Lateral habenula circuit dysregulation in mild traumatic brain injury

摘要 在美国，创伤性脑损伤(TBI)占所有与伤害相关的死亡的近30%， 但大多数颅脑损伤是轻微的(MTBI)。焦虑、抑郁和社交障碍 经常被报道为mTBI的长期后果，可能由脑功能障碍介导 多巴胺(DA)和5-羟色胺(SERT)在mTBI诱导的奖赏回路中的信号转导。侧向 缰核，LHb，是一种高度保守的间脑结构，在编码过程中无疑是重要的 负性奖赏信息通过显著抑制传递厌恶动机信号 对中脑DA神经元和中缝SERT神经元的影响。与不断增长的LHb文献相比 旨在了解LHb对抑郁症、焦虑症和 药物戒断、LHb在实验性脑损伤调节失调中的长期作用 大脑奖励回路尚不清楚。在这项提案中，我们的目的是证明LHb功能障碍 MTBI后的神经回路(特别是丘脑内侧核(EP)-LHb回路) 使用最先进的技术导致社交快感缺乏症潜在的大脑奖励通路失调 生理学、光遗传学和化学遗传学方法。我们还探讨了强啡肽-kappa的变化。 MTBI诱导的阿片受体(Dyn/KOR)系统参与LHb神经调节失调 社交退缩的负性情绪和非享乐状态的环路和部分调节 MTBI。这项研究的结果将促进我们对Dyn/KOR失调的理解 LHb神经系统中的信号对细胞和回路特异性的情绪和奖赏调节至关重要 并有助于开发更有效的治疗干预措施来逆转长期的脑损伤。 MTBI后奖赏通路功能的时程变化。

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.