A lateral hypothalamic neuronal population expressing leptin receptors counteracts anxiety to enable adaptive behavioral responses

Nat Neurosci. 2025 Oct 20. doi: 10.1038/s41593-025-02078-y. Online ahead of print.

ABSTRACT

Neuronal mechanisms that facilitate adaptive strategies to enable an animal to overcome anxiety in threatening situations remain unknown. Using single-cell calcium imaging and cell-type-specific activity manipulations in behaving mice, we identified leptin-sensitive neuronal subpopulations in the lateral hypothalamus (LH; LepR^LH) that encode anxiogenic stimuli. In high-anxiety animals, LepR^LH neurons differentiated poorly among anxiogenic stimuli and were inhibited by input from the prefrontal cortex. The activity of LepR^LH neurons predicted the anxiety level of individual animals, and the activation of LepR^LH neurons enabled adaptive responses under anxiogenic conditions-exploration of new terrain, eating despite anxiogenic environment and limiting maladaptive excessive locomotion in an anorexia nervosa disease model. Thus, leptin-sensitive neuronal subpopulations in the LH enable adaptive fulfillment of vital needs despite anxiogenic conditions, both in healthy and pathological states.

PMID:41116115 | DOI:10.1038/s41593-025-02078-y