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Kaur J, Komi SA, Dmytriyeva O, Houser GA, Bonfils MCA, Berg RW. Pedunculopontine-stimulation obstructs hippocampal theta rhythm and halts movement. Sci Rep 2025; 15:17903. [PMID: 40410186 PMCID: PMC12102179 DOI: 10.1038/s41598-025-01695-8] [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: 02/01/2025] [Accepted: 05/07/2025] [Indexed: 05/25/2025] Open
Abstract
While the movement of rodents can be paused by optogenetic stimulation of a brainstem nucleus, the pedunculopontine nucleus (PPN), it is unknown whether this response has a functional purpose. The arrest appears conspicuously similar to fear-induced freezing behavior and could constitute a general halting mechanism for movement without an emotional component. Further, it is unclear to what extent brain activity is affected by the evoked motor arrest. Here, we investigate this phenomenon by engaging a distinct brain activity, the hippocampal theta rhythm. The theta rhythm is prominent during locomotor activity, absent under normal immobile situations, yet present under vigilant states like fear-induced freezing. Specifically, we ask whether the PPN-induced motor arrest has the same effect on the theta rhythm as if the animal would perform a volitional arrest, which results in the disappearance of the theta rhythm, or whether it would cause a continuation of the theta rhythm as would be expected by a fear-induced motor arrest. An alternative hypothesis is that the theta rhythm represents an ongoing intention to move rather than the movement itself. To distinguish between these two possibilities, we recorded the hippocampal brain rhythm before and during movement arrest induced by optogenetic stimulation of the PPN in rats. The PPN-induced motor arrest was associated with a clear obstruction of the ongoing theta activity. The timescale of movement arrest was less than 200 ms, similar to the obstruction of the theta rhythm. Since fear and behavioral freezing are associated with hippocampal theta rhythm, which we did not see during PPN stimulation, we suggest that induced motor arrest occurs without an associated emotional component. Further, our experiments reveal that the theta rhythm during motor activity does not represent an intention, but rather the ongoing sensory-motor state.
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Affiliation(s)
- Jaspreet Kaur
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark
| | - Salif A Komi
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark
| | - Oksana Dmytriyeva
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Grace A Houser
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark
| | - Madelaine C A Bonfils
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark
| | - Rune W Berg
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
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2
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Beaver ML, Evans RC. Muscarinic Receptor Activation Preferentially Inhibits Rebound in Vulnerable Dopaminergic Neurons. J Neurosci 2025; 45:e1443242025. [PMID: 40000233 PMCID: PMC12005241 DOI: 10.1523/jneurosci.1443-24.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 02/27/2025] Open
Abstract
Dopaminergic subpopulations of the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's disease and are characterized by unique electrophysiological properties. The vulnerable population expresses a T-type calcium channel-mediated afterdepolarization (ADP) and shows rebound activity upon release from inhibition, whereas the resilient population does not have an ADP and is slower to fire after hyperpolarization. This rebound activity can trigger dopamine release in the striatum, an important component of basal ganglia function. Using whole-cell patch-clamp electrophysiology on ex vivo slices from adult mice of both sexes, we find that muscarinic activation with the nonselective muscarinic agonist oxotremorine inhibits rebound activity more strongly in vulnerable versus resilient SNc neurons. Here, we show that this effect depends on the direct activation of muscarinic receptors on the SNc dopaminergic neurons. Through a series of pharmacological and transgenic knock-out experiments, we tested whether the muscarinic inhibition of rebound was mediated through the canonical rebound-related ion channels: T-type calcium channels, hyperpolarization-activated cation channels (HCN), and A-type potassium channels. We find that muscarinic receptor activation inhibits HCN-mediated current (I h) in vulnerable SNc neurons but that I h activity is not necessary for the muscarinic inhibition of rebound activity. Similarly, we find that oxotremorine inhibits rebound activity independently of T-type calcium channels and A-type potassium channels. Together these findings reveal new principles governing acetylcholine and dopamine interactions, showing that muscarinic receptors directly affect SNc rebound activity in the midbrain at the somatodendritic level and differentially modify information processing in distinct SNc subpopulations.
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Affiliation(s)
- Megan L Beaver
- Departments of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC 20007
- Neuroscience, Georgetown University Medical Center, Washington, DC 20007
| | - Rebekah C Evans
- Neuroscience, Georgetown University Medical Center, Washington, DC 20007
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3
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Li H, Chen Z, Tan Y, Luo H, Lu C, Gao C, Shen X, Cai F, Hu J, Chen S. Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice. Cell Biosci 2024; 14:146. [PMID: 39627827 PMCID: PMC11616140 DOI: 10.1186/s13578-024-01328-z] [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: 07/29/2024] [Accepted: 11/21/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND L-DOPA has been considered the first-line therapy for treating Parkinson's disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms. RESULTS Using in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A γ-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice. CONCLUSIONS Our results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients.
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Affiliation(s)
- Hongxia Li
- Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Lab for Translational Research of Neurodegenerative Diseases, Institute of Immunochemistry, ShanghaiTech University, Shanghai, China
| | - Ziluo Chen
- Lab for Translational Research of Neurodegenerative Diseases, Institute of Immunochemistry, ShanghaiTech University, Shanghai, China
| | - Yuyan Tan
- Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huoqing Luo
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Chen Lu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Chao Gao
- Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin Shen
- Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Cai
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Ji Hu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
| | - Shengdi Chen
- Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Lab for Translational Research of Neurodegenerative Diseases, Institute of Immunochemistry, ShanghaiTech University, Shanghai, China.
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Higginson LA, Wang X, He K, Torstrick M, Kim M, Benayoun BA, MacLean A, Chanfreau GF, Morton DJ. The RNA exosome maintains cellular RNA homeostasis by controlling transcript abundance in the brain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.30.620488. [PMID: 39554067 PMCID: PMC11565928 DOI: 10.1101/2024.10.30.620488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Intracellular ribonucleases (RNases) are essential in all aspects of RNA metabolism, including maintaining accurate RNA levels. Inherited mutations in genes encoding ubiquitous RNases are associated with human diseases, primarily affecting the nervous system. Recessive mutations in genes encoding an evolutionarily conserved RNase complex, the RNA exosome, lead to syndromic neurodevelopmental disorders characterized by progressive neurodegeneration, such as Pontocerebellar Hypoplasia Type 1b (PCH1b). We establish a CRISPR/Cas9-engineered Drosophila model of PCH1b to study cell-type-specific post-transcriptional regulatory functions of the nuclear RNA exosome complex within fly head tissue. Here, we report that pathogenic RNA exosome mutations alter activity of the complex, causing widespread dysregulation of brain-enriched cellular transcriptomes, including rRNA processing defects-resulting in tissue-specific, progressive neurodegenerative effects in flies. These findings provide a comprehensive understanding of RNA exosome function within a developed animal brain and underscore the critical role of post-transcriptional regulatory machinery in maintaining cellular RNA homeostasis within the brain.
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Runyon K, Bui T, Mazanek S, Hartle A, Marschalko K, Howe WM. Distinct cholinergic circuits underlie discrete effects of reward on attention. Front Mol Neurosci 2024; 17:1429316. [PMID: 39268248 PMCID: PMC11390659 DOI: 10.3389/fnmol.2024.1429316] [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: 05/07/2024] [Accepted: 08/01/2024] [Indexed: 09/15/2024] Open
Abstract
Attention and reward are functions that are critical for the control of behavior, and massive multi-region neural systems have evolved to support the discrete computations associated with each. Previous research has also identified that attention and reward interact, though our understanding of the neural mechanisms that mediate this interplay is incomplete. Here, we review the basic neuroanatomy of attention, reward, and cholinergic systems. We then examine specific contexts in which attention and reward computations interact. Building on this work, we propose two discrete neural circuits whereby acetylcholine, released from cell groups located in different parts of the brain, mediates the impact of stimulus-reward associations as well as motivation on attentional control. We conclude by examining these circuits as a potential shared loci of dysfunction across diseases states associated with deficits in attention and reward.
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Affiliation(s)
- Kelly Runyon
- School of Neuroscience at Virginia Tech, Blacksburg, VA, United States
| | - Tung Bui
- School of Neuroscience at Virginia Tech, Blacksburg, VA, United States
| | - Sarah Mazanek
- School of Neuroscience at Virginia Tech, Blacksburg, VA, United States
| | - Alec Hartle
- School of Neuroscience at Virginia Tech, Blacksburg, VA, United States
| | - Katie Marschalko
- School of Neuroscience at Virginia Tech, Blacksburg, VA, United States
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Toivainen S, Petrella M, Xu L, Visser E, Weiss T, Vellere S, Zeier Z, Wahlestedt C, Barbier E, Domi E, Heilig M. Generation and Characterization of a Novel Prkcd-Cre Rat Model. J Neurosci 2024; 44:e0528242024. [PMID: 38977300 PMCID: PMC11308323 DOI: 10.1523/jneurosci.0528-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/10/2024] Open
Abstract
Activity of central amygdala (CeA) PKCδ expressing neurons has been linked to appetite regulation, anxiety-like behaviors, pain sensitivity, and addiction-related behaviors. Studies of the role that CeA PKCδ+ neurons play in these behaviors have largely been carried out in mice, and genetic tools that would allow selective manipulation of PKCδ+ cells in rats have been lacking. Here, we used a CRISPR/Cas9 strategy to generate a transgenic Prkcd-cre knock-in rat and characterized this model using anatomical, electrophysiological, and behavioral approaches in both sexes. In the CeA, Cre was selectively expressed in PKCδ+ cells. Anterograde projections of PKCδ+ neurons to cortical regions, subcortical regions, several hypothalamic nuclei, the amygdala complex, and midbrain dopaminergic regions were largely consistent with published mouse data. In a behavioral screen, we found no differences between Cre+ rats and Cre- wild-type littermates. Optogenetic stimulation of CeA PKCδ+ neurons in a palatable food intake assay resulted in an increased latency to first feeding and decreased total food intake, once again replicating published mouse findings. Lastly, using a real-time place preference task, we found that stimulation of PKCδ+ neurons promoted aversion, without affecting locomotor activity. Collectively, these findings establish the novel Prkcd-Cre rat line as a valuable tool that complements available mouse lines for investigating the functional role of PKCδ+ neurons.
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Affiliation(s)
- Sanne Toivainen
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
| | - Michele Petrella
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
| | - Li Xu
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
| | - Esther Visser
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
| | - Tamina Weiss
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
| | - Sofia Vellere
- School of Pharmacy, Center for Neuroscience, Pharmacology Unit, University of Camerino, Camerino 62032, Italy
| | - Zane Zeier
- Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, Florida 33136
| | - Claes Wahlestedt
- Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, Florida 33136
| | - Estelle Barbier
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
| | - Esi Domi
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
- School of Pharmacy, Center for Neuroscience, Pharmacology Unit, University of Camerino, Camerino 62032, Italy
| | - Markus Heilig
- Department of Clinical and Experimental Medicine, Linkoping University, Linkoping 58225, Sweden
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7
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Fallah M, Udobi KC, Swiatek AE, Scott CB, Evans RC. Inhibitory basal ganglia nuclei differentially innervate pedunculopontine nucleus subpopulations and evoke opposite motor and valence behaviors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.05.606694. [PMID: 39149277 PMCID: PMC11326182 DOI: 10.1101/2024.08.05.606694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
The canonical basal ganglia model predicts that the substantia nigra pars reticulata (SNr) and the globus pallidus externa (GPe) will have specific effects on locomotion: the SNr inhibiting locomotion and the GPe enhancing it. In this manuscript, we use in vivo optogenetics to show that a projection-defined neural subpopulation within each structure exerts non-canonical effects on locomotion. These non-canonical subpopulations are defined by their projection to the pedunculopontine nucleus (PPN) and mediate opposing effects on reward. To understand how these structures differentially modulate the PPN, we use ex vivo whole-cell recording with optogenetics to comprehensively dissect the SNr and GPe connections to regionally- and molecularly-defined populations of PPN neurons. The SNr inhibits all PPN subtypes, but most strongly inhibits caudal glutamatergic neurons. The GPe selectively inhibits caudal glutamatergic and GABAergic neurons, avoiding both cholinergic and rostral cells. This circuit characterization reveals non-canonical basal ganglia pathways for locomotion and valence.
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Affiliation(s)
- Michel Fallah
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA 20007
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA 20007
- Senior author
| | - Kenea C Udobi
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA 20007
| | - Aleksandra E Swiatek
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA 20007
| | - Chelsea B Scott
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA 20007
| | - Rebekah C Evans
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA 20007
- Lead contact
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8
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Beaver ML, Evans RC. Muscarinic receptor activation preferentially inhibits rebound in vulnerable dopaminergic neurons. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.30.605819. [PMID: 39131326 PMCID: PMC11312546 DOI: 10.1101/2024.07.30.605819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Dopaminergic subpopulations of the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's disease and are characterized by unique electrophysiological properties. The vulnerable population expresses a T-type calcium channel-mediated afterdepolarization (ADP) and shows rebound activity upon release from inhibition, whereas the resilient population does not have an ADP and is slower to fire after hyperpolarization. This rebound activity can trigger dopamine release in the striatum, an important component of basal ganglia function. Using whole-cell patch clamp electrophysiology on ex vivo slices from adult mice of both sexes, we find that muscarinic activation with the non-selective muscarinic agonist Oxotremorine inhibits rebound activity more strongly in vulnerable vs resilient SNc neurons. Here, we show that this effect depends on the direct activation of muscarinic receptors on the SNc dopaminergic neurons. Through a series of pharmacological and transgenic knock-out experiments, we tested whether the muscarinic inhibition of rebound was mediated through the canonical rebound-related ion channels: T-type calcium channels, hyperpolarization-activated cation channels (HCN), and A-type potassium channels. We find that muscarinic receptor activation inhibits HCN-mediated current (Ih) in vulnerable SNc neurons, but that Ih activity is not necessary for the muscarinic inhibition of rebound activity. Similarly, we find that Oxotremorine inhibits rebound activity independently of T-type calcium channels and A-type potassium channels. Together these findings reveal new principles governing acetylcholine and dopamine interactions, showing that muscarinic receptors directly affect SNc rebound activity in the midbrain at the somatodendritic level and differentially modify information processing in distinct SNc subpopulations.
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Affiliation(s)
- Megan L. Beaver
- Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC, USA 20007
| | - Rebekah C. Evans
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA 20007
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9
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Young PA, Waller O, Ball K, Williams CC, Nashmi R. Phasic Stimulation of Dopaminergic Neurons of the Lateral Substantia Nigra Increases Open Field Exploratory Behaviour and Reduces Habituation Over Time. Neuroscience 2024; 551:276-289. [PMID: 38838978 DOI: 10.1016/j.neuroscience.2024.05.025] [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: 10/05/2023] [Revised: 04/09/2024] [Accepted: 05/20/2024] [Indexed: 06/07/2024]
Abstract
Transient nigrostriatal dopaminergic signalling is well known for its role in reinforcement learning and increasingly so for its role in the initiation of voluntary movement. However, how transient bursts of dopamine modulate voluntary movement remains unclear, likely due to the heterogeneity of the nigrostriatal system, the focus of optogenetic studies on locomotion at sub-sec time intervals, and the overlapping roles of phasic dopamine in behaviour and novelty signalling. In this study we investigated how phasic activity in the lateral substantia nigra pars compacta (lateral SNc) over time affects voluntary behaviours during exploration. Using a transgenic mouse model of both sexes expressing channelrhodopsin (ChR2) in dopamine transporter-expressing cells, we stimulated the lateral SNc while mice explored an open field over two consecutive days. We found that phasic activation of the lateral SNc induced an increase in exploratory behaviours including horizontal movement activity, locomotion initiation, and rearing specifically on the first open field exposure, but not on the second day. In addition, stimulated animals did not habituate to the same extent as their ChR2-negative counterparts, as indicated by a lack of decrease in baseline activity. These findings suggest that rather than prompting voluntary movement in general, phasic nigrostriatal dopamine prompts context-appropriate behaviours. In addition, dopamine signalling that modulates movement acts over longer timescales than the transient signal, affecting behaviour even after the signal has ended.
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Affiliation(s)
- Penelope A Young
- Department of Biology, University of Victoria, British Columbia V8W 2Y2, Canada; Division of Medical Sciences, University of Victoria, British Columbia V8W 2Y2, Canada
| | - Olivia Waller
- Department of Biology, University of Victoria, British Columbia V8W 2Y2, Canada
| | - Katherine Ball
- Department of Biology, University of Victoria, British Columbia V8W 2Y2, Canada
| | - Chad C Williams
- Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA
| | - Raad Nashmi
- Department of Biology, University of Victoria, British Columbia V8W 2Y2, Canada; Division of Medical Sciences, University of Victoria, British Columbia V8W 2Y2, Canada.
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Venegas FC, Rosas D, Delgado N, Estay-Olmos C, Iturriaga-Vásquez P, Rivera-Meza M, Torres GE, Renard GM, Sotomayor-Zárate R. Early-life exposure to sex hormones promotes voluntary ethanol intake in adulthood. A vulnerability factor to drug addiction. Prog Neuropsychopharmacol Biol Psychiatry 2024; 133:111001. [PMID: 38565388 DOI: 10.1016/j.pnpbp.2024.111001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/29/2024] [Accepted: 03/30/2024] [Indexed: 04/04/2024]
Abstract
While there is extensive research on alcohol dependence, the factors that make an individual vulnerable to developing alcoholism haven't been explored much. In this study, we aim to investigate how neonatal exposure to sex hormones affects alcohol intake and the regulation of the mesolimbic pathway in adulthood. The study aimed to investigate the impact of neonatal exposure to a single dose of testosterone propionate (TP) or estradiol valerate (EV) on ethanol consumption in adult rats. The rats were subjected to a two-bottle free-choice paradigm, and the content of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (NAcc) was measured using HPLC-ED. The expression of critical DA-related proteins in the mesolimbic pathway was evaluated through RT-qPCR and western blot analysis. Supraphysiological neonatal exposure to EV or TP resulted in increased ethanol intake over four weeks in adulthood. In addition, the DA and DOPAC content was reduced and increased in the NAcc of EV and TP-treated rats, and β-endorphin content in the hypothalamus decreased in EV-treated rats. The VTA μ receptor and DA type 2 form short receptor (D2S) expression were significantly reduced in EV and TP male rats. Finally, in an extended 6-week protocol, the increase in ethanol consumption induced by EV was mitigated during the initial two hours post-naloxone injection. Neonatal exposure to sex hormones is a detrimental stimulus for the brain, which can facilitate the development of addictive behaviors, including alcohol use disorder.
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Affiliation(s)
- Francisca C Venegas
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile; Department of Biomedical Sciences, University of Padua, Italy
| | - Daniela Rosas
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Nicol Delgado
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Camila Estay-Olmos
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Patricio Iturriaga-Vásquez
- Departamento de Ciencias Químicas y Recursos Naturales, Facultad de Ingeniería y Ciencias, Universidad de la Frontera, Temuco, Chile
| | - Mario Rivera-Meza
- Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Gonzalo E Torres
- Department of Molecular Pharmacology & Neuroscience, Stritch School of Medicine, Loyola University Chicago, USA
| | - Georgina M Renard
- Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile (USACH), Santiago, Chile.
| | - Ramón Sotomayor-Zárate
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
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11
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Bastos-Gonçalves R, Coimbra B, Rodrigues AJ. The mesopontine tegmentum in reward and aversion: From cellular heterogeneity to behaviour. Neurosci Biobehav Rev 2024; 162:105702. [PMID: 38718986 DOI: 10.1016/j.neubiorev.2024.105702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/06/2024] [Accepted: 05/01/2024] [Indexed: 05/18/2024]
Abstract
The mesopontine tegmentum, comprising the pedunculopontine tegmentum (PPN) and the laterodorsal tegmentum (LDT), is intricately connected to various regions of the basal ganglia, motor systems, and limbic systems. The PPN and LDT can regulate the activity of different brain regions of these target systems, and in this way are in a privileged position to modulate motivated behaviours. Despite recent findings, the PPN and LDT have been largely overlooked in discussions about the neural circuits associated with reward and aversion. This review aims to provide a timely and comprehensive resource on past and current research, highlighting the PPN and LDT's connectivity and influence on basal ganglia and limbic, and motor systems. Seminal studies, including lesion, pharmacological, and optogenetic/chemogenetic approaches, demonstrate their critical roles in modulating reward/aversive behaviours. The review emphasizes the need for further investigation into the associated cellular mechanisms, in order to clarify their role in behaviour and contribution for different neuropsychiatric disorders.
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Affiliation(s)
- Ricardo Bastos-Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bárbara Coimbra
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - Ana João Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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12
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Azargoonjahromi A. Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment. Clin Drug Investig 2024; 44:471-493. [PMID: 38904739 DOI: 10.1007/s40261-024-01377-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2024] [Indexed: 06/22/2024]
Abstract
Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.
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Affiliation(s)
- Ali Azargoonjahromi
- Shiraz University of Medical Sciences, Janbazan Blv, 14th Alley, Jahrom, Shiraz, 7417773539, Fars, Iran.
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13
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Lawn T, Giacomel A, Martins D, Veronese M, Howard M, Turkheimer FE, Dipasquale O. Normative modelling of molecular-based functional circuits captures clinical heterogeneity transdiagnostically in psychiatric patients. Commun Biol 2024; 7:689. [PMID: 38839931 PMCID: PMC11153627 DOI: 10.1038/s42003-024-06391-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 05/27/2024] [Indexed: 06/07/2024] Open
Abstract
Advanced methods such as REACT have allowed the integration of fMRI with the brain's receptor landscape, providing novel insights transcending the multiscale organisation of the brain. Similarly, normative modelling has allowed translational neuroscience to move beyond group-average differences and characterise deviations from health at an individual level. Here, we bring these methods together for the first time. We used REACT to create functional networks enriched with the main modulatory, inhibitory, and excitatory neurotransmitter systems and generated normative models of these networks to capture functional connectivity deviations in patients with schizophrenia, bipolar disorder (BPD), and ADHD. Substantial overlap was seen in symptomatology and deviations from normality across groups, but these could be mapped into a common space linking constellations of symptoms through to underlying neurobiology transdiagnostically. This work provides impetus for developing novel biomarkers that characterise molecular- and systems-level dysfunction at the individual level, facilitating the transition towards mechanistically targeted treatments.
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Affiliation(s)
- Timothy Lawn
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | - Alessio Giacomel
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Daniel Martins
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland
| | - Mattia Veronese
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Matthew Howard
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Federico E Turkheimer
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Ottavia Dipasquale
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
- Department of Research & Development Advanced Applications, Olea Medical, La Ciotat, France.
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14
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Han Y, Zhang JQ, Ji YW, Luan YW, Li SY, Geng HZ, Ji Y, Yin C, Liu S, Zhou CY, Xiao C. α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata. Acta Pharmacol Sin 2024; 45:1160-1174. [PMID: 38438581 PMCID: PMC11130268 DOI: 10.1038/s41401-024-01234-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/25/2024] [Indexed: 03/06/2024]
Abstract
Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.
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Affiliation(s)
- Yu Han
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Anesthesiology, Yiwu Central Hospital, Yiwu, 322099, China
| | - Jia-Qi Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Ya-Wei Ji
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yi-Wen Luan
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Wuxi People's Hospital, Wuxi, 214023, China
| | - Shu-Yi Li
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Hui-Zhen Geng
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Ying Ji
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Cui Yin
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Su Liu
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Chun-Yi Zhou
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China.
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Cheng Xiao
- Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
- Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China.
- NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
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15
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Ryczko D. The Mesencephalic Locomotor Region: Multiple Cell Types, Multiple Behavioral Roles, and Multiple Implications for Disease. Neuroscientist 2024; 30:347-366. [PMID: 36575956 PMCID: PMC11107129 DOI: 10.1177/10738584221139136] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The mesencephalic locomotor region (MLR) controls locomotion in vertebrates. In humans with Parkinson disease, locomotor deficits are increasingly associated with decreased activity in the MLR. This brainstem region, commonly considered to include the cuneiform and pedunculopontine nuclei, has been explored as a target for deep brain stimulation to improve locomotor function, but the results are variable, from modest to promising. However, the MLR is a heterogeneous structure, and identification of the best cell type to target is only beginning. Here, I review the studies that uncovered the role of genetically defined MLR cell types, and I highlight the cells whose activation improves locomotor function in animal models of Parkinson disease. The promising cell types to activate comprise some glutamatergic neurons in the cuneiform and caudal pedunculopontine nuclei, as well as some cholinergic neurons of the pedunculopontine nucleus. Activation of MLR GABAergic neurons should be avoided, since they stop locomotion or evoke bouts flanked with numerous stops. MLR is also considered a potential target in spinal cord injury, supranuclear palsy, primary progressive freezing of gait, or stroke. Better targeting of the MLR cell types should be achieved through optimized deep brain stimulation protocols, pharmacotherapy, or the development of optogenetics for human use.
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Affiliation(s)
- Dimitri Ryczko
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Canada
- Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada
- Neurosciences Sherbrooke, Sherbrooke, Canada
- Institut de Pharmacologie de Sherbrooke, Sherbrooke, Canada
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16
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Juárez Tello A, van der Zouwen CI, Dejas L, Duque-Yate J, Boutin J, Medina-Ortiz K, Suresh JS, Swiegers J, Sarret P, Ryczko D. Dopamine-sensitive neurons in the mesencephalic locomotor region control locomotion initiation, stop, and turns. Cell Rep 2024; 43:114187. [PMID: 38722743 PMCID: PMC11157412 DOI: 10.1016/j.celrep.2024.114187] [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: 10/20/2023] [Revised: 03/31/2024] [Accepted: 04/17/2024] [Indexed: 06/01/2024] Open
Abstract
The locomotor role of dopaminergic neurons is traditionally attributed to their ascending projections to the basal ganglia, which project to the mesencephalic locomotor region (MLR). In addition, descending dopaminergic projections to the MLR are present from basal vertebrates to mammals. However, the neurons targeted in the MLR and their behavioral role are unknown in mammals. Here, we identify genetically defined MLR cells that express D1 or D2 receptors and control different motor behaviors in mice. In the cuneiform nucleus, D1-expressing neurons promote locomotion, while D2-expressing neurons stop locomotion. In the pedunculopontine nucleus, D1-expressing neurons promote locomotion, while D2-expressing neurons evoke ipsilateral turns. Using RNAscope, we show that MLR dopamine-sensitive neurons comprise a combination of glutamatergic, GABAergic, and cholinergic neurons, suggesting that different neurotransmitter-based cell types work together to control distinct behavioral modules. Altogether, our study uncovers behaviorally relevant cell types in the mammalian MLR based on the expression of dopaminergic receptors.
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Affiliation(s)
- Andrea Juárez Tello
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Cornelis Immanuel van der Zouwen
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Léonie Dejas
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Juan Duque-Yate
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Joël Boutin
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Katherine Medina-Ortiz
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Jacinthlyn Sylvia Suresh
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Jordan Swiegers
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Philippe Sarret
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada; Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Neurosciences Sherbrooke, Institut de Pharmacologie de Sherbrooke, Sherbrooke, QC, Canada
| | - Dimitri Ryczko
- Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada; Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Neurosciences Sherbrooke, Institut de Pharmacologie de Sherbrooke, Sherbrooke, QC, Canada.
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17
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Zhang S, Zhang J, Yang Y, Zang W, Cao J. Activation of Pedunculopontine Tegmental Nucleus Alleviates the Pain Induced by the Lesion of Midbrain Dopaminergic Neurons. Int J Mol Sci 2024; 25:5636. [PMID: 38891832 PMCID: PMC11171649 DOI: 10.3390/ijms25115636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson's disease (PD). PD causes chronic pain in two-thirds of patients. Recent studies showed that the activation of the pedunculopontine tegmental nucleus (PPTg) can effectively relieve inflammatory pain and neuropathic pain. The PPTg is located in the pontomesencephalic tegmentum, a target of deep brain stimulation (DBS) treatment in PD, and is involved in motor control and sensory integration. To test whether the lesion of midbrain DA neurons induced pain hypersensitivity, and whether the chemogenetic activation of the PPTg could modulate the pain, the AAV-hM3Dq receptor was transfected and expressed into the PPTg neurons of 6-hydroxydopamine-lesioned mice. In this study, von Frey, open field, and adhesive tape removal tests were used to assess animals' pain sensitivity, locomotor activity, and sensorimotor function and somatosensory perception, respectively. Here, we found that the lesion of midbrain DA neurons induced a minor deficit in voluntary movement but did not affect sensorimotor function and somatosensory perception in the tape removal test. The results showed that lesion led to pain hypersensitivity, which could be alleviated both by levodopa and by the chemogenetic activation of the PPTg. Activating the PPTg may be a potential therapeutic strategy to relieve pain phenotypes in PD.
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Affiliation(s)
- Shiqiang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (S.Z.); (J.Z.); (Y.Y.)
- Neuroscience Research Institute, Zhengzhou University, Zhengzhou 450001, China
| | - Jingjing Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (S.Z.); (J.Z.); (Y.Y.)
- Neuroscience Research Institute, Zhengzhou University, Zhengzhou 450001, China
| | - Yihao Yang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (S.Z.); (J.Z.); (Y.Y.)
- Neuroscience Research Institute, Zhengzhou University, Zhengzhou 450001, China
| | - Weidong Zang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (S.Z.); (J.Z.); (Y.Y.)
- Neuroscience Research Institute, Zhengzhou University, Zhengzhou 450001, China
| | - Jing Cao
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (S.Z.); (J.Z.); (Y.Y.)
- Neuroscience Research Institute, Zhengzhou University, Zhengzhou 450001, China
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18
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Zhang AQ, Ralph MR, Stinchcombe AR. A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms. PLoS Comput Biol 2024; 20:e1012082. [PMID: 38701077 PMCID: PMC11095719 DOI: 10.1371/journal.pcbi.1012082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 05/15/2024] [Accepted: 04/17/2024] [Indexed: 05/05/2024] Open
Abstract
Many self-motivated and goal-directed behaviours display highly flexible, approximately 4 hour ultradian (shorter than a day) oscillations. Despite lacking direct correspondence to physical cycles in the environment, these ultradian rhythms may be involved in optimizing functional interactions with the environment and reflect intrinsic neural dynamics. Current evidence supports a role of mesostriatal dopamine (DA) in the expression and propagation of ultradian rhythmicity, however, the biochemical processes underpinning these oscillations remain to be identified. Here, we use a mathematical model to investigate D2 autoreceptor-dependent DA self-regulation as the source of ultradian behavioural rhythms. DA concentration at the midbrain-striatal synapses is governed through a dual-negative feedback-loop structure, which naturally gives rise to rhythmicity. This model shows the propensity of striatal DA to produce an ultradian oscillation characterized by a flexible period that is highly sensitive to parameter variations. Circadian (approximately 24 hour) regulation consolidates the ultradian oscillations and alters their response to the phase-dependent, rapid-resetting effect of a transient excitatory stimulus. Within a circadian framework, the ultradian rhythm orchestrates behavioural activity and enhances responsiveness to an external stimulus. This suggests a role for the circadian-ultradian timekeeping hierarchy in governing organized behaviour and shaping daily experience through coordinating the motivation to engage in recurring, albeit not highly predictable events, such as social interactions.
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Affiliation(s)
- An Qi Zhang
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
| | - Martin R. Ralph
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
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19
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Wu J, Li X, Zhang Q, Li J, Cui R, Li X. Differential effects of intra-RMTg infusions of pilocarpine or 4-DAMP on regulating depression- and anxiety-like behaviors. Behav Brain Res 2024; 462:114833. [PMID: 38220059 DOI: 10.1016/j.bbr.2023.114833] [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: 08/18/2023] [Revised: 12/04/2023] [Accepted: 12/20/2023] [Indexed: 01/16/2024]
Abstract
Depression and anxiety are associated with dysfunction of the mesolimbic dopamine system. The rostromedial tegmental nucleus (RMTg) is predominantly composed of GABAergic neurons that exhibit dense projections and strongly inhibit mesolimbic dopaminergic neurons, proposed as a major "brake" for the system. Consequently, the RMTg may be a crucial brain region for regulating these emotions. The central cholinergic system, particularly the muscarinic receptors, plays an important regulatory role in depression and anxiety. M3 muscarinic receptors are distributed on GABAergic neurons in the RMTg, but their involvement in the regulation of depression and anxiety remains uncertain. This study aimed to examine the effects of RMTg M3 muscarinic receptors on regulating depression- and anxiety-like behaviors in adult male Wistar rats, as assessed through the forced swim, tail suspension, and elevated plus maze tests. The results showed that intra-RMTg injections of the M1/M3 muscarinic receptors agonist, pilocarpine (3, 10, and 30 μg/side), or the M3 muscarinic receptors antagonist, 4-DAMP (0.5, 1, and 2 μg/side), did not alter the immobility time in the forced swim and tail suspension tests. Additionally, pilocarpine (30 μg/side) decreased time spent in open arms and increased time in closed arms in the elevated plus maze; while 4-DAMP (1 and 2 μg/side) played the opposite role by increasing time spent in open arms and decreasing time in closed arms. These findings suggest that RMTg M3 muscarinic receptors have differential effects on regulating depression- and anxiety-like behaviors. Enhancing or inhibiting these receptors can produce anxiogenic or anxiolytic effects, but have no impact on depression-like behavior. Therefore, RMTg M3 muscarinic receptors are involved in regulating anxiety and may be a potential therapeutic target for anxiolytic drugs.
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Affiliation(s)
- Jing Wu
- Beijing Key Laboratory of Learning and Cognition, Capital Normal University, Beijing, China; Faculty of Education, Henan Normal University, Xinxiang, China
| | - Xuhong Li
- Department of Education, Lyuliang University, Lyuliang, China
| | - Qi Zhang
- Beijing Key Laboratory of Learning and Cognition, Capital Normal University, Beijing, China
| | - Jiaxiang Li
- Beijing Key Laboratory of Learning and Cognition, Capital Normal University, Beijing, China
| | - Ruisi Cui
- Beijing Key Laboratory of Learning and Cognition, Capital Normal University, Beijing, China
| | - Xinwang Li
- Beijing Key Laboratory of Learning and Cognition, Capital Normal University, Beijing, China.
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20
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Mulloy SM, Aback EM, Gao R, Engel S, Pawaskar K, Win C, Moua A, Hillukka L, Lee AM. Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum. Sci Rep 2024; 14:46. [PMID: 38168499 PMCID: PMC10762073 DOI: 10.1038/s41598-023-50526-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024] Open
Abstract
Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol activates neurons of the PPN and not the LDT in male mice. Chronic 15 daily injections of 2 g/kg ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas ethanol did not increase cholinergic and glutamatergic neuronal activation in the LDT. A single acute 4 g/kg injection, but not a single 2 g/kg injection, induced cholinergic neuron activation in the male PPN but not the LDT. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher baseline level of activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.
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Affiliation(s)
- S M Mulloy
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - E M Aback
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - R Gao
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - S Engel
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - K Pawaskar
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - C Win
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A Moua
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - L Hillukka
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A M Lee
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
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21
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Morgenstern NA, Esposito MS. The Basal Ganglia and Mesencephalic Locomotor Region Connectivity Matrix. Curr Neuropharmacol 2024; 22:1454-1472. [PMID: 37559244 PMCID: PMC11097982 DOI: 10.2174/1570159x21666230809112840] [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: 12/09/2022] [Revised: 02/16/2023] [Accepted: 02/23/2023] [Indexed: 08/11/2023] Open
Abstract
Although classically considered a relay station for basal ganglia (BG) output, the anatomy, connectivity, and function of the mesencephalic locomotor region (MLR) were redefined during the last two decades. In striking opposition to what was initially thought, MLR and BG are actually reciprocally and intimately interconnected. New viral-based, optogenetic, and mapping technologies revealed that cholinergic, glutamatergic, and GABAergic neurons coexist in this structure, which, in addition to extending descending projections, send long-range ascending fibers to the BG. These MLR projections to the BG convey motor and non-motor information to specific synaptic targets throughout different nuclei. Moreover, MLR efferent fibers originate from precise neuronal subpopulations located in particular MLR subregions, defining independent anatomo-functional subcircuits involved in particular aspects of animal behavior such as fast locomotion, explorative locomotion, posture, forelimb- related movements, speed, reinforcement, among others. In this review, we revised the literature produced during the last decade linking MLR and BG. We conclude that the classic framework considering the MLR as a homogeneous output structure passively receiving input from the BG needs to be revisited. We propose instead that the multiple subcircuits embedded in this region should be taken as independent entities that convey relevant and specific ascending information to the BG and, thus, actively participate in the execution and tuning of behavior.
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Affiliation(s)
- Nicolás A. Morgenstern
- Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal
- Faculty of Medicine, University of Lisbon, Instituto De Medicina Molecular João Lobo Antunes, Lisbon, Portugal
| | - Maria S. Esposito
- Department of Medical Physics, Centro Atomico Bariloche, CNEA, CONICET, Av. Bustillo 9500, San Carlos de Bariloche, Rio Negro, Argentina
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22
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Zhang S, Mena-Segovia J, Gut NK. Inhibitory Pedunculopontine Neurons Gate Dopamine-Mediated Motor Actions of Unsigned Valence. Curr Neuropharmacol 2024; 22:1540-1550. [PMID: 37702175 PMCID: PMC11097985 DOI: 10.2174/1570159x21666230911103520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/22/2023] [Accepted: 05/28/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND The pedunculopontine nucleus (PPN) maintains a bidirectional connectivity with the basal ganglia that supports their shared roles in the selection and execution of motor actions. Previous studies identified a role for PPN neurons in goal-directed behavior, but the cellular substrates underlying this function have not been elucidated. We recently revealed the existence of a monosynaptic GABAergic input from the PPN that inhibits dopamine neurons of the substantia nigra. Activation of this pathway interferes with the execution of learned motor sequences when the actions are rewarded, even though the inhibition of dopamine neurons did not shift the value of the action, hence suggesting executive control over the gating of behavior. OBJECTIVE To test the attributes of the inhibition of dopamine neurons by the PPN in the context of goal-directed behavior regardless of whether the outcome is positively or negatively reinforced. METHODS We delivered optogenetic stimulation to PPN GABAergic axon terminals in the substantia nigra during a battery of behavioral tasks with positive and negative valence. RESULTS Inhibition of dopamine neurons by PPN optogenetic activation during an appetitive task impaired the initiation and overall execution of the behavioral sequence without affecting the consumption of reward. During an active avoidance task, the same activation impaired the ability of mice to avoid a foot shock, but their escape response was unaffected. In addition, responses to potential threats were significantly attenuated. CONCLUSION Our results show that PPN GABAergic neurons modulate learned, goal-directed behavior of unsigned valence without affecting overall motor behavior.
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Affiliation(s)
- Sirin Zhang
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, USA
| | - Juan Mena-Segovia
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, USA
| | - Nadine K. Gut
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, USA
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23
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Dong Y, Li Y, Xiang X, Xiao ZC, Hu J, Li Y, Li H, Hu H. Stress relief as a natural resilience mechanism against depression-like behaviors. Neuron 2023; 111:3789-3801.e6. [PMID: 37776853 DOI: 10.1016/j.neuron.2023.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 08/07/2023] [Accepted: 09/06/2023] [Indexed: 10/02/2023]
Abstract
Relief, the appetitive state after the termination of aversive stimuli, is evolutionarily conserved. Understanding the behavioral role of this well-conserved phenomenon and its underlying neurobiological mechanisms are open and important questions. Here, we discover that the magnitude of relief from physical stress strongly correlates with individual resilience to depression-like behaviors in chronic stressed mice. Notably, blocking stress relief causes vulnerability to depression-like behaviors, whereas natural rewards supplied shortly after stress promotes resilience. Stress relief is mediated by reward-related mesolimbic dopamine neurons, which show minute-long, persistent activation after stress termination. Circuitry-wise, activation or inhibition of circuits downstream of the ventral tegmental area during the transient relief period bi-directionally regulates depression resilience. These results reveal an evolutionary function of stress relief in depression resilience and identify the neural substrate mediating this effect. Importantly, our data suggest a behavioral strategy of augmenting positive valence of stress relief with natural rewards to prevent depression.
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Affiliation(s)
- Yiyan Dong
- Department of Psychiatry and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Yifei Li
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Xinkuan Xiang
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Zhuo-Cheng Xiao
- Courant Institute of Mathematical Sciences, New York University, New York, NY 10003, USA
| | - Ji Hu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Yulong Li
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China
| | - Haohong Li
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Hailan Hu
- Department of Psychiatry and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou 311121, China.
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24
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Mulloy SM, Aback EM, Gao R, Engel S, Pawaskar K, Win C, Moua A, Hillukka L, Lee AM. Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.08.566053. [PMID: 38014248 PMCID: PMC10680559 DOI: 10.1101/2023.11.08.566053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol selectively activates neurons of the PPN and not the LDT in male mice. Acute 4.0 g/kg and chronic 15 daily injections of 2.0 g/kg i.p. ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas cholinergic and glutamatergic neurons of the LDT were unresponsive. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher level of baseline activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.
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Affiliation(s)
- S M Mulloy
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - E M Aback
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - R Gao
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - S Engel
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - K Pawaskar
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - C Win
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A Moua
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - L Hillukka
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A M Lee
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
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25
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Du Y, Zhou S, Ma C, Chen H, Du A, Deng G, Liu Y, Tose AJ, Sun L, Liu Y, Wu H, Lou H, Yu YQ, Zhao T, Lammel S, Duan S, Yang H. Dopamine release and negative valence gated by inhibitory neurons in the laterodorsal tegmental nucleus. Neuron 2023; 111:3102-3118.e7. [PMID: 37499661 DOI: 10.1016/j.neuron.2023.06.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/25/2023] [Accepted: 06/22/2023] [Indexed: 07/29/2023]
Abstract
GABAergic neurons in the laterodorsal tegmental nucleus (LDTGABA) encode aversion by directly inhibiting mesolimbic dopamine (DA). Yet, the detailed cellular and circuit mechanisms by which these cells relay unpleasant stimuli to DA neurons and regulate behavioral output remain largely unclear. Here, we show that LDTGABA neurons bidirectionally respond to rewarding and aversive stimuli in mice. Activation of LDTGABA neurons promotes aversion and reduces DA release in the lateral nucleus accumbens. Furthermore, we identified two molecularly distinct LDTGABA cell populations. Somatostatin-expressing (Sst+) LDTGABA neurons indirectly regulate the mesolimbic DA system by disinhibiting excitatory hypothalamic neurons. In contrast, Reelin-expressing LDTGABA neurons directly inhibit downstream DA neurons. The identification of separate GABAergic subpopulations in a single brainstem nucleus that relay unpleasant stimuli to the mesolimbic DA system through direct and indirect projections is critical for establishing a circuit-level understanding of how negative valence is encoded in the mammalian brain.
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Affiliation(s)
- Yonglan Du
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Siyao Zhou
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Chenyan Ma
- Division of Neurobiology, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Hui Chen
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Ana Du
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Guochuang Deng
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Yige Liu
- NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China; College of Forensic Science, School of Medicine, Xi'an Jiaotong University, No.76, Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Amanda J Tose
- Division of Neurobiology, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Li Sun
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Yijun Liu
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Hangjun Wu
- Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou 310058, China
| | - Huifang Lou
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Yan-Qin Yu
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Ting Zhao
- PKU-Nanjing Joint Institute of Translational Medicine, Nanjing 211800, China
| | - Stephan Lammel
- Division of Neurobiology, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Shumin Duan
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Hongbin Yang
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
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26
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Hu Y, Ma TC, Alberico SL, Ding Y, Jin L, Kang UJ. Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia. Mov Disord 2023; 38:1850-1860. [PMID: 37461292 PMCID: PMC10932617 DOI: 10.1002/mds.29558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/02/2023] [Accepted: 06/29/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID. OBJECTIVE The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model. METHODS We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation. RESULTS Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation. CONCLUSIONS Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Yong Hu
- Department of Neurology, NYU Langone Health, New York, NY 10016, USA
| | - Thong C. Ma
- Department of Neurology, NYU Langone Health, New York, NY 10016, USA
| | | | - Yunmin Ding
- Department of Neurology, NYU Langone Health, New York, NY 10016, USA
| | - Lingjing Jin
- Department of Neurology and Neurological Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai 200092, China
| | - Un Jung Kang
- Department of Neurology, NYU Langone Health, New York, NY 10016, USA
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27
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Eleftheriadis PE, Pothakos K, Sharples SA, Apostolou PE, Mina M, Tetringa E, Tsape E, Miles GB, Zagoraiou L. Peptidergic modulation of motor neuron output via CART signaling at C bouton synapses. Proc Natl Acad Sci U S A 2023; 120:e2300348120. [PMID: 37733738 PMCID: PMC10523464 DOI: 10.1073/pnas.2300348120] [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: 01/17/2023] [Accepted: 07/17/2023] [Indexed: 09/23/2023] Open
Abstract
The intensity of muscle contraction, and therefore movement vigor, needs to be adaptable to enable complex motor behaviors. This can be achieved by adjusting the properties of motor neurons, which form the final common pathway for all motor output from the central nervous system. Here, we identify roles for a neuropeptide, cocaine- and amphetamine-regulated transcript (CART), in the control of movement vigor. We reveal distinct but parallel mechanisms by which CART and acetylcholine, both released at C bouton synapses on motor neurons, selectively amplify the output of subtypes of motor neurons that are recruited during intense movement. We find that mice with broad genetic deletion of CART or selective elimination of acetylcholine from C boutons exhibit deficits in behavioral tasks that require higher levels of motor output. Overall, these data uncover spinal modulatory mechanisms that control movement vigor to support movements that require a high degree of muscle force.
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Affiliation(s)
| | - Konstantinos Pothakos
- Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens11527, Greece
| | - Simon A. Sharples
- School of Psychology and Neuroscience, University of St. Andrews, St. AndrewsKY16 9JP, United Kingdom
| | - Panagiota E. Apostolou
- Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens11527, Greece
| | - Maria Mina
- Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens11527, Greece
| | - Efstathia Tetringa
- Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens11527, Greece
| | - Eirini Tsape
- Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens11527, Greece
| | - Gareth B. Miles
- School of Psychology and Neuroscience, University of St. Andrews, St. AndrewsKY16 9JP, United Kingdom
| | - Laskaro Zagoraiou
- Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens11527, Greece
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28
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Ji YW, Xu XY, Yin C, Zhou C, Xiao C. Protocol to study projection-specific circuits in the basal ganglia of adult mice using viral vector tracing, optogenetics, and patch-clamp technique. STAR Protoc 2023; 4:102551. [PMID: 37660296 PMCID: PMC10491855 DOI: 10.1016/j.xpro.2023.102551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/24/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023] Open
Abstract
Analysis of synaptic strength and plasticity provides functional insights of complicated neural circuits. Here, we describe steps for cell- and projection-specific optogenetic manipulation of divergent basal ganglia circuits using anterograde and retrograde viral vectors. We quantitatively analyze synaptic function of these circuits utilizing a patch-clamp technique. This protocol is applicable to probe potential circuit targets for treatment of brain diseases. For complete details on the use and execution of this protocol, please refer to Ji et al.1.
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Affiliation(s)
- Ya-Wei Ji
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xiang-Ying Xu
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Cui Yin
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Chunyi Zhou
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
| | - Cheng Xiao
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
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29
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Li Y, Zhi W, Qi B, Wang L, Hu X. Update on neurobiological mechanisms of fear: illuminating the direction of mechanism exploration and treatment development of trauma and fear-related disorders. Front Behav Neurosci 2023; 17:1216524. [PMID: 37600761 PMCID: PMC10433239 DOI: 10.3389/fnbeh.2023.1216524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/18/2023] [Indexed: 08/22/2023] Open
Abstract
Fear refers to an adaptive response in the face of danger, and the formed fear memory acts as a warning when the individual faces a dangerous situation again, which is of great significance to the survival of humans and animals. Excessive fear response caused by abnormal fear memory can lead to neuropsychiatric disorders. Fear memory has been studied for a long time, which is of a certain guiding effect on the treatment of fear-related disorders. With continuous technological innovations, the study of fear has gradually shifted from the level of brain regions to deeper neural (micro) circuits between brain regions and even within single brain regions, as well as molecular mechanisms. This article briefly outlines the basic knowledge of fear memory and reviews the neurobiological mechanisms of fear extinction and relapse, which aims to provide new insights for future basic research on fear emotions and new ideas for treating trauma and fear-related disorders.
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Affiliation(s)
- Ying Li
- College of Education, Hebei University, Baoding, China
- Laboratory of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Weijia Zhi
- Laboratory of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Bing Qi
- College of Education, Hebei University, Baoding, China
| | - Lifeng Wang
- Laboratory of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Xiangjun Hu
- College of Education, Hebei University, Baoding, China
- Laboratory of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, China
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30
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Zhao P, Jiang T, Wang H, Jia X, Li A, Gong H, Li X. Upper brainstem cholinergic neurons project to ascending and descending circuits. BMC Biol 2023; 21:135. [PMID: 37280580 DOI: 10.1186/s12915-023-01625-y] [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: 11/25/2022] [Accepted: 05/12/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Based on their anatomical location, rostral projections of nuclei are classified as ascending circuits, while caudal projections are classified as descending circuits. Upper brainstem neurons participate in complex information processing and specific sub-populations preferentially project to participating ascending or descending circuits. Cholinergic neurons in the upper brainstem have extensive collateralizations in both ascending and descending circuits; however, their single-cell projection patterns remain unclear because of the lack of comprehensive characterization of individual neurons. RESULTS By combining fluorescent micro-optical sectional tomography with sparse labeling, we acquired a high-resolution whole-brain dataset of pontine-tegmental cholinergic neurons (PTCNs) and reconstructed their detailed morphology using semi-automatic reconstruction methods. As the main source of acetylcholine in some subcortical areas, individual PTCNs had abundant axons with lengths up to 60 cm and 5000 terminals and innervated multiple brain regions from the spinal cord to the cortex in both hemispheres. Based on various collaterals in the ascending and descending circuits, individual PTCNs were grouped into four subtypes. The morphology of cholinergic neurons in the pedunculopontine nucleus was more divergent, whereas the laterodorsal tegmental nucleus neurons contained richer axonal branches and dendrites. In the ascending circuits, individual PTCNs innervated the thalamus in three different patterns and projected to the cortex via two separate pathways. Moreover, PTCNs targeting the ventral tegmental area and substantia nigra had abundant collaterals in the pontine reticular nuclei, and these two circuits contributed oppositely to locomotion. CONCLUSIONS Our results suggest that individual PTCNs have abundant axons, and most project to various collaterals in the ascending and descending circuits simultaneously. They target regions with multiple patterns, such as the thalamus and cortex. These results provide a detailed organizational characterization of cholinergic neurons to understand the connexional logic of the upper brainstem.
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Affiliation(s)
- Peilin Zhao
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
- Institute of neurological diseases, North Sichuan Medical University, Nanchong, 637100, China
| | - Tao Jiang
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Huading Wang
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Xueyan Jia
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Anan Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Hui Gong
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Xiangning Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China.
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China.
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou, 570228, China.
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Chambers NE, Millett M, Moehle MS. The muscarinic M4 acetylcholine receptor exacerbates symptoms of movement disorders. Biochem Soc Trans 2023; 51:691-702. [PMID: 37013974 PMCID: PMC10212540 DOI: 10.1042/bst20220525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 12/31/2022] [Accepted: 03/14/2023] [Indexed: 04/05/2023]
Abstract
Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the matching efficacy of anticholinergic treatment in movement disorders seem to support this hypothesis. However, evidence from translational and clinical studies in movement disorders indicates that many features of this simple balance are lost, broken, or absent from movement disorders models or in imaging studies of patients with these disorders. This review reappraises the dopamine-acetylcholine balance hypothesis in light of recent evidence and describes how the Gαi/o coupled muscarinic M4 receptor acts in opposition to dopamine signaling in the basal ganglia. We highlight how M4 signaling can ameliorate or exacerbate movement disorders symptoms and physiological correlates of these symptoms in specific disease states. Furthermore, we propose future directions for investigation of this mechanisms to fully understand the potential efficacy of M4 targeting therapeutics in movement disorders. Overall, initial evidence suggest that M4 is a promising pharmaceutical target to ameliorate motor symptoms of hypo- and hyper-dopaminergic disorders.
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Affiliation(s)
- Nicole E. Chambers
- Department of Pharmacology and Therapeutics and Center for Translational Research in Neurodegeneration, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Michael Millett
- Department of Pharmacology and Therapeutics and Center for Translational Research in Neurodegeneration, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Mark S. Moehle
- Department of Pharmacology and Therapeutics and Center for Translational Research in Neurodegeneration, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
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Lacroix-Ouellette P, Dubuc R. Brainstem neural mechanisms controlling locomotion with special reference to basal vertebrates. Front Neural Circuits 2023; 17:910207. [PMID: 37063386 PMCID: PMC10098025 DOI: 10.3389/fncir.2023.910207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 03/13/2023] [Indexed: 04/03/2023] Open
Abstract
Over the last 60 years, the basic neural circuitry responsible for the supraspinal control of locomotion has progressively been uncovered. Initially, significant progress was made in identifying the different supraspinal structures controlling locomotion in mammals as well as some of the underlying mechanisms. It became clear, however, that the complexity of the mammalian central nervous system (CNS) prevented researchers from characterizing the detailed cellular mechanisms involved and that animal models with a simpler nervous system were needed. Basal vertebrate species such as lampreys, xenopus embryos, and zebrafish became models of choice. More recently, optogenetic approaches have considerably revived interest in mammalian models. The mesencephalic locomotor region (MLR) is an important brainstem region known to control locomotion in all vertebrate species examined to date. It controls locomotion through intermediary cells in the hindbrain, the reticulospinal neurons (RSNs). The MLR comprises populations of cholinergic and glutamatergic neurons and their specific contribution to the control of locomotion is not fully resolved yet. Moreover, the downward projections from the MLR to RSNs is still not fully understood. Reporting on discoveries made in different animal models, this review article focuses on the MLR, its projections to RSNs, and the contribution of these neural elements to the control of locomotion. Excellent and detailed reviews on the brainstem control of locomotion have been recently published with emphasis on mammalian species. The present review article focuses on findings made in basal vertebrates such as the lamprey, to help direct new research in mammals, including humans.
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Affiliation(s)
| | - Réjean Dubuc
- Department of Neurosciences, Université de Montréal, Montréal, QC, Canada
- Department of Physical Activity Sciences, Université du Québec à Montréal, Montréal, QC, Canada
- Research Group for Adapted Physical Activity, Université du Québec à Montréal, Montréal, QC, Canada
- *Correspondence: Réjean Dubuc,
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The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons. Mol Psychiatry 2023; 28:1027-1045. [PMID: 33990773 PMCID: PMC8590712 DOI: 10.1038/s41380-021-01137-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 04/08/2021] [Accepted: 04/19/2021] [Indexed: 01/07/2023]
Abstract
Dopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.
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Ji YW, Zhang X, Fan JP, Gu WX, Shen ZL, Wu HC, Cui G, Zhou C, Xiao C. Differential remodeling of subthalamic projections to basal ganglia output nuclei and locomotor deficits in 6-OHDA-induced hemiparkinsonian mice. Cell Rep 2023; 42:112178. [PMID: 36857188 DOI: 10.1016/j.celrep.2023.112178] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 11/04/2022] [Accepted: 02/13/2023] [Indexed: 03/02/2023] Open
Abstract
The subthalamic nucleus (STN) controls basal ganglia outputs via the substantia nigra pars reticulata (SNr) and the globus pallidus internus (GPi). However, the synaptic properties of these projections and their roles in motor control remain unclear. We show that the STN-SNr and STN-GPi projections differ markedly in magnitude and activity-dependent plasticity despite the existence of collateral STN neurons projecting to both the SNr and GPi. Stimulation of either STN projection reduces locomotion; in contrast, inhibition of either the STN-SNr projection or collateral STN neurons facilitates locomotion. In 6-OHDA-hemiparkinsonian mice, the STN-SNr projection is dramatically attenuated, but the STN-GPi projection is robustly enhanced; apomorphine inhibition of the STN-GPi projection through D2 receptors is significantly augmented and improves locomotion. Optogenetic inhibition of either the STN-SNr or STN-GPi projection improves parkinsonian bradykinesia. These results suggest that the STN-GPi and STN-SNr projections are differentially involved in motor control in physiological and parkinsonian conditions.
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Affiliation(s)
- Ya-Wei Ji
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xue Zhang
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou 221006, China
| | - Jiang-Peng Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Province Key Laboratory in Brain Diseases, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Wei-Xin Gu
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210008, China
| | - Zi-Lin Shen
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hai-Chuan Wu
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210008, China
| | - Guiyun Cui
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou 221006, China.
| | - Chunyi Zhou
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
| | - Cheng Xiao
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
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The Pedunculopontine Tegmental Nucleus is not Important for Breathing Impairments Observed in a Parkinson's Disease Model. Neuroscience 2023; 512:32-46. [PMID: 36690033 DOI: 10.1016/j.neuroscience.2022.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 01/21/2023]
Abstract
Parkinson's disease (PD) is a motor disorder resulting from degeneration of dopaminergic neurons of substantia nigra pars compacta (SNpc), with classical and non-classical symptoms such as respiratory instability. An important region for breathing control, the Pedunculopontine Tegmental Nucleus (PPTg), is composed of cholinergic, glutamatergic, and GABAergic neurons. We hypothesize that degenerated PPTg neurons in a PD model contribute to the blunted respiratory activity. Adult mice (40 males and 29 females) that express the fluorescent green protein in cholinergic, glutamatergic or GABAergic cells were used (Chat-cre Ai6, Vglut2-cre Ai6 and Vgat-cre Ai6) and received bilateral intrastriatal injections of vehicle or 6-hydroxydopamine (6-OHDA). Ten days later, the animals were exposed to hypercapnia or hypoxia to activate PPTg neurons. Vglut2-cre Ai6 animals also received retrograde tracer injections (cholera toxin b) into the retrotrapezoid nucleus (RTN) or preBötzinger Complex (preBötC) and anterograde tracer injections (AAV-mCherry) into the SNpc. In 6-OHDA-injected mice, there is a 77% reduction in the number of dopaminergic neurons in SNpc without changing the number of neurons in the PPTg. Hypercapnia activated fewer Vglut2 neurons in PD, and hypoxia did not activate PPTg neurons. PPTg neurons do not input RTN or preBötC regions but receive projections from SNpc. Although our results did not show a reduction in the number of glutamatergic neurons in PPTg, we observed a reduction in the number of neurons activated by hypercapnia in the PD animal model, suggesting that PPTg may participate in the hypercapnia ventilatory response.
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36
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Gamage R, Zaborszky L, Münch G, Gyengesi E. Evaluation of eGFP expression in the ChAT-eGFP transgenic mouse brain. BMC Neurosci 2023; 24:4. [PMID: 36650430 PMCID: PMC9847127 DOI: 10.1186/s12868-023-00773-9] [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: 08/16/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND A historically definitive marker for cholinergic neurons is choline acetyltransferase (ChAT), a synthesizing enzyme for acetylcholine, (ACh), which can be found in high concentrations in cholinergic neurons, both in the central and peripheral nervous systems. ChAT, is produced in the body of the neuron, transported to the nerve terminal (where its concentration is highest), and catalyzes the transfer of an acetyl group from the coenzyme acetyl-CoA to choline, yielding ACh. The creation of bacterial artificial chromosome (BAC) transgenic mice that express promoter-specific fluorescent reporter proteins (green fluorescent protein-[GFP]) provided an enormous advantage for neuroscience. Both in vivo and in vitro experimental methods benefited from the transgenic visualization of cholinergic neurons. Mice were created by adding a BAC clone into the ChAT locus, in which enhanced GFP (eGFP) is inserted into exon 3 at the ChAT initiation codon, robustly and supposedly selectively expressing eGFP in all cholinergic neurons and fibers in the central and peripheral nervous systems as well as in non-neuronal cells. METHODS This project systematically compared the exact distribution of the ChAT-eGFP expressing neurons in the brain with the expression of ChAT by immunohistochemistry using mapping and also made comparisons with in situ hybridization (ISH). RESULTS We qualitatively described the distribution of ChAT-eGFP neurons in the mouse brain by comparing it with the distribution of immunoreactive neurons and ISH data, paying special attention to areas where the expression did not overlap, such as the cortex, striatum, thalamus and hypothalamus. We found a complete overlap between the transgenic expression of eGFP and the immunohistochemical staining in the areas of the cholinergic basal forebrain. However, in the cortex and hippocampus, we found small neurons that were only labeled with the antibody and not expressed eGFP or vice versa. Most importantly, we found no transgenic expression of eGFP in the lateral dorsal, ventral and dorsomedial tegmental nuclei cholinergic cells. CONCLUSION While the majority of the forebrain ChAT expression was aligned in the transgenic animals with immunohistochemistry, other areas of interest, such as the brainstem should be considered before choosing this particular transgenic mouse line.
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Affiliation(s)
- Rashmi Gamage
- grid.1029.a0000 0000 9939 5719Pharmacology Unit, Group of Pharmacology, School of Medicine, Western Sydney University, Penrith, NSW 2751 Australia
| | - Laszlo Zaborszky
- grid.430387.b0000 0004 1936 8796Center for Molecular and Behavioral Neuroscience, Rutgers The State University of New Jersey, Newark, NJ 07102 USA
| | - Gerald Münch
- grid.1029.a0000 0000 9939 5719Pharmacology Unit, Group of Pharmacology, School of Medicine, Western Sydney University, Penrith, NSW 2751 Australia
| | - Erika Gyengesi
- grid.1029.a0000 0000 9939 5719Pharmacology Unit, Group of Pharmacology, School of Medicine, Western Sydney University, Penrith, NSW 2751 Australia
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Lin C, Ridder MC, Sah P. The PPN and motor control: Preclinical studies to deep brain stimulation for Parkinson's disease. Front Neural Circuits 2023; 17:1095441. [PMID: 36925563 PMCID: PMC10011138 DOI: 10.3389/fncir.2023.1095441] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/31/2023] [Indexed: 03/04/2023] Open
Abstract
The pedunculopontine nucleus (PPN) is the major part of the mesencephalic locomotor region, involved in the control of gait and locomotion. The PPN contains glutamatergic, cholinergic, and GABAergic neurons that all make local connections, but also have long-range ascending and descending connections. While initially thought of as a region only involved in gait and locomotion, recent evidence is showing that this structure also participates in decision-making to initiate movement. Clinically, the PPN has been used as a target for deep brain stimulation to manage freezing of gait in late Parkinson's disease. In this review, we will discuss current thinking on the role of the PPN in locomotor control. We will focus on the cytoarchitecture and functional connectivity of the PPN in relationship to motor control.
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Affiliation(s)
- Caixia Lin
- Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia.,Joint Centre for Neuroscience and Neural Engineering, and Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong Province, China
| | - Margreet C Ridder
- Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia
| | - Pankaj Sah
- Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia.,Joint Centre for Neuroscience and Neural Engineering, and Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong Province, China
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Su JH, Hu YW, Song YP, Yang Y, Li RY, Zhou KG, Hu L, Wan XH, Teng F, Jin LJ. Dystonia-like behaviors and impaired sensory-motor integration following neurotoxic lesion of the pedunculopontine tegmental nucleus in mice. Front Neurol 2023; 14:1102837. [PMID: 37064180 PMCID: PMC10101329 DOI: 10.3389/fneur.2023.1102837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/02/2023] [Indexed: 04/18/2023] Open
Abstract
Introduction The pedunculopontine nucleus (PPTg) is a vital interface between the basal ganglia and cerebellum, participating in modulation of the locomotion and muscle tone. Pathological changes of the PPTg have been reported in patients and animal models of dystonia, while its effect and mechanism on the phenotyping of dystonia is still unknown. Methods In this study, a series of behavioral tests focusing on the specific deficits of dystonia were conducted for mice with bilateral and unilateral PPTg excitotoxic lesion, including the dystonia-like movements evaluation, different types of sensory-motor integrations, explorative behaviors and gait. In addition, neural dysfunctions including apoptosis, neuroinflammation, neurodegeneration and neural activation of PPTg-related motor areas in the basal ganglia, reticular formations and cerebellum were also explored. Results Both bilateral and unilateral lesion of the PPTg elicited dystonia-like behaviors featured by the hyperactivity of the hindlimb flexors. Moreover, proprioceptive and auditory sensory-motor integrations were impaired in bilaterally lesioned mice, while no overt alterations were found for the tactile sensory-motor integration, explorative behaviors and gait. Similar but milder behavioral deficits were found in the unilaterally lesioned mice, with an effective compensation was observed for the auditory sensory-motor integration. Histologically, no neural loss, apoptosis, neuroinflammation and neurodegeneration were found in the substantia nigra pars compacta and caudate putamen (CPu) following PPTg lesion, while reduced neural activity was found in the dorsolateral part of the CPu and striatal indirect pathway-related structures including subthalamic nucleus, globus pallidus internus and substantia nigra pars reticular. Moreover, the neural activity was decreased for the reticular formations such as pontine reticular nucleus, parvicellular reticular nucleus and gigantocellular reticular nucleus, while deep cerebellar nuclei were spared. Conclusion In conclusion, lesion of the PPTg could elicit dystonia-like behaviors through its effect on the balance of the striatal pathways and the reticular formations.
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Affiliation(s)
- Jun-Hui Su
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Neurology and Neurological Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
| | - Yao-Wen Hu
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yun-Ping Song
- Department of Neurology and Neurological Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
| | - Yi Yang
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ruo-Yu Li
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Kai-Ge Zhou
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ling Hu
- Department of Laboratory Animal Science, Fudan University, Shanghai, China
| | - Xin-Hua Wan
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Teng
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Fei Teng
| | - Ling-Jing Jin
- Department of Neurology and Neurological Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
- Ling-Jing Jin
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Behavioral Reaction and c-fos Expression after Opioids Injection into the Pedunculopontine Tegmental Nucleus and Electrical Stimulation of the Ventral Tegmental Area. Int J Mol Sci 2022; 24:ijms24010512. [PMID: 36613953 PMCID: PMC9820701 DOI: 10.3390/ijms24010512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/18/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
The pedunculopontine tegmental nucleus (PPN) regulates the activity of dopaminergic cells in the ventral tegmental area (VTA). In this study, the role of opioid receptors (OR) in the PPN on motivated behaviors was investigated by using a model of feeding induced by electrical VTA-stimulation (Es-VTA) in rats (male Wistar; n = 91). We found that the OR excitation by morphine and their blocking by naloxone within the PPN caused a change in the analyzed motivational behavior and neuronal activation. The opioid injections into the PPN resulted in a marked, dose-dependent increase/decrease in latency to feeding response (FR), which corresponded with increased neuronal activity (c-Fos protein), in most of the analyzed brain structures. Morphine dosed at 1.25/1.5 µg into the PPN significantly reduced behavior induced by Es-VTA, whereas morphine dosed at 0.25/0.5 µg into the PPN did not affect this behavior. The opposite effect was observed after the naloxone injection into the PPN, where its lowest doses of 2.5/5.0 μg shortened the FR latency. However, its highest dose of 25.0 μg into the PPN nucleus did not cause FR latency changes. In conclusion, the level of OR arousal in the PPN can modulate the activity of the reward system.
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Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion. Nat Commun 2022; 13:7708. [PMID: 36550097 PMCID: PMC9780347 DOI: 10.1038/s41467-022-35346-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli.
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Nishimaru H, Matsumoto J, Setogawa T, Nishijo H. Neuronal structures controlling locomotor behavior during active and inactive motor states. Neurosci Res 2022; 189:83-93. [PMID: 36549389 DOI: 10.1016/j.neures.2022.12.011] [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: 12/15/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022]
Abstract
Animal behaviors can be divided into two states according to their motor activity: the active motor state, which involves significant body movements, and the inactive motor state, which refers to when the animal is stationary. The timing and duration of these states are determined by the activity of the neuronal circuits involved in motor control. Among these motor circuits, those that generate locomotion are some of the most studied neuronal networks and are widely distributed from the spinal cord to the cerebral cortex. In this review, we discuss recent discoveries, mainly in rodents using state-of-the-art experimental approaches, of the neuronal mechanisms underlying the initiation and termination of locomotion in the brainstem, basal ganglia, and prefrontal cortex. These findings is discussed with reference to studies on the neuronal mechanism of motor control during sleep and the modulation of cortical states in these structures. Accumulating evidence has unraveled the complex yet highly structured network that controls the transition between motor states.
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Affiliation(s)
- Hiroshi Nishimaru
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Graduate school of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan.
| | - Jumpei Matsumoto
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Graduate school of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan
| | - Tsuyoshi Setogawa
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Graduate school of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan
| | - Hisao Nishijo
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Graduate school of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan
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Jia T, Wang YD, Chen J, Zhang X, Cao JL, Xiao C, Zhou C. A nigro-subthalamo-parabrachial pathway modulates pain-like behaviors. Nat Commun 2022; 13:7756. [PMID: 36522327 PMCID: PMC9755217 DOI: 10.1038/s41467-022-35474-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain processing remains unknown. Here, we identify a pathway, consisting of GABAergic neurons in the SNr (SNrGABA) and glutamatergic neurons in the STN (STNGlu) and the lateral parabrachial nucleus (LPBGlu), that modulates acute and persistent pain states in both male and female mice. The activity of STN neurons was enhanced in acute and persistent pain states. This enhancement was accompanied by hypoactivity in SNrGABA neurons and strengthening of the STN-LPB glutamatergic projection. Reversing the dysfunction in the SNrGABA-STNGlu-LPBGlu pathway attenuated activity of LPBGlu neurons and mitigated pain-like behaviors. Therefore, the SNrGABA-STNGlu-LPBGlu pathway regulates pathological pain and is a potential target for pain management.
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Affiliation(s)
- Tao Jia
- grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China
| | - Ying-Di Wang
- grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China
| | - Jing Chen
- grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China
| | - Xue Zhang
- grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China
| | - Jun-Li Cao
- grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China ,grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China ,grid.417303.20000 0000 9927 0537NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China
| | - Cheng Xiao
- grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China ,grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China ,grid.417303.20000 0000 9927 0537NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China
| | - Chunyi Zhou
- grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China ,grid.417303.20000 0000 9927 0537Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China ,grid.417303.20000 0000 9927 0537NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, 221004 Xuzhou, Jiangsu China
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Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic. Trends Pharmacol Sci 2022; 43:1098-1112. [PMID: 36273943 DOI: 10.1016/j.tips.2022.09.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/19/2022] [Accepted: 09/25/2022] [Indexed: 11/11/2022]
Abstract
Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for schizophrenia.
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Su JH, Hu YW, Yang Y, Li RY, Teng F, Li LX, Jin LJ. Dystonia and the pedunculopontine nucleus: Current evidences and potential mechanisms. Front Neurol 2022; 13:1065163. [PMID: 36504662 PMCID: PMC9727297 DOI: 10.3389/fneur.2022.1065163] [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: 10/09/2022] [Accepted: 11/08/2022] [Indexed: 11/24/2022] Open
Abstract
Being a major component of the midbrain locomotion region, the pedunculopontine nucleus (PPN) is known to have various connections with the basal ganglia, the cerebral cortex, thalamus, and motor regions of the brainstem and spinal cord. Functionally, the PPN is associated with muscle tone control and locomotion modulation, including motor initiation, rhythm and speed. In addition to its motor functions, the PPN also contribute to level of arousal, attention, memory and learning. Recent studies have revealed neuropathologic deficits in the PPN in both patients and animal models of dystonia, and deep brain stimulation of the PPN also showed alleviation of axial dystonia in patients of Parkinson's disease. These findings indicate that the PPN might play an important role in the development of dystonia. Moreover, with increasing preclinical evidences showed presence of dystonia-like behaviors, muscle tone changes, impaired cognitive functions and sleep following lesion or neuromodulation of the PPN, it is assumed that the pathological changes of the PPN might contribute to both motor and non-motor manifestations of dystonia. In this review, we aim to summarize the involvement of the PPN in dystonia based on the current preclinical and clinical evidences. Moreover, potential mechanisms for its contributions to the manifestation of dystonia is also discussed base on the dystonia-related basal ganglia-cerebello-thalamo-cortical circuit, providing fundamental insight into the targeting of the PPN for the treatment of dystonia in the future.
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Affiliation(s)
- Jun-hui Su
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China,Department of Neurology and Neurological Rehabilitation, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
| | - Yao-wen Hu
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yi Yang
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ruo-yu Li
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fei Teng
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Li-xi Li
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ling-jing Jin
- Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China,Department of Neurology and Neurological Rehabilitation, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China,*Correspondence: Ling-jing Jin
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Le Gratiet KL, Anderson CK, Puente N, Grandes P, Copas C, Nahirney PC, Delaney KR, Nashmi R. Differential Subcellular Distribution and Release Dynamics of Cotransmitted Cholinergic and GABAergic Synaptic Inputs Modify Dopaminergic Neuronal Excitability. J Neurosci 2022; 42:8670-8693. [PMID: 36195440 PMCID: PMC9671585 DOI: 10.1523/jneurosci.2514-21.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 11/21/2022] Open
Abstract
We identified three types of monosynaptic cholinergic inputs spatially arranged onto medial substantia nigra dopaminergic neurons in male and female mice: cotransmitted acetylcholine (ACh)/GABA, GABA-only, and ACh only. There was a predominant GABA-only conductance along lateral dendrites and soma-centered ACh/GABA cotransmission. In response to repeated stimulation, the GABA conductance found on lateral dendrites decremented less than the proximally located GABA conductance, and was more effective at inhibiting action potentials. While soma-localized ACh/GABA cotransmission showed depression of the GABA component with repeated stimulation, ACh-mediated nicotinic responses were largely maintained. We investigated whether this differential change in inhibitory/excitatory inputs leads to altered neuronal excitability. We found that a depolarizing current or glutamate preceded by cotransmitted ACh/GABA was more effective in eliciting an action potential compared with current, glutamate, or ACh/GABA alone. This enhanced excitability was abolished with nicotinic receptor inhibitors, and modulated by T- and L-type calcium channels, thus establishing that activity of multiple classes of ion channels integrates to shape neuronal excitability.SIGNIFICANCE STATEMENT Our laboratory has previously discovered a population of substantia nigra dopaminegic neurons (DA) that receive cotransmitted ACh and GABA. This study used subcellular optogenetic stimulation of cholinergic presynaptic terminals to map the functional ACh and GABA synaptic inputs across the somatodendritic extent of substantia nigra DA neurons. We determined spatially clustered GABA-only inputs on the lateral dendrites while cotransmitted ACh and GABA clustered close to the soma. We have shown that the action of GABA and ACh in cotransmission spatially clustered near the soma play a critical role in enhancing glutamate-mediated neuronal excitability through the activation of T- and L-type voltage-gated calcium channels.
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Affiliation(s)
| | | | - Nagore Puente
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country Universidad del Pais Vasco / Euskal Herriko Unibertsitatea, Leioa, Spain
- Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, E-48940, Leioa, Spain
| | - Pedro Grandes
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country Universidad del Pais Vasco / Euskal Herriko Unibertsitatea, Leioa, Spain
- Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, E-48940, Leioa, Spain
| | - Charlotte Copas
- Division of Medical Sciences
- Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Patrick C Nahirney
- Division of Medical Sciences
- Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Kerry R Delaney
- Department of Biology
- Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Raad Nashmi
- Department of Biology
- Division of Medical Sciences
- Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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Qian L, Rawashdeh O, Kasas L, Milne MR, Garner N, Sankorrakul K, Marks N, Dean MW, Kim PR, Sharma A, Bellingham MC, Coulson EJ. Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer's disease. Nat Commun 2022; 13:6543. [PMID: 36323689 PMCID: PMC9630433 DOI: 10.1038/s41467-022-33624-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 09/26/2022] [Indexed: 11/07/2022] Open
Abstract
Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer's disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.
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Affiliation(s)
- Lei Qian
- grid.1003.20000 0000 9320 7537Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia ,grid.1003.20000 0000 9320 7537Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia ,grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Oliver Rawashdeh
- grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Leda Kasas
- grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Michael R. Milne
- grid.1003.20000 0000 9320 7537Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia ,grid.1003.20000 0000 9320 7537Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia ,grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Nicholas Garner
- grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Kornraviya Sankorrakul
- grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia ,grid.10223.320000 0004 1937 0490Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Thailand
| | - Nicola Marks
- grid.1003.20000 0000 9320 7537Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Matthew W. Dean
- grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Pu Reum Kim
- grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Aanchal Sharma
- grid.1003.20000 0000 9320 7537Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Mark C. Bellingham
- grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
| | - Elizabeth J. Coulson
- grid.1003.20000 0000 9320 7537Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia ,grid.1003.20000 0000 9320 7537Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 Australia ,grid.1003.20000 0000 9320 7537School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072 Australia
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Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice. Psychopharmacology (Berl) 2022; 239:3263-3276. [PMID: 36006414 DOI: 10.1007/s00213-022-06209-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/02/2022] [Indexed: 10/15/2022]
Abstract
RATIONALE Drug-induced potentiation of ventral tegmental area (VTA) glutamate signaling contributes critically to the induction of sensitization - an enhancement in responding to a drug following exposure which is thought to reflect neural changes underlying drug addiction. The laterodorsal tegmental nucleus (LDTg) provides one of several sources of glutamate input to the VTA. OBJECTIVE We used optogenetic techniques to test either the role of LDTg glutamate cells or their VTA afferents in the development of cocaine sensitization in male VGluT2::Cre mice. These were inhibited using halorhodopsin during each of five daily cocaine exposure injections. The expression of locomotor sensitization was assessed following a cocaine challenge injection 1-week later. RESULTS The locomotor sensitization seen in control mice was absent in male mice subjected to inhibition of LDTg-VTA glutamatergic circuitry during cocaine exposure. As sensitization of nucleus accumbens (NAcc) dopamine (DA) overflow is also induced by this drug exposure regimen, we used microdialysis to measure NAcc DA overflow on the test for sensitization. Consistent with the locomotor sensitization results, inhibition of LDTg glutamate afferents to the VTA during cocaine exposure prevented the sensitization of NAcc DA overflow observed in control mice. CONCLUSIONS These data identify the LDTg as the source of VTA glutamate critical for the development of cocaine sensitization in male mice. Accordingly, the LDTg may give rise to the synapses in the VTA at which glutamatergic plasticity, known to contribute to the enhancement of addictive behaviors, occurs.
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Zhang J, Song C, Dai J, Li L, Yang X, Chen Z. Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu-opioid receptor. MedComm (Beijing) 2022; 3:e148. [PMID: 35774845 PMCID: PMC9218544 DOI: 10.1002/mco2.148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 05/03/2022] [Accepted: 05/07/2022] [Indexed: 11/09/2022] Open
Abstract
Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu-opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR-mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs-mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs-mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented.
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Affiliation(s)
- Jia‐Jia Zhang
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyThe Fourth Military Medical UniversityXi'anChina
| | - Chang‐Geng Song
- Department of NeurologyXijing HospitalThe Fourth Military Medical UniversityXi'anChina
| | - Ji‐Min Dai
- Department of Hepatobiliary SurgeryXijing HospitalThe Fourth Military Medical UniversityXi'anChina
| | - Ling Li
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyThe Fourth Military Medical UniversityXi'anChina
| | - Xiang‐Min Yang
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyThe Fourth Military Medical UniversityXi'anChina
| | - Zhi‐Nan Chen
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyThe Fourth Military Medical UniversityXi'anChina
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Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC. Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia. Am J Psychiatry 2022; 179:611-627. [PMID: 35758639 DOI: 10.1176/appi.ajp.21101083] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders.
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Characterization of social behavior in young and middle-aged ChAT-IRES-Cre mouse. PLoS One 2022; 17:e0272141. [PMID: 35925937 PMCID: PMC9352053 DOI: 10.1371/journal.pone.0272141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/13/2022] [Indexed: 11/19/2022] Open
Abstract
The cholinergic system is an important modulator of brain processes. It contributes to the regulation of several cognitive functions and emotional states, hence altering behaviors. Previous works showed that cholinergic (nicotinic) receptors of the prefrontal cortex are needed for adapted social behaviors. However, these data were obtained in mutant mice that also present alterations of several neurotransmitter systems, in addition to the cholinergic system. ChAT-IRES-Cre mice, that express the Cre recombinase specifically in cholinergic neurons, are useful tools to investigate the role of the cholinergic circuits in behavior. However, their own behavioral phenotype has not yet been fully characterized, in particular social behavior. In addition, the consequences of aging on the cholinergic system of ChAT-IRES-Cre mice has never been studied, despite the fact that aging is known to compromise the cholinergic system efficiency. The aim of the current study was thus to characterize the social phenotype of ChAT-IRES-Cre mice both at young (2–3 months) and middle (10–11 months) ages. Our results reveal an alteration of the cholinergic system, evidenced by a decrease of ChAT, CHT and VAChT gene expression in the striatum of the mice, that was accompanied by mild social disturbances and a tendency towards anxiety. Aging decreased social dominance, without being amplified by the cholinergic alterations. Altogether, this study shows that ChAT-IRES-Cre mice are useful models for studying the cholinergic system‘s role in social behavior using appropriate modulating technics (optogenetic or DREADD).
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