Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury-Induced Motivational Deficits.
Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury-Induced Motivational Deficits.
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DOI：
10.1089/neu.2022.0224
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发表时间：
2023-01
影响因子：
4.2
通讯作者：
Nugent, Fereshteh. S. S.
中科院分区：
文献类型：
--
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.
除了认知缺陷之外，轻度创伤性脑损伤 (mTBI) 的长期后果还包括抑郁（以动机降低、社交退缩和快感缺乏为特征）、焦虑和易怒等情感障碍，这表明情绪/动机神经回路可能存在失调。控制动机和情绪的重要大脑区域之一是外侧缰核 (LHb)，其过度活跃与抑郁有关。在这里，我们使用了与成年雄性小鼠社交缺陷相关的重复性闭合性头部损伤 mTBI 模型，并探讨了损伤后 10-18 天 LHb 活性和动机行为可能发生的长期变化。我们发现 mTBI 增加了自发强直活动 LHb 神经元的比例，但降低了表现出爆发活动的 LHb 神经元的比例。此外，mTBI 减少了 LHb 神经元的自发谷氨酸能和 GABA 能突触活动，而突触兴奋和抑制 (E/I) 平衡通过更大程度地抑制 GABA 能传递而转向兴奋。在行为上，mTBI 增加了蔗糖飞溅测试中梳理行为的潜伏期，表明 mTBI 后自我护理动机行为减少。为了证明限制 LHb 过度活跃是否可以恢复梳理行为的动机缺陷，我们随后在蔗糖飞溅测试中测试了 Gi (hM4Di)-DREADD 介导的 LHb 活性抑制作用。我们发现 LHb 谷氨酸能神经元的化学遗传学抑制足以逆转 mTBI 诱导的梳理行为延迟。总体而言，我们的研究提供了第一个证据，证明由于突触整合改变导致持续性 LHb 神经元功能障碍，这是 mTBI 失调的动机状态的因果神经相关性。
Affective disorders including depression (characterized by reduced motivation, social withdrawal, and anhedonia), anxiety, and irritability are frequently reported as long-term consequences of mild traumatic brain injury (mTBI) in addition to cognitive deficits, suggesting a possible dysregulation within mood/motivational neural circuits. One of the important brain regions that control motivation and mood is the lateral habenula (LHb), whose hyperactivity is associated with depression. Here, we used a repetitive closed-head injury mTBI model that is associated with social deficits in adult male mice and explored the possible long-term alterations in LHb activity and motivated behavior 10-18 days post-injury. We found that mTBI increased the proportion of spontaneous tonically active LHb neurons yet decreased the proportion of LHb neurons displaying bursting activity. Additionally, mTBI diminished spontaneous glutamatergic and GABAergic synaptic activity onto LHb neurons, while synaptic excitation and inhibition (E/I) balance was shifted toward excitation through a greater suppression of GABAergic transmission. Behaviorally, mTBI increased the latency in grooming behavior in the sucrose splash test suggesting reduced self-care motivated behavior following mTBI. To show whether limiting LHb hyperactivity could restore motivational deficits in grooming behavior, we then tested the effects of Gi (hM4Di)-DREADD-mediated inhibition of LHb activity in the sucrose splash test. We found that chemogenetic inhibition of LHb glutamatergic neurons was sufficient to reverse mTBI-induced delays in grooming behavior. Overall, our study provides the first evidence for persistent LHb neuronal dysfunction due to an altered synaptic integration as causal neural correlates of dysregulated motivational states by mTBI.
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影响因子：
10.6
作者：
Howlett JR;Nelson LD;Stein MB
通讯作者：
Stein MB
神经元型特异性信号，用于腹侧对段区域的奖励和惩罚。
影响因子：
64.8
作者：
Cohen, Jeremiah Y.;Haesler, Sebastian;Vong, Linh;Lowell, Bradford B.;Uchida, Naoshige
通讯作者：
Uchida, Naoshige
影响因子：
3.4
作者：
Langlois LD;Berman RY;Shepard RD;Simmons SC;Tsuda MC;Gouty S;Choi KH;Nugent FS
通讯作者：
Nugent FS
影响因子：
16.6
作者：
Faget L;Zell V;Souter E;McPherson A;Ressler R;Gutierrez-Reed N;Yoo JH;Dulcis D;Hnasko TS
通讯作者：
Hnasko TS
DOI：
10.1016/j.apmr.2013.08.299
发表时间：
2014-03-01
影响因子：
4.3
作者：
Cassidy, J David;Cancelliere, Carol;Borg, Jorgen
通讯作者：
Borg, Jorgen