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1
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Chen P, Hu H, Wang M, Li R, Wei J, Wang M, Tan T, Yu Y. Modulating excitation of the mediodorsal thalamus rescues dysfunction after administration of MK-801 in rats. Brain Res 2025; 1855:149532. [PMID: 40090445 DOI: 10.1016/j.brainres.2025.149532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/18/2025]
Abstract
The excitation/inhibition (E/I) balance in the prefrontal cortex (PFC) is a dynamic equilibrium maintained by the concerted efforts of excitatory glutamatergic neurons and inhibitory γ-aminobutyric acid neurons (INs). The medial dorsal nucleus (MD) of the thalamus provides abundant pyramidal glutamatergic neural (PNs) projections to the PFC and regulates the E/I balance within the PFC. In schizophrenia, an imbalance in the E/I ratio in the PFC, along with reduced thalamocortical connectivity, has been observed. Nevertheless, the precise mechanisms underlying the modulation of the MD to PFC activity remain elusive. We posited a hypothesis that the MD may serve as a potential therapeutic target for schizophrenia. To investigate the role of PFC in the pathogenesis of schizophrenia, we induced schizophrenia-related neuronal activation and motor behavioral abnormalities in adult rats through intraperitoneal injection of MK-801. We measured alterations in neuronal firing activity and neural oscillations by monitoring deep brain neuronal signals under resting state and auditory response task conditions, while simultaneously assessing their motor activities. In our study, the results indicated that systemic administration of MK-801 preferentially leads to an increase in the firing frequency of PFC-PNs and disrupts the E/I balance in the PFC. Concurrently, this is accompanied by mid-to-high (14-80 and 130-180 Hz) frequency oscillations and abnormalities in the auditory steady-state responses and autonomous activities. Subsequently, we employed optogenetics to stimulate the activity of MD neurons selectively, aiming to elucidate the role of the MD-to-PFC neural circuit in modulating the PFC E/I ratio. The results confirmed thatincreased activity of MD neurons in schizophrenia leads to heightened excitability of PFC-INs and decreased firing rates of PFC-PNs, thereby restoring the E/I balance in the PFC and improving gamma oscillations, auditory steady-state responses, and behavioral abnormalities. Overall, these findings reveal the pivotal role of MD-to-PFC connectivity in modulating PFC E/I balance and provide valuable insights for potential therapeutic strategies targeting this circuitry in the context of E/I dysregulation seen in schizophrenia.
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Affiliation(s)
- Peiqi Chen
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China; Department of Radiology, Huazhong University of Science and Technology Union Shenzhen, Shenzhen, China
| | - Heshun Hu
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China
| | - Mengke Wang
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China
| | - Ruijiao Li
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China
| | - Jiarong Wei
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China
| | - Menghan Wang
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China
| | - Tao Tan
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China
| | - Yi Yu
- School of Medical Engineering, Xinxiang Medical University, Xinxiang, China; Engineering Technology Research Center of Neuroscience and Control of Henan Province, Xinxiang, China.
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2
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Ageta-Ishihara N, Fukazawa Y, Arima-Yoshida F, Okuno H, Ishii Y, Takao K, Konno K, Fujishima K, Ageta H, Hioki H, Tsuchida K, Sato Y, Kengaku M, Watanabe M, Watabe AM, Manabe T, Miyakawa T, Inokuchi K, Bito H, Kinoshita M. Septin 3 regulates memory and L-LTP-dependent extension of endoplasmic reticulum into spines. Cell Rep 2025; 44:115352. [PMID: 40023151 DOI: 10.1016/j.celrep.2025.115352] [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: 07/17/2024] [Revised: 12/11/2024] [Accepted: 02/05/2025] [Indexed: 03/04/2025] Open
Abstract
Transient memories are converted to persistent memories at the synapse and circuit/systems levels. The synapse-level consolidation parallels electrophysiological transition from early- to late-phase long-term potentiation of synaptic transmission (E-/L-LTP). While glutamate signaling upregulations coupled with dendritic spine enlargement are common underpinnings of E-LTP and L-LTP, synaptic mechanisms conferring persistence on L-LTP remain unclear. Here, we show that L-LTP induced at the perforant path-hippocampal dentate gyrus (DG) synapses accompanies cytoskeletal remodeling that involves actin and the septin subunit SEPT3. L-LTP in DG neurons causes fast spine enlargement, followed by SEPT3-dependent smooth endoplasmic reticulum (sER) extension into enlarged spines. Spines containing sER show greater Ca2+ responses upon synaptic input and local synaptic activity. Consistently, Sept3 knockout in mice (Sept3-/-) impairs memory consolidation and causes a scarcity of sER-containing spines. These findings indicate a concept that sER extension into active spines serves as a synaptic basis of memory consolidation.
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Affiliation(s)
- Natsumi Ageta-Ishihara
- Department of Biomolecular Science, Faculty of Science, Toho University, Funabashi, Chiba 274-8510, Japan; Department of Molecular Biology, Division of Biological Sciences, Nagoya University Graduate School of Science, Chikusa-ku, Nagoya 464-8602, Japan.
| | - Yugo Fukazawa
- Division of Brain Structure and Function, Faculty of Medical Science, University of Fukui, Yoshida-gun, Fukui 910-1193, Japan
| | - Fumiko Arima-Yoshida
- Division of Neuronal Network, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Institute of Clinical Medicine and Research, Research Center for Medical Sciences, The Jikei University School of Medicine, Kashiwa, Chiba 277-8567, Japan
| | - Hiroyuki Okuno
- Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yuichiro Ishii
- Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Keizo Takao
- Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Kohtarou Konno
- Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Kazuto Fujishima
- Institute for Integrated Cell-Material Sciences, Kyoto University Institute for Advanced Study (KUIAS-iCeMS), Sakyo-ku, Kyoto 606-8501, Japan; Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-8686, Japan
| | - Hiroshi Ageta
- Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
| | - Hiroyuki Hioki
- Department of Neuroanatomy, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Kunihiro Tsuchida
- Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
| | - Yoshikatsu Sato
- Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan
| | - Mineko Kengaku
- Institute for Integrated Cell-Material Sciences, Kyoto University Institute for Advanced Study (KUIAS-iCeMS), Sakyo-ku, Kyoto 606-8501, Japan
| | - Masahiko Watanabe
- Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Ayako M Watabe
- Institute of Clinical Medicine and Research, Research Center for Medical Sciences, The Jikei University School of Medicine, Kashiwa, Chiba 277-8567, Japan
| | - Toshiya Manabe
- Division of Neuronal Network, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
| | - Tsuyoshi Miyakawa
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
| | - Kaoru Inokuchi
- Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
| | - Haruhiko Bito
- Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Makoto Kinoshita
- Department of Molecular Biology, Division of Biological Sciences, Nagoya University Graduate School of Science, Chikusa-ku, Nagoya 464-8602, Japan.
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3
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Ko HG, Jung H, Han S, Choi DI, Lee C, Choi JE, Oh J, Kwak C, Han DH, Kim JN, Ye S, Lee J, Lee J, Lee K, Lee JH, Zhuo M, Kaang BK. Processing of pain and itch information by modality-specific neurons within the anterior cingulate cortex in mice. Nat Commun 2025; 16:2137. [PMID: 40038260 PMCID: PMC11880300 DOI: 10.1038/s41467-025-57041-z] [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: 10/31/2023] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
Pain and itch are aversive sensations with distinct qualities, processed in overlapping pathways and brain regions, including the anterior cingulate cortex (ACC), which is critical for their affective dimensions. However, the cellular mechanisms underlying their processing in the ACC remain unclear. Here, we identify modality-specific neuronal populations in layer II/III of the ACC in mice involved in pain and itch processing. Using a synapse labeling tool, we show that pain- and itch-related neurons selectively receive synaptic inputs from mediodorsal thalamic neurons activated by pain and itch stimuli, respectively. Chemogenetic inhibition of these neurons reduced pruriception or nociception without affecting the opposite modality. Conversely, activation of these neurons did not enhance stimulus-specific responses but commonly increased freezing-like behavior. These findings reveal that the processing of itch and pain information in the ACC involves activity-dependent and modality-specific neuronal populations, and that pain and itch are processed by functionally distinct ACC neuronal subsets.
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Affiliation(s)
- Hyoung-Gon Ko
- Department of Anatomy and Neurobiology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, 2177 Dalgubeol-daero, Daegu, South Korea.
- Department of Oral Anatomy and Developmental Biology, Kyung Hee University College of Dentistry, Seoul, South Korea.
| | - Hyunsu Jung
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Seunghyo Han
- Department of Anatomy and Neurobiology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, 2177 Dalgubeol-daero, Daegu, South Korea
| | - Dong Il Choi
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Chiwoo Lee
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Ja Eun Choi
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Jihae Oh
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Chuljung Kwak
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea
| | - Dae Hee Han
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea
| | - Jun-Nyeong Kim
- Department of Anatomy and Neurobiology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, 2177 Dalgubeol-daero, Daegu, South Korea
| | - Sanghyun Ye
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Jiah Lee
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Jaehyun Lee
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea
| | - Kyungmin Lee
- Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science and Engineering Institute, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Daegu, South Korea
| | - Jae-Hyung Lee
- Department of Oral Microbiology, College of Dentistry, Kyung Hee University, 26 Kyungheedae-ro, Seoul, South Korea
| | - Min Zhuo
- Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
- International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China
| | - Bong-Kiun Kaang
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea.
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea.
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4
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Ito T, Yamamoto M, Liu L, Saqib KA, Furuyama T, Ono M. Segregated input to thalamic areas that project differently to core and shell auditory cortical fields. iScience 2025; 28:111721. [PMID: 39898033 PMCID: PMC11787697 DOI: 10.1016/j.isci.2024.111721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 10/15/2024] [Accepted: 12/30/2024] [Indexed: 02/04/2025] Open
Abstract
Perception of the environment is multimodal in nature, with sensory systems intricately interconnected. The ability to integrate multimodal sensations while preserving the distinct characteristics of each sensory modality is crucial, and the underlying mechanisms of the organization that facilitate this process require further elucidation. In the auditory system, although the concept of core and shell pathways is well established, the brain-wide input/output relationships of thalamic regions projecting to auditory-responsive cortical areas remain insufficiently studied, particularly in relation to non-auditory structures. In this study, we utilized functional imaging and viral tracing techniques to map the brain-wide connections of core and shell pathways. We identified three distinct shell pathways, in addition to a core pathway, each exhibiting unique associations with non-auditory structures involved in behavior, emotion, and other functions. This architecture suggests that these pathways contribute differentially to various aspects of multimodal sensory integration.
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Affiliation(s)
- Tetsufumi Ito
- Systems Function and Morphology Laboratory, Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194 Japan
| | - Mamiko Yamamoto
- Systems Function and Morphology Laboratory, Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194 Japan
| | - Li Liu
- Anatomy 2, School of Medicine, Kanazawa Medical University, Uchinada 920-0265 Japan
| | - Khaleeq Ahmad Saqib
- Systems Function and Morphology Laboratory, Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194 Japan
| | - Takafumi Furuyama
- Physiology 1, School of Medicine, Kanazawa Medical University, Uchinada 920-0265, Japan
| | - Munenori Ono
- Physiology 1, School of Medicine, Kanazawa Medical University, Uchinada 920-0265, Japan
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5
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Zhao H, Guillaud L, Emily MF, Xu X, Moshniaha L, Hanayama H, Kabe R, Terenzio M, Narita A. Nanographene-Based Polymeric Nanoparticles as Near-Infrared Emissive Neuronal Tracers. ACS NANO 2024; 18:34730-34740. [PMID: 39668551 PMCID: PMC11673580 DOI: 10.1021/acsnano.4c10754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/07/2024] [Accepted: 11/20/2024] [Indexed: 12/14/2024]
Abstract
Precise tracking of axonal transport is key to deciphering neuronal functions. To achieve long-term imaging at both ultrastructural and macroscopic resolutions, it is critical to develop fluorescent transport tracers with high photostability and biocompatibility. Herein, we report the investigation of nanographene (NG)-based polymeric nanoparticles (NPs) as near-infrared (NIR)-emissive neuronal tracers. Dibenzo[a,m]dinaphtho[3,2,1-ef:1',2',3'-hi]coronene (DBDNC) was employed as the NG, which exhibited a broad NIR emission with a maximum at 711 nm inside the NPs. DBDNC-NPs displayed high photostability and low cytotoxicity, enabling live tracing of retrograde axonal transport in mouse sensory neurons cultured in microfluidic chambers. We also elucidated how DBDNC-NPs undergo retrograde axonal transport following the endolysosomal pathway. This work provides a proof of concept for NIR-emissive, NG-based neuronal tracers with potential for applications in neurobiology.
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Affiliation(s)
- Hao Zhao
- Organic
and Carbon Nanomaterials Unit, Okinawa Institute
of Science and Technology Graduate University, 1919-1 Tancha,
Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
| | - Laurent Guillaud
- Molecular
Neuroscience Unit, Okinawa Institute of
Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
| | - Maria Fransiska Emily
- Molecular
Neuroscience Unit, Okinawa Institute of
Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
| | - Xiushang Xu
- Organic
and Carbon Nanomaterials Unit, Okinawa Institute
of Science and Technology Graduate University, 1919-1 Tancha,
Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
- Max
Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
| | - Liliia Moshniaha
- Organic
Optoelectronics Unit, Okinawa Institute
of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
| | - Hiroki Hanayama
- Organic
and Carbon Nanomaterials Unit, Okinawa Institute
of Science and Technology Graduate University, 1919-1 Tancha,
Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
| | - Ryota Kabe
- Organic
Optoelectronics Unit, Okinawa Institute
of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
| | - Marco Terenzio
- Molecular
Neuroscience Unit, Okinawa Institute of
Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
| | - Akimitsu Narita
- Organic
and Carbon Nanomaterials Unit, Okinawa Institute
of Science and Technology Graduate University, 1919-1 Tancha,
Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
- Max
Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
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6
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Ding TH, Hu YY, Li JW, Sun C, Ma CL. Mediodorsal thalamus nucleus-medial prefrontal cortex circuitry regulates cost-benefit decision-making selections. Cereb Cortex 2024; 34:bhae476. [PMID: 39668425 DOI: 10.1093/cercor/bhae476] [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: 05/28/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 12/14/2024] Open
Abstract
Value-based decision-making involves weighing costs and benefits. The activity of the medial prefrontal cortex reflects cost-benefit assessments, and the mediodorsal thalamus, reciprocally connected with the medial prefrontal cortex, has increasingly been recognized as an active partner in decision-making. However, the specific role of the interaction between the mediodorsal thalamus and the medial prefrontal cortex in regulating the neuronal activity underlying how costs and benefits influence decision-making remains largely unexplored. We investigated this by training the rats to perform a self-determined decision-making task, where longer nose poke durations resulted in correspondingly larger rewards. Our results showed that the inactivation of either the medial prefrontal cortex or the mediodorsal thalamus significantly impaired rat to invest more nose poke duration for larger rewards. Moreover, optogenetic stimulation of the mediodorsal thalamus-medial prefrontal cortex pathway enhanced rats' motivation for larger rewards, whereas inhibition of this pathway resulted in decreased motivation. Notably, we identified a specific population of neurons in the medial prefrontal cortex that exhibited firing patterns correlated with motivation, and these neurons were modulated by the mediodorsal thalamus-medial prefrontal cortex projection. These findings suggest that the motivation during decision-making is encoded primarily by activity of particular neurons in the medial prefrontal cortex and indicate the crucial role of the mediodorsal thalamus-medial prefrontal cortex pathway in maintaining motivation.
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Affiliation(s)
- Tong-Hao Ding
- Institute of Biomedical Innovation, Nanchang University, Nanchang 330031, China
| | - Yu-Ying Hu
- Institute of Biomedical Innovation, Nanchang University, Nanchang 330031, China
- School of Life Science, Nanchang University, Nanchang 330031, China
| | - Jia-Wen Li
- The Second Clinic Medicine School, Nanchang University, Nanchang 330031, China
| | - Chong Sun
- Institute of Biomedical Innovation, Nanchang University, Nanchang 330031, China
| | - Chao-Lin Ma
- Institute of Biomedical Innovation, Nanchang University, Nanchang 330031, China
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7
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Zhang Y, Zhang W, Wang L, Liu D, Xie T, Le Z, Li X, Gong H, Xu XH, Xu M, Yao H. Whole-brain Mapping of Inputs and Outputs of Specific Orbitofrontal Cortical Neurons in Mice. Neurosci Bull 2024; 40:1681-1698. [PMID: 38801564 PMCID: PMC11607251 DOI: 10.1007/s12264-024-01229-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 12/16/2023] [Indexed: 05/29/2024] Open
Abstract
The orbitofrontal cortex (ORB), a region crucial for stimulus-reward association, decision-making, and flexible behaviors, extensively connects with other brain areas. However, brain-wide inputs to projection-defined ORB neurons and the distribution of inhibitory neurons postsynaptic to neurons in specific ORB subregions remain poorly characterized. Here we mapped the inputs of five types of projection-specific ORB neurons and ORB outputs to two types of inhibitory neurons. We found that different projection-defined ORB neurons received inputs from similar cortical and thalamic regions, albeit with quantitative variations, particularly in somatomotor areas and medial groups of the dorsal thalamus. By counting parvalbumin (PV) or somatostatin (SST) interneurons innervated by neurons in specific ORB subregions, we found a higher fraction of PV neurons in sensory cortices and a higher fraction of SST neurons in subcortical regions targeted by medial ORB neurons. These results provide insights into understanding and investigating the function of specific ORB neurons.
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Affiliation(s)
- Yijie Zhang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wen Zhang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Lizhao Wang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Dechen Liu
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Taorong Xie
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ziwei Le
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiangning Li
- HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Hui Gong
- HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
- CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xiao-Hong Xu
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
- Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China
| | - Min Xu
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
- Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China
| | - Haishan Yao
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
- Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China.
- Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Shanghai, 200031, China.
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8
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Lian YN, Cao XW, Wu C, Pei CY, Liu L, Zhang C, Li XY. Deconstruction the feedforward inhibition changes in the layer III of anterior cingulate cortex after peripheral nerve injury. Commun Biol 2024; 7:1237. [PMID: 39354145 PMCID: PMC11445484 DOI: 10.1038/s42003-024-06849-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 09/05/2024] [Indexed: 10/03/2024] Open
Abstract
The anterior cingulate cortex (ACC) is one of the critical brain areas for processing noxious information. Previous studies showed that peripheral nerve injury induced broad changes in the ACC, contributing to pain hypersensitivity. The neurons in layer 3 (L3) of the ACC receive the inputs from the mediodorsal thalamus (MD) and form the feedforward inhibition (FFI) microcircuits. The effects of peripheral nerve injury on the MD-driven FFI in L3 of ACC are unknown. In our study, we record the enhanced excitatory synaptic transmissions from the MD to L3 of the ACC in mice with common peroneal nerve ligation, affecting FFI. Chemogenetically activating the MD-to-ACC projections induces pain sensitivity and place aversion in naive mice. Furthermore, chemogenetically inactivating MD-to-ACC projections decreases pain sensitivity and promotes place preference in nerve-injured mice. Our results indicate that the peripheral nerve injury changes the MD-to-ACC projections, contributing to pain hypersensitivity and aversion.
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Affiliation(s)
- Yan-Na Lian
- Department of Psychiatry, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, China
- Key Laboratory of Medical Neurobiology of the Ministry of Health of China, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Xiao-Wen Cao
- Department of Psychiatry, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, China
- Key Laboratory of Medical Neurobiology of the Ministry of Health of China, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Cheng Wu
- Department of Psychiatry, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang, 314400, China
| | - Chen-Yu Pei
- Department of Psychiatry, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, China
- Key Laboratory of Medical Neurobiology of the Ministry of Health of China, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Li Liu
- Core Facilities of the School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Chen Zhang
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu, 210000, China.
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Laboratory of Oral Health, Capital Medical University, Beijing, 100069, China.
- Chinese Institute for Brain Research, Beijing, 102206, China.
| | - Xiang-Yao Li
- Department of Psychiatry, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, China.
- Key Laboratory of Medical Neurobiology of the Ministry of Health of China, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang, 314400, China.
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9
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Negishi K, Montes LP, Navarro VI, Arzate LS, Oliveros C, Khan AM. Topographic organization of bidirectional connections between the cingulate region (infralimbic area and anterior cingulate area, dorsal part) and the interbrain (diencephalon) of the adult male rat. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.29.615708. [PMID: 40093037 PMCID: PMC11908189 DOI: 10.1101/2024.09.29.615708] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
The medial prefrontal cortex [cingulate region (Brodmann, 1909) (CNG)] in the rat is a connectionally and functionally diverse structure. It harbors cerebral nuclei that use long-range connections to promote adaptive changes to ongoing behaviors. The CNG is often described across functional and anatomical gradients, a dorsalventral gradient being the most prominent. Topographic organization is a general feature of the nervous system, and it is becoming clear that such spatial arrangements can reflect connectional, functional, and cellular differences. Portions of the CNG are known to form reciprocal connections with cortical areas and thalamus; however, these connectional features have not been described in detail or mapped to standardized rat brain atlases. Here, we used co-injected anterograde (Phaseolus vulgaris leucoagglutinin) and retrograde (cholera toxin B subunit) tracers throughout the CNG to identify zones of reciprocal connectivity in the diencephalon [or interbrain (Baer, 1837) (IB)]. Tracer distributions were observed using a Nissl-based atlas-mapping approach that facilitates description of topographic organization. This draft report describes CNG connections of the infralimbic area (Rose & Woolsey, 1948) (ILA) and the anterior cingulate area, dorsal part (Krettek & Price, 1977) (ACAd) throughout the IB. We found that corticothalamic connections are predominantly reciprocal, and that ILA and ACAd connections tended to be spatially segregated with minimal overlap. In the hypothalamus (Kuhlenbeck, 1927), we found dense and specific ILA-originating terminals in the following Brain Maps 4.0 atlas territories: dorsal region (Swanson, 2004) (LHAd) and suprafornical region (Swanson, 2004) (LHAs) of the lateral hypothalamic area (Nissl, 1913), parasubthalamic nucleus (Wang & Zhang, 1995) (PSTN), tuberal nucleus, terete part (Petrovich et al., 2001) (TUte), and an ill-defined dorsal cap of the medial mammillary nucleus (Gudden, 1881) (MM). We discuss these findings in the context of feeding behaviors.
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Affiliation(s)
- Kenichiro Negishi
- UTEP Systems Neuroscience Laboratory, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
- Ph.D. Program in Bioscience, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
- Present address: Behavioral Neuroscience Branch, IRP/NIDA/NIH, Baltimore, MD 21224, USA
| | - Laura P Montes
- UTEP Systems Neuroscience Laboratory, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
- Ph.D. Program in Bioscience, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
| | - Vanessa I Navarro
- UTEP Systems Neuroscience Laboratory, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
- Ph.D. Program in Bioscience, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
| | - Lidice Soto Arzate
- UTEP Systems Neuroscience Laboratory, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
| | - Cindy Oliveros
- UTEP Systems Neuroscience Laboratory, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
- Undergraduate Baccalaureate Program in Nursing, College of Nursing, The University of Texas at El Paso, El Paso, Texas, 79968, USA
| | - Arshad M Khan
- UTEP Systems Neuroscience Laboratory, Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, 79968, USA
- Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, 79968, USA
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10
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Jaeckel ER, Arias-Hervert ER, Perez-Medina AL, Schulz S, Birdsong WT. Chronic morphine treatment induces sex- and synapse-specific cellular tolerance on thalamo-cortical mu opioid receptor signaling. J Neurophysiol 2024; 132:968-978. [PMID: 39110512 PMCID: PMC11427077 DOI: 10.1152/jn.00265.2024] [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: 06/24/2024] [Revised: 08/05/2024] [Accepted: 08/05/2024] [Indexed: 09/12/2024] Open
Abstract
How cellular adaptations give rise to opioid analgesic tolerance to opioids like morphine is not well understood. For one, pain is a complex phenomenon comprising both sensory and affective components, largely mediated through separate circuits. Glutamatergic projections from the medial thalamus (MThal) to the anterior cingulate cortex (ACC) are implicated in processing of affective pain, a relatively understudied component of the pain experience. The goal of this study was to determine the effects of chronic morphine exposure on mu-opioid receptor (MOR) signaling on MThal-ACC synaptic transmission within the excitatory and feedforward inhibitory pathways. Using whole cell patch-clamp electrophysiology and optogenetics to selectively target these projections, we measured morphine-mediated inhibition of optically evoked postsynaptic currents in ACC layer V pyramidal neurons in drug-naïve and chronically morphine-treated mice. We found that morphine perfusion inhibited the excitatory and feedforward inhibitory pathways similarly in females but caused greater inhibition of the inhibitory pathway in males. Chronic morphine treatment robustly attenuated morphine presynaptic inhibition within the inhibitory pathway in males, but not females, and mildly attenuated presynaptic inhibition within the excitatory pathway in both sexes. These effects were not observed in MOR phosphorylation-deficient mice. This study indicates that chronic morphine treatment induces cellular tolerance to morphine within a thalamo-cortical circuit relevant to pain and opioid analgesia. Furthermore, it suggests this tolerance may be driven by MOR phosphorylation. Overall, these findings improve our understanding of how chronic opioid exposure alters cellular signaling in ways that may contribute to opioid analgesic tolerance.NEW & NOTEWORTHY Opioid signaling within the anterior cingulate cortex (ACC) is important for opioid modulation of affective pain. Glutamatergic medial thalamus (MThal) neurons synapse in the ACC and opioids, acting through mu opioid receptors (MORs), acutely inhibit synaptic transmission from MThal synapses. However, the effect of chronic opioid exposure on MThal-ACC synaptic transmission is not known. Here, we demonstrate that chronic morphine treatment induces cellular tolerance at these synapses in a sex-specific and phosphorylation-dependent manner.
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Affiliation(s)
- Elizabeth R Jaeckel
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States
| | - Erwin R Arias-Hervert
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States
| | | | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - William T Birdsong
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States
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11
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Scott DN, Mukherjee A, Nassar MR, Halassa MM. Thalamocortical architectures for flexible cognition and efficient learning. Trends Cogn Sci 2024; 28:739-756. [PMID: 38886139 PMCID: PMC11305962 DOI: 10.1016/j.tics.2024.05.006] [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: 10/14/2023] [Revised: 05/12/2024] [Accepted: 05/13/2024] [Indexed: 06/20/2024]
Abstract
The brain exhibits a remarkable ability to learn and execute context-appropriate behaviors. How it achieves such flexibility, without sacrificing learning efficiency, is an important open question. Neuroscience, psychology, and engineering suggest that reusing and repurposing computations are part of the answer. Here, we review evidence that thalamocortical architectures may have evolved to facilitate these objectives of flexibility and efficiency by coordinating distributed computations. Recent work suggests that distributed prefrontal cortical networks compute with flexible codes, and that the mediodorsal thalamus provides regularization to promote efficient reuse. Thalamocortical interactions resemble hierarchical Bayesian computations, and their network implementation can be related to existing gating, synchronization, and hub theories of thalamic function. By reviewing recent findings and providing a novel synthesis, we highlight key research horizons integrating computation, cognition, and systems neuroscience.
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Affiliation(s)
- Daniel N Scott
- Department of Neuroscience, Brown University, Providence, RI, USA; Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI, USA.
| | - Arghya Mukherjee
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
| | - Matthew R Nassar
- Department of Neuroscience, Brown University, Providence, RI, USA; Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI, USA
| | - Michael M Halassa
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA; Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA.
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12
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Li J, Qin Y, Zhong Z, Meng L, Huang L, Li B. Pain experience reduces social avoidance to others in pain: a c-Fos-based functional connectivity network study in mice. Cereb Cortex 2024; 34:bhae207. [PMID: 38798004 DOI: 10.1093/cercor/bhae207] [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: 10/27/2023] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/29/2024] Open
Abstract
Pain experience increases individuals' perception and contagion of others' pain, but whether pain experience affects individuals' affiliative or antagonistic responses to others' pain is largely unknown. Additionally, the neural mechanisms underlying how pain experience modulates individuals' responses to others' pain remain unclear. In this study, we explored the effects of pain experience on individuals' responses to others' pain and the underlying neural mechanisms. By comparing locomotion, social, exploration, stereotyped, and anxiety-like behaviors of mice without any pain experience (naïve observers) and mice with a similar pain experience (experienced observers) when they observed the pain-free demonstrator with intraperitoneal injection of normal saline and the painful demonstrator with intraperitoneal injection of acetic acid, we found that pain experience of the observers led to decreased social avoidance to the painful demonstrator. Through whole-brain c-Fos quantification, we discovered that pain experience altered neuronal activity and enhanced functional connectivity in the mouse brain. The analysis of complex network and graph theory exhibited that functional connectivity networks and activated hub regions were altered by pain experience. Together, these findings reveal that neuronal activity and functional connectivity networks are involved in the modulation of individuals' responses to others' pain by pain experience.
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Affiliation(s)
- Jiali Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Neuroscience Program, Zhongshan School of Medicine and the Fifth Affiliated Hospital, Sun Yat-sen University, 74 Zhongshan Second Road, Yuexiu District, 510080 Guangzhou, China
| | - Yuxin Qin
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Neuroscience Program, Zhongshan School of Medicine and the Fifth Affiliated Hospital, Sun Yat-sen University, 74 Zhongshan Second Road, Yuexiu District, 510080 Guangzhou, China
| | - Zifeng Zhong
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Neuroscience Program, Zhongshan School of Medicine and the Fifth Affiliated Hospital, Sun Yat-sen University, 74 Zhongshan Second Road, Yuexiu District, 510080 Guangzhou, China
| | - Linjie Meng
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Neuroscience Program, Zhongshan School of Medicine and the Fifth Affiliated Hospital, Sun Yat-sen University, 74 Zhongshan Second Road, Yuexiu District, 510080 Guangzhou, China
| | - Lianyan Huang
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Neuroscience Program, Zhongshan School of Medicine and the Fifth Affiliated Hospital, Sun Yat-sen University, 74 Zhongshan Second Road, Yuexiu District, 510080 Guangzhou, China
| | - Boxing Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Neuroscience Program, Zhongshan School of Medicine and the Fifth Affiliated Hospital, Sun Yat-sen University, 74 Zhongshan Second Road, Yuexiu District, 510080 Guangzhou, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Second Road, Yuexiu District, 510080 Guangzhou, China
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13
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Lyuboslavsky P, Ordemann GJ, Kizimenko A, Brumback AC. Two contrasting mediodorsal thalamic circuits target the mouse medial prefrontal cortex. J Neurophysiol 2024; 131:876-890. [PMID: 38568510 PMCID: PMC11383385 DOI: 10.1152/jn.00456.2023] [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: 12/11/2023] [Revised: 02/28/2024] [Accepted: 03/17/2024] [Indexed: 05/09/2024] Open
Abstract
At the heart of the prefrontal network is the mediodorsal (MD) thalamus. Despite the importance of MD in a broad range of behaviors and neuropsychiatric disorders, little is known about the physiology of neurons in MD. We injected the retrograde tracer cholera toxin subunit B (CTB) into the medial prefrontal cortex (mPFC) of adult wild-type mice. We prepared acute brain slices and used current clamp electrophysiology to measure and compare the intrinsic properties of the neurons in MD that project to mPFC (MD→mPFC neurons). We show that MD→mPFC neurons are located predominantly in the medial (MD-M) and lateral (MD-L) subnuclei of MD. MD-L→mPFC neurons had shorter membrane time constants and lower membrane resistance than MD-M→mPFC neurons. Relatively increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity in MD-L neurons accounted for the difference in membrane resistance. MD-L neurons had a higher rheobase that resulted in less readily generated action potentials compared with MD-M→mPFC neurons. In both cell types, HCN channels supported generation of burst spiking. Increased HCN channel activity in MD-L neurons results in larger after-hyperpolarization potentials compared with MD-M neurons. These data demonstrate that the two populations of MD→mPFC neurons have divergent physiologies and support a differential role in thalamocortical information processing and potentially behavior.NEW & NOTEWORTHY To realize the potential of circuit-based therapies for psychiatric disorders that localize to the prefrontal network, we need to understand the properties of the populations of neurons that make up this network. The mediodorsal (MD) thalamus has garnered attention for its roles in executive functioning and social/emotional behaviors mediated, at least in part, by its projections to the medial prefrontal cortex (mPFC). Here, we identify and compare the physiology of the projection neurons in the two MD subnuclei that provide ascending inputs to mPFC in mice. Differences in intrinsic excitability between the two populations of neurons suggest that neuromodulation strategies targeting the prefrontal thalamocortical network will have differential effects on these two streams of thalamic input to mPFC.
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Affiliation(s)
- Polina Lyuboslavsky
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
| | - Gregory J Ordemann
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
| | - Alena Kizimenko
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
| | - Audrey C Brumback
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
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14
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Soto NN, Gaspar P, Bacci A. Not Just a Mood Disorder─Is Depression a Neurodevelopmental, Cognitive Disorder? Focus on Prefronto-Thalamic Circuits. ACS Chem Neurosci 2024; 15:1611-1618. [PMID: 38580316 PMCID: PMC11027097 DOI: 10.1021/acschemneuro.3c00828] [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: 12/20/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 04/07/2024] Open
Abstract
Depression is one of the most burdensome psychiatric disorders, affecting hundreds of millions of people worldwide. The disease is characterized not only by severe emotional and affective impairments, but also by disturbed vegetative and cognitive functions. Although many candidate mechanisms have been proposed to cause the disease, the pathophysiology of cognitive impairments in depression remains unclear. In this article, we aim to assess the link between cognitive alterations in depression and possible developmental changes in neuronal circuit wiring during critical periods of susceptibility. We review the existing literature and propose a role of serotonin signaling during development in shaping the functional states of prefrontal neuronal circuits and prefronto-thalamic loops. We discuss how early life insults affecting the serotonergic system could be important in the alterations of these local and long-range circuits, thus favoring the emergence of neurodevelopmental disorders, such as depression.
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Affiliation(s)
- Nina Nitzan Soto
- ICM−Paris
Brain Institute, CNRS, INSERM, Sorbonne
Université, 47 Boulevard de l’Hopital, 75013 Paris, France
| | - Patricia Gaspar
- ICM−Paris
Brain Institute, CNRS, INSERM, Sorbonne
Université, 47 Boulevard de l’Hopital, 75013 Paris, France
| | - Alberto Bacci
- ICM−Paris
Brain Institute, CNRS, INSERM, Sorbonne
Université, 47 Boulevard de l’Hopital, 75013 Paris, France
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15
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Wolff M, Halassa MM. The mediodorsal thalamus in executive control. Neuron 2024; 112:893-908. [PMID: 38295791 DOI: 10.1016/j.neuron.2024.01.002] [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: 09/01/2023] [Revised: 11/15/2023] [Accepted: 01/03/2024] [Indexed: 03/23/2024]
Abstract
Executive control, the ability to organize thoughts and action plans in real time, is a defining feature of higher cognition. Classical theories have emphasized cortical contributions to this process, but recent studies have reinvigorated interest in the role of the thalamus. Although it is well established that local thalamic damage diminishes cognitive capacity, such observations have been difficult to inform functional models. Recent progress in experimental techniques is beginning to enrich our understanding of the anatomical, physiological, and computational substrates underlying thalamic engagement in executive control. In this review, we discuss this progress and particularly focus on the mediodorsal thalamus, which regulates the activity within and across frontal cortical areas. We end with a synthesis that highlights frontal thalamocortical interactions in cognitive computations and discusses its functional implications in normal and pathological conditions.
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Affiliation(s)
- Mathieu Wolff
- University of Bordeaux, CNRS, INCIA, UMR 5287, 33000 Bordeaux, France.
| | - Michael M Halassa
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA; Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA.
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16
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Sohn J. Synaptic configuration and reconfiguration in the neocortex are spatiotemporally selective. Anat Sci Int 2024; 99:17-33. [PMID: 37837522 PMCID: PMC10771605 DOI: 10.1007/s12565-023-00743-5] [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] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/14/2023] [Indexed: 10/16/2023]
Abstract
Brain computation relies on the neural networks. Neurons extend the neurites such as dendrites and axons, and the contacts of these neurites that form chemical synapses are the biological basis of signal transmissions in the central nervous system. Individual neuronal outputs can influence the other neurons within the range of the axonal spread, while the activities of single neurons can be affected by the afferents in their somatodendritic fields. The morphological profile, therefore, binds the functional role each neuron can play. In addition, synaptic connectivity among neurons displays preference based on the characteristics of presynaptic and postsynaptic neurons. Here, the author reviews the "spatial" and "temporal" connection selectivity in the neocortex. The histological description of the neocortical circuitry depends primarily on the classification of cell types, and the development of gene engineering techniques allows the cell type-specific visualization of dendrites and axons as well as somata. Using genetic labeling of particular cell populations combined with immunohistochemistry and imaging at a subcellular spatial resolution, we revealed the "spatial selectivity" of cortical wirings in which synapses are non-uniformly distributed on the subcellular somatodendritic domains in a presynaptic cell type-specific manner. In addition, cortical synaptic dynamics in learning exhibit presynaptic cell type-dependent "temporal selectivity": corticocortical synapses appear only transiently during the learning phase, while learning-induced new thalamocortical synapses persist, indicating that distinct circuits may supervise learning-specific ephemeral synapse and memory-specific immortal synapse formation. The selectivity of spatial configuration and temporal reconfiguration in the neural circuitry may govern diverse functions in the neocortex.
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Affiliation(s)
- Jaerin Sohn
- Department of Systematic Anatomy and Neurobiology, Graduate School of Dentistry, Osaka University, Suita, Osaka, 565-0871, Japan.
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17
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Mengxing L, Lerma-Usabiaga G, Clascá F, Paz-Alonso PM. High-Resolution Tractography Protocol to Investigate the Pathways between Human Mediodorsal Thalamic Nucleus and Prefrontal Cortex. J Neurosci 2023; 43:7780-7798. [PMID: 37709539 PMCID: PMC10648582 DOI: 10.1523/jneurosci.0721-23.2023] [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: 04/23/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/16/2023] Open
Abstract
Animal studies have established that the mediodorsal nucleus (MD) of the thalamus is heavily and reciprocally connected with all areas of the prefrontal cortex (PFC). In humans, however, these connections are difficult to investigate. High-resolution imaging protocols capable of reliably tracing the axonal tracts linking the human MD with each of the PFC areas may thus be key to advance our understanding of the variation, development, and plastic changes of these important circuits, in health and disease. Here, we tested in adult female and male humans the reliability of a new reconstruction protocol based on in vivo diffusion MRI to trace, measure, and characterize the fiber tracts interconnecting the MD with 39 human PFC areas per hemisphere. Our protocol comprised the following three components: (1) defining regions of interest; (2) preprocessing diffusion data; and, (3) modeling white matter tracts and tractometry. This analysis revealed largely separate PFC territories of reciprocal MD-PFC tracts bearing striking resemblance with the topographic layout observed in macaque connection-tracing studies. We then examined whether our protocol could reliably reconstruct each of these MD-PFC tracts and their profiles across test and retest sessions. Results revealed that this protocol was able to trace and measure, in both left and right hemispheres, the trajectories of these 39 area-specific axon bundles with good-to-excellent test-retest reproducibility. This protocol, which has been made publicly available, may be relevant for cognitive neuroscience and clinical studies of normal and abnormal PFC function, development, and plasticity.SIGNIFICANCE STATEMENT Reciprocal MD-PFC interactions are critical for complex human cognition and learning. Reliably tracing, measuring and characterizing MD-PFC white matter tracts using high-resolution noninvasive methods is key to assess individual variation of these systems in humans. Here, we propose a high-resolution tractography protocol that reliably reconstructs 39 area-specific MD-PFC white matter tracts per hemisphere and quantifies structural information from diffusion MRI data. This protocol revealed a detailed mapping of thalamocortical and corticothalamic MD-PFC tracts in four different PFC territories (dorsal, medial, orbital/frontal pole, inferior frontal) showing structural connections resembling those observed in tracing studies with macaques. Furthermore, our automated protocol revealed high test-retest reproducibility and is made publicly available, constituting a step forward in mapping human MD-PFC circuits in clinical and academic research.
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Affiliation(s)
- Liu Mengxing
- Basque Center on Cognition, Brain and Language, 20009 Donostia-San Sebastián, Spain
| | - Garikoitz Lerma-Usabiaga
- Basque Center on Cognition, Brain and Language, 20009 Donostia-San Sebastián, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
| | - Francisco Clascá
- Department of Anatomy and Neuroscience, School of Medicine, Autónoma de Madrid University, 28029 Madrid, Spain
| | - Pedro M Paz-Alonso
- Basque Center on Cognition, Brain and Language, 20009 Donostia-San Sebastián, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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18
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Baratta MV, Seligman MEP, Maier SF. From helplessness to controllability: toward a neuroscience of resilience. Front Psychiatry 2023; 14:1170417. [PMID: 37229393 PMCID: PMC10205144 DOI: 10.3389/fpsyt.2023.1170417] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/13/2023] [Indexed: 05/27/2023] Open
Abstract
"Learned helplessness" refers to debilitating outcomes, such as passivity and increased fear, that follow an uncontrollable adverse event, but do not when that event is controllable. The original explanation argued that when events are uncontrollable the animal learns that outcomes are independent of its behavior, and that this is the active ingredient in producing the effects. Controllable adverse events, in contrast, fail to produce these outcomes because they lack the active uncontrollability element. Recent work on the neural basis of helplessness, however, takes the opposite view. Prolonged exposure to aversive stimulation per se produces the debilitation by potent activation of serotonergic neurons in the brainstem dorsal raphe nucleus. Debilitation is prevented with an instrumental controlling response, which activates prefrontal circuitry detecting control and subsequently blunting the dorsal raphe nucleus response. Furthermore, learning control alters the prefrontal response to future adverse events, thereby preventing debilitation and producing long-term resiliency. The general implications of these neuroscience findings may apply to psychological therapy and prevention, in particular by suggesting the importance of cognitions and control, rather than habits of control.
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Affiliation(s)
- Michael V. Baratta
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, United States
| | - Martin E. P. Seligman
- Positive Psychology Center, University of Pennsylvania, Philadelphia, PA, United States
| | - Steven F. Maier
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, United States
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19
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Heck DH, Fox MB, Correia Chapman B, McAfee SS, Liu Y. Cerebellar control of thalamocortical circuits for cognitive function: A review of pathways and a proposed mechanism. Front Syst Neurosci 2023; 17:1126508. [PMID: 37064161 PMCID: PMC10097962 DOI: 10.3389/fnsys.2023.1126508] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 03/13/2023] [Indexed: 04/18/2023] Open
Abstract
There is general agreement that cerebrocerebellar interactions via cerebellothalamocortical pathways are essential for a cerebellar cognitive and motor functions. Cerebellothalamic projections were long believed target mainly the ventral lateral (VL) and part of the ventral anterior (VA) nuclei, which project to cortical motor and premotor areas. Here we review new insights from detailed tracing studies, which show that projections from the cerebellum to the thalamus are widespread and reach almost every thalamic subnucleus, including nuclei involved in cognitive functions. These new insights into cerebellothalamic pathways beyond the motor thalamus are consistent with the increasing evidence of cerebellar cognitive function. However, the function of cerebellothalamic pathways and how they are involved in the various motor and cognitive functions of the cerebellum is still unknown. We briefly review literature on the role of the thalamus in coordinating the coherence of neuronal oscillations in the neocortex. The coherence of oscillations, which measures the stability of the phase relationship between two oscillations of the same frequency, is considered an indicator of increased functional connectivity between two structures showing coherent oscillations. Through thalamocortical interactions coherence patterns dynamically create and dissolve functional cerebral cortical networks in a task dependent manner. Finally, we review evidence for an involvement of the cerebellum in coordinating coherence of oscillations between cerebral cortical structures. We conclude that cerebellothalamic pathways provide the necessary anatomical substrate for a proposed role of the cerebellum in coordinating neuronal communication between cerebral cortical areas by coordinating the coherence of oscillations.
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Affiliation(s)
- Detlef H. Heck
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, United States
| | - Mia B. Fox
- Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Brittany Correia Chapman
- Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Samuel S. McAfee
- St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Yu Liu
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, United States
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20
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Frontera JL, Sala RW, Georgescu IA, Baba Aissa H, d'Almeida MN, Popa D, Léna C. The cerebellum regulates fear extinction through thalamo-prefrontal cortex interactions in male mice. Nat Commun 2023; 14:1508. [PMID: 36932068 PMCID: PMC10023697 DOI: 10.1038/s41467-023-36943-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 02/22/2023] [Indexed: 03/19/2023] Open
Abstract
Fear extinction is a form of inhibitory learning that suppresses the expression of aversive memories and plays a key role in the recovery of anxiety and trauma-related disorders. Here, using male mice, we identify a cerebello-thalamo-cortical pathway regulating fear extinction. The cerebellar fastigial nucleus (FN) projects to the lateral subregion of the mediodorsal thalamic nucleus (MD), which is reciprocally connected with the dorsomedial prefrontal cortex (dmPFC). The inhibition of FN inputs to MD in male mice impairs fear extinction in animals with high fear responses and increases the bursting of MD neurons, a firing pattern known to prevent extinction learning. Indeed, this MD bursting is followed by high levels of the dmPFC 4 Hz oscillations causally associated with fear responses during fear extinction, and the inhibition of FN-MD neurons increases the coherence of MD bursts and oscillations with dmPFC 4 Hz oscillations. Overall, these findings reveal a regulation of fear-related thalamo-cortical dynamics by the cerebellum and its contribution to fear extinction.
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Affiliation(s)
- Jimena L Frontera
- Neurophysiology of Brain Circuits Team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France
| | - Romain W Sala
- Neurophysiology of Brain Circuits Team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France
| | - Ioana A Georgescu
- Neurophysiology of Brain Circuits Team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France
| | - Hind Baba Aissa
- Neurophysiology of Brain Circuits Team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France
| | - Marion N d'Almeida
- Neurophysiology of Brain Circuits Team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France
| | - Daniela Popa
- Neurophysiology of Brain Circuits Team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France
| | - Clément Léna
- Neurophysiology of Brain Circuits Team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France.
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21
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Jaeckel ER, Arias-Hervert ER, Perez-Medina AL, Herrera YN, Schulz S, Birdsong WT. Chronic morphine induces adaptations in opioid receptor signaling in a thalamo-cortico-striatal circuit that are projection-dependent, sex-specific and regulated by mu opioid receptor phosphorylation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.13.528057. [PMID: 36824766 PMCID: PMC9949156 DOI: 10.1101/2023.02.13.528057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well-understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) and anterior cingulate cortex (ACC) via activity at μ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in both the DMS and ACC. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses, MThal-ACC synapses, and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation), but decreased subsequent morphine inhibition of transmission at MThal-ACC synapses (morphine tolerance) in a sex-specific manner; these adaptations were present in male but not female mice. Additionally, these adaptations were not observed in knockin mice expressing phosphorylation-deficient MORs, suggesting a role of MOR phosphorylation in mediating both facilitation and tolerance to morphine within this circuit. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry and sex.
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Affiliation(s)
| | | | | | - Yoani N. Herrera
- Department of Pharmacology, University of Michigan, Ann Arbor, MI
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
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22
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Parallel Pathways Provide Hippocampal Spatial Information to Prefrontal Cortex. J Neurosci 2023; 43:68-81. [PMID: 36414405 PMCID: PMC9838712 DOI: 10.1523/jneurosci.0846-22.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 10/06/2022] [Accepted: 11/07/2022] [Indexed: 11/23/2022] Open
Abstract
Long-range synaptic connections define how information flows through neuronal networks. Here, we combined retrograde and anterograde trans-synaptic viruses to delineate areas that exert direct and indirect influence over the dorsal and ventral prefrontal cortex (PFC) of the rat (both sexes). Notably, retrograde tracing using pseudorabies virus (PRV) revealed that both dorsal and ventral areas of the PFC receive prominent disynaptic input from the dorsal CA3 (dCA3) region of the hippocampus. The PRV experiments also identified candidate anatomical relays for this disynaptic pathway, namely, the ventral hippocampus, lateral septum, thalamus, amygdala, and basal forebrain. To determine the viability of each of these relays, we performed three additional experiments. In the first, we injected the retrograde monosynaptic tracer Fluoro-Gold into the PFC and the anterograde monosynaptic tracer Fluoro-Ruby into the dCA3 to confirm the first-order connecting areas and revealed several potential relay regions between the PFC and dCA3. In the second, we combined PRV injection in the PFC with polysynaptic anterograde viral tracer (HSV-1) in the dCA3 to reveal colabeled connecting neurons, which were evident only in the ventral hippocampus. In the third, we combined retrograde adeno-associated virus (AAV) injections in the PFC with an anterograde AAV in the dCA3 to reveal anatomical relay neurons in the ventral hippocampus and dorsal lateral septum. Together, these findings reveal parallel disynaptic pathways from the dCA3 to the PFC, illuminating a new anatomical framework for understanding hippocampal-prefrontal interactions. We suggest that the representation of context and space may be a universal feature of prefrontal function.SIGNIFICANCE STATEMENT The known functions of the prefrontal cortex are shaped by input from multiple brain areas. We used transneuronal viral tracing to discover multiple prominent disynaptic pathways through which the dorsal hippocampus (specifically, the dorsal CA3) has the potential to shape the actions of the prefrontal cortex. The demonstration of neuronal relays in the ventral hippocampus and lateral septum presents a new foundation for understanding long-range influences over prefrontal interactions, including the specific contribution of the dorsal CA3 to prefrontal function.
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23
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Banaei-Boroujeni G, Rezayof A, Alijanpour S, Nazari-Serenjeh F. Targeting mediodorsal thalamic CB1 receptors to inhibit dextromethorphan-induced anxiety/exploratory-related behaviors in rats: The post-weaning effect of exercise and enriched environment on adulthood anxiety. J Psychiatr Res 2023; 157:212-222. [PMID: 36495603 DOI: 10.1016/j.jpsychires.2022.11.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/08/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022]
Abstract
Dextromethorphan (DXM) is an effective over-the-counter antitussive with an alarming increase as an abused drug for recreational purposes. Although reports of the association between DXM administration and anxiety, there are few investigations into the underlying DMX mechanisms of anxiogenic action. Thus, the present study aimed to investigate the role of the mediodorsal thalamus (MD) cannabinoid CB1 receptors (CB1Rs) in DXM-induced anxiety/exploratory-related behaviors in adult male Wistar rats. Animals were bilaterally cannulated in the MD regions. After one week, anxiety and exploratory behaviors were measured using an elevated plus-maze task (EPM) and a hole-board apparatus. Results showed that DXM (3-7 mg/kg, i. p.) dose-dependently increased anxiety-like behaviors. Intra-MD administration of ACPA (2.5-10 ng/rat), a selective CB1 receptor agonist, decreased anxiety-like effects of DXM. The blockade of MD CB1 receptors by AM-251 (40-120 ng/rat) did not affect the EPM task. However, it potentiated the anxiogenic response of an ineffective dose of DXM (3 mg/kg) in the animals. Moreover, the effect of post-weaning treadmill exercise (TEX) and enriched environment (EE) were examined in adulthood anxiety under the drug treatments. Juvenile rats were divided into TEX/EE and control groups. The TEX/EE-juvenile rats were placed on a treadmill and then exposed to EE for five weeks. Interestingly, compared to untreated animals, post-weaning TEX/EE inhibited the anxiety induced by DXM or AM-251/DXM. It can be concluded that the MD endocannabinoid system plays an essential role in the anxiogenic effect of dextromethorphan. Moreover, post-weaning exercise alongside an enriched environment may have an inhibitory effect on adulthood anxiety-like behaviors.
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Affiliation(s)
- Golnoush Banaei-Boroujeni
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Ameneh Rezayof
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
| | - Sakineh Alijanpour
- Department of Biology, Faculty of Science, Gonbad Kavous University, Gonbad Kavous, Iran
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24
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Fredericksen KE, Samuelsen CL. Neural Representation of Intraoral Olfactory and Gustatory Signals by the Mediodorsal Thalamus in Alert Rats. J Neurosci 2022; 42:8136-8153. [PMID: 36171086 PMCID: PMC9636993 DOI: 10.1523/jneurosci.0674-22.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 11/21/2022] Open
Abstract
The mediodorsal thalamus is a multimodal region involved in a variety of cognitive behaviors, including olfactory attention, odor discrimination, and the hedonic perception of flavors. Although the mediodorsal thalamus forms connections with principal regions of the olfactory and gustatory networks, its role in processing olfactory and gustatory signals originating from the mouth remains unclear. Here, we recorded single-unit activity in the mediodorsal thalamus of behaving female rats during the intraoral delivery of individual odors, individual tastes, and odor-taste mixtures. Our results are the first to demonstrate that neurons in the mediodorsal thalamus dynamically encode chemosensory signals originating from the mouth. This chemoselective population is broadly tuned, exhibits excited and suppressed responses, and responds to odor-taste mixtures differently than an odor or taste alone. Furthermore, a subset of chemoselective neurons encodes the palatability-related features of tastes and may represent associations between previously experienced odor-taste pairs. Our results further demonstrate the multidimensionality of the mediodorsal thalamus and provide additional evidence of its involvement in processing chemosensory information important for ingestive behaviors.SIGNIFICANCE STATEMENT The perception of food relies on the concurrent processing of olfactory and gustatory signals originating from the mouth. The mediodorsal thalamus is a higher-order thalamic nucleus involved in a variety of chemosensory-dependent behaviors and connects the olfactory and gustatory cortices with the prefrontal cortex. However, it is unknown how neurons in the mediodorsal thalamus process intraoral chemosensory signals. Using tetrode recordings in alert rats, our results are the first to show that neurons in the mediodorsal thalamus dynamically represent olfactory and gustatory signals from the mouth. Our findings are consistent with the mediodorsal thalamus being a key node between sensory and prefrontal cortical areas for processing chemosensory information underlying ingestive behavior.
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Affiliation(s)
- Kelly E Fredericksen
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40292
| | - Chad L Samuelsen
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40292
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25
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The mediodorsal thalamus supports adaptive responding based on stimulus-outcome associations. CURRENT RESEARCH IN NEUROBIOLOGY 2022; 3:100057. [PMID: 36281274 PMCID: PMC9587292 DOI: 10.1016/j.crneur.2022.100057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/12/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
The ability to engage into flexible behaviors is crucial in dynamic environments. We recently showed that in addition to the well described role of the orbitofrontal cortex (OFC), its thalamic input from the submedius thalamic nucleus (Sub) also contributes to adaptive responding during Pavlovian degradation. In the present study, we examined the role of the mediodorsal thalamus (MD) which is the other main thalamic input to the OFC. To this end, we assessed the effect of both pre- and post-training MD lesions in rats performing a Pavlovian contingency degradation task. Pre-training lesions mildly impeded the establishment of stimulus-outcome associations during the initial training of Pavlovian conditioning without interfering with Pavlovian degradation training when the sensory feedback provided by the outcome rewards were available to animals. However, we found that both pre- and post-training MD lesions produced a selective impairment during a test conducted under extinction conditions, during which only current mental representation could guide behavior. Altogether, these data suggest a role for the MD in the successful encoding and representation of Pavlovian associations.
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26
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Transition of distinct context-dependent ensembles from secondary to primary motor cortex in skilled motor performance. Cell Rep 2022; 41:111494. [DOI: 10.1016/j.celrep.2022.111494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 06/27/2022] [Accepted: 09/21/2022] [Indexed: 11/19/2022] Open
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27
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Hummos A, Wang BA, Drammis S, Halassa MM, Pleger B. Thalamic regulation of frontal interactions in human cognitive flexibility. PLoS Comput Biol 2022; 18:e1010500. [PMID: 36094955 PMCID: PMC9499289 DOI: 10.1371/journal.pcbi.1010500] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 09/22/2022] [Accepted: 08/19/2022] [Indexed: 11/19/2022] Open
Abstract
Interactions across frontal cortex are critical for cognition. Animal studies suggest a role for mediodorsal thalamus (MD) in these interactions, but the computations performed and direct relevance to human decision making are unclear. Here, inspired by animal work, we extended a neural model of an executive frontal-MD network and trained it on a human decision-making task for which neuroimaging data were collected. Using a biologically-plausible learning rule, we found that the model MD thalamus compressed its cortical inputs (dorsolateral prefrontal cortex, dlPFC) underlying stimulus-response representations. Through direct feedback to dlPFC, this thalamic operation efficiently partitioned cortical activity patterns and enhanced task switching across different contingencies. To account for interactions with other frontal regions, we expanded the model to compute higher-order strategy signals outside dlPFC, and found that the MD offered a more efficient route for such signals to switch dlPFC activity patterns. Human fMRI data provided evidence that the MD engaged in feedback to dlPFC, and had a role in routing orbitofrontal cortex inputs when subjects switched behavioral strategy. Collectively, our findings contribute to the emerging evidence for thalamic regulation of frontal interactions in the human brain.
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Affiliation(s)
- Ali Hummos
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Bin A. Wang
- Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
- Collaborative Research Centre 874 "Integration and Representation of Sensory Processes", Ruhr University Bochum, Bochum, Germany
| | - Sabrina Drammis
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- Computer Science & Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Michael M. Halassa
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Burkhard Pleger
- Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
- Collaborative Research Centre 874 "Integration and Representation of Sensory Processes", Ruhr University Bochum, Bochum, Germany
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28
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Pathway-specific inhibition of critical projections from the mediodorsal thalamus to the frontal cortex controls kindled seizures. Prog Neurobiol 2022; 214:102286. [PMID: 35537572 DOI: 10.1016/j.pneurobio.2022.102286] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 04/22/2022] [Accepted: 05/04/2022] [Indexed: 02/07/2023]
Abstract
There is a large unmet need for improved treatment for temporal lobe epilepsy (TLE); circuit-specific manipulation that disrupts the initiation and propagation of seizures is promising in this regard. The midline thalamus, including the mediodorsal nucleus (MD) is a critical distributor of seizure activity, but its afferent and efferent pathways that mediate seizure activity are unknown. Here, we used chemogenetics to silence input and output projections of the MD to discrete regions of the frontal cortex in the kindling model of TLE in rats. Chemogenetic inhibition of the projection from the amygdala to the MD abolished seizures, an effect that was replicated using optogenetic inhibition. Chemogenetic inhibition of projections from the MD to the prelimbic cortex likewise abolished seizures. By contrast, inhibition of projections from the MD to other frontal regions produced partial (orbitofrontal cortex, infralimbic cortex) or no (cingulate, insular cortex) attenuation of behavioral or electrographic seizure activity. These results highlight the particular importance of projections from MD to prelimbic cortex in the propagation of amygdala-kindled seizures.
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29
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Ouhaz Z, Perry BAL, Nakamura K, Mitchell AS. Mediodorsal Thalamus Is Critical for Updating during Extradimensional Shifts But Not Reversals in the Attentional Set-Shifting Task. eNeuro 2022; 9:ENEURO.0162-21.2022. [PMID: 35105661 PMCID: PMC8906789 DOI: 10.1523/eneuro.0162-21.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 01/05/2022] [Accepted: 01/11/2022] [Indexed: 11/21/2022] Open
Abstract
Cognitive flexibility, attributed to frontal cortex, is vital for navigating the complexities of everyday life. The mediodorsal thalamus (MD), interconnected to frontal cortex, may influence cognitive flexibility. Here, male rats performed an attentional set-shifting task measuring intradimensional (ID) and extradimensional (ED) shifts in sensory discriminations. MD lesion rats needed more trials to learn the rewarded sensory dimension. However, once the choice response strategy was established, learning further two-choice discriminations in the same sensory dimension, and reversals of the reward contingencies in the same dimension, were unimpaired. Critically though, MD lesion rats were impaired during the ED shift, when they must rapidly update the optimal choice response strategy. Behavioral analyses showed MD lesion rats had significantly reduced correct within-trial second choice responses. This evidence shows that transfer of information via the MD is critical when rapid within-trial updates in established choice response strategies are required after a rule change.
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Affiliation(s)
- Zakaria Ouhaz
- Department of Experimental Psychology, University of Oxford, Oxford OX1 3SR, United Kingdom
- Institut Supérieur des Professions Infirmières et Techniques de la Santé, Marrakech 40000, Morocco
| | - Brook A L Perry
- Department of Experimental Psychology, University of Oxford, Oxford OX1 3SR, United Kingdom
| | - Kouichi Nakamura
- Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX1 3TH, United Kingdom
| | - Anna S Mitchell
- Department of Experimental Psychology, University of Oxford, Oxford OX1 3SR, United Kingdom
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30
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Roy DS, Zhang Y, Halassa MM, Feng G. Thalamic subnetworks as units of function. Nat Neurosci 2022; 25:140-153. [PMID: 35102334 PMCID: PMC9400132 DOI: 10.1038/s41593-021-00996-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 12/07/2021] [Indexed: 01/15/2023]
Abstract
The thalamus engages in various functions including sensory processing, attention, decision making and memory. Classically, this diversity of function has been attributed to the nuclear organization of the thalamus, with each nucleus performing a well-defined function. Here, we highlight recent studies that used state-of-the-art expression profiling, which have revealed gene expression gradients at the single-cell level within and across thalamic nuclei. These gradients, combined with anatomical tracing and physiological analyses, point to previously unappreciated heterogeneity and redefine thalamic units of function on the basis of unique input-output connectivity patterns and gene expression. We propose that thalamic subnetworks, defined by the intersection of genetics, connectivity and computation, provide a more appropriate level of functional description; this notion is supported by behavioral phenotypes resulting from appropriately tailored perturbations. We provide several examples of thalamic subnetworks and suggest how this new perspective may both propel progress in basic neuroscience and reveal unique targets with therapeutic potential.
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Affiliation(s)
- Dheeraj S Roy
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Ying Zhang
- Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, MIT, Cambridge, MA, USA
| | - Michael M Halassa
- Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, MIT, Cambridge, MA, USA
| | - Guoping Feng
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, MIT, Cambridge, MA, USA.
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31
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Jefferson T, Kelly CJ, Martina M. Differential Rearrangement of Excitatory Inputs to the Medial Prefrontal Cortex in Chronic Pain Models. Front Neural Circuits 2022; 15:791043. [PMID: 35002635 PMCID: PMC8738091 DOI: 10.3389/fncir.2021.791043] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/02/2021] [Indexed: 11/16/2022] Open
Abstract
Chronic pain patients suffer a disrupted quality of life not only from the experience of pain itself, but also from comorbid symptoms such as depression, anxiety, cognitive impairment, and sleep disturbances. The heterogeneity of these symptoms support the idea of a major involvement of the cerebral cortex in the chronic pain condition. Accordingly, abundant evidence shows that in chronic pain the activity of the medial prefrontal cortex (mPFC), a brain region that is critical for executive function and working memory, is severely impaired. Excitability of the mPFC depends on the integrated effects of intrinsic excitability and excitatory and inhibitory inputs. The main extracortical sources of excitatory input to the mPFC originate in the thalamus, hippocampus, and amygdala, which allow the mPFC to integrate multiple information streams necessary for cognitive control of pain including sensory information, context, and emotional salience. Recent techniques, such as optogenetic methods of circuit dissection, have made it possible to tease apart the contributions of individual circuit components. Here we review the synaptic properties of these main glutamatergic inputs to the rodent mPFC, how each is altered in animal models of chronic pain, and how these alterations contribute to pain-associated mPFC deactivation. By understanding the contributions of these individual circuit components, we strive to understand the broad spectrum of chronic pain and comorbid pathologies, how they are generated, and how they might be alleviated.
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Affiliation(s)
- Taylor Jefferson
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | | | - Marco Martina
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.,Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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32
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Rubio-Teves M, Díez-Hermano S, Porrero C, Sánchez-Jiménez A, Prensa L, Clascá F, García-Amado M, Villacorta-Atienza JA. Benchmarking of tools for axon length measurement in individually-labeled projection neurons. PLoS Comput Biol 2021; 17:e1009051. [PMID: 34879058 PMCID: PMC8824366 DOI: 10.1371/journal.pcbi.1009051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 02/08/2022] [Accepted: 11/19/2021] [Indexed: 11/18/2022] Open
Abstract
Projection neurons are the commonest neuronal type in the mammalian forebrain and their individual characterization is a crucial step to understand how neural circuitry operates. These cells have an axon whose arborizations extend over long distances, branching in complex patterns and/or in multiple brain regions. Axon length is a principal estimate of the functional impact of the neuron, as it directly correlates with the number of synapses formed by the axon in its target regions; however, its measurement by direct 3D axonal tracing is a slow and labor-intensive method. On the contrary, axon length estimations have been recently proposed as an effective and accessible alternative, allowing a fast approach to the functional significance of the single neuron. Here, we analyze the accuracy and efficiency of the most used length estimation tools—design-based stereology by virtual planes or spheres, and mathematical correction of the 2D projected-axon length—in contrast with direct measurement, to quantify individual axon length. To this end, we computationally simulated each tool, applied them over a dataset of 951 3D-reconstructed axons (from NeuroMorpho.org), and compared the generated length values with their 3D reconstruction counterparts. The evaluated reliability of each axon length estimation method was then balanced with the required human effort, experience and know-how, and economic affordability. Subsequently, computational results were contrasted with measurements performed on actual brain tissue sections. We show that the plane-based stereological method balances acceptable errors (~5%) with robustness to biases, whereas the projection-based method, despite its accuracy, is prone to inherent biases when implemented in the laboratory. This work, therefore, aims to provide a constructive benchmark to help guide the selection of the most efficient method for measuring specific axonal morphologies according to the particular circumstances of the conducted research. Characterization of single neurons is a crucial step to understand how neural circuitry operates. Visualization of individual neurons is feasible thanks to labelling techniques that allow precise measurements at cellular resolution. This milestone gave access to powerful estimators of the functional impact of a neuron, such as axon length. Although techniques relying on direct 3D reconstruction of individual axons are the gold standard, handiness and accessibility are still an issue. Indirect estimations of axon length have been proposed as agile and effective alternatives, each offering different solutions to the accuracy-cost tradeoff. In this work we report a computational benchmarking between three experimental tools used for axon length estimation on brain tissue sections. Performance of each tool was simulated and tested for 951 3D-reconstructed axons, by comparing estimated axon lengths against direct measurements. Assessment of suitability to different research and funding circumstances is also provided, taking into consideration factors such as training expertise, economic cost and required equipment, alongside methodological results. These findings could be an important reference for research on neuronal wiring, as well as for broader studies involving neuroanatomical and neural circuit modelling.
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Affiliation(s)
- Mario Rubio-Teves
- Department of Anatomy & Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain
| | - Sergio Díez-Hermano
- Department of Biodiversity, ecology and evolution, Biomathematics Unit, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
| | - César Porrero
- Department of Anatomy & Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain
| | - Abel Sánchez-Jiménez
- Department of Biodiversity, ecology and evolution, Biomathematics Unit, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
| | - Lucía Prensa
- Department of Anatomy & Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain
| | - Francisco Clascá
- Department of Anatomy & Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain
| | - María García-Amado
- Department of Anatomy & Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain
| | - José Antonio Villacorta-Atienza
- Department of Biodiversity, ecology and evolution, Biomathematics Unit, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
- * E-mail:
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Mercer Lindsay N, Chen C, Gilam G, Mackey S, Scherrer G. Brain circuits for pain and its treatment. Sci Transl Med 2021; 13:eabj7360. [PMID: 34757810 DOI: 10.1126/scitranslmed.abj7360] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Nicole Mercer Lindsay
- Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Department of Biology, CNC Program, Department of Applied Physics, Stanford University, Stanford, CA 94305, USA
| | - Chong Chen
- Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Gadi Gilam
- Division of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Sean Mackey
- Division of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Grégory Scherrer
- Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,New York Stem Cell Foundation-Robertson Investigator, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Ríos-Flórez JA, Lima RRM, Morais PLAG, de Medeiros HHA, Cavalcante JS, Junior ESN. Medial prefrontal cortex (A32 and A25) projections in the common marmoset: a subcortical anterograde study. Sci Rep 2021; 11:14565. [PMID: 34267273 PMCID: PMC8282874 DOI: 10.1038/s41598-021-93819-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 06/30/2021] [Indexed: 01/19/2023] Open
Abstract
This study was aimed at establishing the subcorticals substrates of the cognitive and visceromotor circuits of the A32 and A25 cortices of the medial prefrontal cortex and their projections and interactions with subcortical complexes in the common marmoset monkey (Callithrix jacchus). The study was primarily restricted to the nuclei of the diencephalon and amygdala. The common marmoset is a neotropical primate of the new world, and the absence of telencephalic gyrus favors the mapping of neuronal fibers. The biotinylated dextran amine was employed as an anterograde tracer. There was an evident pattern of rostrocaudal distribution of fibers within the subcortical nuclei, with medial orientation. Considering this distribution, fibers originating from the A25 cortex were found to be more clustered in the diencephalon and amygdala than those originating in the A32 cortex. Most areas of the amygdala received fibers from both cortices. In the diencephalon, all regions received projections from the A32, while the A25 fibers were restricted to the thalamus, hypothalamus, and epithalamus at different densities. Precise deposits of neuronal tracers provided here may significantly contribute to expand our understanding of specific connectivity among the medial prefrontal cortex with limbic regions and diencephalic areas, key elements to the viscerocognitive process.
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Affiliation(s)
- Jorge Alexander Ríos-Flórez
- Neuroanatomy Laboratory, Department of Morphology, Federal University of Rio Grande Do Norte, Natal, Brazil.
| | - Ruthnaldo R M Lima
- Neuroanatomy Laboratory, Department of Morphology, Federal University of Rio Grande Do Norte, Natal, Brazil
| | - Paulo Leonardo A G Morais
- Laboratory of Experimental Neurology, the University of the State of Rio Grande Do Norte, Mossoro, Brazil
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McCarty MJ, Brumback AC. Rethinking Stereotypies in Autism. Semin Pediatr Neurol 2021; 38:100897. [PMID: 34183141 PMCID: PMC8654322 DOI: 10.1016/j.spen.2021.100897] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/06/2021] [Accepted: 05/09/2021] [Indexed: 11/30/2022]
Abstract
Stereotyped movements ("stereotypies") are semi-voluntary repetitive movements that are a prominent clinical feature of autism spectrum disorder. They are described in first-person accounts by people with autism as relaxing and that they help focus the mind and cope in overwhelming sensory environments. Therefore, we generally recommend against techniques that aim to suppress stereotypies in individuals with autism. Further, we hypothesize that understanding the neurobiology of stereotypies could guide development of treatments to produce the benefits of stereotypies without the need to generate repetitive motor movements. Here, we link first-person reports and clinical findings with basic neuroanatomy and physiology to produce a testable model of stereotypies. We hypothesize that stereotypies improve sensory processing and attention by regulating brain rhythms, either directly from the rhythmic motor command, or via rhythmic sensory feedback generated by the movements.
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Perry BAL, Lomi E, Mitchell AS. Thalamocortical interactions in cognition and disease: the mediodorsal and anterior thalamic nuclei. Neurosci Biobehav Rev 2021; 130:162-177. [PMID: 34216651 DOI: 10.1016/j.neubiorev.2021.05.032] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 04/12/2021] [Accepted: 05/17/2021] [Indexed: 01/15/2023]
Abstract
The mediodorsal thalamus (MD) and anterior thalamic nuclei (ATN) are two adjacent brain nodes that support our ability to make decisions, learn, update information, form and retrieve memories, and find our way around. The MD and PFC work in partnerships to support cognitive processes linked to successful learning and decision-making, while the ATN and extended hippocampal system together coordinate the encoding and retrieval of memories and successful spatial navigation. Yet, while these distinctions may appear to be segregated, both the MD and ATN together support our higher cognitive functions as they regulate and are influenced by interconnected fronto-temporal neural networks and subcortical inputs. Our review focuses on recent studies in animal models and in humans. This evidence is re-shaping our understanding of the importance of MD and ATN cortico-thalamocortical pathways in influencing complex cognitive functions. Given the evidence from clinical settings and neuroscience research labs, the MD and ATN should be considered targets for effective treatments in neuropsychiatric diseases and disorders and neurodegeneration.
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Affiliation(s)
- Brook A L Perry
- Department of Experimental Psychology, Oxford University, The Tinsley Building, Mansfield Road, OX1 3SR, United Kingdom
| | - Eleonora Lomi
- Department of Experimental Psychology, Oxford University, The Tinsley Building, Mansfield Road, OX1 3SR, United Kingdom
| | - Anna S Mitchell
- Department of Experimental Psychology, Oxford University, The Tinsley Building, Mansfield Road, OX1 3SR, United Kingdom.
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Onishi K, Kikuchi SS, Abe T, Tokuhara T, Shimogori T. Molecular cell identities in the mediodorsal thalamus of infant mice and marmoset. J Comp Neurol 2021; 530:963-977. [PMID: 34184265 PMCID: PMC8714865 DOI: 10.1002/cne.25203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/21/2021] [Accepted: 06/24/2021] [Indexed: 11/10/2022]
Abstract
The mediodorsal thalamus (MD) is a higher-order nucleus located within the central thalamus in many mammalian species. Emerging evidence from MD lesions and tracer injections suggests that the MD is reciprocally connected to the prefrontal cortex (PFC) and plays an essential role in specific cognitive processes and tasks. MD subdivisions (medial, central, and lateral) are poorly segregated at the molecular level in rodents, leading to a lack of MD subdivision-specific Cre driver mice. Moreover, this lack of molecular identifiers hinders MD subdivision- and cell-type-specific circuit formation and function analysis. Therefore, using publicly available databases, we explored molecules separately expressed in MD subdivisions. In addition to MD subdivision markers, we identified several genes expressed in a subdivision-specific combination and classified them. Furthermore, after developing medial MD (MDm) or central MD (MDc) region-specific Cre mouse lines, we identified diverse region- and layer-specific PFC projection patterns. Comparison between classified MD marker genes in mice and common marmosets, a nonhuman primate model, revealed diverging gene expression patterns. These results highlight the species-specific organization of cell types and their projections in the MD thalamus.
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Affiliation(s)
- Kohei Onishi
- Laboratory for Molecular Mechanisms of Brain Development, Center for Brain Science (CBS), RIKEN, Wako, Saitama, Japan
| | - Satomi S Kikuchi
- Laboratory for Molecular Mechanisms of Brain Development, Center for Brain Science (CBS), RIKEN, Wako, Saitama, Japan
| | - Takaya Abe
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research (BDR), Chuou-ku, Kobe, Japan
| | - Tomoko Tokuhara
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research (BDR), Chuou-ku, Kobe, Japan
| | - Tomomi Shimogori
- Laboratory for Molecular Mechanisms of Brain Development, Center for Brain Science (CBS), RIKEN, Wako, Saitama, Japan
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Ito T, Ono M, Matsui R, Watanabe D, Ohmori H. Avian adeno-associated virus as an anterograde transsynaptic vector. J Neurosci Methods 2021; 359:109221. [PMID: 34004203 DOI: 10.1016/j.jneumeth.2021.109221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/06/2021] [Accepted: 05/09/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Retrograde and anterograde transsynaptic viral vectors are useful tools for studying the input and output organization of neuronal circuitry, respectively. While retrograde transsynaptic viral vectors are widely used, viral vectors that show anterograde transsynaptic transduction are not common. NEW METHOD We chose recombinant avian adeno-associated virus (A3V) carrying the mCherry gene and injected it into the eyeball, cochlear duct, and midbrain auditory center of chickens. We observed different survival times to examine the virus transcellular transport and the resulting mCherry expression. To confirm the transcellular transduction mode, we co-injected A3V and cholera toxin B subunit. RESULTS Injecting A3V into the eyeball and cochlea labeled neurons in the visual and auditory pathways, respectively. Second-, and third-order labeling occurred approximately two and seven days, respectively, after injection into the midbrain. The distribution of labeled neurons strongly suggests that A3V transport is preferentially anterograde and transduces postsynaptic neurons. COMPARISON WITH EXISTING METHOD(S) A3V displays no extrasynaptic leakage and moderate speed of synapse passage, which is better than other viruses previously reported. Compared with AAV1&9, which have been shown to pass one synapse anterogradely, A3V passes several synapses in the anterograde direction. CONCLUSIONS A3V would be a good tool to study the topographic organization of projection axons and their target neurons.
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Affiliation(s)
- Tetsufumi Ito
- Systems Function and Morphology Laboratory, Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan.
| | - Munenori Ono
- Department of Physiology, School of Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Ryosuke Matsui
- Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Dai Watanabe
- Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Harunori Ohmori
- Department of Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Untangling the cortico-thalamo-cortical loop: cellular pieces of a knotty circuit puzzle. Nat Rev Neurosci 2021; 22:389-406. [PMID: 33958775 DOI: 10.1038/s41583-021-00459-3] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2021] [Indexed: 12/22/2022]
Abstract
Functions of the neocortex depend on its bidirectional communication with the thalamus, via cortico-thalamo-cortical (CTC) loops. Recent work dissecting the synaptic connectivity in these loops is generating a clearer picture of their cellular organization. Here, we review findings across sensory, motor and cognitive areas, focusing on patterns of cell type-specific synaptic connections between the major types of cortical and thalamic neurons. We outline simple and complex CTC loops, and note features of these loops that appear to be general versus specialized. CTC loops are tightly interlinked with local cortical and corticocortical (CC) circuits, forming extended chains of loops that are probably critical for communication across hierarchically organized cerebral networks. Such CTC-CC loop chains appear to constitute a modular unit of organization, serving as scaffolding for area-specific structural and functional modifications. Inhibitory neurons and circuits are embedded throughout CTC loops, shaping the flow of excitation. We consider recent findings in the context of established CTC and CC circuit models, and highlight current efforts to pinpoint cell type-specific mechanisms in CTC loops involved in consciousness and perception. As pieces of the connectivity puzzle fall increasingly into place, this knowledge can guide further efforts to understand structure-function relationships in CTC loops.
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Mair RG, Francoeur MJ, Gibson BM. Central Thalamic-Medial Prefrontal Control of Adaptive Responding in the Rat: Many Players in the Chamber. Front Behav Neurosci 2021; 15:642204. [PMID: 33897387 PMCID: PMC8060444 DOI: 10.3389/fnbeh.2021.642204] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/08/2021] [Indexed: 11/13/2022] Open
Abstract
The medial prefrontal cortex (mPFC) has robust afferent and efferent connections with multiple nuclei clustered in the central thalamus. These nuclei are elements in large-scale networks linking mPFC with the hippocampus, basal ganglia, amygdala, other cortical areas, and visceral and arousal systems in the brainstem that give rise to adaptive goal-directed behavior. Lesions of the mediodorsal nucleus (MD), the main source of thalamic input to middle layers of PFC, have limited effects on delayed conditional discriminations, like DMTP and DNMTP, that depend on mPFC. Recent evidence suggests that MD sustains and amplifies neuronal responses in mPFC that represent salient task-related information and is important for detecting and encoding contingencies between actions and their consequences. Lesions of rostral intralaminar (rIL) and ventromedial (VM) nuclei produce delay-independent impairments of egocentric DMTP and DNMTP that resemble effects of mPFC lesions on response speed and accuracy: results consistent with projections of rIL to striatum and VM to motor cortices. The ventral midline and anterior thalamic nuclei affect allocentric spatial cognition and memory consistent with their connections to mPFC and hippocampus. The dorsal midline nuclei spare DMTP and DNMTP. They have been implicated in behavioral-state control and response to salient stimuli in associative learning. mPFC functions are served during DNMTP by discrete populations of neurons with responses related to motor preparation, movements, lever press responses, reinforcement anticipation, reinforcement delivery, and memory delay. Population analyses show that different responses are timed so that they effectively tile the temporal interval from when DNMTP trials are initiated until the end. Event-related responses of MD neurons during DNMTP are predominantly related to movement and reinforcement, information important for DNMTP choice. These responses closely mirror the activity of mPFC neurons with similar responses. Pharmacological inactivation of MD and adjacent rIL affects the expression of diverse action- and outcome-related responses of mPFC neurons. Lesions of MD before training are associated with a shift away from movement-related responses in mPFC important for DNMTP choice. These results suggest that MD has short-term effects on the expression of event-related activity in mPFC and long-term effects that tune mPFC neurons to respond to task-specific information.
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Affiliation(s)
- Robert G Mair
- Department of Psychology, University of New Hampshire, Durham, NH, United States
| | - Miranda J Francoeur
- Department of Psychology, University of New Hampshire, Durham, NH, United States.,Neural Engineering and Translation Lab, University of California, San Diego, San Diego, CA, United States
| | - Brett M Gibson
- Department of Psychology, University of New Hampshire, Durham, NH, United States
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Schuman B, Dellal S, Prönneke A, Machold R, Rudy B. Neocortical Layer 1: An Elegant Solution to Top-Down and Bottom-Up Integration. Annu Rev Neurosci 2021; 44:221-252. [PMID: 33730511 DOI: 10.1146/annurev-neuro-100520-012117] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Many of our daily activities, such as riding a bike to work or reading a book in a noisy cafe, and highly skilled activities, such as a professional playing a tennis match or a violin concerto, depend upon the ability of the brain to quickly make moment-to-moment adjustments to our behavior in response to the results of our actions. Particularly, they depend upon the ability of the neocortex to integrate the information provided by the sensory organs (bottom-up information) with internally generated signals such as expectations or attentional signals (top-down information). This integration occurs in pyramidal cells (PCs) and their long apical dendrite, which branches extensively into a dendritic tuft in layer 1 (L1). The outermost layer of the neocortex, L1 is highly conserved across cortical areas and species. Importantly, L1 is the predominant input layer for top-down information, relayed by a rich, dense mesh of long-range projections that provide signals to the tuft branches of the PCs. Here, we discuss recent progress in our understanding of the composition of L1 and review evidence that L1 processing contributes to functions such as sensory perception, cross-modal integration, controlling states of consciousness, attention, and learning.
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Affiliation(s)
- Benjamin Schuman
- Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA;
| | - Shlomo Dellal
- Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA;
| | - Alvar Prönneke
- Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA;
| | - Robert Machold
- Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA;
| | - Bernardo Rudy
- Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA; .,Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University School of Medicine, New York, NY 10016, USA
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Zhou K, Zhu L, Hou G, Chen X, Chen B, Yang C, Zhu Y. The Contribution of Thalamic Nuclei in Salience Processing. Front Behav Neurosci 2021; 15:634618. [PMID: 33664657 PMCID: PMC7920982 DOI: 10.3389/fnbeh.2021.634618] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/11/2021] [Indexed: 12/13/2022] Open
Abstract
The brain continuously receives diverse information about the external environment and changes in the homeostatic state. The attribution of salience determines which stimuli capture attention and, therefore, plays an essential role in regulating emotions and guiding behaviors. Although the thalamus is included in the salience network, the neural mechanism of how the thalamus contributes to salience processing remains elusive. In this mini-review, we will focus on recent advances in understanding the specific roles of distinct thalamic nuclei in salience processing. We will summarize the functional connections between thalamus nuclei and other key nodes in the salience network. We will highlight the convergence of neural circuits involved in reward and pain processing, arousal, and attention control in thalamic structures. We will discuss how thalamic activities represent salience information in associative learning and how thalamic neurons modulate adaptive behaviors. Lastly, we will review recent studies which investigate the contribution of thalamic dysfunction to aberrant salience processing in neuropsychiatric disorders, such as drug addiction, posttraumatic stress disorder (PTSD), and schizophrenia. Based on emerging evidence from both human and rodent research, we propose that the thalamus, different from previous studies that as an information relay, has a broader role in coordinating the cognitive process and regulating emotions.
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Affiliation(s)
- Kuikui Zhou
- Shenzhen Key Laboratory of Drug Addiction, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China
| | - Lin Zhu
- Department of Neonatology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Guoqiang Hou
- Shenzhen Key Laboratory of Drug Addiction, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China
| | - Xueyu Chen
- Department of Neonatology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Bo Chen
- Shenzhen Key Laboratory of Drug Addiction, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China
| | - Chuanzhong Yang
- Department of Neonatology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Yingjie Zhu
- Shenzhen Key Laboratory of Drug Addiction, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China
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Nadeau SE. Basal Ganglia and Thalamic Contributions to Language Function: Insights from A Parallel Distributed Processing Perspective. Neuropsychol Rev 2021; 31:495-515. [PMID: 33512608 DOI: 10.1007/s11065-020-09466-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 11/10/2020] [Indexed: 11/25/2022]
Abstract
Cerebral representations are encoded as patterns of activity involving billions of neurons. Parallel distributed processing (PDP) across these neuronal populations provides the basis for a number of emergent properties: 1) processing occurs and knowledge (long term memories) is stored (as synaptic connection strengths) in exactly the same networks; 2) networks have the capacity for setting into stable attractor states corresponding to concepts, symbols, implicit rules, or data transformations; 3) networks provide the scaffold for the acquisition of knowledge but knowledge is acquired through experience; 4) PDP networks are adept at incorporating the statistical regularities of experience as well as frequency and age of acquisition effects; 5) networks enable content-addressable memory; 6) because knowledge is distributed throughout networks, they exhibit the property of graceful degradation; 7) networks intrinsically provide the capacity for inference. This paper details the features of the basal ganglia and thalamic systems (recurrent and distributed connectivity) that support PDP. The PDP lens and an understanding of the attractor trench dynamics of the basal ganglia provide a natural explanation for the peculiar dysfunctions of Parkinson's disease and the mechanisms by which dopamine deficiency is causal. The PDP lens, coupled with the fact that the basal ganglia of humans bears strong homology to the basal ganglia of lampreys and the central complex of arthropods, reveals that the fundamental function of the basal ganglia is computational and involves the reduction of the vast dimensionality of a complex multi-dimensional array of sensorimotor input into the optimal choice from a small repertoire of behavioral options - the essence of reactive intention (automatic responses to sensory input). There is strong evidence that the sensorimotor basal ganglia make no contributions to cognitive or motor function in humans but can cause serious dysfunction when pathological. It appears that humans, through the course of evolution, have developed cortical capacities (working memory and volitional and reactive attention) for managing sensory input, however complex, that obviate the need for the basal ganglia. The functions of the dorsal tier thalamus, however, even viewed with an understanding of the properties of population encoded representations, remain somewhat more obscure. Possibilities include the enabling of attractor state constellations that optimize function by taking advantage of simultaneous input from multiple cortical areas; selective engagement of cortical representations; and support of the gamma frequency synchrony that enables binding of the multiple network representations that comprise a full concept representation.
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Affiliation(s)
- Stephen E Nadeau
- Research Service and the Brain Rehabilitation Research Center, Malcom Randall VA Medical Center and the Department of Neurology, University of Florida College of Medicine, 1601 SW Archer Road, Gainesville, FL, 32608-1197, US.
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Anastasiades PG, Collins DP, Carter AG. Mediodorsal and Ventromedial Thalamus Engage Distinct L1 Circuits in the Prefrontal Cortex. Neuron 2021; 109:314-330.e4. [PMID: 33188733 PMCID: PMC7855187 DOI: 10.1016/j.neuron.2020.10.031] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 09/03/2020] [Accepted: 10/26/2020] [Indexed: 11/25/2022]
Abstract
Interactions between the thalamus and prefrontal cortex (PFC) play a critical role in cognitive function and arousal. Here, we use anatomical tracing, electrophysiology, optogenetics, and 2-photon Ca2+ imaging to determine how ventromedial (VM) and mediodorsal (MD) thalamus target specific cell types and subcellular compartments in layer 1 (L1) of mouse PFC. We find thalamic inputs make distinct connections in L1, where VM engages neuron-derived neurotrophic factor (NDNF+) cells in L1a and MD drives vasoactive intestinal peptide (VIP+) cells in L1b. These separate populations of L1 interneurons participate in different inhibitory networks in superficial layers by targeting either parvalbumin (PV+) or somatostatin (SOM+) interneurons. NDNF+ cells also inhibit the apical dendrites of L5 pyramidal tract (PT) cells to suppress action potential (AP)-evoked Ca2+ signals. Lastly, NDNF+ cells mediate a unique form of thalamus-evoked inhibition at PT cells, selectively blocking VM-evoked dendritic Ca2+ spikes. Together, our findings reveal how two thalamic nuclei differentially communicate with the PFC through distinct L1 micro-circuits.
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Affiliation(s)
- Paul G Anastasiades
- Center for Neural Science, New York University, 4 Washington Place, New York, NY 10003, USA
| | - David P Collins
- Center for Neural Science, New York University, 4 Washington Place, New York, NY 10003, USA
| | - Adam G Carter
- Center for Neural Science, New York University, 4 Washington Place, New York, NY 10003, USA.
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Wolff M, Morceau S, Folkard R, Martin-Cortecero J, Groh A. A thalamic bridge from sensory perception to cognition. Neurosci Biobehav Rev 2021; 120:222-235. [PMID: 33246018 DOI: 10.1016/j.neubiorev.2020.11.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 10/07/2020] [Accepted: 11/02/2020] [Indexed: 12/13/2022]
Abstract
The ability to adapt to dynamic environments requires tracking multiple signals with variable sensory salience and fluctuating behavioral relevance. This complex process requires integrative crosstalk between sensory and cognitive brain circuits. Functional interactions between cortical and thalamic regions are now considered essential for both sensory perception and cognition but a clear account of the functional link between sensory and cognitive circuits is currently lacking. This review aims to document how thalamic nuclei may effectively act as a bridge allowing to fuse perceptual and cognitive events into meaningful experiences. After highlighting key aspects of thalamocortical circuits such as the classic first-order/higher-order dichotomy, we consider the role of the thalamic reticular nucleus from directed attention to cognition. We next summarize research relying on Pavlovian learning paradigms, showing that both first-order and higher-order thalamic nuclei contribute to associative learning. Finally, we propose that modulator inputs reaching all thalamic nuclei may be critical for integrative purposes when environmental signals are computed. Altogether, the thalamus appears as the bridge linking perception, cognition and possibly affect.
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Affiliation(s)
- M Wolff
- CNRS, INCIA, UMR 5287, Bordeaux, France; University of Bordeaux, INCIA, UMR 5287, Bordeaux, France.
| | - S Morceau
- CNRS, INCIA, UMR 5287, Bordeaux, France; University of Bordeaux, INCIA, UMR 5287, Bordeaux, France
| | - R Folkard
- Institute of Physiology and Pathophysiology, Medical Biophysics, Heidelberg University, INF 326, 69120, Heidelberg, Germany
| | - J Martin-Cortecero
- Institute of Physiology and Pathophysiology, Medical Biophysics, Heidelberg University, INF 326, 69120, Heidelberg, Germany
| | - A Groh
- Institute of Physiology and Pathophysiology, Medical Biophysics, Heidelberg University, INF 326, 69120, Heidelberg, Germany
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Mukherjee A, Bajwa N, Lam NH, Porrero C, Clasca F, Halassa MM. Variation of connectivity across exemplar sensory and associative thalamocortical loops in the mouse. eLife 2020; 9:e62554. [PMID: 33103997 PMCID: PMC7644223 DOI: 10.7554/elife.62554] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/23/2020] [Indexed: 12/22/2022] Open
Abstract
The thalamus engages in sensation, action, and cognition, but the structure underlying these functions is poorly understood. Thalamic innervation of associative cortex targets several interneuron types, modulating dynamics and influencing plasticity. Is this structure-function relationship distinct from that of sensory thalamocortical systems? Here, we systematically compared function and structure across a sensory and an associative thalamocortical loop in the mouse. Enhancing excitability of mediodorsal thalamus, an associative structure, resulted in prefrontal activity dominated by inhibition. Equivalent enhancement of medial geniculate excitability robustly drove auditory cortical excitation. Structurally, geniculate axons innervated excitatory cortical targets in a preferential manner and with larger synaptic terminals, providing a putative explanation for functional divergence. The two thalamic circuits also had distinct input patterns, with mediodorsal thalamus receiving innervation from a diverse set of cortical areas. Altogether, our findings contribute to the emerging view of functional diversity across thalamic microcircuits and its structural basis.
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Affiliation(s)
- Arghya Mukherjee
- McGovern Institute for Brain ResearchCambridgeUnited States
- Department of Brain and Cognitive Sciences, Massachusetts Institute of TechnologyCambridgeUnited States
| | - Navdeep Bajwa
- McGovern Institute for Brain ResearchCambridgeUnited States
- Department of Brain and Cognitive Sciences, Massachusetts Institute of TechnologyCambridgeUnited States
| | - Norman H Lam
- McGovern Institute for Brain ResearchCambridgeUnited States
- Department of Brain and Cognitive Sciences, Massachusetts Institute of TechnologyCambridgeUnited States
| | - César Porrero
- Department of Anatomy and Neuroscience, School of Medicine, Autónoma de Madrid UniversityMadridSpain
| | - Francisco Clasca
- Department of Anatomy and Neuroscience, School of Medicine, Autónoma de Madrid UniversityMadridSpain
| | - Michael M Halassa
- McGovern Institute for Brain ResearchCambridgeUnited States
- Department of Brain and Cognitive Sciences, Massachusetts Institute of TechnologyCambridgeUnited States
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Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions. Int J Mol Sci 2020; 21:ijms21217951. [PMID: 33114753 PMCID: PMC7662754 DOI: 10.3390/ijms21217951] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/19/2020] [Accepted: 10/23/2020] [Indexed: 02/08/2023] Open
Abstract
Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.
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Fujita H, Kodama T, du Lac S. Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis. eLife 2020; 9:e58613. [PMID: 32639229 PMCID: PMC7438114 DOI: 10.7554/elife.58613] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions could be mediated by modular synaptic connections of distinct fastigial cell types with posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.
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Affiliation(s)
- Hirofumi Fujita
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins UniversityBaltimoreUnited States
| | - Takashi Kodama
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins UniversityBaltimoreUnited States
| | - Sascha du Lac
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins UniversityBaltimoreUnited States
- Department of Neuroscience, Johns Hopkins UniversityBaltimoreUnited States
- Department of Neurology, Johns Hopkins Medical InstituteBaltimoreUnited States
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Aoki S, Coulon P, Ruigrok TJH. Multizonal Cerebellar Influence Over Sensorimotor Areas of the Rat Cerebral Cortex. Cereb Cortex 2020; 29:598-614. [PMID: 29300895 DOI: 10.1093/cercor/bhx343] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 12/04/2017] [Indexed: 12/13/2022] Open
Abstract
The cerebral cortex requires cerebellar input for optimizing sensorimotor processing. However, how the sensorimotor cortex uses cerebellar information is far from understood. One critical and unanswered question is how cerebellar functional entities (zones or modules) are connected to distinct parts of the sensorimotor cortices. Here, we utilized retrograde transneuronal infection of rabies virus (RABV) to study the organization of connections from the cerebellar cortex to M1, M2, and S1 of the rat cerebral cortex. RABV was co-injected with cholera toxin β-subunit (CTb) into each of these cortical regions and a survival time of 66-70 h allowed for third-order retrograde RABV infection of Purkinje cells. CTb served to identify the injection site. RABV+ Purkinje cells throughout cerebellar zones were identified by reference to the cerebellar zebrin pattern. All injections, including those into S1, resulted in multiple, zonally arranged, strips of RABV+ Purkinje cells. M1 injections were characterized by input from Purkinje cells in the vermal X-zone, medial paravermis (C1- and Cx-zones), and lateral hemisphere (D2-zone); M2 receives input from D2- and C3-zones; connections to S1 originate from X-, Cx-, C3-, and D2-zones. We hypothesize that individual domains of the sensorimotor cortex require information from a specific combination of cerebellar modules.
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Affiliation(s)
- Sho Aoki
- Department of Neuroscience, Erasmus MC, Rotterdam, the Netherlands.,Present address: Neurobiology Research Unit, Okinawa Institute of Science and Technology, Okinawa, Japan
| | - Patrice Coulon
- Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université, Marseille, France
| | - Tom J H Ruigrok
- Department of Neuroscience, Erasmus MC, Rotterdam, the Netherlands
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50
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Halassa MM, Sherman SM. Thalamocortical Circuit Motifs: A General Framework. Neuron 2020; 103:762-770. [PMID: 31487527 DOI: 10.1016/j.neuron.2019.06.005] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/28/2019] [Accepted: 06/11/2019] [Indexed: 12/13/2022]
Abstract
The role of the thalamus in cortical sensory transmission is well known, but its broader role in cognition is less appreciated. Recent studies have shown thalamic engagement in dynamic regulation of cortical activity in attention, executive control, and perceptual decision-making, but the circuit mechanisms underlying such functionality are unknown. Because the thalamus is composed of excitatory neurons that are devoid of local recurrent excitatory connectivity, delineating long-range, input-output connectivity patterns of single thalamic neurons is critical for building functional models. We discuss this need in relation to existing organizational schemes such as core versus matrix and first-order versus higher-order relay nuclei. We propose that a new classification is needed based on thalamocortical motifs, where structure naturally informs function. Overall, our synthesis puts understanding thalamic organization at the forefront of existing research in systems and computational neuroscience, with both basic and translational applications.
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Affiliation(s)
- Michael M Halassa
- Department of Brain and Cognitive Science and the McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - S Murray Sherman
- Department of Neurobiology, University of Chicago School of Medicine, Chicago, IL, USA.
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