Monday, December 30, 2024
12/30/2024
Abstract Anxiety and fear related disorders comprise some of most common mental illnesses. For anxiety disorders alone, approximately 1 in 3 U.S adults will be affected at some point in their life. Currently available treatments leave approximately 40% of patients without symptom resolution underscoring the need for new therapies to be developed. A key to the rational development of new treatments is improved understanding of the neurobiological mechanisms that regulate the neurons and circuits involved in fear and anxiety behaviors. Areas of the brain involved in emotion, such as the basolateral amygdala (BLa) and medial prefrontal cortex (mPFC) rely on synchronized neuronal oscillations in the theta band (4-12 Hz) to entrain local pyramidal neurons (PNs) and synchronize activity across brain regions for proper long-range communication, and information processing. Aberrant synchronization in these circuits contributes to deficits in emotion that underlie fear disorders. However, despite the established role for theta oscillations in mPFC and BLa during fear states, the mechanisms through which oscillations are generated in the BLa and synchronize with mPFC are poorly understood. Critical to the function of these regions is the neurotransmitter acetylcholine (ACh), which promotes emotional learning and theta oscillations in BLa and mPFC. Supporting the vital role of ACh in emotional circuits is the finding that perturbations of cholinergic signaling produce a range of behavioral effects, including anxiogenic, or anxiolytic states, depressive symptoms, and disrupted fear and extinction learning. Moreover, in all mammals, including humans, the BLa receives by far the most robust cholinergic innervation of any target of the cholinergic basal forebrain. Despite its remarkably dense cholinergic innervation, and critical importance in emotional memory, surprisingly little is known about the mechanisms through which ACh modulates BLa circuits. Therefore, the objective of these studies is to determine at a cellular and circuit level how endogenously released ACh modulates amygdalar microcircuits to regulate fear behaviors. Our central hypothesis is that ACh acts on distinct inhibitory microcircuits in the BLa to promote local oscillations and synchrony between BLa and mPFC and enhance emotional memory. Our hypothesis is based on preliminary data showing that basal forebrain-derived ACh alters BLa circuitry and facilitates oscillatory synchrony with mPFC by differentially modulating distinct types of inhibitory interneurons in BLa. Here, we propose to use electrophysiology, intracranial EEG recording, cell type specific targeting, optogenetics, and behavior to determine the circuit mechanism by which synaptic acetylcholine modulates local BLa oscillations (Aim 1), facilitates BLa-mPFC oscillatory synchrony and gates fear learning (Aim 2) and regulates discrimination between safe and threatening cues (Aim 3). These studies will shed new light on mechanisms underlying anxiety and fear disorders and the role of ACh in emotional processing.
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