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Prairie voles (Microtus ochrogaster) are a powerful model for studying the neurobiology of social bonding, yet tools for region- and cell type-specific gene regulation remain underdeveloped in this species. Here, we present a lentivirus-mediated CRISPR activation and interference (CRISPRa/i) platform for somatic gene modulation in the prairie vole brain. This system enables non-mutagenic, titratable regulation of gene expression in the adult brain without germline modification. Our dual-vector system includes one construct expressing dCas9-VPR (VP64-p65-Rta) referred to as CRISPRa or dCas9-KRAB-MeCP2 (Kruppel-associated box-methyl CpG binding protein 2), referred to as CRISPRi under a neuron-specific promoter, and a second construct delivering a U6-driven sgRNA (single guide RNA) alongside an elongation factor 1 alpha (EF1α)-driven mCherry reporter. We detail the design, production, and stereotaxic delivery of these tools and demonstrate their application by targeting four genes implicated in social behavior (Oxtr, Avpr1a, Drd1,andDrd2) across two mesolimbic brain regions: the nucleus accumbens and ventral pallidum. Gene expression analyses confirmed robust, bidirectional transcriptional modulation for selected targets, establishing a proof of concept for CRISPRa/i in this non-traditional model. The dual-vector design is readily adaptable to other gene targets, cell types, and brain regions, and can be multiplexed to provide a flexible and scalable framework for investigating gene function in behaviorally relevant circuits. These advances represent the first successful implementation of somatic CRISPRa/i in prairie voles and expand the genetic toolkit available for this species. 

Loss of a loved one is a painful event that substantially elevates the risk for physical and mental illness and impaired daily function. Socially monogamous prairie voles are laboratory‐amenable rodents that form life‐long pair bonds and exhibit distress upon partner separation, mirroring phenotypes seen in humans. These attributes make voles an excellent model for studying the biology of loss. In this review, we highlight parallels between humans and prairie voles, focusing on reward system engagement during pair bonding and loss. As yearning is a unique feature that differentiates loss from other negative mental states, we posit a model in which the homeostatic reward mechanisms that help to maintain bonds are disrupted upon loss, resulting in yearning and other negative impacts. Finally, we synthesize studies in humans and voles that delineate the remodeling of reward systems during loss adaptation. The stalling of these processes likely contributes to prolonged grief disorder, a diagnosis recently added to the Diagnostic and Statistical Manual for Psychiatry. 

In monogamous species, prosocial behaviors directed toward partners are dramatically different from those directed toward unknown individuals and potential threats. Dopamine release in the nucleus accumbens has a well-established role in social reward and motivation, but how this mechanism may be engaged to drive the highly divergent social behaviors directed at a partner or unfamiliar conspecific remains unknown. Using monogamous prairie voles, we first employed receptor pharmacology in partner preference and social operant tasks to show that dopamine is critical for the appetitive drive for social interaction but not for low-effort, unconditioned consummatory behaviors. We then leveraged the subsecond temporal resolution of the fluorescent biosensor, GRABDA, to ask whether differential dopamine release might distinguish between partner and novel social access and interaction. We found that partner seeking, anticipation, and interaction resulted in more accumbal dopamine release than the same events directed toward a novel vole. Further, partnerassociated dopamine release decreased after prolonged partner separation. Our results are consistent with a model in which dopamine signaling plays a prominent role in the appetitive aspects of social interactions. Within this framework, differences in partner- and novel-associated dopamine release reflect the selective nature of pair bonds and may drive the partner- and novel-directed social behaviors that reinforce and cement bonds over time. This provides a potential mechanism by which highly conserved reward systems can enable selective, species-appropriate social behaviors.