Naumenko, S. | Search bioRxiv

bioRxiv2024

Sensory Input, Sex, and Function Shape Hypothalamic Cell Type Development

Mammalian behavior and physiology undergo dramatic changes in early life. Young animals rely on conspecifics to meet their homeostatic needs, until weaning and puberty initiate nutritional independence and sex-specific social interactions, respectively. How neuronal populations regulating homeostatic functions and social behaviors develop and mature during these transitions remains unclear. We used paired transcriptomic and chromatin accessibility profiling to examine the developmental trajectories of neuronal populations in the hypothalamic preoptic region, where cell types with key roles in physiological and behavioral control have been identified1-6. These data reveal a remarkable diversity of developmental trajectories shaped by the sex of the animal, and the location and behavioral or physiological function of the corresponding cell types. We identify key stages of preoptic development, including the perinatal emergence of sex differences, postnatal maturation and subsequent refinement of signaling networks, and nonlinear transcriptional changes accelerating at the time of weaning and puberty. We assessed preoptic development in various sensory mutants and find a major role for vomeronasal sensing in the timing of preoptic cell type maturation. These results provide novel insights into the development of neurons controlling homeostatic functions and social behaviors and lay ground for examining the dynamics of these functions in early life.

neuroscience↗

bioRxiv2021

Cell-type specific induction of cyclo-oxygenase-2 in layer II/III prefrontal cortical neurons mediates stress-induced anxiety phenotypes in mice.

The ability of the medial prefrontal cortex (mPFC) to exert top-down control of behavior is affected by stress. The molecular response of mPFC to stress is incompletely understood, however, in part because of the regions cellular heterogeneity. Here we used single nucleus RNA sequencing (snRNAseq) to map specific molecular cell types within the mPFC and to detect cell-type specific transcriptional changes to foot-shock stress. We identified Ptgs2, encoding cyclo-oxygenase 2, as an important candidate that is upregulated in layer II/III excitatory neurons after stress. Specifically, Ptgs2 was transiently upregulated with shock-induced fear learning and fear expression, along with Bdnf, Nptx2, and Lingo1, in a layer II/III neuronal population marked by the neuronal excitatory gene Slc17a7 and cell-type specific neuropeptide Penk. These dynamic cell-type specific expression patterns identified with snRNAseq were validated with quantitative fluorescent in situ hybridization. Using a pharmacological approach, we found that systemic lumiracoxib, a selective Ptgs2-inhibitor, led to a significant reduction in fear expression. Furthermore, genetic ablation of Ptgs2 in excitatory Camk2a-expressing neurons led to reduced stress-induced anxiety-like behaviors. Together these findings suggest that Ptgs2 is expressed in a dynamic, cell-type specific way in Layer II/III Penk+ neurons in mPFC, and that its role in prostaglandin and /or endocannabinoid regulation within these neurons may be an important mediator of stress-related behavior.

neuroscience↗