innovation Institute of Defense Technology, Beijing 100071, China
| | - Kaijie Wu
- Innovation Laboratory of Terahertz Biophysics,
National Innovation Institute of Defense Technology, Beijing 100071, China
| | - Xiao Yang
- Innovation Laboratory of Terahertz Biophysics,
National Innovation Institute of Defense Technology, Beijing 100071, China
| | - Jiangang Long
- School of Life Science and Technology,
Xi’an Jiaotong University, Xi’an 710049, China
| | - Chao Chang
- Innovation Laboratory of Terahertz Biophysics,
National Innovation Institute of Defense Technology, Beijing 100071, China
- School of Physics,
Peking University, Beijing 100871, China
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25
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Koller WN, Cannon TD. Intrusive-like memory errors associate with positive schizotypy. Schizophr Res Cogn 2023; 34:100291. [PMID: 37869417 PMCID: PMC10585314 DOI: 10.1016/j.scog.2023.100291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/02/2023] [Accepted: 10/07/2023] [Indexed: 10/24/2023]
Abstract
Schizophrenia is characterized by memory impairments, yet the relationships between its distinct symptom clusters (i.e., positive, negative, disorganized) and specific aspects of memory dysfunction remain poorly characterized. In the present study, we compiled a large analog sample (N = 795) to test whether positive symptoms, versus negative and disorganized symptoms, were uniquely and differentially related to false alarm versus miss errors during recognition memory. Mixed-effects beta regression analyses revealed that both positive schizotypy and paranoia were more strongly associated with false alarms than misses. Disorganized schizotypy showed a similar pattern, though to a lesser extent; negative schizotypy showed a significant relationship with neither false alarm nor miss errors. We suggest that those higher in positive schizotypy are especially prone to misattribute signal to noise stimuli during recognition memory - characteristic of an "intrusive-like" profile of memory impairment, wherein context-irrelevant stimuli trigger spurious retrieval events - and speculate on the neural processes that might give rise to this asymmetry.
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Affiliation(s)
| | - Tyrone D. Cannon
- Department of Psychology, Yale University, United States of America
- Department of Psychiatry, Yale University, United States of America
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26
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Atucha E, Ku SP, Lippert MT, Sauvage MM. Recalling gist memory depends on CA1 hippocampal neurons for lifetime retention and CA3 neurons for memory precision. Cell Rep 2023; 42:113317. [PMID: 37897725 DOI: 10.1016/j.celrep.2023.113317] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 07/05/2023] [Accepted: 10/05/2023] [Indexed: 10/30/2023] Open
Abstract
Why some of us remember events more clearly than others and why memory loses precision over time is a major focus in memory research. Here, we show that the recruitment of specific neuroanatomical pathways within the medial temporal lobe (MTL) of the brain defines the precision of the memory recalled over the lifespan. Using optogenetics, neuronal activity mapping, and studying recent to very remote memories, we report that the hippocampal subfield CA1 is necessary for retrieving the gist of events and receives maximal support from MTL cortical areas (MEC, LEC, PER, and POR) for recalling the most remote memories. In contrast, reduction of CA3's activity alone coincides with the loss of memory precision over time. We propose that a shift between specific MTL subnetworks over time might be a fundamental mechanism of memory consolidation.
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Affiliation(s)
- Erika Atucha
- Functional Architecture of Memory Department, Leibniz Institute for Neurobiology, Magdeburg, Germany.
| | - Shih-Pi Ku
- Functional Architecture of Memory Department, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Michael T Lippert
- Systems Physiology of Learning Department, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Magdalena M Sauvage
- Functional Architecture of Memory Department, Leibniz Institute for Neurobiology, Magdeburg, Germany; Otto von Guericke University, Medical Faculty, Functional Neuroplasticity Department, Magdeburg, Germany; Otto von Guericke University, Center for Behavioral Brain Sciences, Magdeburg, Germany.
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27
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Mattova S, Simko P, Urbanska N, Kiskova T. Bioactive Compounds and Their Influence on Postnatal Neurogenesis. Int J Mol Sci 2023; 24:16614. [PMID: 38068936 PMCID: PMC10706651 DOI: 10.3390/ijms242316614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 12/18/2023] Open
Abstract
Since postnatal neurogenesis was revealed to have significant implications for cognition and neurological health, researchers have been increasingly exploring the impact of natural compounds on this process, aiming to uncover strategies for enhancing brain plasticity. This review provides an overview of postnatal neurogenesis, neurogenic zones, and disorders characterized by suppressed neurogenesis and neurogenesis-stimulating bioactive compounds. Examining recent studies, this review underscores the multifaceted effects of natural compounds on postnatal neurogenesis. In essence, understanding the interplay between postnatal neurogenesis and natural compounds could bring novel insights into brain health interventions. Exploiting the therapeutic abilities of these compounds may unlock innovative approaches to enhance cognitive function, mitigate neurodegenerative diseases, and promote overall brain well-being.
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Affiliation(s)
| | | | | | - Terezia Kiskova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University in Kosice, 041 54 Kosice, Slovakia; (S.M.); (P.S.); (N.U.)
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28
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Robert V, O'Neil K, Rashid SK, Johnson CD, De La Torre RG, Zemelman BV, Clopath C, Basu J. Entorhinal cortex glutamatergic and GABAergic projections bidirectionally control discrimination and generalization of hippocampal representations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.08.566107. [PMID: 37986793 PMCID: PMC10659280 DOI: 10.1101/2023.11.08.566107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Discrimination and generalization are crucial brain-wide functions for memory and object recognition that utilize pattern separation and completion computations. Circuit mechanisms supporting these operations remain enigmatic. We show lateral entorhinal cortex glutamatergic (LEC GLU ) and GABAergic (LEC GABA ) projections are essential for object recognition memory. Silencing LEC GLU during in vivo two-photon imaging increased the population of active CA3 pyramidal cells but decreased activity rates, suggesting a sparse coding function through local inhibition. Silencing LEC GLU also decreased place cell remapping between different environments validating this circuit drives pattern separation and context discrimination. Optogenetic circuit mapping confirmed that LEC GLU drives dominant feedforward inhibition to prevent CA3 somatic and dendritic spikes. However, conjunctively active LEC GABA suppresses this local inhibition to disinhibit CA3 pyramidal neuron soma and selectively boost integrative output of LEC and CA3 recurrent network. LEC GABA thus promotes pattern completion and context generalization. Indeed, without this disinhibitory input, CA3 place maps show decreased similarity between contexts. Our findings provide circuit mechanisms whereby long-range glutamatergic and GABAergic cortico-hippocampal inputs bidirectionally modulate pattern separation and completion, providing neuronal representations with a dynamic range for context discrimination and generalization.
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29
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Vanrobaeys Y, Peterson ZJ, Walsh EN, Chatterjee S, Lin LC, Lyons LC, Nickl-Jockschat T, Abel T. Spatial transcriptomics reveals unique gene expression changes in different brain regions after sleep deprivation. Nat Commun 2023; 14:7095. [PMID: 37925446 PMCID: PMC10625558 DOI: 10.1038/s41467-023-42751-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 10/20/2023] [Indexed: 11/06/2023] Open
Abstract
Sleep deprivation has far-reaching consequences on the brain and behavior, impacting memory, attention, and metabolism. Previous research has focused on gene expression changes in individual brain regions, such as the hippocampus or cortex. Therefore, it is unclear how uniformly or heterogeneously sleep loss affects the brain. Here, we use spatial transcriptomics to define the impact of a brief period of sleep deprivation across the brain in male mice. We find that sleep deprivation induced pronounced differences in gene expression across the brain, with the greatest changes in the hippocampus, neocortex, hypothalamus, and thalamus. Both the differentially expressed genes and the direction of regulation differed markedly across regions. Importantly, we developed bioinformatic tools to register tissue sections and gene expression data into a common anatomical space, allowing a brain-wide comparison of gene expression patterns between samples. Our results suggest that distinct molecular mechanisms acting in discrete brain regions underlie the biological effects of sleep deprivation.
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Affiliation(s)
- Yann Vanrobaeys
- Interdisciplinary Graduate Program in Genetics, University of Iowa, 357 Medical Research Center Iowa City, Iowa, IA, USA
- Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, Iowa City, IA, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, 51 Newton Road, 2-417B Bowen Science Building, Iowa City, IA, USA
| | - Zeru J Peterson
- Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, Iowa City, IA, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Emily N Walsh
- Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, Iowa City, IA, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, 51 Newton Road, 2-417B Bowen Science Building, Iowa City, IA, USA
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, 356 Medical Research Center, Iowa City, IA, USA
| | - Snehajyoti Chatterjee
- Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, Iowa City, IA, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, 51 Newton Road, 2-417B Bowen Science Building, Iowa City, IA, USA
| | - Li-Chun Lin
- Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, Iowa City, IA, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, 51 Newton Road, 2-417B Bowen Science Building, Iowa City, IA, USA
- Department of Neurology, University of Iowa, Iowa City, IA, USA
| | - Lisa C Lyons
- Program in Neuroscience, Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Thomas Nickl-Jockschat
- Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, Iowa City, IA, USA.
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, 51 Newton Road, 2-417B Bowen Science Building, Iowa City, IA, USA.
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
| | - Ted Abel
- Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, Iowa City, IA, USA.
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, 51 Newton Road, 2-417B Bowen Science Building, Iowa City, IA, USA.
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30
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Griego E, Galván EJ. BDNF and Lactate as Modulators of Hippocampal CA3 Network Physiology. Cell Mol Neurobiol 2023; 43:4007-4022. [PMID: 37874456 PMCID: PMC11407739 DOI: 10.1007/s10571-023-01425-6] [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: 07/02/2023] [Accepted: 10/14/2023] [Indexed: 10/25/2023]
Abstract
Growing evidence supports the notion that brain-derived neurotrophic factor (BDNF) and lactate are potent modulators of mammalian brain function. The modulatory actions of those biomolecules influence a wide range of neuronal responses, from the shaping of neuronal excitability to the induction and expression of structural and synaptic plasticity. The biological actions of BDNF and lactate are mediated by their cognate receptors and specific transporters located in the neuronal membrane. Canonical functions of BDNF occur via the tropomyosin-related kinase B receptor (TrkB), whereas lactate acts via monocarboxylate transporters or the hydroxycarboxylic acid receptor 1 (HCAR1). Both receptors are highly expressed in the central nervous system, and some of their physiological actions are particularly well characterized in the hippocampus, a brain structure involved in the neurophysiology of learning and memory. The multifarious neuronal circuitry between the axons of the dentate gyrus granule cells, mossy fibers (MF), and pyramidal neurons of area CA3 is of great interest given its role in specific mnemonic processes and involvement in a growing number of brain disorders. Whereas the modulation exerted by BDNF via TrkB has been extensively studied, the influence of lactate via HCAR1 on the properties of the MF-CA3 circuit is an emerging field. In this review, we discuss the role of both systems in the modulation of brain physiology, with emphasis on the hippocampal CA3 network. We complement this review with original data that suggest cross-modulation is exerted by these two independent neuromodulatory systems.
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Affiliation(s)
- Ernesto Griego
- Departamento de Farmacobiología, Cinvestav Sur, Mexico City, Mexico.
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, USA.
- Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Calzada de los Tenorios No. 235, Col. Granjas Coapa, C.P. 14330, Mexico City, Mexico.
| | - Emilio J Galván
- Departamento de Farmacobiología, Cinvestav Sur, Mexico City, Mexico
- Centro de Investigaciones sobre el Envejecimiento, Mexico City, Mexico
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31
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Liu C, Todorova R, Tang W, Oliva A, Fernandez-Ruiz A. Associative and predictive hippocampal codes support memory-guided behaviors. Science 2023; 382:eadi8237. [PMID: 37856604 PMCID: PMC10894649 DOI: 10.1126/science.adi8237] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 08/21/2023] [Indexed: 10/21/2023]
Abstract
Episodic memory involves learning and recalling associations between items and their spatiotemporal context. Those memories can be further used to generate internal models of the world that enable predictions to be made. The mechanisms that support these associative and predictive aspects of memory are not yet understood. In this study, we used an optogenetic manipulation to perturb the sequential structure, but not global network dynamics, of place cells as rats traversed specific spatial trajectories. This perturbation abolished replay of those trajectories and the development of predictive representations, leading to impaired learning of new optimal trajectories during memory-guided navigation. However, place cell assembly reactivation and reward-context associative learning were unaffected. Our results show a mechanistic dissociation between two complementary hippocampal codes: an associative code (through coactivity) and a predictive code (through sequences).
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Affiliation(s)
| | | | - Wenbo Tang
- Department of Neurobiology and Behavior, Cornell University, Ithaca, NY, USA
| | - Azahara Oliva
- Department of Neurobiology and Behavior, Cornell University, Ithaca, NY, USA
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32
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Yang M, Singh A, McDougle M, Décarie-Spain L, Kanoski S, de Lartigue G. Separate orexigenic hippocampal ensembles shape dietary choice by enhancing contextual memory and motivation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.09.561580. [PMID: 37873148 PMCID: PMC10592764 DOI: 10.1101/2023.10.09.561580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
The hippocampus (HPC), traditionally known for its role in learning and memory, has emerged as a controller of food intake. While prior studies primarily associated the HPC with food intake inhibition, recent research suggests a critical role in appetitive processes. We hypothesized that orexigenic HPC neurons differentially respond to fats and/or sugars, potent natural reinforcers that contribute to obesity development. Results uncover previously-unrecognized, spatially-distinct neuronal ensembles within the dorsal HPC (dHPC) that are responsive to separate nutrient signals originating from the gut. Using activity-dependent genetic capture of nutrient-responsive HPC neurons, we demonstrate a causal role of both populations in promoting nutrient-specific preference through different mechanisms. Sugar-responsive neurons encode an appetitive spatial memory engram for meal location, whereas fat-responsive neurons selectively enhance the preference and motivation for fat intake. Collectively, these findings uncover a neural basis for the exquisite specificity in processing macronutrient signals from a meal that shape dietary choices.
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33
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Vanrobaeys Y, Mukherjee U, Langmack L, Beyer SE, Bahl E, Lin LC, Michaelson JJ, Abel T, Chatterjee S. Mapping the spatial transcriptomic signature of the hippocampus during memory consolidation. Nat Commun 2023; 14:6100. [PMID: 37773230 PMCID: PMC10541893 DOI: 10.1038/s41467-023-41715-7] [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] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 09/15/2023] [Indexed: 10/01/2023] Open
Abstract
Memory consolidation involves discrete patterns of transcriptional events in the hippocampus. Despite the emergence of single-cell transcriptomic profiling techniques, mapping the transcriptomic signature across subregions of the hippocampus has remained challenging. Here, we utilized unbiased spatial sequencing to delineate transcriptome-wide gene expression changes across subregions of the dorsal hippocampus of male mice following learning. We find that each subregion of the hippocampus exhibits distinct yet overlapping transcriptomic signatures. The CA1 region exhibited increased expression of genes related to transcriptional regulation, while the DG showed upregulation of genes associated with protein folding. Importantly, our approach enabled us to define the transcriptomic signature of learning within two less-defined hippocampal subregions, CA1 stratum radiatum, and oriens. We demonstrated that CA1 subregion-specific expression of a transcription factor subfamily has a critical functional role in the consolidation of long-term memory. This work demonstrates the power of spatial molecular approaches to reveal simultaneous transcriptional events across the hippocampus during memory consolidation.
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Affiliation(s)
- Yann Vanrobaeys
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, 52242, USA
| | - Utsav Mukherjee
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA, 52242, USA
| | - Lucy Langmack
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Biochemistry and Molecular Biology Graduate Program, University of Iowa, Iowa City, IA, USA
| | - Stacy E Beyer
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Ethan Bahl
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, 52242, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Li-Chun Lin
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Jacob J Michaelson
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Ted Abel
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
| | - Snehajyoti Chatterjee
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
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34
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Parra-Barrero E, Vijayabaskaran S, Seabrook E, Wiskott L, Cheng S. A map of spatial navigation for neuroscience. Neurosci Biobehav Rev 2023; 152:105200. [PMID: 37178943 DOI: 10.1016/j.neubiorev.2023.105200] [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: 01/25/2023] [Revised: 04/13/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023]
Abstract
Spatial navigation has received much attention from neuroscientists, leading to the identification of key brain areas and the discovery of numerous spatially selective cells. Despite this progress, our understanding of how the pieces fit together to drive behavior is generally lacking. We argue that this is partly caused by insufficient communication between behavioral and neuroscientific researchers. This has led the latter to under-appreciate the relevance and complexity of spatial behavior, and to focus too narrowly on characterizing neural representations of space-disconnected from the computations these representations are meant to enable. We therefore propose a taxonomy of navigation processes in mammals that can serve as a common framework for structuring and facilitating interdisciplinary research in the field. Using the taxonomy as a guide, we review behavioral and neural studies of spatial navigation. In doing so, we validate the taxonomy and showcase its usefulness in identifying potential issues with common experimental approaches, designing experiments that adequately target particular behaviors, correctly interpreting neural activity, and pointing to new avenues of research.
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Affiliation(s)
- Eloy Parra-Barrero
- Institute for Neural Computation, Faculty of Computer Science, Ruhr University Bochum, Bochum, Germany; International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Sandhiya Vijayabaskaran
- Institute for Neural Computation, Faculty of Computer Science, Ruhr University Bochum, Bochum, Germany
| | - Eddie Seabrook
- Institute for Neural Computation, Faculty of Computer Science, Ruhr University Bochum, Bochum, Germany
| | - Laurenz Wiskott
- Institute for Neural Computation, Faculty of Computer Science, Ruhr University Bochum, Bochum, Germany; International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Sen Cheng
- Institute for Neural Computation, Faculty of Computer Science, Ruhr University Bochum, Bochum, Germany; International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany.
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35
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Li M, Kinney JL, Jiang YQ, Lee DK, Wu Q, Lee D, Xiong WC, Sun Q. Hypothalamic Supramammillary Nucleus Selectively Excites Hippocampal CA3 Interneurons to Suppress CA3 Pyramidal Neuron Activity. J Neurosci 2023; 43:4612-4624. [PMID: 37117012 PMCID: PMC10286942 DOI: 10.1523/jneurosci.1910-22.2023] [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: 10/09/2022] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 04/30/2023] Open
Abstract
A key mode of neuronal communication between distant brain regions is through excitatory synaptic transmission mediated by long-range glutamatergic projections emitted from principal neurons. The long-range glutamatergic projection normally forms numerous en passant excitatory synapses onto both principal neurons and interneurons along its path. Under physiological conditions, the monosynaptic excitatory drive onto postsynaptic principal neurons outweighs disynaptic feedforward inhibition, with the net effect of depolarizing principal neurons. In contrast with this conventional doctrine, here we report that a glutamatergic projection from the hypothalamic supramammillary nucleus (SuM) largely evades postsynaptic pyramidal neurons (PNs), but preferentially target interneurons in the hippocampal CA3 region to predominantly provide feedforward inhibition. Using viral-based retrograde and anterograde tracing and ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording in mice of either sex, we show that SuM projects sparsely to CA3 and provides minimal excitation onto CA3 PNs. Surprisingly, despite its sparse innervation, the SuM input inhibits all CA3 PNs along the transverse axis. Further, we find that SuM provides strong monosynaptic excitation onto CA3 parvalbumin-expressing interneurons evenly along the transverse axis, which likely mediates the SuM-driven feedforward inhibition. Together, our results demonstrate that a novel long-range glutamatergic pathway largely evades principal neurons, but rather preferentially innervates interneurons in a distant brain region to suppress principal neuron activity. Moreover, our findings reveal a new means by which SuM regulates hippocampal activity through SuM-to-CA3 circuit, independent of the previously focused projections from SuM to CA2 or dentate gyrus.SIGNIFICANCE STATEMENT The dominant mode of neuronal communication between brain regions is the excitatory synaptic transmission mediated by long-range glutamatergic projections, which form en passant excitatory synapses onto both pyramidal neurons and interneurons along its path. Under normal conditions, the excitation onto postsynaptic neurons outweighs feedforward inhibition, with the net effect of depolarization. In contrast with this conventional doctrine, here we report that a glutamatergic input from hypothalamic supramammillary nucleus (SuM) largely evades PNs but selectively targets interneurons to almost exclusively provide disynaptic feedforward inhibition onto hippocampal CA3 PNs. Thus, our findings reveal a novel subcortical-hippocampal circuit that enables SuM to regulate hippocampal activity via SuM-CA3 circuit, independent of its projections to CA2 or dentate gyrus.
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Affiliation(s)
- Minghua Li
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Jessica L Kinney
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Yu-Qiu Jiang
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Daniel K Lee
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Qiwen Wu
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Daehoon Lee
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Wen-Cheng Xiong
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Qian Sun
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
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36
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Lutzu S, Alviña K, Puente N, Grandes P, Castillo PE. Target cell-specific plasticity rules of NMDA receptor-mediated synaptic transmission in the hippocampus. Front Cell Neurosci 2023; 17:1068472. [PMID: 37091922 PMCID: PMC10113460 DOI: 10.3389/fncel.2023.1068472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 03/20/2023] [Indexed: 04/08/2023] Open
Abstract
Long-term potentiation and depression of NMDA receptor-mediated synaptic transmission (NMDAR LTP/LTD) can significantly impact synapse function and information transfer in several brain areas. However, the mechanisms that determine the direction of NMDAR plasticity are poorly understood. Here, using physiologically relevant patterns of presynaptic and postsynaptic burst activities, whole-cell patch clamp recordings, 2-photon laser calcium imaging in acute rat hippocampal slices and immunoelectron microscopy, we tested whether distinct calcium dynamics and group I metabotropic glutamate receptor (I-mGluR) subtypes control the sign of NMDAR plasticity. We found that postsynaptic calcium transients (CaTs) in response to hippocampal MF stimulation were significantly larger during the induction of NMDAR-LTP compared to NMDAR-LTD at the MF-to-CA3 pyramidal cell (MF-CA3) synapse. This difference was abolished by pharmacological blockade of mGluR5 and was significantly reduced by depletion of intracellular calcium stores, whereas blocking mGluR1 had no effect on these CaTs. In addition, we discovered that MF to hilar mossy cell (MF-MC) synapses, which share several structural and functional commonalities with MF-CA3 synapses, also undergoes NMDAR plasticity. To our surprise, however, we found that the postsynaptic distribution of I-mGluR subtypes at these two synapses differ, and the same induction protocol that induces NMDAR-LTD at MF-CA3 synapses, only triggered NMDAR-LTP at MF-MC synapses, despite a comparable calcium dynamics. Thus, postsynaptic calcium dynamics alone cannot predict the sign of NMDAR plasticity, indicating that both postsynaptic calcium rise and the relative contribution of I-mGluR subtypes likely determine the learning rules of NMDAR plasticity.
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Affiliation(s)
- Stefano Lutzu
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Karina Alviña
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Nagore Puente
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
- Achucarro Basque Center for Neuroscience, Science Park of the University of the Basque Country UPV/EHU, Leioa, Spain
| | - Pedro Grandes
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
- Achucarro Basque Center for Neuroscience, Science Park of the University of the Basque Country UPV/EHU, Leioa, Spain
| | - Pablo E. Castillo
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States
- *Correspondence: Pablo E. Castillo,
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37
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Márquez LA, Griego E, López Rubalcava C, Galván EJ. NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long-term potentiation of CA3 pyramidal cells. Hippocampus 2023. [PMID: 36938755 DOI: 10.1002/hipo.23524] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/30/2023] [Accepted: 02/23/2023] [Indexed: 03/21/2023]
Abstract
Experimental manipulations that interfere with the functional expression of N-methyl-D-aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK-801 during early postnatal development alters glutamate release and impairs the induction of NMDAR-dependent long-term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated short- and long-term potentiation, are compromised in response to neonatal treatment with MK-801. Consistent with this tenet, short- and long-term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole-cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre- and postsynaptic modifications at the MF-CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired-pulse ratio, and reduced AMPAR-mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK-801-treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR-independent forms of synaptic plasticity of the hippocampus.
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Affiliation(s)
- Luis A Márquez
- Departamento de Farmacobiología, CINVESTAV Unidad Sur, Ciudad de México, Mexico
| | - Ernesto Griego
- Departamento de Farmacobiología, CINVESTAV Unidad Sur, Ciudad de México, Mexico
| | | | - Emilio J Galván
- Departamento de Farmacobiología, CINVESTAV Unidad Sur, Ciudad de México, Mexico.,Centro de Investigaciones sobre el Envejecimiento, CIE-Cinvestav, Ciudad de México, Mexico
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38
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Marsool MDM, Prajjwal P, Reddy YB, Marsool ADM, Lam JR, Nandwana V. Newer modalities in the management of Alzheimer's dementia along with the role of aducanumab and lecanemab in the treatment of its refractory cases. Dis Mon 2023; 69:101547. [PMID: 36931947 DOI: 10.1016/j.disamonth.2023.101547] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Alzheimer's disease (AD) is a common neurological condition characterized by a gradual and progressive decline in memory, language, emotion, and cognition. It mainly affects elderly people. Due to the effects of AD, pharmaceutical medications and anticholinesterases have been vigorously promoted and approved by the FDA as a form of AD therapy. However, it was progressively found that these drugs did not address the underlying causes of AD pathogenesis; rather, they focused on the symptoms in order to enhance patients' cognitive outcomes. Consequently, a hunt for superior disease-modifying options is launched. Designing new therapeutic agents requires a thorough understanding of the neuroprotective processes and varied functions carried out by certain genes, and antibodies. In this comprehensive review article, we give an overview of the history of Alzheimer's disease, the significance of the blood-brain barrier in determining the scope of treatment options, as well as the advantages and disadvantages of the current therapeutic treatment options for stem cell therapy, immunotherapy, regenerative therapy, and improved Alzheimer's disease care and diagnosis. We have also included a discussion on the potential role of aducanumab and Lecanemab as a cutting-edge therapy in refractory Alzheimer's disease patients. Lecanemab has been recently approved by the FDA for the treatment of Alzheimer's disease.
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Affiliation(s)
| | | | | | | | - Justin Riley Lam
- Internal Medicine, Cebu Institute of Medicine, Cebu, Philippines
| | - Varsha Nandwana
- Neurology, Virginia Tech Carilion School of Medicine, Virginia, USA
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39
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Vancura B, Geiller T, Losonczy A. Organization and Plasticity of Inhibition in Hippocampal Recurrent Circuits. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.13.532296. [PMID: 36993553 PMCID: PMC10054977 DOI: 10.1101/2023.03.13.532296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Excitatory-inhibitory interactions structure recurrent network dynamics for efficient cortical computations. In the CA3 area of the hippocampus, recurrent circuit dynamics, including experience-induced plasticity at excitatory synapses, are thought to play a key role in episodic memory encoding and consolidation via rapid generation and flexible selection of neural ensembles. However, in vivo activity of identified inhibitory motifs supporting this recurrent circuitry has remained largely inaccessible, and it is unknown whether CA3 inhibition is also modifiable upon experience. Here we use large-scale, 3-dimensional calcium imaging and retrospective molecular identification in the mouse hippocampus to obtain the first comprehensive description of molecularly-identified CA3 interneuron dynamics during both spatial navigation and sharp-wave ripple (SWR)-associated memory consolidation. Our results uncover subtype-specific dynamics during behaviorally distinct brain-states. Our data also demonstrate predictive, reflective, and experience-driven plastic recruitment of specific inhibitory motifs during SWR-related memory reactivation. Together these results assign active roles for inhibitory circuits in coordinating operations and plasticity in hippocampal recurrent circuits.
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40
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Ku T, Liu Y, Xie Y, Hu J, Hou Y, Tan X, Ning X, Li G, Sang N. Tebuconazole mediates cognitive impairment via the microbe-gut-brain axis (MGBA) in mice. ENVIRONMENT INTERNATIONAL 2023; 173:107821. [PMID: 36827814 DOI: 10.1016/j.envint.2023.107821] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/19/2023] [Accepted: 02/11/2023] [Indexed: 06/18/2023]
Abstract
Tebuconazole, one of the most widely used triazole fungicides, is reported to potentially pose a risk of inducing neurological disorders in human beings. Considering the increasing exposure, whether it could influence cognitive function remains to be elucidated. Herein, we used a mouse model to evaluate the potential cognitive risks and possible mechanisms from the continuous edible application of tebuconazole at low concentrations. Our study revealed that tebuconazole deteriorated spatial learning and memory and downregulated the expression of glutamate receptor subunits. Importantly, metagenomic analysis indicated that tebuconazole not only led to significant shifts in the composition and diversity of the gut microbiota but also changed intestinal homeostasis. Specifically, after exposure, tebuconazole circulated in the bloodstream and largely entered the gut-brain axis for disruption, including disturbing the Firmicutes/Bacteroidetes ratio, interrelated neurotransmitters and systemic immune factors. Moreover, pretreatment with probiotics improved immune factor expression and restored the deterioration of synaptic function and spatial learning and memory. The current study provides novel insights concerning perturbations of the gut microbiome and its functions as a potential new mechanism by which tebuconazole exposes cognitive function-related human health.
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Affiliation(s)
- Tingting Ku
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Yutong Liu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Yuanyuan Xie
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Jindong Hu
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Yanwen Hou
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Xin Tan
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Xia Ning
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Guangke Li
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China.
| | - Nan Sang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, China.
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41
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Shinohara Y, Kohara K. Projections of hippocampal CA2 pyramidal neurons: Distinct innervation patterns of CA2 compared to CA3 in rodents. Hippocampus 2023; 33:691-699. [PMID: 36855258 DOI: 10.1002/hipo.23519] [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: 09/01/2022] [Revised: 02/01/2023] [Accepted: 02/14/2023] [Indexed: 03/02/2023]
Abstract
The hippocampus is a center for spatial and episodic memory formation in rodents. Understanding the composition of subregions and circuitry maps of the hippocampus is essential for elucidating the mechanism of memory formation and recall. For decades, the trisynaptic circuit (entorhinal cortex layer II-dentate gyrus - CA3-CA1) has been considered the neural network substrate responsible for learning and memory. Recently, CA2 has emerged as an important area in the hippocampal circuitry, with distinct functions from those of CA3. In this article, we review the historical definition of the hippocampal area CA2 and the differential projection patterns between CA2 and CA3 pyramidal neurons. We provide a concise and comprehensive map of CA2 outputs by comparing (1) ipsi versus contra projections, (2) septal versus temporal projections, and (3) lamellar structures of CA2 and CA3 pyramidal neurons.
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Affiliation(s)
- Yoshiaki Shinohara
- Department of Anatomy and Cell Biology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Keigo Kohara
- KMU Biobank Center, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, Japan
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42
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Single-Cell Labeling Strategies to Dissect Neuronal Structures and Local Functions. BIOLOGY 2023; 12:biology12020321. [PMID: 36829594 PMCID: PMC9953318 DOI: 10.3390/biology12020321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023]
Abstract
The brain network consists of ten billion neurons and is the most complex structure in the universe. Understanding the structure of complex brain networks and neuronal functions is one of the main goals of modern neuroscience. Since the seminal invention of Golgi staining, single-cell labeling methods have been among the most potent approaches for dissecting neuronal structures and neural circuits. Furthermore, the development of sparse single-cell transgenic methods has enabled single-cell gene knockout studies to examine the local functions of various genes in neural circuits and synapses. Here, we review non-transgenic single-cell labeling methods and recent advances in transgenic strategies for sparse single neuronal labeling. These methods and strategies will fundamentally contribute to the understanding of brain structure and function.
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Zhuang M, Geng X, Han P, Che P, Liang F, Liu C, Yang L, Yu J, Zhang Z, Dong W, Ji SJ. YTHDF2 in dentate gyrus is the m 6A reader mediating m 6A modification in hippocampus-dependent learning and memory. Mol Psychiatry 2023; 28:1679-1691. [PMID: 36670199 DOI: 10.1038/s41380-023-01953-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/28/2022] [Accepted: 01/10/2023] [Indexed: 01/21/2023]
Abstract
N6-methyladenosine (m6A) has been demonstrated to regulate learning and memory in mice. To investigate the mechanism by which m6A modification exerts its function through its reader proteins in the hippocampus, as well as to unveil the specific subregions of the hippocampus that are crucial for memory formation, we generated dentate gyrus (DG)-, CA3-, and CA1-specific Ythdf1 and Ythdf2 conditional knockout (cKO) mice, respectively. Surprisingly, we found that only the DG-specific Ythdf2 cKO mice displayed impaired memory formation, which is inconsistent with the previous report showing that YTHDF1 was involved in this process. YTHDF2 controls the stability of its target transcripts which encode proteins that regulate the elongation of mossy fibers (MF), the axons of DG granule cells. DG-specific Ythdf2 ablation caused MF overgrowth and impairment of the MF-CA3 excitatory synapse development and transmission in the stratum lucidum. Thus, this study identifies the m6A reader YTHDF2 in dentate gyrus as the only regulator that mediates m6A modification in hippocampus-dependent learning and memory.
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Affiliation(s)
- Mengru Zhuang
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.,SUSTech-HKUST Joint PhD Program, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Xiaoqi Geng
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China.,Department of Neurosurgery, Neurosurgical Clinical Research Center of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Peng Han
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China
| | - Pengfei Che
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China
| | - Fanghao Liang
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China
| | - Chao Liu
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Lixin Yang
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China
| | - Jun Yu
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China
| | - Zhuxia Zhang
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China
| | - Wei Dong
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China. .,Department of Neurosurgery, Neurosurgical Clinical Research Center of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
| | - Sheng-Jian Ji
- School of Life Sciences, Department of Neuroscience and Department of Biology, Brain Research Center, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
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44
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Nomoto M, Ohkawa N, Inokuchi K, Oishi N. Requirement for hippocampal CA3 NMDA receptors in artificial association of memory events stored in CA3 cell ensembles. Mol Brain 2023; 16:12. [PMID: 36670484 PMCID: PMC9854113 DOI: 10.1186/s13041-023-01004-2] [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: 12/13/2022] [Accepted: 01/12/2023] [Indexed: 01/21/2023] Open
Abstract
The N-methyl-D-aspartate receptors (NRs) in hippocampal CA3 are crucial for the synaptic transmission and plasticity within the CA3 recurrent circuit, which supports the hippocampal functions, such as pattern completion, and reverberatory association of sensory inputs. Previous study showed that synchronous activation of distinct cell populations in CA3, which correspond to distinct events, associated independent events, suggesting that the recurrent circuit expressing NRs in CA3 mediates the artificial association of memory events stored in CA3 ensembles. However, it is still unclear whether CA3 NRs are crucial for the artificial association of memory events stored in the CA3 ensembles. Here we report that the triple transgenic mice (cfos-tTA/KA1-Cre/NR1 flox/flox), which specifically lack NRs in the CA3 cell ensembles, showed impairment in artificial association between two events, which in control mice triggered artificial association. This result indicates that NRs in the hippocampal CA3 are required for the artificial association of memory events stored in the CA3 cell ensembles.
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Affiliation(s)
- Masanori Nomoto
- Research Centre for Idling Brain Science, University of Toyama, Toyama, 930-0194, Japan. .,Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. .,CREST, JST, University of Toyama, Toyama, 930-0194, Japan.
| | - Noriaki Ohkawa
- Division for Memory and Cognitive Function, Research Center for Advanced Medical Science, Comprehensive Research Facilities for Advanced Medical Science, Dokkyo Medical University, Shimotsuga-Gun, Tochigi, 321-0293, Japan
| | - Kaoru Inokuchi
- Research Centre for Idling Brain Science, University of Toyama, Toyama, 930-0194, Japan. .,Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. .,CREST, JST, University of Toyama, Toyama, 930-0194, Japan.
| | - Naoya Oishi
- Research Centre for Idling Brain Science, University of Toyama, Toyama, 930-0194, Japan.,Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.,CREST, JST, University of Toyama, Toyama, 930-0194, Japan.,Pharmaceutical Division, Pharmaceutical Research Laboratory, Drug Discovery and Pharmacology Group, Ube Corporation, 1978-5, Kogushi, Ube, Yamaguchi, 755-8633, Japan
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45
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Vanrobeys Y, Mukherjee U, Langmack L, Bahl E, Lin LC, Michaelson JJ, Abel T, Chatterjee S. Mapping the spatial transcriptomic signature of the hippocampus during memory consolidation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.18.524576. [PMID: 36711475 PMCID: PMC9882356 DOI: 10.1101/2023.01.18.524576] [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] [Indexed: 01/21/2023]
Abstract
Memory consolidation involves discrete patterns of transcriptional events in the hippocampus. Despite the emergence of single-cell transcriptomic profiling techniques, defining learning-responsive gene expression across subregions of the hippocampus has remained challenging. Here, we utilized unbiased spatial sequencing to elucidate transcriptome-wide changes in gene expression in the hippocampus following learning, enabling us to define molecular signatures unique to each hippocampal subregion. We find that each subregion of the hippocampus exhibits distinct yet overlapping transcriptomic signatures. Although the CA1 region exhibited increased expression of genes related to transcriptional regulation, the DG showed upregulation of genes associated with protein folding. We demonstrate the functional relevance of subregion-specific gene expression by genetic manipulation of a transcription factor selectively in the CA1 hippocampal subregion, leading to long-term memory deficits. This work demonstrates the power of using spatial molecular approaches to reveal transcriptional events during memory consolidation.
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Affiliation(s)
- Yann Vanrobeys
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
| | - Utsav Mukherjee
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA
| | - Lucy Langmack
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Biochemistry and Molecular Biology Graduate Program, University of Iowa, Iowa City, IA, USA
| | - Ethan Bahl
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Li-Chun Lin
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Jacob J Michaelson
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Ted Abel
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Snehajyoti Chatterjee
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
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Vanrobaeys Y, Peterson ZJ, Walsh EN, Chatterjee S, Lin LC, Lyons LC, Nickl-Jockschat T, Abel T. Spatial transcriptomics reveals unique gene expression changes in different brain regions after sleep deprivation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.18.524406. [PMID: 36712009 PMCID: PMC9882298 DOI: 10.1101/2023.01.18.524406] [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: 01/22/2023]
Abstract
Sleep deprivation has far-reaching consequences on the brain and behavior, impacting memory, attention, and metabolism. Previous research has focused on gene expression changes in individual brain regions, such as the hippocampus or cortex. Therefore, it is unclear how uniformly or heterogeneously sleep loss affects the brain. Here, we use spatial transcriptomics to define the impact of a brief period of sleep deprivation across the brain. We find that sleep deprivation induced pronounced differences in gene expression across the brain, with the greatest changes in the hippocampus, neocortex, hypothalamus, and thalamus. Both the differentially expressed genes and the direction of regulation differed markedly across regions. Importantly, we developed bioinformatic tools to register tissue sections and gene expression data into a common anatomical space, allowing a brain-wide comparison of gene expression patterns between samples. Our results suggest that distinct molecular mechanisms acting in discrete brain regions underlie the biological effects of sleep deprivation.
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Affiliation(s)
- Yann Vanrobaeys
- Interdisciplinary Graduate Program in Genetics, University of Iowa, 357 Medical Research Center Iowa City, IA 52242, USA
- Iowa Neuroscience Institute, Carver College of Medicine, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, 51 Newton Road, 2-417B Bowen Science Building, University of Iowa, Iowa City, IA 52242, USA
| | - Zeru J. Peterson
- Iowa Neuroscience Institute, Carver College of Medicine, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Emily. N. Walsh
- Iowa Neuroscience Institute, Carver College of Medicine, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, 51 Newton Road, 2-417B Bowen Science Building, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, 356 Medical Research Center, Iowa City, IA 52242, USA
| | - Snehajyoti Chatterjee
- Iowa Neuroscience Institute, Carver College of Medicine, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, 51 Newton Road, 2-417B Bowen Science Building, University of Iowa, Iowa City, IA 52242, USA
| | - Li-Chun Lin
- Iowa Neuroscience Institute, Carver College of Medicine, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, 51 Newton Road, 2-417B Bowen Science Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Neurology, University of Iowa, Iowa City, IA, USA
| | - Lisa C. Lyons
- Program in Neuroscience, Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Thomas Nickl-Jockschat
- Iowa Neuroscience Institute, Carver College of Medicine, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, 51 Newton Road, 2-417B Bowen Science Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Ted Abel
- Iowa Neuroscience Institute, Carver College of Medicine, 169 Newton Road, 2312 Pappajohn Biomedical Discovery Building, University of Iowa, Iowa City, IA 52242, USA
- Department of Neuroscience and Pharmacology, Carver College of Medicine, 51 Newton Road, 2-417B Bowen Science Building, University of Iowa, Iowa City, IA 52242, USA
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Stress disrupts insight-driven mnemonic reconfiguration in the medial temporal lobe. Neuroimage 2023; 265:119804. [PMID: 36503160 PMCID: PMC9878442 DOI: 10.1016/j.neuroimage.2022.119804] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022] Open
Abstract
Memories are not stored in isolation. Insight into the relationship of initially unrelated events may trigger a flexible reconfiguration of the mnemonic representation of these events. Such representational changes allow the integration of events into coherent episodes and help to build up-to-date-models of the world around us. This process is, however, frequently impaired in stress-related mental disorders resulting in symptoms such as fragmented memories in PTSD. Here, we combined a real life-like narrative-insight task, in which participants learned how initially separate events are linked, with fMRI-based representational similarity analysis to test if and how acute stress interferes with the insight-driven reconfiguration of memories. Our results showed that stress reduced the activity of medial temporal and prefrontal areas when participants gained insight into the link between events. Moreover, stress abolished the insight-related increase in representational dissimilarity for linked events in the anterior part of the hippocampus as well as its association with measures of subsequent memory that we observed in non-stressed controls. However, memory performance, as assessed in a forced-choice recognition test, was even enhanced in the stress group. Our findings suggest that acute stress impedes the neural integration of events into coherent episodes but promotes long-term memory for these integrated narratives and may thus have implications for understanding memory distortions in stress-related mental disorders.
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48
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The potential role of the cholecystokinin system in declarative memory. Neurochem Int 2023; 162:105440. [PMID: 36375634 DOI: 10.1016/j.neuint.2022.105440] [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: 08/18/2022] [Revised: 10/24/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
As one of the most abundant neuropeptides in the central nervous system, cholecystokinin (CCK) has been suggested to be associated with higher brain functions, including learning and memory. In this review, we examined the potential role of the CCK system in declarative memory. First, we summarized behavioral studies that provide evidence for an important role of CCK in two forms of declarative memory-fear memory and spatial memory. Subsequently, we examined the electrophysiological studies that support the diverse roles of CCK-2 receptor activation in neocortical and hippocampal synaptic plasticity, and discussed the potential mechanisms that may be involved. Last but not least, we discussed whether the reported CCK-mediated synaptic plasticity can explain the strong influence of the CCK signaling system in neocortex and hippocampus dependent declarative memory. The available research supports the role of CCK-mediated synaptic plasticity in neocortex dependent declarative memory acquisition, but further study on the association between CCK-mediated synaptic plasticity and neocortex dependent declarative memory consolidation and retrieval is necessary. Although a direct link between CCK-mediated synaptic plasticity and hippocampus dependent declarative memory is missing, noticeable evidence from morphological, behavioral, and electrophysiological studies encourages further investigation regarding the potential role of CCK-dependent synaptic plasticity in hippocampus dependent declarative memory.
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Nomoto M, Murayama E, Ohno S, Okubo-Suzuki R, Muramatsu SI, Inokuchi K. Hippocampus as a sorter and reverberatory integrator of sensory inputs. Nat Commun 2022; 13:7413. [PMID: 36539403 PMCID: PMC9768143 DOI: 10.1038/s41467-022-35119-2] [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: 03/13/2022] [Accepted: 11/17/2022] [Indexed: 12/24/2022] Open
Abstract
The hippocampus must be capable of sorting and integrating multiple sensory inputs separately but simultaneously. However, it remains to be elucidated how the hippocampus executes these processes simultaneously during learning. Here we found that synchrony between conditioned stimulus (CS)-, unconditioned stimulus (US)- and future retrieval-responsible cells occurs in the CA1 during the reverberatory phase that emerges after sensory inputs have ceased, but not during CS and US inputs. Mutant mice lacking N-methyl-D-aspartate receptors (NRs) in CA3 showed a cued-fear memory impairment and a decrease in synchronized reverberatory activities between CS- and US-responsive CA1 cells. Optogenetic CA3 silencing at the reverberatory phase during learning impaired cued-fear memory. Thus, the hippocampus uses reverberatory activity to link CS and US inputs, and avoid crosstalk during sensory inputs.
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Affiliation(s)
- Masanori Nomoto
- grid.267346.20000 0001 2171 836XResearch Centre for Idling Brain Science, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XDepartment of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XCREST, JST, University of Toyama, Toyama, 930−0194 Japan
| | - Emi Murayama
- grid.267346.20000 0001 2171 836XResearch Centre for Idling Brain Science, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XDepartment of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XCREST, JST, University of Toyama, Toyama, 930−0194 Japan
| | - Shuntaro Ohno
- grid.267346.20000 0001 2171 836XResearch Centre for Idling Brain Science, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XDepartment of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XCREST, JST, University of Toyama, Toyama, 930−0194 Japan
| | - Reiko Okubo-Suzuki
- grid.267346.20000 0001 2171 836XResearch Centre for Idling Brain Science, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XDepartment of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XCREST, JST, University of Toyama, Toyama, 930−0194 Japan
| | - Shin-ichi Muramatsu
- grid.410804.90000000123090000Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, 329−0498 Japan ,grid.26999.3d0000 0001 2151 536XCenter for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108−8639 Japan
| | - Kaoru Inokuchi
- grid.267346.20000 0001 2171 836XResearch Centre for Idling Brain Science, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XDepartment of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930−0194 Japan ,grid.267346.20000 0001 2171 836XCREST, JST, University of Toyama, Toyama, 930−0194 Japan
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Shin J, Lee HW, Jin SW, Lee I. Subtle visual change in a virtual environment induces heterogeneous remapping systematically in CA1, but not CA3. Cell Rep 2022; 41:111823. [PMID: 36516763 DOI: 10.1016/j.celrep.2022.111823] [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: 03/18/2022] [Revised: 08/10/2022] [Accepted: 11/22/2022] [Indexed: 12/15/2022] Open
Abstract
Environmental change may lead to new memories or modify old ones, but the underlying neural mechanisms are largely unclear. We recorded hippocampal place cells simultaneously from CA1 and CA3 in a virtual reality environment. Compared with CA1, place cells in CA3 are more tolerant of individual landmark changes but undergo orthogonal changes to code distinctively different environments. As visual noise (virtual fog) is introduced to a visually enriched environment, place cells in CA1 split into two subpopulations: in one, place cells maintain their field locations while changing their firing rates to reflect sensory changes; in the other, place cells exhibit global remapping in response to the contextual change. In contrast, place cells in CA3 exhibit mainly rate remapping under the same conditions. Our results suggest that CA1 may simultaneously represent heterogeneous maps of the same environment when subtle visual noise induces both sensory and contextual changes.
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Affiliation(s)
- Jhoseph Shin
- Department of Brain and Cognitive Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Republic of Korea
| | - Hyun-Woo Lee
- Department of Brain and Cognitive Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Republic of Korea
| | - Seung-Woo Jin
- Department of Brain and Cognitive Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Republic of Korea
| | - Inah Lee
- Department of Brain and Cognitive Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Republic of Korea.
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