UC Riverside

Determining the appropriate circumstances in which to express fear-related behavior is a difficult yet important cognitive challenge for behaving animals; insufficient fear increases vulnerability to predation and other threats, but excessive fear may lead to lost opportunities and foregone resources. Despite considerable research, the neural circuitry that enables the mammalian brain to successfully associate danger and safety cues with appropriate behavioral responses is not yet fully understood. However, recent studies have identified a pivotal role of the medial prefrontal cortex (mPFC), particularly for complex tasks requiring an appropriate balancing of fear versus safety learning and/or involving complex or ambiguous danger-associated cues. In the present work, we investigated the involvement of the prelimbic (PL) and infralimbic (IL) subdivisions of mPFC in the acquisition of contextual fear discrimination learning, a task in which subjects are challenged to maintain appropriate expression of fear to an aversive context (CS+) while suppressing the inappropriate expression of fear to a similar yet harmless context (CS-). We tested the role of PL and IL by selectively transforming these subregions with CBP∆HAT, a dominant-negative mutation of CBP (CREB Binding Protein) with eliminated intrinsic histone acetyltransferase activity but intact transcriptional facilitation, which induces hypofunction of local memory storage by impairing neuronal capacity for activity-dependent histone acetylation. We found that transforming either PL or IL with CBP∆HAT impairs the acquisition of contextual fear discrimination. Furthermore, we found that selectively transforming the subpopulation of PL neurons which projects to the basolateral amygdala (BLA) is sufficient to recapitulate the impairment produced by indiscriminately transforming the entire PL. These results show that both PL and IL are important loci for the storage of contextual fear discrimination learning, and that the PL→BLA pathway is a key component of PL’s role as such. These findings further build and clarify our understanding of what neural perturbations can upset the delicate balance between fear and safety, and suggest new insights into the possible etiology of anxiety disorders such as Post-Traumatic Stress Disorder.