Role of GABAergic inhibition in the hippocampal contribution to stress susceptibility

压力神经生物学领域的一个基本问题是为什么我们对压力的反应不同。研究压力易感性个体差异的生物学机制对压力对记忆的影响具有重要意义。海马体是对压力敏感性至关重要的大脑区域之一。海马体不仅在记忆中发挥重要作用，而且对压力高度敏感。虽然应激易感性与海马的高活性有关，但海马变化的机制尚不清楚。本研究计划的长期目标是研究海马GABA能抑制在应激易感性中的作用。海马神经元活动受兴奋性和抑制性突触传递之间的平衡调节。除了神经抑制外，GABA能神经元的活性对于记忆形成的感觉信息的处理至关重要。由于GABA能抑制对应激高度敏感，我们推测应激敏感性受海马GABA能神经元活性的调节。我们的短期目标是研究两种类型的GABA能中间神经元的功能特性的变化：小白蛋白（PV神经元）和生长抑素表达神经元（SOM神经元）在小鼠中，无论是敏感的或弹性的慢性社会失败压力。在第一个目标中，我们将使用体外技术来检查具有不同应激易感性的小鼠中GABA能抑制的变化。我们将首先使用电生理学来检查这些小鼠中突触传递的变化。接下来，我们将研究不同应激敏感性小鼠PV和SOM神经元的兴奋性和突触输入。我们还将研究通过光遗传学方法调节PV或SOM神经元活性是否能挽救易感小鼠中GABA能传递的减少。最后，我们将研究GABA能传递的变化是否是雌性小鼠更高应激易感性的原因。在第二个目标中，我们将使用UCLA微型显微镜监测PV和SOM神经元活动在自由移动的小鼠。这些神经元活性的变化将在慢性社会失败应激之前、期间和之后在对这种应激源敏感或有弹性的小鼠中进行检查。我们也将使用化学发生技术来研究调节PV或SOM神经元活动对应激易感性的影响。这项研究计划将促进我们对海马GABA能神经元如何调节应激易感性的理解。我们的研究结果还将揭示这些GABA能中间神经元如何促进重复厌恶体验的处理，这是慢性应激对记忆影响的基础机制。

A fundamental question in the field of stress neurobiology is why we respond to stress differently. Investigating the biological mechanism of individual differences in stress susceptibility has important implications for the impact of stress on memory. One of the brain regions that is imperative for stress susceptibility is the hippocampus. The hippocampus not only is well-known for its roles in memory, but also is highly sensitive to stress. Although stress susceptibility has been associated with high hippocampal activity, mechanisms underlying this hippocampal change remain unclear. The long-term goal of this research program is to investigate the role of hippocampal GABAergic inhibition in stress susceptibility. Hippocampal activity is regulated by the balance between excitatory and inhibitory synaptic transmission. Apart from neural inhibition, activity of GABAergic neurons is crucial for the processing of sensory information for memory formation. Since GABAergic inhibition is highly sensitive to stress, we hypothesize that stress susceptibility is regulated by the activity of GABAergic neurons in the hippocampus. Our short-term goal is to examine changes in the functional property of two types of GABAergic interneurons: parvalbumin- (PV neurons) and somatostatin-expressing neurons (SOM neurons) in mice that are either susceptible or resilient to chronic social defeat stress. In the first objective, we will use in vitro techniques to examine changes in GABAergic inhibition in mice with different stress susceptibilities. We will first use electrophysiology to examine changes in synaptic transmission in these mice. Next, we will study the excitability of and synaptic inputs onto PV and SOM neurons in mice with different stress susceptibilities. We will also examine if modulating PV or SOM neuronal activity by optogenetic approaches rescues the reduction of GABAergic transmission in susceptible mice. Finally, we will investigate if changes in GABAergic transmission are responsible for the higher stress susceptibility in female mice. In the second objective, we will use the UCLA miniscope to monitor PV and SOM neuronal activity in freely moving mice. Changes in the activity of these neurons will be examined before, during and after chronic social defeat stress in mice that are either susceptible or resilient to this stressor. We will also use the chemogenetic technique to study the effect of modulating PV or SOM neuronal activity on stress susceptibility. This research program will advance our understanding of how stress susceptibility is regulated by hippocampal GABAergic neurons. Our findings will also reveal how these GABAergic interneurons contribute to the processing of repeated aversive experiences, a mechanism that underlies the impact of chronic stress on memory.