Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia
Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia
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DOI：
10.1523/jneurosci.1802-19.2019
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发表时间：
2020-01-15
影响因子：
5.3
通讯作者：
Dulcis, Davide
中科院分区：
文献类型：
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作者：
Prakash, Nandkishore;Stark, Christiana J.;Dulcis, Davide
慢性压力会在易感但不具有弹性的个体中诱导快感缺失，这是在人类和动物模型中观察到的现象，但易感性和弹性的分子机制尚未得到很好的理解。我们假设，与压力、奖励和抗抑郁治疗有关的多巴胺能系统可能发挥作用。我们发现，可塑性的β-肾上腺素能系统有助于差异脆弱性的敏感性和弹性的动物所显示的压力。在成年雄性大鼠中使用社会失败和颅内自我刺激评估应激诱导的快感缺失，同时使用免疫组织化学和原位杂交研究了多巴胺能表型的变化。敏感，但没有弹性，大鼠表现出增加的神经元表达的生物合成酶5-羟色胺，色氨酸羟化酶-2（TPH 2），中缝背核（DRy）的腹侧亚核。此外，在所有应激大鼠中观察到DRv介导的（VGLUT 3+）神经元的数量减少。这种神经递质的可塑性是活动依赖性的，如中央杏仁核的化学发生操纵所揭示的，中央杏仁核是一种应激敏感核，形成对DR的主要输入。杏仁核促肾上腺皮质激素释放激素（CRH）+神经元的激活废除了DRy TPH 2+神经元的增加，并改善了易感大鼠中应激诱导的快感缺失。这些发现表明，杏仁核CRH+神经元的激活诱导恢复力，并抑制DRY中的多巴胺能表型的获得，这是易感大鼠的特征。这种易受压力诱导的快感缺失的分子特征和弹性的积极性质可以有针对性地开发与压力相关的疾病（如抑郁症）的新疗法。
Chronic stress induces anhedonia in susceptible but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward, and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation, while changes in serotonergic phenotype were investigated using immunohistochemistry and in situ hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the biosynthetic enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRy). Further, a decrease in the number of DRv glutamatergic (VGLUT3+ ) neurons was observed in all stressed rats. This neurotransmitter plasticity is activity-dependent, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin-releasing hormone (CRH)+ neurons abolished the increase in DRy TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRH+ neurons induces resilience, and suppresses the gain of serotonergic phenotype in the DRy that is characteristic of susceptible rats. This molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be targeted to develop new treatments for stress-related disorders like depression.