Role of cortical long-range GABAergic inhibition in emotional learning

Cortical function is characterized by the dynamic interplay of two major forces: excitation and inhibition. A current belief is that dysfunction of inhibition. mediated by local GABAergic interneurons. leads to a wide range of neurological diseases such as epilepsy. autism. schizophrenia. PTSD. A well-established principle of the cortical circuit organization is that inhibition is local while excitation is both local and long-range; however. this ignores that inhibition may be long-range as well. A considerable amount of research on cortico-amygdala communication (coordination of sensory input between the auditory cortex and the lateral amygdala) relies on the reductionist view that the auditory cortex transmits only excitatory signals. It has long been known that long-range GABAergic neurons are important circuits element in many brain areas such as the spiny projection neurons in the striatum and the Purkinje neurons in the cerebellum. Although the existence of cortical long-range GABAergic neurons has been proven anatomically previous studies have primarily focused on the local cortical circuit organization of GABAergic interneurons. and inhibition is frequently described as being exclusively local. Corticofugal long-range subtypes have been described in several cortical areas. including the auditory cortex. Current studies suggest that between 1% to 10% of the cortical GABAergic neurons in rodents. cats. and monkeys are categorized as long-range cortical projections.A growing body of evidence from our lab and others suggests that many of these projections arise from somatostatin-expressing neurons. parvalbumin expressing neurons. and more recently from vasoactive intestinal peptide expressing neurons. Abnormal circuitry underlying cortico-amygdala communication may explain deficits in communication and social behavior observed in autism spectrum disorders and PTSD. What remains largely missing. and is crucial to understanding the cell-type organization and the precise synaptic connectivity of GABAergic neurons with long-range axonal arborization. Preliminary results show that somatostatin-expressing (CLA-Som) neurons project to the lateral amygdala. Determining the circuit organization and behavioral relevance of CLA-Som neurons is critical for understanding the role of long-range GABAergic inhibition in fear/aversive behavior driven by auditory signals.The objective of this proposal is to dissect the CLA-Som ??? LA neurons microcircuits and behavior responsible for cortical amygdala communication. Findings from this proposal will establish a new framework for understanding the roles of long-range GABAergic projections in the modulation of cortical-amygdala pathway.The specific aims of this proposal are to: (1) Establish the anatomical. electrophysiological. gene expression properties of CLA-Som neurons; (2) Determine the impact of CLA-Som neurons on the amygdala network and dissect the circuit mechanisms of inhibition; and (3) Determine the behavioral condition that recruit CLA-Som neurons and their role in fear learning. The approach for addressing these aims will use the mouse as the experimental model. retrograde and optogenetic labeling. specific opto-physiological recordings of synaptic connectivity in defined pathways (e.g.. lateral amygdala and cortical). and fear condition behavioral approaches. Discoveries from this work will be significant because they will provide foundational knowledge regarding circuit and functional aspects of auditory cortex neurons contributing to long-range GABAergic cortical-amygdala communication which is clinically relevant to cortical neuropathologies involving anxiety and phobias.