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

Nathaniel S Rieger,John P Christianson,Alexandra J Ng,Anthony Djerdjaj,Lauren Granata,Juan A Varela,Heather C Brenhouse

doi:10.1038/s41386-022-01292-7

Nathaniel S Rieger, John P Christianson + Show 5 more

Open Access

https://doi.org/10.1038/s41386-022-01292-7

Copy DOI

Journal: Neuropsychopharmacology	Publication Date: Feb 26, 2022
Citations: 23	License type: open-access

Affiliation: Boston College, Northeastern University

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.

Highlights

Stressors and other salient emotional stimuli trigger a shift in attention and cognitive resources in order to orient attention and organize situationally adaptive behaviors
We focused on the neuropeptide corticotropin-releasing factor (CRF), which is released during social interactions with stressed conspecifics [12], and the posterior insular cortex (IC), a structure needed for social affective behavior [29]
Electrophysiology, pharmacology, behavior and molecular experiments revealed a sex-specific role for CRF as a modulator of insular synaptic physiology and social behavior

Summary

Introduction

Stressors and other salient emotional stimuli trigger a shift in attention and cognitive resources in order to orient attention and organize situationally adaptive behaviors. Aberrant activity and functional connectivity of the posterior insula and associated network structures leads to hypervigilance, increased interoception and poor emotion regulation—hallmark symptoms of many neuropsychiatric disorders including autism spectrum disorders, schizophrenia, and posttraumatic stress disorder [11]. Exposure to either a perceived threat to one’s own well-being (self stress), or to a social contact that is undergoing distress initiate the hypothalamic–pituitary–adrenocortical axis response by activation of corticotropin-releasing factor (CRF) neurons in the paraventricular hypothalamus (PVN) [12]. CRF may shape social behaviors by actions at CRF receptors located among the distributed network of neural structures, including the insular cortex, that are engaged by social stress signals and organize social behavior [23]

Methods

Results

Conclusion