Rationale-Early-life environment influences reinforcer and drug motivation in adulthood; however, the impact on specific components of motivation, including hedonic value ("liking"), remains unknown.Objectives-The current study determined whether differential rearing alters liking and aversive responding to ethanol, sucrose, and quinine in an ethanol-naïve rat model.Methods-Male and female rats were reared for 30 days starting at postnatal day 21 in either an enriched (EC), isolated (IC), or standard condition (SC). Thereafter, all rats had indwelling intraoral fistulae implanted and their taste reactivity to water, ethanol (5, 10, 20, 30, 40% v/v), sucrose (0.1, 0.25, 0.5 M), and quinine (0.1, 0.5 mM) was recorded and analyzed.Results-EC rats had higher amounts of liking responses to ethanol, sucrose, and quinine and higher amounts of aversive responses to ethanol and quinine compared to IC rats. While EC and IC rats' responses were different from each other, they both tended to be similar to SCs, who fell in between the EC and IC groups.Conclusions-These results suggest that environmental enrichment may enhance sensitivity to a variety of tastants, thereby enhancing liking, while isolation may dull sensitivity, thereby dulling liking. Altogether, the evidence suggests that isolated rats have a shift in the allostatic set-point which may, in part, drive increased responding for a variety of rewards including ethanol and sucrose. Enriched rats have enhanced liking of both sucrose and ethanol suggesting that enrichment may offer a unique phenotype with divergent preferences for incentive motivation.
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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