Insular Cortex Projections to Nucleus Accumbens Core Mediate Social Approach to Stressed Juvenile Rats

Abstract

Social interactions are shaped by features of the interactants including age, emotion, sex and familiarity. Age-specific responses to social affect are evident when an adult male rat is presented with a pair of unfamiliar male conspecifics, one of which is stressed via 2 footshocks and the other naïve to treatment. Adult test rats prefer to interact with stressed juvenile (PN30) conspecifics, but avoid stressed adult (PN50) conspecifics. This pattern depends upon the insular cortex (IC) which is anatomically connected to the nucleus accumbens core (NAc). The goal of this work was to test the necessity of IC projections to NAc during social affective behavior. Here, bilateral pharmacological inhibition of the NAc with tetrodotoxin (1µM; 0.5ul/side) abolished the preference for stressed PN30, but did not alter interactions with PN50 conspecifics. Using a combination of retrograding tracing and c-Fos immunohistochemistry, we report that social interactions with stressed PN30 conspecifics elicit greater Fos immunoreactivity in IC → NAc neurons than interactions with naïve PN30 conspecifics. Chemogenetic stimulation of IC terminals in the NAc increased social exploration with juvenile, but not adult, conspecifics, while chemogenetic inhibition of this tract blocked the preference to investigate stressed PN30 conspecifics, which expands upon our previous finding that optogenetic inhibition of IC projection neurons mediated approach and avoidance. These new findings suggest that outputs of IC to the NAc modulate social approach, which provides new insight to the neural circuitry underlying social decision-making. Significance StatementSocial decision-making underlies an animal's behavioral response to others in a range of social contexts. Previous findings indicate the insular cortex (IC) and the nucleus accumbens (NAc) play important roles in a range of social behaviors, and human neuroimaging implicates both IC and NAc in autism and other psychiatric disorders characterized by aberrant social cognition. To test whether IC projections to the NAc are involved in social decision making, circuit-specific chemogenetic manipulations demonstrated that the IC → NAc pathway mediates social approach toward distressed juvenile, but not adult, conspecifics. This finding is the first to implicate this circuit in rodent socioemotional behaviors and may be a neuroanatomical substrate for integration of emotion with social reward.

Encoding of social exploration by neural ensembles in the insular cortex

“…Recent rodent studies have demonstrated the role of the anterior IC in relapse to drug-seeking and alcohol self-administration [ 38 , 39 ] and that of the posterior IC in social emotional behavior and aversive state processing [ 18 – 20 ]. In addition to these functional characterizations, contrasting gradient distribution of projections to the core of the nucleus accumbens and the central amygdala [ 18 ], distinct taste and valence coding in the gustatory IC [ 22 ], and intensive functional and anatomical intra-insular connectivity [ 18 , 19 ] suggest that anterior and posterior ICs serve distinct yet interrelated functions.…”

“…Furthermore, hypoactivity and dysfunctional connectivity of the IC are hallmarks of individuals with autism spectrum disorder (ASD) [ 30 , 31 ]. These findings imply that the IC constitutes a key node for the social brain network and plays a pivotal role in social cognition and behavior [ 18 – 20 , 32 ]. In this study, we therefore sought to examine how neurons in the IC encode information regarding social behavior by visualizing neuronal dynamics using microendoscopic calcium imaging in freely moving, socially interacting mice.…”

Intrinsic excitability in layer IV-VI anterior insula to basolateral amygdala projection neurons encodes the confidence of taste valence

“…For example, deletions of either Fos or Stk11 in BLA-aIC neurons, alter intrinsic properties at the aIC, and impair CTA acquisition (Levitan et al, 2020). Furthermore, approach behaviors in social decision-making are modulated by subjective and sex-specific affective states that regulate cell-type-specific changes in intrinsic properties at IC terminals receiving hypothalamic input (Rogers-Carter et al, 2018, 2019; Rieger et al, 2022). The posterior IC (pIC) integrates visceral-sensory signals of current physiological states with hypothalamus-gated amygdala anticipatory inputs relating to food or water ingestion, to predict future physiological states (Livneh et al, 2017, 2020).…”

Dissection of insular cortex layer 5 reveals two sublayers with opposing modulatory roles in appetitive behavior

“…The insular cortex (insula) mediates top-down modulation of feeding and drinking behaviors in response to taste quality (1, 2), homeostatic/visceral states (3,4), innate threat (3), and learned stimuli (5)(6)(7)(8)(9)(10), as well as the modulation of emotional (11) and social (3,12,13) behaviors. In particular, the modulation of feeding or drinking is differentially regulated by distinct regions of the insula along the anterior-posterior (A-P) axis (1), and region-specific projections to the amygdala complex are suggested to underlie the behavioral control.…”