NPAS4 in the medial prefrontal cortex mediates chronic social defeat stress-induced anhedonia-like behavior and reductions in excitatory synapses

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    This is a very interesting manuscript that will be of interest to the field of stress neurobiology and neuropsychiatry. Claims about the interactions between stress and medial prefrontal cortex NPAS4 on anhedonia and motivation remain to be firmly established, yet clear evidence is provided for NPAS4 function on medial prefrontal cortex pyramidal neuron dendritic morphology and gene expression.

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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 it is required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation in the mice. 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 reductions in pyramidal neuron dendritic spine density, excitatory synaptic transmission, and presynaptic function, revealing a relationship between perturbation in excitatory synaptic transmission and the expression of anhedonia-like behavior in the mice. Finally, analysis of the mice mPFC tissues revealed that NPAS4 regulates the expression of numerous genes linked to glutamatergic synapses and ribosomal function, the expression of upregulated genes in CSDS-susceptible animals, and differentially expressed genes in postmortem human brains of patients with common neuropsychiatric disorders, including depression. Together, our findings position NPAS4 as a key mediator of chronic stress-induced hypofrontal states and anhedonia-like behavior.

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  1. Author Response

    Reviewer #1 (Public Review):

    The current study uses microbiology, biochemistry, microscopy, and viral vectors to establish a role for prefrontal cortex expression of the immediate early gene NPAS4 in sucrose preference and dendritic spine morphology in the mouse social defeat stress model. The experimental designs are appropriate and the hypotheses addressed are interesting. The paper is generally very well-written and the figures are clear. Most of the statistical analyses are appropriate, and they are reported in clear and useful tables. Thus, the general potential for the studies is quite high. The authors conclusively show that NPAS4 is induced in mPFC in response to social defeat stress and that NPAS4 is important for stress-induced changes in mPFC dendritic spine number. However, some of the key data regarding …

  2. eLife assessment

    This is a very interesting manuscript that will be of interest to the field of stress neurobiology and neuropsychiatry. Claims about the interactions between stress and medial prefrontal cortex NPAS4 on anhedonia and motivation remain to be firmly established, yet clear evidence is provided for NPAS4 function on medial prefrontal cortex pyramidal neuron dendritic morphology and gene expression.

  3. Reviewer #1 (Public Review):

    The current study uses microbiology, biochemistry, microscopy, and viral vectors to establish a role for prefrontal cortex expression of the immediate early gene NPAS4 in sucrose preference and dendritic spine morphology in the mouse social defeat stress model. The experimental designs are appropriate and the hypotheses addressed are interesting. The paper is generally very well-written and the figures are clear. Most of the statistical analyses are appropriate, and they are reported in clear and useful tables. Thus, the general potential for the studies is quite high. The authors conclusively show that NPAS4 is induced in mPFC in response to social defeat stress and that NPAS4 is important for stress-induced changes in mPFC dendritic spine number. However, some of the key data regarding reward motivation …

  4. Reviewer #2 (Public Review):

    The authors investigate whether neuronal activity-regulated transcription factor 4 (NPAS4) in the medial prefrontal cortex (mPFC) is involved in stress-induced effects on neuronal spine synapse density (as a proxy for synaptic activity) and reward behaviors. A major strength of the manuscript is that NPAS4 is shown to be necessary for stress-induced reward deficits and pyramidal neuron spine density. In addition, whole transcriptome analysis of NPAS4 target genes identify a number of genes previously found to be regulated in the postmortem brain of humans with MDD, providing translational relevance to these studies. A weakness is that studies were only performed in male mice so its unclear how generalizable these effects are to females. Despite this, the work will likely impact the field of neuropsychiatry …

  5. Reviewer #3 (Public Review):

    Hughes et al. report a role for the transcription factor NPAS4 in mediating chronic stress-induced reward-related behavioral changes, but not other depression-like behaviors. The authors find that NPAS4 is transiently upregulated in Camk2a+ PFC neurons following a single bout or repeated social defeat stress, and that knocking down PFC Npas4 prevents anhedonia. Presentation of linked individual data for social interaction/avoidance measures with/without interaction partners (Fig2C, E) is commended - all CSDS papers should show data this way. Npas4 also appears to mediate the known effect of stress on spines in PFC, providing novel mechanistic insight into this phenomenon. Npas4 knockdown altered baseline transcription in PFC, which overlapped with other stress and MDD-associated transcriptional changes and …