Insular cortex corticotropin-releasing factor integrates stress signaling with social affective behavior

Abstract

Impairments in identifying and responding to the emotions of others manifest in a variety of psychopathologies. Therefore, elaborating the neurobiological mechanisms that underpin social responses to social emotions, or social affective behavior, is a translationally important goal. The insular cortex is consistently implicated in stress-related social and anxiety disorders, which are associated with diminished ability to make and use inferences about the emotions of others to guide behavior. We investigated how corticotropin-releasing factor (CRF), a neuromodulator evoked upon exposure to stressed conspecifics, influenced the insula. We hypothesized that social affective behavior requires CRF signaling in the insular cortex in order to detect stress in social interactions. In acute slices from male and female rats, CRF depolarized insular pyramidal neurons. In males, but not females, CRF suppressed presynaptic GABAergic inhibition leading to greater excitatory synaptic efficacy in a CRF receptor 1 (CRF1)- and cannabinoid receptor 1 (CB1)-dependent fashion. In males only, insular CRF increased social investigation, and CRF1 and CB1 antagonists interfered with social interactions with stressed conspecifics. To investigate the molecular and cellular basis for the effect of CRF we examined insular CRF1 and CB1 mRNAs and found greater total insula CRF1 mRNA in females but greater CRF1 and CB1 mRNA colocalization in male insular cortex glutamatergic neurons that suggest complex, sex-specific organization of CRF and endocannabinoid systems. Together these results reveal a new mechanism by which stress and affect contribute to social affective behavior.

Maternal immune activation alters social affective behavior and sensitivity to corticotropin releasing factor in male but not female rats

“…We targeted the CRF system in this study because CRF is important for both social decision making (Rieger et al, 2022) and the social transfer of stress (Sterley and Bains, 2021; Sterley et al, 2018) -- two processes which we believe are prime targets to be affected by MIA which alters sociability and stress reactivity (Carlezon et al, 2019; Howerton and Bale, 2012; Zhao et al, 2021). Little is known about how the CRF system and CRF receptor distribution is affected by MIA (Perry et al, 2021).…”

“…Evoked field excitatory postsynaptic potentials (fEPSPs) were recorded on a 6 × 10 perforated multielectrode array (MCSMEA-S4-GR with 60pMEA100/30iR-Ti Array, Multichannel Systems) with integrated acquisition hardware (MCSUSB60) and analyzed with MC_RACK software (version 3.9) exactly as described previously (Rieger et al, 2022; Rogers-Carter et al, 2018). Slices were placed onto the array and affixed by downward suction through the perforated array.…”

“…Test animals were placed in a standard cage (18 cm x 24 cm x 18 cm) for 1h. 40 min prior to testing animals were microinjected with 300 nM CRF in the insula, a dose shown to increase social interaction in male rats (Rieger et al, 2022). At the start of testing, a juvenile same-sex conspecific was placed in the chamber with the test rat and they were allowed to freely interact for five minutes.…”

Cannabinoids regulate an insula circuit controlling water intake

“…Both aIC and pIC neurons send projections to the BLA [30][31][32]. A recent study reported that CB1 receptors are expressed in IC glutamatergic neurons [42], but the distribution of CB1 receptors in axonal terminals of IC neurons is unclear. Interestingly, our targeted histological analyses revealed that CB1 receptors of IC neurons are intensively located on BLA but not CeA axon terminals.…”

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).…”