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