biostudies-literatureUnknown11(47)Contesse TThe lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Here, we define a striosomal Tac1+/Tshz1+/Oprm1+ neuron subtype in the nucleus accumbens (ACB) that targets Esr1+ LHA neurons that project to the lateral habenula (LHb). Intersectional cell type-specific and input-output defined optogenetic activation of this ACB-LHA-LHb pathway can progressively induce a negative behavioral state that depends on Esr1+ LHA-LHb neural activity. We found that either activation of the D1+ ACB-LHA projection or inhibition of LHA-LHb neurons defined by ACB inputs can drive reward-independent compulsive-like behaviors that generalize across contexts. We found that these complex yet stereotyped behaScience advanceseadx9450https://www.ebi.ac.uk/biostudies/studies/S-EPMC12637280biostudies-literatureA striosomal accumbens pathway drives stereotyped behavior through an aversive Esr1+ hypothalamic-habenula circuit.PMC12637280Jung FMeletis KSandberg RBektash BYForastieri CSkara VMantas IHahne SContestabile ACalvigioni DNikolakopoulou IGraziano MCao XGiatrellis SContesse TCarlen MRubino EfalseA striosomal accumbens pathway drives stereotyped behavior through an aversive Esr1+ hypothalamic-habenula circuit.The lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Here, we define a striosomal Tac1+/Tshz1+/Oprm1+ neuron subtype in the nucleus accumbens (ACB) that targets Esr1+ LHA neurons that project to the lateral habenula (LHb). Intersectional cell type-specific and input-output defined optogenetic activation of this ACB-LHA-LHb pathway can progressively induce a negative behavioral state that depends on Esr1+ LHA-LHb neural activity. We found that either activation of the D1+ ACB-LHA projection or inhibition of LHA-LHb neurons defined by ACB inputs can drive reward-independent compulsive-like behaviors that generalize across contexts. We found that these complex yet stereotyped beha2025-01-01T00:00:00Z2025 Nov2026-06-05T16:51:26.735Z2026-05-19T03:11:53.143ZS-EPMC126372804127015810.1126/sciadv.adx9450