2 The abbreviations used are: RyR, ryanodine receptor ion channel; FKBP, FK506-binding protein; ANOVA, analysis of variance; PDB, Protein Data Bank; IP 3 , inositol 1,4,5-trisphosphate.

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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.

Introduction: There are numerous pharmacologic treatments for opioid use disorder (OUD), but none that directly target the underlying addictive effects of opioids. Oxytocin, a peptide hormone produced in the paraventricular nucleus of the hypothalamus (PVN), has been investigated as a potential therapeutic for OUD. Promising preclinical and clinical results have been reported, but the brain region(s) and mechanism(s) by which oxytocin impacts reward processes remain undetermined. Methods: Here, we assess peripherally administered oxytocin’s impacts on cued reinstatement of heroin seeking following forced abstinence and its effects on neuronal activation in the PVN and key projection regions. We also examine how DREADD-mediated activation or inhibition of oxytocinergic PVN neurons alters cued heroin seeking and social interaction. Results: As predicted, peripheral oxytocin administration successfully decreased cued heroin seeking on days 1 and 30 of abstinence. Oxytocin administration also led to increased neuronal activity within the PVN and the central amygdala (CeA). Activation of oxytocinergic PVN neurons with an excitatory (Gq) DREADD did not impact cued reinstatement or social interaction. In contrast, suppression with an inhibitory (Gi) DREADD reduced heroin seeking on abstinence day 30 and decreased time spent interacting with a novel conspecific. Discussion: These findings reinforce oxytocin’s therapeutic potential for OUD, the basis for which may be driven in part by increased PVN-CeA circuit activity. Our results also suggest that oxytocin has distinct signaling and/or other mechanisms of action to produce these effects, as inhibition, but not activation, of oxytocinergic PVN neurons did not recapitulate the suppression in heroin seeking.

Rationale: Stress plays a dual role in substance use disorders as a precursor to drug intake and a relapse precipitant. With heroin use at epidemic proportions in the United States, understanding interactions between stress disorders and opioid use disorder is vital and will aid in treatment of these frequently comorbid conditions.Objectives: Here, we combine assays of stress and contingent heroin self-administration (SA) to study behavioral adaptations in response to stress and heroin associated cues in male and female rats.Methods: Rats underwent acute restraint stress paired with an odor stimulus and heroin SA for subsequent analysis of stress and heroin cue reactivity. Lofexidine was administered during heroin SA and reinstatement testing to evaluate its therapeutic potential. Rats also underwent tests on the elevated plus maze, locomotor activity in a novel environment, and object recognition memory following stress and/or heroin.Results: A history of stress and heroin resulted in disrupted behavior on multiple levels. Stress rats avoided the stress conditioned stimulus and reinstated heroin seeking in response to it, with males reinstating to a greater extent than females. Lofexidine decreased heroin intake, reinstatement, and motor activity. Previous heroin exposure increased time spent in the closed arms of an elevated plus maze, activity in a round novel field, and resulted in object recognition memory deficits.Discussion: These studies report that a history of stress and heroin results in maladaptive coping strategies and suggests a need for future studies seeking to understand circuits recruited in this pathology and eventually help develop therapeutic approaches.

Background: 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 poorly understood. Methods: C57BL/6 adult male mice were subjected to chronic social defeat stress (CSDS). Neuronal PAS domain-containing protein 4 (NPAS4) or the Npas4 lnc-eRNA were reduced using a viral-mediated shRNA approach. CSDS-induced behaviors, including social avoidance, sucrose preference, natural reward motivation, and anxiety-like behavior, were then measured. CSDS-induced changes in mPFC dendritic spine density were assessed using confocal imaging, and the mPFC NPAS4-regulated transcriptome was assessed using RNA-seq analysis. Results: Social defeat stress induced transient expression of NPAS4 in the mPFC. Viral-mediated knockdown of mPFC NPAS4 blocked CSDS-induced reduction in sucrose preference and changes in natural reward motivation, but without influencing social avoidance. NPAS4 was also required for CSDS-induced reduction of pyramidal neuron dendritic spine density in mPFC. RNA-seq analysis from mPFC tissues revealed that NPAS4 influences expression of numerous genes linked to glutamatergic synapses and ribosomal function, and to genes dysregulated in multiple neuropsychiatric disorders, including depression. Finally, we found that stress-induced expression of NPAS4 in mPFC requires a novel, activity-regulated lnc-eRNA, and that this Npas4 lnc-eRNA in mPFC was required for CSDS-induced anhedonia-like behavior. Conclusion: Together our findings reveal a novel, stress-regulated and lnc-eRNA-dependent transcriptional mechanism in the mPFC that promotes dendritic spine loss and development of anhedonia-like behaviors.

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