A Disinhibitory Microcircuit Mediates Conditioned Social Fear in the Prefrontal Cortex

Abstract

Fear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with celltype-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses. These results reveal a previously unknown disinhibitory microcircuit in prefrontal cortex through interactions between IN subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior.

Morphine coordinates SST and PV interneurons in the prelimbic cortex to disinhibit pyramidal neurons and enhance reward

“…SST-INs not only innervate pyramidal neurons but also strongly innervate other types of INs in the cortex [33,34,46]. The increased frequency of mIPSC in PV-INs indicates an increased inhibitory input.…”

Learning-induced plasticity in the barrel cortex is disrupted by inhibition of layer 4 somatostatin-containing interneurons

“…SOM-PV disinhibition in the thalamocortical input layer during CS+UCS pairing may allow for wider spreading of the signal from the active vibrissae in the barrel cortex. A similar disinhibitory circuit was proposed to underlie social fear in the dorsomedial prefrontal cortex, and it was shown that SOM-IN inhibition alleviates the behavioral social fear response in conditioned mice and reduces the firing rates of PV-INs, which are elevated during social fear expression (Xu et al, 2019).…”

“…to release thalamorecipient excitatory projection neurons from inhibition and enhance information flow into the upper cortical layers (Xu et al, 2013). The mechanism of disinhibition is particularly important during learning and plasticity, and the role of SOM-INs in these phenomena has been intensively investigated (Wolff et al, 2014;Xu et al, 2019). In the visual cortex, visual discrimination reduced the activity of L3 SOM-INs (Makino and Komiyama, 2015) but enhanced their stimulus selectivity, implicating them in gating selectivity changes (Khan et al, 2018).…”

Social recognition in rats and mice requires integration of olfactory, somatosensory and auditory cues

“…The ability of SFC to overcome the innate attractiveness of social interactions in small rodents was recently demonstrated by several laboratories 63,64 . Although these studies used SFC to induce general avoidance of social stimuli, we, nevertheless, developed a protocol that enables induction of avoidance behavior towards a specific individual, allowing other conspecifics to retain their attractiveness.…”