Non-coding enhancer RNA regulates NPAS4 in the mPFC to control chronic stress-induced anhedonia-like behavior

Hughes, B. W.; Siemsen, B. M.; Berto, S.; Kumar, J.; Cornbrooks, R. G.; Akiki, R. M.; Carter, J. S.; Brase, E. C.; Koike, N.; Scofield, M. D.; Cowan, C. W.; Taniguchi, M.

doi:10.1101/2021.03.04.433930

bioRxiv · 10.1101/2021.03.04.433930

Non-coding enhancer RNA regulates NPAS4 in the mPFC to control chronic stress-induced anhedonia-like behavior

Hughes, B. W.·Siemsen, B. M.·Berto, S.·Kumar, J.·Cornbrooks, R. G.·Akiki, R. M.·Carter, J. S.·Brase, E. C.·Koike, N.·Scofield, M. D.·Cowan, C. W.·Taniguchi, M.

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Abstract

Chronic stress can produce reward system deficits (i.e. anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain unclear. We show here that the neuronal activity-regulated transcription factor, NPAS4, in the mPFC is regulated by chronic social defeat stress (CSDS), and its required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation. Interestingly, NPAS4 is not required for CSDS-induced social avoidance or anxiety-like behavior. We also find that mPFC NPAS4 is required for CSDS-induced reduction of pyramidal cell dendritic spine density, revealing a relationship between mPFC dendritic spine changes and anhedonia-like behavior, but not social avoidance behavior. Finally, transcriptomic analysis from the mPFC revealed that NPAS4 influences expression of numerous genes linked to glutamatergic synapses and ribosomal function, as well as many dysregulated genes observed in common neuropsychiatric disorders, including depression. Together our findings reveal an essential role for the activity-regulated transcription factor, NPAS4, in chronic stress-induced mPFC hypofunction and anhedonia.

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Hughes, B. W., Siemsen, B. M., Berto, S., Kumar, J., Cornbrooks, R. G., Akiki, R. M., Carter, J. S., Brase, E. C., Koike, N., Scofield, M. D., Cowan, C. W., Taniguchi, M.. 2021-03-04. Non-coding enhancer RNA regulates NPAS4 in the mPFC to control chronic stress-induced anhedonia-like behavior. https://doi.org/10.1101/2021.03.04.433930

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