The role of basal forebrain GABAergic neurons in fear expression and inhibition.

项目总结 高度的威胁反应和情绪学习和记忆的失调是 与恐惧相关的障碍，如创伤后应激障碍。基底前脑(BF)被认为是 通过调节觉醒、警觉和记忆调节恐惧学习和记忆的结构 动机突显。然而，特定的BF细胞类型在条件性恐惧行为表达中的作用 目前仍不清楚。含γ-氨基丁酸(GABA)的神经元是最丰富的BF细胞之一 类型，是对威胁预测线索的反应而被激活，并广泛地投射到整个大脑。更多 重要的是，它们投射到内侧前额叶皮质(MPFC)和基底外侧杏仁核(BLA)，这两个区域 恐惧联想和表达的基本大脑区域。在这份提案中，我将调查BF的角色 GABA能神经元及其在线索恐惧表达和抑制中的长程投射。在目标1中，我 探讨BF GABA能活动对线索恐惧记忆表达和消退的影响。我的 研究揭示了这一群体在线索诱发的冻结中的时间依赖性作用，其中GABA能 记忆表达需要在学习后较远的时间点进行活动，而不是在学习的早期时间点。为了目标2，我会 在恐惧表达时，检查BF GABA能投射到BLA和mPFC。用于Exp.2.1和Exp.2.2 i 将使用体内钙成像和光遗传学方法来评估基底前脑投射在 线索恐惧记忆表达过程中的mPFC和BLA。BF-GABA能传入神经在大鼠脑内的作用 实验中的mPFC和BLA活性。2.3、我将使用体外电生理学。在目标3中，我勾勒出以下计划 博士后研究，包括确定博士后奖学金导师和机构，以及 在风险评估行为分析中使用计算方法来检查神经回路。结果是 这一提议将拓宽我们对恐惧表达和恐惧背后的抑制回路的理解 洞察恐惧记忆电路在远程时间点的变化。

PROJECT SUMMARY Heightened threat response and dysregulation of emotional learning and memory are key characteristics of fear-related disorders such as post-traumatic stress disorder. The basal forebrain (BF) is considered a crucial structure in the regulation of fear learning and memory through the modulation of arousal, vigilance, and motivation salience. However, the role of specific BF cell types in the expression of conditioned fear behaviors remains unclear. Gamma-Aminobutyric acid (GABA)-containing neurons are one of the most abundant BF cell types, are activated in response to threat-predictive cues, and project broadly throughout the brain. More importantly they project to the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) which are essential brain regions in fear association and expression. In this proposal I will investigate the role of BF GABAergic neurons and their long-range projections in cued fear expression and inhibition. In Aim 1 I investigated the contribution of BF GABAergic activity on expression and extinction of cued fear memory. My research revealed a time-dependent role for this population in cue-evoked freezing, wherein GABAergic activity was required for memory expression at remote but not early time points after learning. For Aim 2 I will examine BF GABAergic projections to the BLA and mPFC during fear expression. For Exp. 2.1 and Exp. 2.2 I will use in vivo calcium imaging and optogenetic approaches to assesses the role basal forebrain projections to mPFC and BLA during cued fear memory expression. To examine the effect of BF GABAergic afferents in mPFC and BLA activity in Exp. 2.3, I will use in vitro electrophysiology. In Aim 3, I delineate plans for postdoctoral research, including the identification of a postdoctoral fellowship mentor and institution, and the use of computational methods to examine neural circuits in risk assessment behavioral assays. The results from this proposal will broaden our understanding on inhibitory circuits that underlie fear expression and provide an insight for how fear memory circuits shift at remote timepoints.