How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry

Abstract

Metabolic status impacts on the emotional brain to induce behavior that maintains energy balance. While hunger suppresses the fear circuitry to promote explorative food-seeking behavior, satiety or obesity may increase fear to prevent unnecessary risk-taking. Here we aimed to unravel which metabolic factors, that transfer information about the acute and the chronic metabolic status, are of primary importance to regulate fear, and to identify their sites of action within fear-related brain regions. We performed a de novo analysis of central and peripheral metabolic factors that can penetrate the blood–brain barrier using genome-wide expression data across the mouse brain from the Allen Brain Atlas (ABA). The central fear circuitry, as defined by subnuclei of the amygdala, the afferent hippocampus, the medial prefrontal cortex and the efferent periaqueductal gray, was enriched with metabolic receptors. Some of their corresponding ligands were known to modulate fear (e.g., estrogen and thyroid hormones) while others had not been associated with fear before (e.g., glucagon, ACTH). Additionally, several of these enriched metabolic receptors were coexpressed with well-described fear-modulating genes (Crh, Crhr1, or Crhr2). Co-expression analysis of monoamine markers and metabolic receptors suggested that monoaminergic nuclei have differential sensitivity to metabolic alterations. Serotonergic neurons expressed a large number of metabolic receptors (e.g., estrogen receptors, fatty acid receptors), suggesting a wide responsivity to metabolic changes. The noradrenergic system seemed to be specifically sensitive to hypocretin/orexin modulation. Taken together, we identified a number of novel metabolic factors (glucagon, ACTH) that have the potential to modulate the fear response. We additionally propose novel cerebral targets for metabolic factors (e.g., thyroid hormones) that modulate fear, but of which the sites of action are (largely) unknown.

Top‐down and bottom‐up control of stress‐coping

“…Interestingly, data mining revealed a remarkable abundance of receptors for metabolic signals (eg, leptin, insulin-like growth factor-1, ghrelin and insulin) linked to the fear circuitry, which may explain how metabolic status can regulate emotional state. 178,179 How, within the brain, energy is redistributed during large-scale circuit dynamics over time 180 is still poorly understood. In this respect, the action of glucocorticoids on mitochondrial function 84 is opening novel insights into stress-coping and adaptation.…”

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

“…CRH-CRHR1 signaling has emerged as a potential neuromodulator of food intake energy expenditure (Arase et al, 1988). Interestingly, CRHR1 is co-expressed with various metabolic receptors in corticolimbic structures (Koorneef et al, 2018), supporting an interplay between metabolism and fear. Our findings indicate that CRHR1 upregulation represents an early molecular adaptation to the obesogenic diet.…”

Effects of Long-Term Endogenous Corticosteroid Exposure on Brain Volume and Glial Cells in the AdKO Mouse

“…GCs also affect brain function. The effects on peripheral energy metabolism and immunity alone may already do this ( Koorneef et al, 2018 ), but MR and GR are also widely (but differentially) expressed in neurons and other cell populations in the brain. Cortisol affects a wide range of brain processes, including food intake (mirroring peripheral effects on metabolism), cognition, emotion, and autonomic responses.…”