Lateral habenula circuit dysregulation in mild traumatic brain injury

轻度创伤性脑损伤中的外侧缰核回路失调

基本信息

批准号：
10323062
负责人：
Fereshteh S Nugent
金额：
$ 19.06万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323062
关键词：
Affect Affective Anhedonia Anterior Anxiety Behavior Biochemical Brain Brain Concussion Brain Injuries Brain region Cells Clinical Research Closed head injuries Cognition Development Disease Dissection Dopamine Dynorphins Economic Burden Electrophysiology (science)Employment Frequencies Functional disorder Genetic Glutamates Goals Grant Habenula Human Impairment Individual Injury Laboratories Lateral Literature Long-Term Effects Mediating Mental Depression Mental disorders Midbrain structure Modeling Molecular Target Mood Disorders Moods Motivation Mus Neuronal Plasticity Neurons Nucleus Accumbens Pathogenesis Pathway interactions Patients Physiological Play Prefrontal Cortex Psychopathology Quality of life Receptor Signaling Regulation Reporting Research Rewards Rodent Role Serotonergic System Serotonin Signal Transduction Slice Social Behavior Social Interaction Societies Stress Structure Synapses Synaptic Transmission System Testing Therapeutic Therapeutic Intervention Thinness Transgenic Organisms Traumatic Brain Injury United States Withdrawal Work axon injury behavioral response brain dysfunction cingulate cortex dopaminergic neuron drug withdrawal dysphoria emotion regulation emotional behavior endopeduncular nucleus gamma-Aminobutyric Acid genetic approach injured injury-related death insight kappa opioid receptors mild traumatic brain injury mouse model negative affect neural neural circuit neuronal excitability neuroregulation novel novel therapeutic intervention optogenetics pre-clinical preclinical study reward circuitry social social deficits social relationships spinal cord and brain injury stress related disorder synaptic function therapeutically effective

项目摘要

Summary Traumatic brain injury (TBI) contributes to almost 30% of all injury-related deaths in the United States, but the majority of TBI injuries are mild (mTBI). Anxiety, depression and social impairments are frequently reported as long-term consequences of mTBI that are likely mediated by dysfunction of brain dopamine (DA) and serotonin (SERT) signaling in reward circuits induced by mTBI. The lateral habenula, LHb, is a highly conserved diencephalic structure that is unequivocally important in encoding negative reward information and conveying aversive motivational signals through its prominent inhibitory influence on midbrain DA neurons and raphe SERT neurons. Compared to the growing literature of LHb studies aimed at understanding the contribution of the LHb to development of depression, anxiety and drug withdrawal, the role of LHb in long-term effects of experimental brain injuries on dysregulation of the brain reward circuits is unclear. In this proposal, we aim to demonstrate that dysfunction of LHb neural circuits (specifically focusing on the entopeduncular nucleus (EP)-LHb circuitry) following mTBI contributes to dysregulation of brain reward pathways underlying social anhedonia using state‐of‐the‐art physiological, optogenetic and chemogenetic approaches. We also explore alterations in dynorphin-kappa opioid receptor (DYN/KOR) system induced by mTBI that can contribute to dysregulation of LHb neural circuits and mediate part of the negative affective and anhedonic states of social withdrawal following mTBI. The results of this research will advance our understanding of dysregulation of DYN/KOR signaling in LHb neural systems critical to mood and reward regulation in a cell- and circuit-specific manner following mTBI and help to develop more effective therapeutic intervention to reverse the long- term changes in the function of reward pathways after mTBI.

概括创伤性脑损伤（TBI）在美国所有与伤害相关的死亡中近30％，但是大多数TBI受伤是轻度的（MTBI）。焦虑，抑郁和社会障碍是经常报道是MTBI的长期后果，可能是由大脑功能障碍介导的 MTBI引起的奖励电路中的多巴胺（DA）和5-羟色胺（SERT）信号传导。后来 Habenula，LHB是一种高度保守的双脑结构，在编码中明确重要负面奖励信息并通过其突出的抑制作用传达厌恶动机信号对中脑DA神经元和Raphe Sert神经元的影响。与不断增长的LHB文献相比旨在了解LHB对抑郁，动画和发展的贡献的研究药物提取，LHB在实验性脑损伤对失调失调的长期影响中的作用大脑奖励电路尚不清楚。在此提案中，我们旨在证明LHB功能障碍 MTBI之后的神经回路（专门针对肠核（EP）-LHB电路）通过最先进生理，光遗传学和化学遗传学方法。我们还探索了Dynorphin-kappa的变化 MTBI引起的阿片类药物接收器（DYN/KOR）系统可能导致LHB神经元失调电路和媒体是负面情感和肛门社会退出的一部分 mtbi。这项研究的结果将提高我们对Dyn/Kor失调的理解 LHB神经元系统中的信号传导对于细胞和电路特异性中的情绪和奖励调节至关重要 MTBI之后的方式并有助于开发更有效的治疗干预措施，以扭转长期 MTBI后奖励途径功能的项变化。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Blast-Induced Mild Traumatic Brain Injury Alterations of Corticotropin-Releasing Factor Neuronal Activity in the Mouse Hypothalamic Paraventricular Nucleus.

DOI：
10.3389/fnsyn.2021.804898
发表时间：
2021
期刊：
Frontiers in synaptic neuroscience
影响因子：
3.7
作者：
Simmons S;Langlois LD;Oyola MG;Gouty S;Wu TJ;Nugent FS
通讯作者：
Nugent FS

Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury-Induced Motivational Deficits.

DOI：
10.1089/neu.2022.0224
发表时间：
2023-01
期刊：
JOURNAL OF NEUROTRAUMA
影响因子：
4.2
作者：
Flerlage, William. J. J.;Langlois, Ludovic. D. D.;Rusnak, Milan;Simmons, Sarah. C. C.;Gouty, Shawn;Armstrong, Regina. C. C.;Cox, Brian. M. M.;Symes, Aviva. J. J.;Tsuda, Mumeko. C. C.;Nugent, Fereshteh. S. S.
通讯作者：
Nugent, Fereshteh. S. S.

Repetitive mild traumatic brain injury induces persistent alterations in spontaneous synaptic activity of hippocampal CA1 pyramidal neurons.

DOI：
10.1016/j.ibneur.2022.02.002
发表时间：
2022-06
期刊：
IBRO NEUROSCIENCE REPORTS
影响因子：
1.5
作者：
Langlois, Ludovic D.;Selvaraj, Prabhuanand;Simmons, Sarah C.;Gouty, Shawn;Zhang, Yumin;Nugent, Fereshteh S.
通讯作者：
Nugent, Fereshteh S.

Lateral Habenula Beyond Avoidance: Roles in Stress, Memory, and Decision-Making With Implications for Psychiatric Disorders.