Parvalbumin-expressing basal forebrain neurons mediate learning from negative experience

Parvalbumin (PV)-expressing GABAergic neurons of the basal forebrain (BFPVNs) were proposed to serve as a rapid and transient arousal system. While they have a well-documented role in the regulation of sleep-wake states, whether and how BFPVNs participate in mediating awake behaviors is not known. To address this, we performed bulk calcium imaging and recorded single neuronal activity from the horizontal band of the diagonal band of Broca (HDB) while mice were performing an associative learning task. Genetically identified BFPVNs of the HDB responded with a distinctive, phasic activation to punishment. In contrast, reward only elicited slow and delayed responses, while stimuli predicting behavioral reinforcement (reward or punishment) were followed by a gradual increase of HDB BFPVN firing rates. Optogenetic inhibition of HDB BFPVNs during punishment impaired the formation of cue-outcome associations, suggesting a causal role of these neurons in associative learning. Mapping the input-output connectivity of HDB BFPVNs by anterograde and mono-transsynaptic retrograde tracing experiments showed that these neurons received strong inputs from the hypothalamus, the septal complex and the median raphe region, while they synapsed on diverse cell types in key structures of the limbic system including the medial septum, the retrosplenial cortex and the hippocampus. Bulk calcium imaging performed in these termination regions indicated that HDB BFPVNs broadcast information about aversive stimuli to multiple downstream targets. We propose that the arousing effect of BFPVNs is recruited by aversive stimuli to serve crucial associative learning functions during awake behaviors. ### Competing Interest Statement The authors have declared no competing interest.