Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
Biol Psychiatry. 2021 Mar 15;89(6):588-599. doi: 10.1016/j.biopsych.2020.07.023. Epub 2020 Aug 6.
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.
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 D receptor-expressing [D1(+)] medium spiny neurons (MSNs) in the NAc core.
HA negatively regulates excitatory gain onto D1(+)-MSNs via presynaptic H receptor-dependent long-term depression that requires G-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 H receptor signaling in the NAc at glutamatergic synapses onto D1(+)-MSNs.
Stress-evoked HA signaling in the NAc recruits H 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.
组胺（HA）是一种促觉醒的单胺类物质，与应激相关的觉醒状态有关，它在丘脑中表达组氨酸脱羧酶的神经元中合成。含组氨酸脱羧酶的轴突突末梢广泛地支配纹状体和中脑边缘网络，包括伏隔核（NAc）。NAc 整合了各种单胺能输入，以协调动机行为。虽然 NAc 表达了各种 HA 受体亚型，但 HA 调节 NAc 回路动力学的机制尚不清楚。
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研究 HA 信号在 NAc 中的谷氨酸能突触处激活的突触机制。我们加入了固定应激方案，以评估急性应激是否在 NAc 核心中 D 受体表达 [D1(+)] 中型多棘神经元（MSNs）的谷氨酸能突触处激活这些机制。
HA 通过 H 受体依赖性的长时程抑郁（需要 G 定向的 Akt-GSK3β 信号）负调节 D1(+)-MSNs 的兴奋性输入。此外，HA 不对称地调节来自前额叶皮层和中脑背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 诱导的长时程抑郁。最后，我们报告说，急性固定应激通过在 NAc 中招募内源性 H 受体信号，减弱了 D1(+)-MSNs 上谷氨酸能突触的这种长时程抑郁。
NAc 中的应激诱导的 HA 信号通过招募 H 异源受体信号，在 NAc 中改变了来自前额叶皮层和中脑背侧丘脑的谷氨酸能输入到 D1(+)-MSNs 的投射。我们的发现为 NAc 中一个研究较少的神经调节系统提供了新的见解，并暗示 HA 参与了与应激相关的生理状态。
