Authors:

Anastasia Tchernikov

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About Paper:

Post-traumatic stress disorder (PTSD) is a severe psychiatric condition often marked by fear generalization, in which threat responses extend to stimuli beyond the original traumatic event. The medial prefrontal cortex (mPFC) plays a central role in fear learning and expression, making it a key target for studying anxiety disorders and PTSD. Corticotropin-releasing factor (CRF), a stress-related neuropeptide, is expressed in a subset of inhibitory interneurons in the mPFC and is often elevated in the cerebrospinal fluid of individuals with PTSD, suggesting persistent CRF neuron hyperactivity. Within the mPFC, CRF primarily acts on corticotropin-releasing factor receptor type 1 (CRF 1), located on excitatory projection neurons that influence downstream fear circuits. However, the specific role of mPFC CRF-CRF1 signaling in fear behaviors, particularly fear generalization, remains unclear. We hypothesized that fear expression would increase CRF release, and that inhibiting or activating mPFC CRF neurons would decrease or increase fear behaviors, respectively. To test this, we used a classical auditory Pavlovian fear conditioning task, pairing a tone with a shock in mice. We then used fiber photometry with a CRF sensor to measure mPFC CRF release, optogenetics to test the causal role of mPFC CRF neurons, and pharmacology to test the necessity of CRF1 signaling. Fear conditioning increased both freezing behavior and CRF release during acquisition and generalization. In males, inhibiting mPFC CRF neurons reduced freezing during fear generalization, but not during acquisition or recall, an effect not observed in females. Conversely, activation of mPFC CRF neurons increased freezing during generalization in males, suggesting a causal role of mPFC CRF neurons in regulating fear generalization. Also, pharmacological inhibition of CRF1 showed a general trend toward reduced freezing. These findings support a sex-specific circuit mechanism in which mPFC CRF-CRF1 signaling selectively regulates fear generalization, advancing our understanding of neural mechanisms underlying PTSD and anxiety disorders.

Source:

Northwestern University

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Co-authors:

Anastasia Tchernikov