Akiki, R. M. | Search bioRxiv

bioRxiv2022

NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

Use of addictive substances creates powerful drug-cue associations that often trigger relapse. Drug seeking is gated in the nucleus accumbens (NAc) by competing activation of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs) that promote, and D2 dopamine receptor-expressing neurons (D2-MSNs) that oppose, drug seeking. We show here that the ensemble of neurons in the NAc that induce the neuronal activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), is required for cocaine-context associations. In addition, NPAS4 functions within NAc D2-MSNs to govern the activation balance of NAc D1-MSNs and D2-MSNs necessary for drug-context memories and cue-induced cocaine, but not sucrose, seeking. NPAS4 regulates drug-cue associations and preponderant D1-MSN activation by influencing a program of gene expression that blocks cocaine-induced potentiation of prefrontal cortical excitatory drive onto D2-MSNs. Together our findings reveal that NPAS4 is a key player governing NAc MSN cell-type activation balance and promoting drug-cue associations and relapse vulnerability.

neuroscience↗

bioRxiv2021

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

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.

neuroscience↗