Proper emotional responses are 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 psychopathologies including phobias and anxiety disorders. A well-established principle of the circuit organization underlying emotional learning is that inhibition is local while excitation is both local and long- range. Specifically, 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. However, 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. Therefore, despite the fact that the existence of cortical long-range GABAergic neurons has been proven anatomically, previous studies have primarily focused on the local circuit organization of GABAergic interneurons, and inhibition is frequently described as being exclusively local. A growing body of evidence from our lab and others indicates that many of these long-range GABAergic projections arise from neurons expressing somatostatin, parvalbumin, and more recently from vasoactive intestinal peptide. Since somatostatin neurons form synapses primarily on the distal dendrites of target neurons, it has been suggested that this subpopulation of GABAergic cells plays a critical role modulating the plasticity of incoming sensory inputs. Importantly, strong preliminary evidence from our labs show that somatostatin- expressing neurons project to the lateral amygdala (CLA-Som). This proposal aims at determining the circuit organization and behavioral relevance of CLA-Som neurons in fear learning driven by auditory signals. Specifically, this proposal will dissect the CLA-Som microcircuits and behavior responsible for cortical amygdala communication answering the following questions: What are the anatomical, electrophysiological, and gene expression properties of CLA-Som neurons? What is the impact of CLA-Som neurons on the amygdala network and which are the circuit mechanisms through which they produce inhibition? Which are the behavioral conditions that recruit CLA-Som neurons and their role in fear learning? These questions will be investigated using retrograde and optogenetic labeling, specific neuronal-tagging-physiological recordings, in vivo patch clamping and linear probe recordings, calcium imaging in freely moving mice, and pathway selective chemogentic tools during actual learning. Discoveries from this work will be significant because they will provide foundational knowledge regarding cortical modulation of fear learning, describe a new GABAergic cortical-amygdala pathway, and provide new therapeutic targets for neuropathologies involving anxiety and phobias.
Most studies of fear learning have focused on the excitatory connections involved in fear circuits and/or local inhibitory interactions, with no attention to the role of long-range GABAergic connections across regions. This proposal investigates the physiological and functional role of a novel inhibitory pathway from auditory cortex to the lateral amygdala. Elucidating the contribution of long-range cortical inhibition will provide new therapeutic targets for the treatment of anxiety disorders.
