Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors.
Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors.
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DOI：
10.1073/pnas.2008456117
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发表时间：
2020-12-15
影响因子：
11.1
通讯作者：
Zhu JN
中科院分区：
文献类型：
--
作者：
Zhang XY;Peng SY;Shen LP;Zhuang QX;Li B;Xie ST;Li QX;Shi MR;Ma TY;Zhang Q;Wang JJ;Zhu JN
焦虑症和强迫症(OCD)是高度普遍和衰弱的精神疾病，通常在我们紧张的现代生活中共存。然而，常见的有效治疗靶点仍不清楚。在此，我们报道了激活伏隔核(NAC)核心的组胺能传入系统，特别是组胺H3受体，抑制了从前额叶皮质(PRL)到NAC的回路中的谷氨酸能突触传递，并改善了束缚应激诱导的焦虑和强迫样行为。我们的结果定义了一个共同的谷氨酸能PRL-NAC环路，参与H3突触前异型受体调节的焦虑和强迫样行为，为开发潜在的焦虑和强迫症临床治疗策略铺平了道路。焦虑通常与强迫症(OCD)并存。这两者都与压力密切相关。然而，共有的神经生物学底物和治疗靶点仍然不清楚。在这里，我们报道了一种通过谷氨酸能传入终末上的组胺突触前H3异型受体改善焦虑和强迫症的方法，谷氨酸能传入终末从前额叶皮质(PRL)到伏隔核(NAC)核心，伏隔核是边缘环中的一个重要节点。NAC核心直接接受下丘脑组胺能投射，而下丘脑NAC核心组胺能传入的光遗传激活通过H3受体选择性地抑制NAC核心内的谷氨酸能而不是GABA能突触传递，从而产生抗焦虑作用，并改善束缚应激诱导的焦虑和强迫症行为。虽然H3受体在来自PRL、杏仁基底外侧核(BLA)和腹侧海马(VHipp)的谷氨酸能传入终末表达，而不是丘脑，但在NAC核心的谷氨酸能传入通路中，只有PRL-而不是BLA-和vHipp-NAC核心谷氨酸能通路与焦虑和强迫样行为的共存有关。此外，H3受体的激活可改善由PRL-NAC谷氨酸能传入的光遗传兴奋引起的焦虑和强迫样行为。这些结果显示了调节焦虑和强迫症行为的共同机制，并为通过靶向NAC核心的组胺H3受体来治疗强迫症合并焦虑的临床治疗策略提供了洞察力。
Anxiety disorders and obsessive-compulsive disorder (OCD) are highly prevalent and debilitating psychiatric disorders commonly co-occurring in our stressful modern life. Yet the common effective therapeutic target is still unknown. Here we report that activation of the histaminergic afferent system, particularly the histamine H3 receptor, in the nucleus accumbens (NAc) core, a vital node in the limbic loop, inhibits glutamatergic synaptic transmission in the circuit from the prelimbic prefrontal cortex (PrL) to NAc and improves both anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Our results define a common glutamatergic PrL–NAc circuit involved in both anxiety- and obsessive-compulsive-like behaviors modulated by the H3 presynaptic heteroreceptor and pave a path for developing potential strategies for clinical treatment of anxiety and OCD. Anxiety commonly co‐occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL– and not BLA– and vHipp–NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL–NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.
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影响因子：
11
作者：
Ji MJ;Zhang XY;Chen Z;Wang JJ;Zhu JN
通讯作者：
Zhu JN
DOI：
10.1073/pnas.1819978116
发表时间：
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影响因子：
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通讯作者：
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DOI：
10.1192/bjp.2018.62
发表时间：
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期刊：
The British journal of psychiatry : the journal of mental science
影响因子：
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Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Consortium and International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC)
影响因子：
7.6
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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