Photopharmacological interrogation of presynaptic neuromodulation of cortico-amygdalar circuits

项目总结

PROJECT SUMMARY The basolateral amygdala (BLA) serves as a neural hub for the integration of various inputs from across the brain to, in turn, control fear and anxiety-related behaviors and the response to chronic stress. Given this central role in neuropsychiatric disease-relevant emotional processing, neuromodulatory G protein-coupled receptors (GPCRs) that can control BLA function have been proposed as targets for the treatment of anxiety disorders and post-traumatic stress disorder. However, due to the complexity of BLA circuits and the lack of tools for spatiotemporally and genetically precise manipulation of GPCRs in vivo, it remains difficult to understand how specific receptors in defined cell types or projections mediate their effects on BLA circuit function and behavior. Here we will focus on an understanding of how metabotropic glutamate receptor 2 (mGluR2) modulates anxiety and fear-related behaviors using recently developed genetically-targeted photopharmacology in conjunction with slice electrophysiology, behavior, fiber photometry and RNA sequencing. mGluR2 is a critical presynaptic G protein-coupled receptor (GPCR) which mediates both rapid synaptic inhibition and the induction of long-term depression (LTD), although connecting these dynamic synaptic processes to behavioral modulation has been challenging. Our preliminary mapping studies using a Grm2-Cre mouse have shown that mGluR2 is enriched in projections from the ventromedial prefrontal cortex (vmPFC) and posterior insular cortex (pIC) to the BLA, motivating our comparative analysis of these two projection classes. We will define the ability of mGluR2 in each projection to control the synaptic strength of cortical connection to BLA pyramidal neurons and interneurons and use our photopharmacological toolset to link presynaptic modulation to behavioral changes across a battery of measures of avoidance to aversive stimuli and auditory fear conditioning (aim 1, aim 2). We hypothesize that depending on the nature of the aversive stimulus (spatial, somatosensory, social) either inputs from the vmPFC or pIC will play primary roles in behavioral control. In aim 3, we will use a dual optogenetic and projection-targeted RNA sequencing approach to define the synaptic and molecular adaptations that occur in each pathway in response to chronic unpredictable stress. Such analysis should inform future studies of novel projection-defined drug targets that can have desired effects on different aspects of fear and anxiety. Together this project will introduce a novel approach to mapping the synaptic and circuit mechanisms of behavioral control by neuromodulatory GPCRs while providing new insights into neuromodulatory control of the BLA by presynaptic mGluR2.