Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress

Abstract

Women are more likely than men to suffer from post-traumatic stress disorder (PTSD) and major depression. In addition to their sex bias, these disorders share stress as an etiological factor and hyperarousal as a symptom. Thus, sex differences in brain arousal systems and their regulation by stress could help explain increased vulnerability to these disorders in women. Here we review preclinical studies that have identified sex differences in the locus coeruleus (LC)-norepinephrine (NE) arousal system. First, we detail how structural sex differences in the LC can bias females towards increased arousal in response to emotional events. Second, we highlight studies demonstrating that estrogen can increase NE in LC target regions by enhancing the capacity for NE synthesis, while reducing NE degradation, potentially increasing arousal in females. Third, we review data revealing how sex differences in the stress receptor, corticotropin releasing factor 1 (CRF1), can increase LC neuronal sensitivity to CRF in females compared to males. This effect could translate into hyperarousal in women under conditions of CRF hypersecretion that occur in PTSD and depression. The implications of these sex differences for the treatment of stress-related psychiatric disorders are discussed. Moreover, the value of using information regarding biological sex differences to aid in the development of novel pharmacotherapies to better treat men and women with PTSD and depression is also highlighted. This article is part of a Special Issue entitled SI: Noradrenergic System.

Keywords: Arousal; Corticotropin releasing hormone; Major depression; Noradrenergic; Post-traumatic stress disorder; Sex differences.

Figure 1

This image depicts the LC core and peri-LC regions, along with important LC afferents and structural sex differences in the rat LC. It has been reported that the female LC contains more noradrenergic neurons than the male LC. Additionally, the dendrites of female LC neurons are larger and more complex, extending further in the peri-LC region. This structure increases the probability that female LC dendrites will contact afferents that terminate in the peri-LC regions. Bar, Barrington’s nucleus; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; DL Peri-LC; dorsolateral pericoerulear locus coeruleus; LC Core, locus coeruleus core; NTS, nucleus of the solitary tract; PAG, periaqueductal gray; PGi, nucleus paragigantoceullaris; VM Peri-LC, ventromedial pericoerulear locus coeruleus

Figure 2

This schematic illustrates how estrogen can regulate the NE system. Estrogen can increase NE levels by increasing NE synthesis within the LC neuron (blue) and reducing NE degradation. Estrogen also decreases adrenergic receptor (purple) levels on postsynaptic neurons (green), an effect that may be compensatory. DA, dopamine; DBH, dopamine β-hydroxylase; DOPA, L-dihydroxyphenylalanine; COMT, catechol-O-methyltransferase; NE, norepinephrine

Figure 3

This schematic depicts sex differences in the CRF₁ receptor. The image on the left depicts increased β-arrestin2 binding to the CRF₁ receptor (gray) and internalization in a male LC neuron (blue). The image on the right depicts CRF (red circle) binding to the CRF₁ receptor (gray), which increases Gs coupling and signaling through the cAMP pathway in a female LC neuron (blue). AC, adenylyl cyclase; ATP, adenosine triphosphate; βarr., β-arrestin2; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A