Modulation of intrinsic excitability in mPFC neurons

Ponce School Of Medicine, Ponce PR

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Abstract

[unreadable] DESCRIPTION (provided by applicant): This proposal addresses a fundamental question in emotion research; can fear extinction be pharmacologically enhanced? Fear extinction is the decrease in fear responses that normally occurs when a conditioned stimulus like a tone is repeatedly presented in the absence of the unconditioned stimulus such as a shock. Our overall goal is to understand the neural mechanisms by which fear extinction can be enhanced. Although behavioral and in vivo electrophysiological studies implicate an increase in medial prefrontal cortex (mPFC) activity in fear extinction, nothing is known about the cellular mechanisms involved. Our current working hypothesis is that pharmacological enhancement of the intrinsic excitability of mPFC neurons projecting to the amygdala will lead to an increase in the recall of extinction. Because the mPFC projection to the amygdala is central to our model of extinction expression, we will concentrate our efforts on mPFC neurons which are known to project to the amygdala. Aim 1 will examine the mechanisms by which the intrinsic excitability of mPFC neurons projecting to the amygdala can be enhanced in vitro through the stimulation of glutamate receptors. Aim 2 will determine whether intrinsic excitability of mPFC neurons is enhanced by synaptic stimulation. Aim 3 will determine whether receptor agonists which enhance the intrinsic excitability of mPFC neurons in vitro enhance extinction learning. Because extinction-based exposure therapies are the main treatment for post-traumatic stress disorder (PTSD) and phobias, there is considerable interest in facilitating extinction with pharmacological agents. [unreadable] [unreadable]