Dysregulation of kappa opioid receptor neuromodulation of lateral habenula synaptic function following a repetitive mild traumatic brain injury

IF 3.3 3区 心理学 Q1 BEHAVIORAL SCIENCES Pharmacology Biochemistry and Behavior Pub Date : 2024-07-26 DOI:10.1016/j.pbb.2024.173838
William J. Flerlage, Sarah C. Simmons, Emily H. Thomas, Shawn Gouty, Brian M. Cox, Fereshteh S. Nugent
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Abstract

Mild traumatic brain injury (mTBI) increases the risk of affective disorders, anxiety and substance use disorder. The lateral habenula (LHb) plays an important role in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between mTBI-induced LHb hyperactivity due to excitation/inhibition (E/I) imbalance and motivational deficits in male mice using a repetitive closed head injury mTBI model. A major neuromodulatory system that is responsive to traumatic brain injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function are unknown. Here, we first used retrograde tracing in male and female Cre mouse lines and identified several major KOR-expressing and two prominent Dyn-expressing inputs projecting to the mouse LHb, highlighting the medial prefrontal cortex (mPFC) and the ventromedial nucleus of the hypothalamus (VMH) as the main LHb-projecting Dyn inputs that regulate KOR signaling to the LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4 week post-injury. We observed sex-specific differences in spontaneous release of glutamate and GABA from presynaptic terminals onto LHb neurons with higher levels of presynaptic glutamate and GABA release in females compared to male mice. However, KOR effects on the spontaneous E/I ratios and synaptic drive ratio within the LHb did not differ between male and female sham and mTBI mice. KOR activation generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant but sex-similar reduction in net spontaneous E/I and synaptic drive ratios in LHb neurons of sham mice. Following mTBI, while responses to KOR activation at LHb glutamatergic synapses remained intact, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition where we observed a reduction in GABA release probability in response to KOR stimulation in LHb neurons of mTBI mice. Further analysis of percent change in spontaneous synaptic ratios induced by KOR activation revealed that independent of sex mTBI switches KOR-driven synaptic inhibition of LHb neurons (normally observed in sham mice) in a subset of mTBI mice toward synaptic excitation resulting in mTBI-induced divergence of KOR actions within the LHb. Overall, we uncovered the sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. We demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global KOR-driven synaptic inhibition within the mouse LHb independent of sex. The additional engagement of KOR-mediated action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons of a subset of mTBI mice.

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重复性轻度脑外伤后kappa类阿片受体神经调节外侧脑突触功能的失调。
轻度创伤性脑损伤(mTBI)会增加情感障碍、焦虑和药物使用障碍的风险。外侧脑叶(LHb)在精神障碍的病理生理学中扮演着重要角色。最近,我们利用重复性闭合性头部损伤 mTBI 模型证明了雄性小鼠因兴奋/抑制(E/I)失衡而导致的 mTBI 诱导的 LHb 过度活跃与动机缺陷之间的因果关系。对创伤性脑损伤有反应、影响情感状态并调节 LHb 活动的一个主要神经调节系统是达因啡肽/卡巴阿片受体(Dyn/KOR)系统。然而,mTBI 对 KOR 神经调节 LHb 功能的影响尚不清楚。在这里,我们首先在雄性和雌性Cre小鼠品系中进行逆行追踪,确定了投射到小鼠LHb的几个主要的KOR表达输入端和两个突出的Dyn表达输入端,强调了内侧前额叶皮层(mPFC)和下丘脑腹内侧核(VMH)是投射到LHb的主要Dyn输入端,可调节KOR对LHb的信号传导。然后,我们从功能上评估了体外 KOR 调节损伤后 4 周雌雄假小鼠和 mTBI 小鼠 LHb 内自发突触活动的影响。我们观察到 LHb 神经元突触前终端自发释放谷氨酸和 GABA 的性别差异,雌性小鼠的突触前谷氨酸和 GABA 释放水平高于雄性小鼠。然而,KOR 对 LHb 内自发 E/I 比率和突触驱动比率的影响在雌雄假小鼠和 mTBI 小鼠之间并无差异。KOR 激活通常会抑制自发的谷氨酸能传递,而不会改变 GABA 能传递,从而导致假小鼠 LHb 神经元的净自发 E/I 和突触驱动比显著降低,但降低的程度与性别相似。mTBI 后,虽然 LHb 谷氨酸能突触对 KOR 激活的反应保持不变,但 LHb GABA 能突触对 KOR 介导的抑制获得了额外的敏感性,我们观察到 mTBI 小鼠 LHb 神经元对 KOR 刺激的 GABA 释放概率降低。对 KOR 激活引起的自发突触比率百分比变化的进一步分析表明,与性别无关,mTBI 将 KOR 驱动的 LHb 神经元突触抑制(通常在假小鼠中观察到)在 mTBI 小鼠的一个亚群中转向突触兴奋,导致 mTBI 引起的 KOR 在 LHb 内的作用分化。总之,我们发现了投射到小鼠 LHb 的主要 Dyn/KOR 表达突触输入的来源。我们证明,小鼠LHb内Dyn/KOR信号的参与提供了一种与性别无关的、由KOR驱动的全球性突触抑制。mTBI对LHb GABA能传导的额外KOR介导作用可能会导致mTBI后的E/I失衡,Dyn/KOR信号转导成为mTBI小鼠亚群LHb神经元的去抑制机制。
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来源期刊
CiteScore
6.40
自引率
2.80%
发文量
122
审稿时长
38 days
期刊介绍: Pharmacology Biochemistry & Behavior publishes original reports in the areas of pharmacology and biochemistry in which the primary emphasis and theoretical context are behavioral. Contributions may involve clinical, preclinical, or basic research. Purely biochemical or toxicology studies will not be published. Papers describing the behavioral effects of novel drugs in models of psychiatric, neurological and cognitive disorders, and central pain must include a positive control unless the paper is on a disease where such a drug is not available yet. Papers focusing on physiological processes (e.g., peripheral pain mechanisms, body temperature regulation, seizure activity) are not accepted as we would like to retain the focus of Pharmacology Biochemistry & Behavior on behavior and its interaction with the biochemistry and neurochemistry of the central nervous system. Papers describing the effects of plant materials are generally not considered, unless the active ingredients are studied, the extraction method is well described, the doses tested are known, and clear and definite experimental evidence on the mechanism of action of the active ingredients is provided.
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