Amygdala Inhibitory Circuits

Project Title: Role of amygdala inhibitory circuit neuromodulation in stress disorders

Project Summary
Traumatic stress exposure can lead to long-term stress disorders and represents a considerable risk factor for suicide. Stress disorders such as generalized anxiety and posttraumatic stress disorder (PTSD) have significant links with suicidality and are characterized by plasticity of neural circuits and neurochemical signaling in the amygdala, particularly in the basolateral complex of the amygdala (BLA). The BLA integrates neural inputs from multiple sources and assigns emotional valence to information by establishing distinct streams of information outflow. BLA circuits process inputs to form emotional memories based on the excitation/inhibition balance set by the relative excitatory and inhibitory synaptic inputs to the principal output cells of the BLA. While potentiation at excitatory synapses is the foundation of memory formation, inhibitory circuits regulate the excitation/inhibition balance to control synaptic potentiation, and neuromodulatory signals tune the synaptic interactions. Noradrenergic modulation is thought to signal arousal and contribute significantly to the emotional salience of information processed in the amygdala. Our preliminary preclinical findings in mice suggest that norepinephrine (NE) exerts robust regulatory control over GABAergic parvalbumin (PV) and CCK inhibitory inputs to the BLA principal neurons, and that this control is compromised following traumatic stress exposure. We propose to characterize the noradrenergic modulation of PV and CCK synaptic inputs to BLA principal neurons, and to define the role of noradrenergic modulation of synaptic inhibition in BLA-mediated fear memory formation and anxiogenesis. We will target the noradrenergic afferent regulation of PV and CCK interneuronal circuits using chemogenetic and optogenetic strategies. We will interrogate local PV and CCK interneuron inhibitory synaptic signaling in the BLA for noradrenergic neuromodulation using patch clamp recordings in slices of amygdala. We will use behavioral paradigms to determine the role of the noradrenergic modulation of BLA inhibitory circuits in fear consolidation and extinction and anxiety-like behaviors. Finally, we will test for traumatic stress-induced plasticity of the noradrenergic modulation of inhibitory circuits and the PV and CCK circuit regulation of fear and anxiety-like behaviors. These studies together will reveal the mechanisms of the noradrenergic modulation of BLA circuits and provide important insights into the role(s) of distinct perisomatic inhibitory circuits in the control of BLA-dependent fear memory formation and anxiogenesis, as well as into how these circuits are disrupted by traumatic stress exposure.