The Varodayan Lab

Varodayan et al., Neuropharmacology, 2019

The pituitary adenylate cyclase-activating polypeptide (PACAP) system acts as a master regulator of the brain’s emotional response to psychological stress, and its actions in the central amygdala (CeA) are implicated in anxiogenic and stress coping behaviors. In this study, we have identified a novel mechanism for PACAP’s actions; PACAP activates presynaptic PAC1 receptors to facilitate CeA GABA release. This mechanism was suppressed after a single restraint stress, but recovered after repeated sessions, perhaps as a coping mechanism. Collectively, our work demonstrates the critical role of the PACAP/PAC1 system in maintaining local inhibitory control within the CeA. Moreover, dynamic PACAPergic regulation of CeA inhibitory synapses may represent an adaptive mechanism within a key stress circuit after psychological stress, potentially leading to changes in downstream brain regions that mediate anxiety and stress-related behaviors.

Varodayan et al., Neuropharmacology, 2018

Excessive ethanol consumption can lead to significant cognitive deficits, such as risky decision-making, impulse control issues and difficulties with emotional processing. These deficits are generally linked to prefrontal cortex dysfunction, but the underlying neurobiological mechanisms remain unknown. In this study, we identified morphological and functional evidence of excitatory synapse remodeling in the medial prefrontal cortex (mPFC) after one week withdrawal from chronic ethanol exposure. Specifically, withdrawal increased the maturity of dendritic spines and enhanced glutamate signaling in layer 2/3 pyramidal neurons of the prelimbic mPFC. In contrast, dendritic spines in neurons from prelimbic mPFC layer 5 and infralimbic mPFC layers 2/3 and 5 were not affected. Thus, prelimbic layer 2/3 pyramidal neurons form a distinct mPFC cell population that is particularly vulnerable to chronic ethanol exposure and withdrawal. Ongoing work in the lab is exploring how prelimbic layer 2/3 pyramidal neuron activity may contribute to normal cognitive function and ethanol-induced dysfunction using a variety of behavioral tasks.

Varodayan et al., Journal of Neuroscience, 2017

L-type voltage-gated calcium channels (LTCCs) are implicated in several psychiatric disorders that are co-morbid with alcohol use disorder and involve amygdala dysfunction. Within the amygdala, the central nucleus (CeA) is critical in acute alcohol’s reinforcing actions, and its dysregulation in human alcoholics drives their negative emotional state and motivation to drink. Here we investigated the specific role of CeA LTCCs in the effects of acute alcohol at the molecular, cellular physiology and behavioral levels, and their potential neuroadaptation with dependence. We found that acute alcohol increases CeA neuronal activity by engaging LTCCs and that intra-CeA LTCC blockade reduces alcohol intake in non-dependent control individuals. Chronic alcohol exposure disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF₁s) mediate alcohol’s effects on CeA activity and drive the excessive alcohol intake of dependence. Therefore, LTCCs are a critical molecular substrate in the CeA’s neurobiological response to alcohol, and their neuroadaptation with chronic alcohol exposure likely contributes to the pathophysiology of alcohol use disorder.