Single-Cell Resolution of Individual Variation in Hypothalamic Neurons Allows Targeted Manipulation Affecting Social Motivation DOI Creative Commons
Simona Sarafinovska, Sarah K. Koester, Li Fang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Abstract Despite decades of research, connecting molecular and cellular phenotypes to complex behavioral traits remains an elusive goal 1 . Social motivation exhibits individual trait variation 2 , which we hypothesize is mediated by variability across hypothalamic neurons. To test this, generated single-nucleus RNA-sequencing profiles 3,4 >120,000 neurons from tuberal hypothalamus adjacent thalamus in 36 mice, balanced sex autism-associated mutation 5 with all mice assessed for social First, show that activation patterns predict behavior individuals: specifically, paraventricular Agtr1a + (angiotensin receptor 1a) predicted reduced behavior. Subsequent inhibition AGTR1A telmisartan—an FDA-approved antihypertensive 6 —improved orienting. Second, natural neuronal proportions—likely arising stochastic developmental events 7 —is sufficient shape adult even among genetically-identical identified multiple populations whose relative abundance reward-seeking Chemogenetic one such population, Nxph4 the postero-lateral 8 suppressed aspects motivation. This work establishes proof-of-principle approach where single-cell genomics precisely maps neural substrates governing revealed variations architecture deterministically influence motivation, enabled identification therapeutically-actionable targets immediate translational potential disorders deficits.

Language: Английский

Single-Cell Resolution of Individual Variation in Hypothalamic Neurons Allows Targeted Manipulation Affecting Social Motivation DOI Creative Commons
Simona Sarafinovska, Sarah K. Koester, Li Fang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Abstract Despite decades of research, connecting molecular and cellular phenotypes to complex behavioral traits remains an elusive goal 1 . Social motivation exhibits individual trait variation 2 , which we hypothesize is mediated by variability across hypothalamic neurons. To test this, generated single-nucleus RNA-sequencing profiles 3,4 >120,000 neurons from tuberal hypothalamus adjacent thalamus in 36 mice, balanced sex autism-associated mutation 5 with all mice assessed for social First, show that activation patterns predict behavior individuals: specifically, paraventricular Agtr1a + (angiotensin receptor 1a) predicted reduced behavior. Subsequent inhibition AGTR1A telmisartan—an FDA-approved antihypertensive 6 —improved orienting. Second, natural neuronal proportions—likely arising stochastic developmental events 7 —is sufficient shape adult even among genetically-identical identified multiple populations whose relative abundance reward-seeking Chemogenetic one such population, Nxph4 the postero-lateral 8 suppressed aspects motivation. This work establishes proof-of-principle approach where single-cell genomics precisely maps neural substrates governing revealed variations architecture deterministically influence motivation, enabled identification therapeutically-actionable targets immediate translational potential disorders deficits.

Language: Английский

Citations

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