IMPACT OF JUVENILE STRESS ON HILAR NPY INTERNEURONS AND CONTEXT SPECIFIC FEAR MEMORY

Juvenile stress (JS) is a rodent model for childhood adversities consisting of stress applied during the postweaning/ prepubertal life phase, causing predispositions to stress-induced neuropsychopathologies such as posttraumatic stress disorder. In humans, resilience to PTSD has been associated with higher levels of neuropeptide Y (NPY) and increase of NPY-positive interneuron activation in the dorsal dentate gyrus (DG). These interneurons regulate the excitability of DG granule cells modulating hippocampus-dependent contextual fear memory.
In this study, adult male mice after JS showed a deficit in NPY-positive neurons in the dorsal DG. These mice responded with increased risk assessment during retrieval to a context that shared features with the original training context while control mice showed more explorative behavior. Immunohistochemistry for NPY showed a 16% decrease of hilar NPY-positive cells in adult mice with JS background compared to control.
To dissect a possible contribution of NPY-positive DG interneurons to context fear memory retrieval, chemogenetic inhibition of these interneurons was performed in retrieval contexts with variing similarity to the training context. Contrary to control animals, mice with inactivated NPY interneurons lacked a differentiated context-dependent freezing response.
A CRISPR-Cas-mediated NPY knock down in the same paradigm was used to discriminate the contribution of NPY from its interneuron effect. Neuronal activity was assessed (via cFos staining) in the DG blades and proximal vs distal CA3.
These results underline the importance of DG NPY interneurons for context specificity during fear memory retrieval and their potential relevance for PTSD, where specificity is impaired leading to generalized fear responses.