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Single-Cell Resolution of Individual Variation in Hypothalamic Neurons Allows Targeted Manipulation Affecting Social Motivation

ABSTRACT: One great challenge in neuroscience is connecting molecular and cellular phenotypes to behavioral consequences. Using social motivation as a test case, we propose that individual behavioral trait variation can be leveraged to identify novel components of social reward circuits in the brain. Specifically, we hypothesized that either proportion or molecular features of distinct neuron classes in the hypothalamus can predict individual differences in social motivation. To test this, we generated high-precision single-nucleus RNA-sequencing profiles of >120,000 neurons from the hypothalamus and adjacent thalamus from 36 mice assessed for social motivation, balancing across sex and an autism-associated mutation genotype. Analysis of IEG patterns revealed that PVN Agtr1a+ neurons negatively predict social behavior. Consistent with this, FDA-approved AGTR1A antagonists increase social orienting. Next, analyzing neuronal subtype proportions as predictors of social behavior, we identified multiple neuronal populations whose relative abundance correlated with individual differences in social reward-seeking, particularly the Nxph4+ neurons of the posterior and lateral hypothalamus. Subsequent chemogenetic inhibition of these suppressed multiple aspects of social motivation. This work establishes a proof-of-principle for a new approach using single-cellsingle cell genomics to identify neural substrates for behavior and identifies cellular determinants of social motivation, which suggest therapeutic avenues for disorders with social deficits.

ORGANISM(S): Mus musculus

PROVIDER: GSE291295 | GEO | 2025/03/11

REPOSITORIES: GEO

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Project description:Background Appropriate social interactions influence animal fitness by impacting several processes, such as mating, territory defense, and offspring care. Many studies shedding light on the neurobiological underpinnings of social behavior have focused on nonapeptides (vasopressin, oxytocin, and homologues) and on sexual or parent-offspring interactions. Furthermore, animals have been studied under artificial laboratory conditions, where the consequences of behavioral responses may not be as critical as when expressed under natural environments, therefore obscuring certain physiological responses. We used automated recording of social interactions of wild house mice outside of the breeding season to detect individuals at both tails of a distribution of egocentric network sizes (characterized by number of different partners encountered per day). We then used RNA-seq to perform an unbiased assessment of neural differences in gene expression in the prefrontal cortex, the hippocampus and the hypothalamus between these mice with naturally occurring extreme differences in social network size. Results We found that the neurogenomic pathways associated with having extreme social network sizes differed between the sexes. In females, hundreds of genes were differentially expressed between animals with small and large social network sizes, whereas in males very few were. In males, X-chromosome inactivation pathways in the prefrontal cortex were the ones that better differentiated animals with small from those with large social network sizes animals. In females, animals with small network size showed up-regulation of dopaminergic production and transport pathways in the hypothalamus. Additionally, in females, extracellular matrix deposition on hippocampal neurons was higher in individuals with small relative to large social network size. Conclusions Studying neural substrates of natural variation in social behavior in traditional model organisms in their habitat can open new targets of research for understanding variation in social behavior in other taxa.

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Single-Cell Resolution of Individual Variation in Hypothalamic Neurons Allows Targeted Manipulation Affecting Social Motivation

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