Author: Jean-Philippe Krieger1, Mohammed Asker1, Pauline van der Velden2, Stina Börchers1, Jennifer E Richard1, Ivana Maric1, Francesco Longo1, Arashdeep Singh3, Guillaume de Lartigue3, Karolina P Skibicka4
Affiliation: <sup>1</sup> Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, Gothenburg, Sweden. <sup>2</sup> Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden. <sup>3</sup> Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida; Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, Florida. <sup>4</sup> Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, Gothenburg, Sweden; Nutritional Sciences, College of Health and Human Development, Pennsylvania State University, State College, Pennsylvania. Electronic address: Karolina.Skibicka@neuro.gu.se.
Conference/Journal: Biol Psychiatry
Date published: 2022 May 18
Other: Special Notes: doi: 10.1016/j.biopsych.2022.04.020. , Word Count: 269
Anxiety disorders are associated with an altered perception of the body's internal state. Therefore, understanding the neuronal basis of interoception can foster novel anxiety therapies. In rodents, the feeding status bidirectionally modulates anxiety-like behavior but how the sensing of gastrointestinal state affects anxiety remains unclear.
We combined chemogenetics, neuropharmacology, and behavioral approaches in male and female rats to test whether vagal afferents terminating in the gastrointestinal tract mediate feeding-induced tuning of anxiety. Using saporin-based lesions and transcriptomics, we investigated the chronic impact of this gut-brain circuit on anxiety-like behavior.
Both feeding and selective chemogenetic activation of gut-innervating vagal afferents increased anxiety-like behavior. Conversely, chemogenetic inhibition blocked the increase in anxiety-like behavior induced by feeding. Using a selective saporin-based lesion, we demonstrate that the loss of gut-innervating vagal afferent signaling chronically reduces anxiety-like behavior in male rats but not in female rats. We next identify a vagal circuit that connects the gut to the central nucleus of the amygdala, using anterograde transsynaptic tracing from the nodose ganglia. Lesion of this gut-brain vagal circuit modulated the central amygdala transcriptome in both sexes but selectively affected a network of GABA (gamma-aminobutyric acid)-related genes only in males, suggesting a potentiation of inhibitory control. Blocking GABAergic signaling in the central amygdala re-established normal anxiety levels in male rats.
Vagal sensory signals from the gastrointestinal tract are critical for baseline and feeding-induced tuning of anxiety via the central amygdala in rats. Our results suggest vagal gut-brain signaling as a target to normalize interoception in anxiety disorders.
Keywords: Amygdala; Anxiety; Gut-brains axis; Interoception; Sex differences; Vagus nerve.
PMID: 35965105 DOI: 10.1016/j.biopsych.2022.04.020