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

doi:10.1016/j.brainres.2015.11.021

Brain Research

Volume 1641, Part B, 15 June 2016, Pages 177-188

https://doi.org/10.1016/j.brainres.2015.11.021 Get rights and content

Highlights

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Psychiatric disorders linked to stress and hyperarousal are more prevalent in women.
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There are structural sex differences in the locus coeruleus (LC) arousal center.
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Estrogens increase norepinephrine levels in LC target regions.
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Female LC neurons are more sensitive to the stress neuropeptide CRF.
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Collectively, these effects may contribute to sex biases in psychiatric disorders.

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.

Introduction

Women are roughly twice as likely as men to suffer from certain psychiatric disorders, such as posttraumatic stress disorder (PTSD) and major depression (Breslau, 2002, Freedman et al., 2002, Kessler, 2003, Kessler et al., 2012, Tolin and Foa, 2006). In addition to their shared sex bias, PTSD and depression are characterized by symptoms of hyperarousal that include: irritability, restlessness, agitation, sleep disturbance, and an inability to concentrate (American Psychiatric Association, 2013). There is some evidence that these hyperarousal symptoms are more pronounced in women. For example, women with these disorders suffer from insomnia more often than men (Hall et al., 2000, Kobayashi and Mellman, 2012). Additionally, ruminations, which are associated with high arousal states (Pedersen et al., 2011, Thomsen et al., 2003), are more common in depressed women than men (Mezo and Baker, 2012, Nolen-Hoeksema et al., 1999). One possible explanation for these data is that sex differences in brain arousal centers predispose women to disorders with hyperarousal as a core symptom. One candidate region for such sex differences is the locus coeruleus (LC), which regulates levels of arousal by releasing norepinephrine (NE) into forebrain regions (Aston-Jones and Cohen, 2005, Berridge and Waterhouse, 2003). A focus of this review will be to highlight preclinical literature revealing mechanisms by which estrogens can increase NE levels in LC target regions, perhaps contributing to hyperarousal in females.

This review also will detail the literature revealing sex differences in LC regulation by stress. Clinically, stress is of interest because it is linked to the etiology of PTSD and depression. In particular, the development of these disorders is attributed, at least in part, to the hypersecretion of the stress-related neuropeptide, corticotropin releasing factor (CRF; Hauger et al., 2009, 2012; Nemeroff, 1996). Although CRF is primarily known for its role in initiating the hypothalamic pituitary adrenal axis in response to stress (Vale et al., 1981), it is the central effects of CRF that are thought to regulate behavioral stress responses and contribute to the symptoms of these “stress-related” psychiatric disorders (Bale and Vale, 2004, Bangasser and Kawasumi, 2015, Hauger et al., 2009, Owens and Nemeroff, 1991, Valentino and Van Bockstaele, 2002). There is evidence that the LC, in particular, is a target of CRF hypersecretion in depressed patients (Austin et al., 2003). Moreover, it has been proposed that subtypes of depression with symptoms of hyperarousal are attributable to a combined high CRF and high NE state (Gold and Chrousos, 1999, Gold and Chrousos, 2002, Koob, 1999). These studies, along with higher rates of stress-related psychiatric disorders in women, have prompted basic research revealing increased female LC neuronal sensitivity to CRF and the mechanisms underlying this effect (Bangasser et al., 2010, Bangasser et al., 2013, Curtis et al., 2006). These studies will be discussed, as will their implications for facilitating the treatment of stress-related psychiatric disorders in both men and women.

Section snippets

Sex difference in LC neuronal number

The LC comprises cluster of noradrenergic containing neurons located in the rostral rhombencephalic tegmental area within the pons (Aston-Jones, 2004). Despite its relatively small size (~2200 neurons in the adult rat), the LC has a wide efferent projection system that allows for regulation of brain regions throughout the neuroaxis (Aston-Jones, 2004, Guillamon et al., 1988, Swanson and Hartman, 1975). In fact, the LC is the major source of NE for the forebrain and the only NE source for the

Estrogens increase NE in LC terminal regions

As noted, the LC has a wide efferent projection system through which it can release NE into the forebrain (Aston-Jones, 2004, Swanson and Hartman, 1975). It is through regulation of forebrain target regions that the LC alters states of arousal, attention, and vigilance (Chamberlain and Robbins, 2013, Sara, 2009, Szabadi, 2013). Thus, sex differences in LC-induced NE release could result in sex differences in these functions. There is evidence from microdialysis studies that ovarian hormones

CRF regulation of LC physiology

Changes in the electrophysiological responses of LC neurons shift states of arousal and attention. In awake animals, LC neurons discharge in a tonic fashion, and the rate of this tonic firing is positively correlated with electroencephalographic (EEG) activity and arousal (Aston-Jones and Bloom, 1981b, Berridge and Foote, 1991, Berridge et al., 1993). In addition to tonic firing, salient sensory stimuli can evoke a burst of synchronous discharge known as a phasic response (Aston-Jones and

Implications of sex differences in LC-NE system and its regulation by stress

Taken together, these studies reveal that the LC-NE system is regulated by estrogens and stress in a way that, under certain conditions, can increase susceptibility to states of high arousal in females relative to males. Despite this body of knowledge, the majority of studies have focused on understanding sex differences in the LC-NE system were conducted in adult rodents. It will be important to extend these findings to early development and aging to determine if, and how, sex differences in

Acknowledgments

We would like to thank David Waxler for his helpful comments on the manuscript. This work was supported by NIH grant MH092438 to D.A.B.

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

Highlights

Abstract

Introduction

Section snippets

Sex difference in LC neuronal number

Estrogens increase NE in LC terminal regions

CRF regulation of LC physiology

Implications of sex differences in LC-NE system and its regulation by stress

Acknowledgments

Neuroscience

J. Biol. Chem.

Eur. J. Pharmacol.

J. Affect. Disord.

Brain Res.

Neurosci. Lett.

Physiol. Behav.

Brain Res. Brain Res. Rev.

Am. J. Hum. Genet.

Neurobiol. Aging

Am. J. Hum. Genet.

Neuroscience

Brain Res.

Neuroscience

Brain Res.

Horm. Behav.

Brain Res.

Brain Res.

Brain Res.

Neuropharmacology

Eur. J. Pharmacol.

Biol. Psychiatry.

Neuropharmacology

Neuroscience

Eur. J. Pharmacol.

J. Affect. Disord.

J. Affect. Disord.

Biol. Psychiatry

Neuroimage

Neuropharmacology

J. Steroid Biochem. Mol. Biol.

Brain Res. Dev. Brain Res.

Behav. Brain Res.

Neurobiol. Aging

Neurosci. Lett.

Brain Res. Bull.

Biol. Psychiatry

Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues

J. Neuroendocrinol.

The locus coeruleus, A5 and A7 noradrenergic cell groups

Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli

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Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle

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