Early Life Stress Effects on Ventral Hippocampal Microcircuitry during Emotional Behaviors

我是一名精神病学的物理学家兼科学家，研究精神疾病的神经回路， 动物模型，使我们能够记录和操纵单细胞分辨率的实时神经元活动。 我的职业目标是成为发育风险因素，微电路生理学和情绪方面的专家。 处理.这个职业发展奖将支持我的工作，以确定早期生活压力的影响 腹侧海马微电路以及这如何影响焦虑和快感缺乏相关行为， 成年早期生活压力（ELS）会增加成年精神疾病的风险，因此了解ELS如何 影响控制情绪行为的神经回路将提供一种机制， 脆弱性和指向治疗目标。我们可以通过诱导片段化的 产妇护理在产后早期，然后检查神经活动期间的焦虑和奖励- 在成年期寻求行为。海马体的腹侧部分直接与恐惧 和奖励回路，并与情绪处理密切相关。兴奋性锥体细胞 海马中的神经元和抑制性中间神经元对于控制信息流和 这些电路的其他区域。ELS改变了中间神经元的发育， 和抑制性突触密度。我们还不知道ELS如何影响海马 体内兴奋性和抑制性细胞活性以及这些变化与观察到的行为 差异该提案将通过三个具体目标解决这些问题。在目标1中，我将测试 ELS后成年小鼠焦虑样行为改变和奖赏寻求减少的假设是 与腹侧海马CA 1输出区（vCA 1）锥体细胞活性增加相关。 在目标2中，我将确定ELS在发育和成年期间对vCA 1中PV神经元的影响。 首先，我将测试ELS在焦虑样和奖励性刺激期间降低vCA 1 PV细胞活性的假设。 行为。然后，我将检验这一假设，即ELS后海马中PV的过早表达是 与全球海马神经活动的变化，积极和消极的刺激作出反应。在 目的3，我将检验这样的假设，即在正常饲养的成年小鼠中抑制vCA 1 PV细胞活性可以改变 焦虑和快感缺乏的行为我将在纽约州立精神病研究所进行这项工作 以及哥伦比亚大学，由René Hen博士和Kevin Bath博士指导。的培养目标 这个K 08将成为体内钙成像和光遗传学操纵的专家， 小鼠，ELS和神经发育的动物模型，检查任务相关的计算技术 在神经放电中的表征，以及用免疫染色的体积显微镜成像。一旦完成 有了这些科学目标和培训目标，我将准备好过渡到职业生涯的下一阶段， 在学术医学中心指导研究小组的独立调查员。

I am a physician-scientist in psychiatry studying neural circuits involved in psychiatric illness using animal models that enable us to record and manipulate real-time neuronal activity with single-cell resolution. My career goal is to become an expert on developmental risk factors, microcircuit physiology, and emotional processing. This career development award will support my work to determine the impact of early life stress on ventral hippocampal microcircuitry and how this influences anxiety- and anhedonia-related behaviors in adulthood. Early life stress (ELS) increases the risk of adult psychiatric illnesses, so understanding how ELS affects the neural circuits controlling emotional behaviors would provide a mechanism for this increased vulnerability and point towards therapeutic targets. We can model ELS in rodents by inducing fragmented maternal care in the early postnatal period and then examine neural activity during anxiety-like and reward- seeking behaviors in adulthood. The ventral portion of the hippocampus is directly connected to both fear and reward circuits, and heavily involved in emotional processing. The balance between excitatory pyramidal cells and inhibitory interneurons in the hippocampus is important for controlling the flow of information to and from other regions of these circuits. ELS alters the development of interneurons and decreases excitatory and inhibitory synaptic density in the hippocampus. We do not yet know how ELS affects hippocampal excitatory and inhibitory cell activity in vivo and how these changes relate to observed behavioral differences. This proposal will address these questions through three Specific Aims. In Aim 1, I will test the hypothesis that altered anxiety-like behavior and decreased reward-seeking in adult mice after ELS are correlated with increased pyramidal cell activity in the CA1 output region of the ventral hippocampus (vCA1). In Aim 2, I will determine the effects of ELS on PV neurons in the vCA1 during development and adulthood. First, I will test the hypothesis that ELS decreases vCA1 PV cell activity during anxiety-like and reward behaviors. Then, I will test the hypothesis that precocious expression of PV in the hippocampus after ELS is associated with changes in global hippocampal neural activity in response to positive and negative stimuli. In Aim 3, I will test the hypothesis that inhibition of vCA1 PV cell activity in normally-reared adult mice can alter anxiety- and anhedonia-like behaviors. I will conduct this work within the New York State Psychiatric Institute and Columbia University under the mentorship of Drs. René Hen and Kevin Bath. The training objectives of this K08 are to become an expert in in vivo calcium imaging and optogenetic manipulations in freely moving mice, animal models for ELS and neurodevelopment, computational techniques for examining task-related representations in neural firing, and volume microscopy imaging with immunostaining. Upon completing these scientific aims and training objectives, I will be prepared to transition to the next phase of my career as an independent investigator directing a research group at an academic medical center.