Projection-specific gene expression in resilience to chronic stress

摘要 压力和创伤经历会导致一些人的情绪障碍，而另一些人则是 对这一过程具有弹性，用于治疗重度抑郁症(MDD)的药理工具仅对 患者的子集。此外，MDD影响女性的频率几乎是男性的两倍，但神经生物学上的 这种差异的基础尚不清楚。在目前获得资助的项目的过去五年里，我们 证实海马腹侧向伏核的谷氨酸能投射兴奋性较低 (vHPC-NAC)使雄性小鼠比雌性小鼠对应激诱导的快感丧失有更强的抵抗力，并且 这种影响是由男性体内的睾丸激素直接引起的。然而，睾丸激素的作用机制 调节vHPC-NAC兴奋性的机制尚不清楚。睾丸素通过以下途径产生许多作用 雄激素受体(AR)的激活可以通过胞浆中的信号级联来改变细胞功能 或通过直接与DNA结合和改变基因表达。我们已经证明vHPC-NAC神经元 产生AR并对AR拮抗剂做出反应，我们的初步数据表明，在vHPC-NAC中消除AR 神经元增加兴奋性。这就引出了我们6-10年的首要假设：睾丸激素 VHPC-NAC中AR的激活通过改变驱动行为的基因表达来降低兴奋性 对压力的恢复能力。这一点意义重大，因为识别AR目标/驱动弹性的机制可能会产生 对女性特别有益的新治疗策略，这是由于性行为导致的未得到满足的需求 情绪障碍的差异。我们将通过三个具体目标来解决这个问题：1)揭示 使用新的转基因小鼠和经典药理学，睾丸激素驱动的vHPC-NAC兴奋性的降低； 2)使用新的小鼠品系和电路来揭示睾丸激素驱动的应激恢复机制- 特异性交叉双病毒载体方法；3)确定性别驱动的电路特异性基因表达， 睾酮、雄激素受体采用翻译核糖体亲和纯化。鉴于已建立的 VHPC回路在情绪调节中的作用，这里提出的基因表达研究将是有意义的 影响基础精神病学研究，并可能阐明精神障碍的新治疗策略， 可能对女性患者特别有益。此外，我们对大脑基础性别差异的理解 电路是缺乏的，所以这项工作不仅将为应激研究提供信息，还将增强性作为一种 参与vHPC电路的所有行为中都存在生物变量。

SUMMARY Stressful and traumatic experiences can contribute to mood disorders in some individuals while others are resilient to this process, and pharmacological tools for treating major depression (MDD) are effective on only a subset of patients. Moreover, MDD affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Over the past five years of the current funded project, we demonstrated that lower excitability of ventral hippocampal glutamatergic projections to nucleus accumbens (vHPC-NAc) drives increased resilience to stress-induced anhedonia in male mice compared to females, and that this effect is caused directly by testosterone in males. However, the mechanisms by which testosterone regulates excitability of the vHPC-NAc remain unknown. Testosterone produces many of its effects through activation of the androgen receptor (AR) which can alter cell function through signaling cascades in the cytosol or through directly binding to DNA and altering gene expression. We have shown that vHPC-NAc neurons produce AR and respond to AR antagonists, and our preliminary data show that eliminating AR in vHPC-NAc neurons increases excitability. This leads to our overarching hypothesis for years 6-10: that testosterone activation of ARs in vHPC-NAc decreases excitability through changes in gene expression to drive behavioral resilience to stress. This is significant, as identification of AR targets/mechanisms driving resilience may generate novel therapeutic strategies that would be particularly beneficial in females, an unmet need due to the sexual disparity in mood disorders. We will address this using three specific aims: 1) Uncover the mechanisms of testosterone-driven reduction in vHPC-NAc excitability using novel transgenic mice and classical pharmacology; 2) Uncover the mechanisms of testosterone-driven resilience to stress using novel mouse lines and a circuit- specific intersection dual viral vector approach; and 3) Determine circuit-specific gene expression driven by sex, testosterone, and the androgen receptor using translating ribosome affinity purification. Given the established role of vHPC circuitry in emotional regulation, the gene expression studies proposed here will meaningfully impact basic psychiatric research and may elucidate novel treatment strategies for psychiatric disorders that could be particularly beneficial to female patients. Moreover, our understanding of basal sex differences in brain circuitry is lacking, so this work will inform not only stress studies, but will increase understanding of sex as a biological variable in all behaviors that engage vHPC circuitry.