BACKGROUND Histamine (HA), a wake-promoting monoamine implicated in stress-related arousal states, is synthesized in histidine decarboxylase-expressing hypothalamic neurons of the tuberomammillary nucleus. Histidine decarboxylase-containing varicosities diffusely innervate striatal and mesolimbic networks, including the nucleus accumbens (NAc). The NAc integrates diverse monoaminergic inputs to coordinate motivated behavior. While the NAc expresses various HA receptor subtypes, mechanisms by which HA modulates NAc circuit dynamics are undefined. METHODS Using male D1tdTomato transgenic reporter mice, whole-cell patch-clamp electrophysiology, and input-specific optogenetics, we employed a targeted pharmacological approach to interrogate synaptic mechanisms recruited by HA signaling at glutamatergic synapses in the NAc. We incorporated an immobilization stress protocol to assess whether acute stress engages these mechanisms at glutamatergic synapses onto D1 receptor-expressing [D1(+)] medium spiny neurons (MSNs) in the NAc core. RESULTS HA negatively regulates excitatory gain onto D1(+)-MSNs via presynaptic H3 receptor-dependent long-term depression that requires Gβγ-directed Akt-GSK3β signaling. Furthermore, HA asymmetrically regulates glutamatergic transmission from the prefrontal cortex and mediodorsal thalamus, with inputs from the prefrontal cortex undergoing robust HA-induced long-term depression. Finally, we report that acute immobilization stress attenuates this long-term depression by recruiting endogenous H3 receptor signaling in the NAc at glutamatergic synapses onto D1(+)-MSNs. CONCLUSIONS Stress-evoked HA signaling in the NAc recruits H3 heteroreceptor signaling to shift thalamocortical input onto D1(+)-MSNs in the NAc. Our findings provide novel insight into an understudied neuromodulatory system within the NAc and implicate HA in stress-associated physiological states.

中文翻译：

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组胺 H3 受体功能偏向伏隔核的兴奋性增益

背景技术组胺(HA)是一种与应激相关的觉醒状态有关的促醒单胺，在结节乳头核的表达组氨酸脱羧酶的下丘脑神经元中合成。含组氨酸脱羧酶的静脉曲张广泛支配纹状体和中脑边缘网络，包括伏隔核 (NAc)。NAc 整合了多种单胺能输入来协调动机行为。虽然 NAc 表达各种 HA 受体亚型，但 HA 调节 NAc 电路动力学的机制尚不明确。方法 使用雄性 D1tdTomato 转基因报告小鼠、全细胞膜片钳电生理学和输入特异性光遗传学，我们采用靶向药理学方法来询问由 HA 信号传导在 NAc 中的谷氨酸能突触中募集的突触机制。我们合并了一个固定应力协议来评估急性应力是否在 NAc 核心中的 D1 受体表达 [D1(+)] 中型多刺神经元 (MSN) 上参与这些机制的谷氨酸能突触。结果 HA 通过需要 Gβγ 定向 Akt-GSK3β 信号传导的突触前 H3 受体依赖性长期抑制负调节 D1(+)-MSNs 的兴奋性增益。此外，HA 不对称地调节来自前额叶皮层和内侧丘脑的谷氨酸能传递，来自前额叶皮层的输入经历了强烈的 HA 诱导的长期抑郁症。最后，我们报告说，急性固定应力通过在 D1(+)-MSN 上招募 NAc 中的内源性 H3 受体信号传导来减轻这种长期抑郁症。结论 NAc 中压力诱发的 HA 信号会募集 H3 异源受体信号以将丘脑皮质​​输入转移到 NAc 中的 D1(+)-MSNs。我们的研究结果提供了对 NAc 内未充分研究的神经调节系统的新见解，并暗示 HA 与压力相关的生理状态有关。