The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn/KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABA_AR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABA_AR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

外侧哈贝努拉（LHb）是一个上丘脑区域，通过调节多巴胺（DA）介导的奖励电路，与基于价值的决策和压力回避相关。具体而言，LHb活性增加与药物成瘾，精神分裂症和与压力有关的疾病（如抑郁症，焦虑症和创伤后应激障碍）有关。强啡肽（Dyn）/κ阿片受体（KOR）信号传导是奖励电路中应激反应的介体。以前，我们已经表明，严重的早期生活压力母亲剥夺（MD）会增加LHb自发神经元活动和内在兴奋性，同时使LHb神经元对另一种应激介质下丘脑外促肾上腺皮质激素释放因子（CRF）信号的响应减弱。CRF途径还与Dyn / KOR信号传导相互作用。出奇，尽管LHb在压力，奖赏和厌恶过程中有独特的作用，但对LHb的直接KOR调控的研究很少。为了测试Dyn / KOR信号在LHb中的功能作用，我们在大鼠LHb切片中利用离体电生理学结合药理学工具。我们显示，由KOR激动剂（U50,488）激活KOR会对LHb神经元的两个不同亚群的兴奋性产生不同的影响，这些亚群在其超极化激活阳离子电流（HCN，Ih）的表达上有所不同。具体而言，KOR刺激在具有较大Ih电流（Ih +）的LHb神经元中增加了神经元兴奋性，而在小型/阴性Ih（Ih-）神经元中降低了神经元兴奋性。我们发现，U50的作用需要完整的快速突触传递，488关于Ih-和Ih + LHb神经元亚群的兴奋性。而AMPAR-，GABA单独_的R或NMDAR介导的突触传递足以介导U50,488对Ih神经元（GABA _A）兴奋性的影响R或NMDAR介导的突触传递可在Ih +神经元中介导这些作用。一致地，KOR激活还改变了谷氨酸能和GABA能的突触传递，其中突触前KOR的刺激一致地抑制了谷氨酸释放到LHb神经元上，同时主要降低了谷氨酸释放或在某些情况下增加了GABA释放。我们还发现，与非母体剥夺（非MD）对照大鼠相比，MD显着增加LHb神经元纤维中免疫标记的Dyn（内源性KOR激动剂）标记，同时显着降低LHb组织中KOR的mRNA水平。此外，在MD后没有在U50,488介导的在非MD大鼠中观察到的LHb神经元放电增加。共，