Project Summary
The prevalence of post-traumatic stress disorder (PTSD) is nearly 2:1 in women compared with men, yet the
neurobiological basis of this sex difference is unknown. This project addresses this gap, in accordance with
NIMH Strategic Objective 1, by determining how the stress neuropeptide pituitary adenylate cyclase-activating
polypeptide (PACAP) functionally modulates fear circuitry and complex fear behavior, differentially in females
and males. The central hypothesis driving this work is informed by clinical data linking this peptide system with
PTSD. Women, but not men, with a genetic polymorphism within the gene encoding the type 1 receptor for
PACAP (PAC1R) exhibit maladaptive responding to threat-related stimuli: heightened reactivity to threatening
cues and deficits in the ability to learn to discriminate fear and safe cues. Recent work by the PI showed that
interfering with PAC1R signaling within the prefrontal cortex impairs the formation of cued fear memory in female
but not male rats, using a variant of fear conditioning called trace fear conditioning, which requires sustained
attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex.
Females also had higher levels of PAC1R compared with males in that study. The objective of this proposal is
to determine how PACAP-PAC1R signaling modulates activity within the fear circuitry needed for learning about
threat and safety: the prefrontal cortex and its connection with the amygdala. The approach uses multiple levels
of analysis to elucidate the basic biology linking sex-driven changes in peptidergic signaling and physiological
changes in prefrontal-amygdala circuits to alterations in complex fear behavior (NIMH Strategy 1.1, Research
Priority D). The central hypothesis is that PACAP-PAC1R signaling in the prefrontal cortex is dynamically
regulated by estradiol and promotes both the strength and accuracy of fear memories in females, in part by
increasing the excitability and synaptic regulation of amygdala-projecting prefrontal neurons. In Aim 1, the
capacity for PACAP-PAC1R signaling to modulate intrinsic excitability and synaptic regulation of prefrontal cells
connected with the basolateral amygdala will be assessed using ex vivo electrophysiology. In Aim 2, the ability
of PACAP to enhance fear memories yet protect against fear generalization will be tested with local manipulation
of PACAP signaling in the prefrontal cortex during trace conditioning and fear discrimination learning. In Aim 3,
the capacity for estradiol to drive the expression of PAC1R and the consequence on memory of knocking down
PAC1R locally in the prefrontal cortex using shRNA will be examined. Importantly, males and females will be
included in all experiments to determine how PACAP contributes to the sexual dimorphism of the prefrontal
cortex and the degree to which PACAP has the capacity to influence fear learning and behavior in males. The
proposed work is significant because it is expected to advance our current understanding of sexual dimorphism
in the prefrontal cortex as well as to provide a neurobiological substrate for maladaptive fear learning observed
in women with PTSD.