A midbrain circuit mechanism for noise-induced negative valence coding

Unpleasant sounds elicit a range of negative emotional reactions, yet the underlying neural mechanisms remain largely unknown. Here we show that glutamatergic neurons in the central inferior colliculus (CIC^glu) relay noise information to GABAergic neurons in the ventral tegmental area (VTA^GABA) via the cuneiform nucleus (CnF), encoding negative emotions in mice. In contrast, the CIC^glu→medial geniculate (MG) canonical auditory pathway processes salient stimuli. By combining viral tracing, calcium imaging, and optrode recording, we demonstrate that the CnF acts downstream of CIC^glu to convey negative valence to the mesolimbic dopamine system by activating VTA^GABA neurons. Optogenetic or chemogenetic inhibition of any connection within the CIC^glu→CnF^glu → VTA^GABA circuit, or direct excitation of the mesolimbic dopamine (DA) system is sufficient to alleviate noise-induced negative emotion perception. Our findings highlight the significance of the CIC^glu→CnF^glu → VTA^GABA circuit in coping with acoustic stressors.