Biology subjects

Fang, L. Z.

Publications and source records attributed to Fang, L. Z..

3 recordsLinked to original sources

bioRxiv2026

Ventral pallidal GABAergic neurons control hedonic feeding and obesity

Food intake is governed by two interacting drives. The homeostatic hunger drive regulates food intake to fulfill caloric needs while the hedonic drive promotes intake of palatable foods outside of caloric need. It is unclear which neural substrates can control the hedonic drive and thereby reduce overeating of palatable foods and associated obesity. Here, we show that ventral pallidal GABAergic neurons (VPGABA) preferentially control hedonic feeding and are necessary for diet-induced obesity in mice. Stimulating VPGABA neurons drove robust consumption of high-fat diet and liquids, but not regular laboratory chow. Despite driving intake of palatable foods, VPGABA neurons are relatively insensitive to homeostatic signals - they express few hunger-hormone receptors and are not activated by ghrelin administration or fasting. Single-cell calcium imaging revealed stronger engagement of VPGABA neurons during long vs short feeding bouts, suggesting control over bout duration, which has been linked to palatability. This was confirmed with closed-loop optogenetic stimulation. Finally, taCasp3-mediated ablation of VPGABA neurons reduced intake of palatable liquids and blocked high-fat diet-induced obesity without impacting homeostatic feeding. Together, these findings establish VPGABA neurons as a neural population that preferentially controls hedonic over homeostatic feeding and can be leveraged to block obesity in mice.

neuroscience↗

bioRxiv2025

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

Despite decades of research, connecting molecular and cellular phenotypes to complex behavioral traits remains an elusive goal1. Social motivation exhibits individual trait variation2, which we hypothesize is mediated by molecular and cellular variability across hypothalamic neurons. To test this, we generated single-nucleus RNA-sequencing profiles3,4 of >120,000 neurons from tuberal hypothalamus and adjacent thalamus in 36 mice, balanced across sex and autism-associated mutation5, with all mice assessed for social motivation2. First, we show that molecular activation patterns predict behavior across individuals: specifically, activation of paraventricular Agtr1a+ (angiotensin receptor 1a) neurons predicted reduced social behavior. Subsequent inhibition of AGTR1A with telmisartan--an FDA-approved antihypertensive6--improved social orienting. Second, we show natural variation in neuronal proportions--likely arising from stochastic developmental events7--is sufficient to shape adult behavior even among genetically-identical individuals: we identified multiple neuronal populations whose relative abundance predicted social reward-seeking behavior. Chemogenetic inhibition of one such population, Nxph4+ neurons of the postero-lateral hypothalamus8, suppressed multiple aspects of social motivation. This work establishes proof-of-principle for an approach where single-cell genomics precisely maps neural substrates governing behavior. This approach revealed that stochastic variations in neuronal architecture deterministically influence social motivation, and enabled identification of therapeutically-actionable targets with immediate translational potential for disorders with social deficits.

genetics↗

bioRxiv2024

Transcriptomic landscape of mammalian ventral pallidum at single-cell resolution

The ventral pallidum (VP) is critical for motivated behaviors. While contemporary work has begun to elucidate the functional diversity of VP neurons, the molecular heterogeneity underlying this functional diversity remains incompletely understood. We used snRNA-seq and in situ hybridization to define the transcriptional taxonomy of VP cell types in mice, macaques, and baboons. We found transcriptional conservation between all three species, within the broader neurochemical cell types. Unique dopaminoceptive and cholinergic subclusters were identified and conserved across both primate species but had no homolog in mice. This harmonized consensus VP cellular atlas will pave the way for understanding the structure and function of the VP and identified key neuropeptides, neurotransmitters, and neuro receptors that could be targeted within specific VP cell types for functional investigations. TeaserGenetic identity of ventral pallidum cell types is conserved across rodents and primates at the transcriptional level

neuroscience↗