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In mammals, threat-related behavior is typically induced by a noxious physical stressor and is associated with a broad range of behavioral responses such as freezing and avoidance. These behavioral responses are associated with the regulation of pain responses allowing individuals to cope with noxious stimuli. Whereas the structures and mechanisms involved in pain behavior are well documented, little is known about the precise neuronal circuits mediating the emotional regulation of pain behavior. Here we used a combination of behavioral, anatomical, optogenetic, and electrophysiological approaches to show that somatostatin-expressing neurons in the ventrolateral periaqueductal gray matter (vlPAG SST cells) promote antinociceptive responses during the presentation of conditioned stimuli (CS) predicting footshocks. Whereas the optogenetic inhibition of vlPAG SST cells during CS presentation promoted analgesia, their optogenetic activation reduced analgesia by potentiating pain responses in the spinal cord through a relay in the rostral ventromedial medulla (RVM). Together these results identify a brainstem circuit composed of vlPAG SST cells specifically projecting to the RVM and mediating fear conditioned analgesia (FCA) to regulate pain responses during threatful situations.

International audience; Reward-processing impairment is a common symptomatic dimension of several psychiatric disorders. However, whether the underlying pathological mechanisms are common is unknown. Herein, we asked if the decrease in the n-3 polyunsaturated fatty acid (PUFA) lipid species, consistently described in these pathologies, could underlie reward-processing deficits. We show that reduced n-3 PUFA biostatus in mice leads to selective motivational impairments. Electrophysiological recordings revealed increased collateral inhibition of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) onto dopamine D1 receptor-expressing MSNs in the nucleus accumbens, a main brain region for the modulation of motivation. Strikingly, transgenically preventing n-3 PUFA deficiency selectively in D2-expressing neurons normalizes MSN collateral inhibition and enhances motivation. These results constitute the first demonstration of a causal link between a behavioral deficit and n-3 PUFA decrease in a discrete neuronal population and suggest that lower n-3 PUFA biostatus in psychopathologies could participate in the etiology of reward-related symptoms.