权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Serotonergic modulation of the circuits and cell-types of the lateral habenula

外侧缰核电路和细胞类型的血清素调节

基本信息

批准号：
10713125
负责人：
Michael L Wallace
金额：
$ 62.04万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713125
关键词：
Action Potentials Acute Affect Anhedonia Antidepressive Agents Arousal Axon Behavior Behavioral Brain Brain region Calcium Cells Chronic stress Color Data Disease Dopamine Electrophysiology (science)Emotional Exhibits Fire - disasters Foundations G-Protein-Coupled Receptors Genes Habenula Head Human Hyperactivity In Vitro Individual Ion Channel Lateral Learning Link Longitudinal Studies Major Depressive Disorder Measures Mediator Mental Depression Mental disorders Methods Midbrain structure Mus Neuromodulator Neurons Norepinephrine Optics Outcome Pattern Pharmaceutical Preparations Pharmacologic Substance Prosencephalon Psychiatric therapeutic procedure Psychological reinforcement Reporting Rodent Model Selective Serotonin Reuptake Inhibitor Serotonin Stress Structure Synapses Synaptic Transmission Techniques Testing Therapeutic Therapeutic Intervention Time Work behavioral phenotyping cell type cognitive process common treatment differential expression fluorophore hindbrain improved in vivo memory process motivated behavior motor control nervous system disorder neural circuit neuronal circuitry receptor sensor serotonin receptor spatiotemporal transcriptome transcriptomics

项目摘要

Project Summary Serotonin (5-HT)-releasing neurons in the mammalian mid/hindbrain are critical for fundamental behaviors and cognitive processes, including emotional control, arousal, and motor control. Selective serotonin reuptake inhibitors (SSRIs) increase brain 5-HT levels and are the most commonly prescribed treatment for major- depression in humans. However, our understanding of the mechanisms by which 5-HT influences synapses, cells, and circuits is limited, prohibiting improvement of depression therapeutics. A major target of 5-HT neurons is the lateral habenula (LHb), a subcortical structure principally implicated in evaluating the outcome (positive or negative) of an action. The LHb is the only brain region that shows consistent hyperactivity several rodent models of chronic stress and additional studies have recently refined this observation indicating “burst- firing” in LHb is causally related several behavioral phenotypes (including anhedonia) following chronic stress. Recently, using single-cell transcriptome wide sequencing, we genetically defined the neuronal subclasses within the LHb for the first time revealing cell-type specific expression of both 5-HT receptors and genes related to burst-firing. Our central hypothesis is that 5-HT release dynamically modulates the habenula circuit though neuron-type specific expression of 5-HT receptors and that burst-firing in specific, genetically defined LHb neuron-types is required for anhedonia following chronic stress. This proposal seeks to 1) identify the neuron-type(s) in the LHb that exhibit burst-firing in vitro and in vivo, 2) determine how 5-HT modulates neuron-types and local connectivity within the LHb and 3) define the neuron-types in the LHb required for chronic stress induced anhedonia. By revealing how 5-HT modulates habenular circuits, the proposed work will provide a comprehensive understanding of the cellular and circuit targets of this important neuromodulator. These findings will form the foundation for understanding the principal mechanisms by which SSRIs impact synapses and circuits of the LHb, uncovering new avenues for therapeutic intervention in major depressive disorder and other neurological disorders treated by these drugs.

项目总结