The expression of prosocial behavior holds significance across various species, and its disruption stands out as a characteristic symptom in numerous neurodevelopmental and neuropsychiatric disorders such as autism, schizophrenia, and depression. Neuronal activity in the nucleus accumbens, particularly modulated by the neurotransmitter- dopamine, plays a pivotal role in regulating reward-motivated behavior towards both food and social interaction. Although the influence of dopamine on social behavior is extensively researched, there exists a notable gap in our understanding of neuronal activity within the nucleus accumbens during social interactions. In this study, a viral vector was employed to induce the expression of a genetically encoded fluorescent calcium sensor, coupled with mini-scope imaging, to observe calcium dynamics in the nucleus accumbens. The recording of calcium dynamics occurred during an operant task where an experimental mouse pressed a lever to interact with a social partner or in separate sessions to receive a food reward. Our investigation revealed distinct subpopulations of neurons within the striatum that specifically encode food reward, as opposed to other discrete cues or actions associated with the task. The insights gained from this research contribute to a more comprehensive understanding of how signals related to general reward-motivated behavior and prosocial behavior may contribute to disruptions observed in social behavior, particularly in disorders characterized by impaired prosocial behavior.

The ventral tegmental area (VTA) is a key region in the brain’s mesolimbic circuitry playing a role in regulating reward processing, aversion, motivation, and stress-related behaviors, housing both dopamine (DA) and GABA-expressing neurons. GABA neurons in the VTA form direct connections with DA neurons, modulating dopamine and influencing reward-related behaviors. This study aims to characterize two distinct VTA GABA populations marked by expression of the nociceptin gene (Pnoc) and corticotropin-releasing hormone binding protein (Crhbp). Using double transgenic mice and viral targeting, we aim to map the projection patterns of these two populations. We anticipate that Crhbp-GABA expressing populations will innervate the Ventral Pallidum and Lateral Habenula brain areas as these neurons also coexpress Vglut2, a marker for glutamate neurons which are known to project to these regions, whereas, Pnoc-GABA expressing populations might represent the local GABA population that synapses onto DA neurons within the VTA. To assess their functional role, we will optically activate these populations during a real-time place preference task (RTPT) using channelrhodopsin-2 (ChR2). We hypothesize that activation of Pnoc-GABA neurons will result in a negative valence response and support real time place aversion. On the other hand, Crhbp-GABA neurons may have a more varied effect on valence response, based on their coexpression of Vglut2, during the RTPP task. By understanding the roles of VTA GABAergic populations marked by Pnoc and Crhbp expression, we can gain insights into the neural mechanisms involved in reward processing, motivation, and stress, often dysregulated in psychiatric disorders. This understanding could ultimately inform the development of targeted therapeutic interventions for psychiatric conditions characterized by maladaptive behavioral responses to stress and other stimuli.

Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental condition affecting approximately 1% of the world population. Characterized by impaired social interactions, the precise etiology of ASD remains elusive, but emerging research suggests deficits in the mesostriatal pathway may contribute to deficits in social reward processing. In order to better understand the role of the mesostriatal pathway in social reward processing, I performed in vivo microscopy coupled with viral delivery of genetically encoded fluorescent sensors to record nucleus accumbens (NAc) neuronal ensemble activity during an operant task in which mice were trained to press a lever in order to gain access to a social partner mouse. I found distinct populations of neurons that were more active or less active during the social reward task at discrete time points. Understanding the neurobiological mechanisms involved in social reward may pave the way for novel medications and treatments for ASD.

Dopamine (DA) producing neurons of the ventral tegmental area (VTA) in the midbrain regulate reward association learning and motivation. These DA neurons are modulated by neuropeptides and can be separated into distinct subpopulations based on differential gene expression, regulation of activity, and projection patterns. But how these different patterns are established and contribute to distinct functions of DA subpopulations remain poorly understood. One potential key component for these neuropeptides is the transient receptor potential canonical (TRPC) channels. Specifically, we identified the gene encoding TRPC type 6 channel (Trpc6) as having enriched expression in the VTA DA neurons. To determine whether Trpc6 is differentially expressed in VTA DA subpopulations, I utilized the quantitative, multiplexed in situ hybridization methods. Using wild-type mice, I probed for the expression of tyrosine hydroxylase (Th), a marker of all DA neurons, and Trpc6 as well as markers of two subpopulations, corticotropin releasing hormone receptor 1 (Crhr1) and cholecystokinin (Cck). The analysis showed that Trpc6 expression is significantly higher in the Crhr1 subpopulation, of 81%, than in the Cck subpopulation, of 66%. Because neuropeptides like neurotensin increase calcium concentration in DA neurons, we hypothesized that TRPC6 contributes to these neuropeptide-evoked calcium signals. To investigate the role of TRPC6 in DA signaling, I used a viral-based CRISPR/Cas9 approach to induce selective mutagenesis of TRPC6 in specific DA subpopulations. Then, I assessed the calcium responses of subpopulations to neurotensin by measuring the amplitude and neurotensin-evoked oscillations using acute brain slices. We expect the calcium responses to decrease more in the Crhr1 subpopulation than in the Cck subpopulation compared to the control as the Crhr1 population has higher Trpc6 expression. By elucidating the role of TRPC6, we hope to contribute to discovering pharmacological interventions for diseases caused by dopaminergic system dysfunctions such as Parkinson’s disease and substance use disorders.

Prosocial behavior is important to many species and its disruption is a hallmark symptom of many diseases and disorders such as autism. Previous research has shown that the mesostriatal network, which consists in part of neurons located in the midbrain that make the neurotransmitter dopamine and release it downstream in the nucleus accumbens, plays an important role in prosocial behavior. Dopamine neurons express the potassium ion channel Kv7.3 and mutant variants of Kv7.3 have been identified in individuals with autism spectrum disorder (ASD). Here we investigate how the Kv7.3-R2C variant found in ASD patients impacts social behavior and dopamine release in mice. We use viral strategies to express human Kv7.3-R2C in mouse dopamine neurons and a genetically encoded dopamine sensor (dLight1.3) in the nucleus accumbens during a social operant task. We found that while Kv7.3-R2C expression decreased social reward in an operant task rewarded with social behavior, dopamine release was similar between groups. Findings from this study help improve our understanding of how deficits in the mesostriatal pathway may lead to decreased social interaction in patients with ASD.