Distinct hypothalamus-habenula circuits govern risk preference

Appropriate evaluation of risk is essential for survival in complex, uncertain environments. Confronted with choosing between a certain (safe) and an uncertain (risky) option, animals of various species show strong preferential traits which are stable across extended periods of time[1][1]-[8][2]. How such risk preference is encoded in the neural circuitry of the brain remains poorly understood. A candidate brain region is the lateral habenula (LHb), which has been shown to be prominently involved in various value-guided behaviors[9][3]-[12][4]. Here, using a balanced two-alternative choice task involving risk of loss, we find that neuronal activity in the LHb prior to action selection reflects risk preference and is governed by distinct inputs from hypothalamic subregions. Specifically, by employing multi-fiber photometry and targeted optogenetic perturbations, we identified glutamatergic LHb projections from both lateral and medial hypothalamus (LH/MH) that provide functionally distinct synaptic inputs to the LHb before action selection. Microendoscopic two-photon calcium imaging revealed risk-preference-selective LHb neurons that decreased their selectivity upon chemogenetic silencing of MH but not LH inputs. Finally, optogenetic stimulation of MH→LHb axons evoked both excitatory and inhibitory postsynaptic responses in LHb neurons (indicative of glutamate/GABA co-release for fine-tuned gain control[13][5]), whereas LH→LHb projections were purely excitatory. Our results thus reveal functionally distinct hypothalamus-habenula circuits that govern risk preference in situations of economic decision-making. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-8 [3]: #ref-9 [4]: #ref-12 [5]: #ref-13