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

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

References (140)

E.D. Abercrombie et al.
Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies
Neuroscience
(1988)
S. Ahn et al.
Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor
J. Biol. Chem.
(2004)
P.D. Alfinito et al.
Estradiol increases catecholamine levels in the hypothalamus of ovariectomized rats during the dark-phase
Eur. J. Pharmacol.
(2009)
American Psychiatric Association
(2013)
A. Angold et al.
Puberty onset of gender differences in rates of depression: a developmental, epidemiologic and neuroendocrine perspective
J. Affect. Disord.
(1993)
M.A. Ansonoff et al.
Estrogen increases G protein coupled receptor kinase 2 in the cortex of female rats
Brain Res.
(2001)
A.P. Arnold
Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues
J. Neuroendocrinol.
(2009)
G. Aston-Jones
The locus coeruleus, A5 and A7 noradrenergic cell groups
G. Aston-Jones et al.
Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli
J. Neurosci.
(1981)
G. Aston-Jones et al.
Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle
J. Neurosci.
(1981)

G. Aston-Jones et al.

An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance

Annu. Rev. Neurosci.

(2005)

G. Aston-Jones et al.

The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network

Science

(1986)

M.C. Austin et al.

Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men

Mol. Psychiatry

(2003)

D. Babstock et al.

The dorsal locus coeruleus is larger in male than in female Sprague-Dawley rats

Neurosci. Lett.

(1997)

T.L. Bale et al.

CRF and CRF receptors: role in stress responsivity and other behaviors

Annu. Rev. Pharmacol. Toxicol.

(2004)

D.A. Bangasser et al.

Sex differences in molecular and cellular substrates of stress

Cell. Mol. Neurobiol.

(2012)

D.A. Bangasser et al.

Cognitive disruptions in stress-related psychiatric disorders: a role for corticotropin releasing factor (CRF)

Horm. Behav.

(2015)

D.A. Bangasser et al.

Sexual dimorphism in locus coeruleus dendritic morphology: a structural basis for sex differences in emotional arousal

Physiol. Behav.

(2011)

D.A. Bangasser et al.

Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology

Mol. Psychiatry

(2010)

D.A. Bangasser et al.

Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression

Mol. Psychiatry

(2013)

C.W. Berridge et al.

Effects of locus coeruleus activation on electroencephalographic activity in the neocortex and hippocampus

J. Neurosci.

(1991)

C.W. Berridge et al.

The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes

Brain Res. Brain Res. Rev.

(2003)

C.W. Berridge et al.

Effects of locus coeruleus inactivation on electroencephalographic activity in neocortex and hippocampus

Neuroscience

(1993)

N.J. Bray et al.

A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain

Am. J. Hum. Genet.

(2003)

N. Breslau

Gender differences in trauma and posttraumatic stress disorder

J. Gend. Specif. Med.

(2002)

C. Busch et al.

Spatial, temporal and numeric analysis of alzheimer changes in the nucleus coeruleus

Neurobiol. Aging

(1997)

L. Cahill et al.

Beta-adrenergic activation and memory for emotional events

Nature

(1994)

S.R. Chamberlain et al.

Noradrenergic modulation of cognition: therapeutic implications

J. Psychopharmacol.

(2013)

F.M. Chen et al.

Corticotropin releasing factor receptor-mediated stimulation of adenylate cyclase activity in the rat brain

Brain Res.

(1986)

J. Chen et al.

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain

Am. J. Hum. Genet.

(2004)

W.C. Chung et al.

Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain

J. Neurobiol.

(2000)

E.C. Clayton et al.

Phasic activation of monkey locus ceruleus neurons by simple decisions in a forced-choice task

J. Neurosci.

(2004)

L.H. Conti et al.

Effects of pretreatment with corticotropin-releasing factor (CRF) on the electrophysiological responsivity of the locus coeruleus to subsequent CRF challenge

Neuroscience

(1995)

L.H. Conti et al.

Reciprocal cross-desensitization of locus coeruleus electrophysiological responsivity to corticotropin-releasing factor and stress

Brain Res.

(1996)

A.L. Curtis et al.

Long-term regulation of locus ceruleus sensitivity to corticotropin-releasing factor by swim stress

J. Pharmacol. Exp. Ther.

(1999)

A.L. Curtis et al.

Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor

Neuropsychopharmacology

(2006)

A.L. Curtis et al.

Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus

Neuroscience

(1995)

A.L. Curtis et al.

Activation of the locus coeruleus noradrenergic system by intracoerulear microinfusion of corticotropin-releasing factor: effects on discharge rate, cortical norepinephrine levels and cortical electroencephalographic activity

J. Pharmacol. Exp. Ther.

(1997)

A.L. Curtis et al.

Pharmacological comparison of two corticotropin-releasing factor antagonists: in vivo and in vitro studies

J. Pharmacol. Exp. Ther.

(1994)

E.C. Davis et al.

The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area

Brain Res.

(1996)

K. Domschke et al.

Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity

Am. J. Med. Genet. Part B Neuropsychiatr. Genet.: Off. Publ. Int. Soc. Psychiatr. Genet.

(2007)

K. Domschke et al.

Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women

Int. J. Neuropsychopharmacol.

(2004)

T.C. Eley et al.

Association analysis of MAOA and COMT with neuroticism assessed by peers

Am. J. Med. Genet.. Part B Neuropsychiatr. Genet.: Off. Publ. Int. Soc. Psychiatr. Genet.

(2003)

M.A. Enoch et al.

Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism

Psychiatr. Genet.

(2003)

A.M. Etgen et al.

Estradiol and progesterone modulation of norepinephrine neurotransmission: implications for the regulation of female reproductive behavior

J. Neuroendocrinol.

(1992)

A.M. Etgen et al.

Mechanisms of ovarian steroid regulation of norepinephrine receptor-mediated signal transduction in the hypothalamus: implications for female reproductive physiology

Horm. Behav.

(2001)

S.L. Foote et al.

Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal

Proc. Natl. Acad. Sci. USA

(1980)

S.A. Freedman et al.

Gender differences in responses to traumatic events: a prospective study

J. Trauma. Stress

(2002)

A. Garcia-Falgueras et al.

The expression of brain sexual dimorphism in artificial selection of rat strains

Brain Res.

(2005)

A. Garcia-Falgueras et al.

Sexual dimorphism in hybrids rats

Brain Res.

(2006)

Cited by (152)

Sex-specific threat responding and neuronal engagement in carbon dioxide associated fear and extinction: Noradrenergic involvement in female mice
2024, Neurobiology of Stress
Difficulty in appropriately responding to threats is a key feature of psychiatric disorders, especially fear-related conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD). Most prior work on threat and fear regulation involves exposure to external threatful cues. However, fear can also be triggered by aversive, within-the-body, sensations. This interoceptive signaling of fear is highly relevant to PD and PTSD but is not well understood, especially in the context of sex. Using female and male mice, the current study investigated fear-associated spontaneous and conditioned behaviors to carbon dioxide (CO₂) inhalation, a potent interoceptive threat that induces fear and panic. We also investigated whether behavioral sensitivity to CO₂ is associated with delayed PTSD-relevant behaviors. CO₂ evoked heterogenous freezing behaviors in both male and female animals. However, active, rearing behavior was significantly reduced in CO₂-exposed male but not female mice. Interestingly, behavioral sensitivity to CO₂ was associated with compromised fear extinction, independent of sex. However, in comparison to CO₂-exposed males, females elicited less freezing and higher rearing during extinction suggesting an engagement of active versus passive defensive coping. Persistent neuronal activation marker ΔFosB immuno-mapping revealed attenuated engagement of infralimbic-prefrontal areas in both sexes but higher activation of brain stem locus coeruleus (LC) area in females. Inter-regional co-activation mapping revealed sex-independent disruptions in the infralimbic-amygdala associations but altered LC associations only in CO₂-exposed female mice. Lastly, dopamine β hydroxylase positive (DβH ^+ ve) noradrenergic neuronal cell counts in the LC correlated with freezing and rearing behaviors during CO₂ inhalation and extinction only in female but not male mice. Collectively, these data provide evidence for higher active defensive responding to interoceptive threat CO₂-associated fear in females that may stem from increased recruitment of the brainstem noradrenergic system. Our findings reveal distinct contributory mechanisms that may promote sex differences in fear and panic associated pathologies.
Perineuronal nets are associated with decision making under conditions of uncertainty in female but not male mice
2024, Behavioural Brain Research
Biological sex influences decision-making processes in significant ways, differentiating the responses animals choose when faced with a range of stimuli. The neurobiological underpinnings that dictate sex differences in decision-making tasks remains an important open question, yet single-sex studies of males form most studies in behavioural neuroscience. Here we used female and male BALB/c mice on two spatial learning and memory tasks and examined the expression of perineuronal nets (PNNs) and parvalbumin interneurons (PV) in regions correlated with spatial memory. Mice underwent the aversive active place avoidance (APA) task or the appetitive trial-unique nonmatching-to-location (TUNL) touchscreen task. Mice in the APA cohort learnt to avoid the foot-shock and no differences were observed on key measures of the task nor in the number and intensity of PNNs and PV. On the delay but not separation manipulation in the TUNL task, females received more incorrect trials and less correct trials compared to males. Furthermore, females in this cohort exhibited higher intensity PNNs and PV cells in the agranular and granular retrosplenial cortex, compared to males. These data show that female and male mice perform similarly on spatial learning tasks. However, sex differences in neural circuitry may underly differences in making decisions under conditions of uncertainty on an appetitive task. These data emphasise the importance of using mice of both sexes in studies of decision-making neuroscience.
Sex difference affects fear extinction but not lithium efficacy in rats following fear-conditioning with respect to the hippocampal level of BDNF
2024, Pharmacology Biochemistry and Behavior
In rodents, exposure to electrical shock and creating a strong fear memory using fear-conditioning model can induce PTSD-like behavior. In this study, we induced a fear-conditioning model in rats and investigated freezing (PTSD-like) behavior, 21 days after three shocks exposure (0.6 mA, 3 s, 30 seconds interval) in both male and female rats. Lithium was injected intraperitoneally (100 mg/kg) in three protocols: (1) 1 h after fear-conditioning (2) 1 h, 24 h, and 48 h after fear-conditioning (3), 1 h, 24 h, 48 h, 72 h, and 96 h after fear-conditioning. Extinction training (20 sounds without shocks, 75 dB, 3 s, 30 seconds interval) was performed in three protocols: (1) 1 h after fear-conditioning (one session), (2) 1 h, 24 h, and 48 h after fear-conditioning (three sessions), (3), 1 h, 24 h, 48 h, 72 h, and 96 h after fear-conditioning (five sessions). Forced swim test (FST) and hot plate were used to assess behavior. Results showed that lithium in all protocols had no effect on freezing behavior, FST, and pain subthreshold in all rats. Extinction training decreased freezing behavior, with more efficacy in females. In males, only 5-session training was effective, while in females all protocols were effective. Extinction training also altered pain perception and the results of FST, depending on the sessions and was different in males and females. Brain-derived neurotrophic factor (BDNF) mRNA level was increased in females following 3 and 5 sessions, and in males following 5 sessions extinction training. In conclusion, we suggested that there is a sex difference for the effect of extinction training on freezing behavior and BDNF mRNA level in a rat model of fear-conditioning.
Partial or Complete Loss of Norepinephrine Differentially Alters Contextual Fear and Catecholamine Release Dynamics in Hippocampal CA1
2024, Biological Psychiatry Global Open Science
Contextual fear learning is heavily dependent on the hippocampus. Despite evidence that catecholamines contribute to contextual encoding and memory retrieval, the precise temporal dynamics of their release in the hippocampus during behavior is unknown. In addition, new animal models are required to probe the effects of altered catecholamine synthesis on release dynamics and contextual learning.
We generated 2 new mouse models of altered locus coeruleus–norepinephrine (NE) synthesis and utilized them together with GRAB_NE and GRAB_DA sensors and in vivo fiber photometry to investigate NE and dopamine (DA) release dynamics in the dorsal hippocampal CA1 during contextual fear conditioning.
Aversive foot shock increased both NE and DA release in the dorsal CA1, while freezing behavior associated with recall of fear memory was accompanied by decreased release. Moreover, we found that freezing at the recent time point was sensitive to both partial and complete loss of locus coeruleus–NE synthesis throughout prenatal and postnatal development, similar to previous observations of mice with global loss of NE synthesis beginning postnatally. In contrast, freezing at the remote time point was compromised only by complete loss of locus coeruleus–NE synthesis beginning prenatally.
Overall, these findings provide novel insights into the role of NE in contextual fear and the precise temporal dynamics of both NE and DA during freezing behavior and highlight complex relationships between genotype, sex, and NE signaling.
A 4-session written emotional disclosure intervention lowers 6-month sympathoadrenal urinary output in persons living with HIV
2024, Psychoneuroendocrinology
We previously reported that a brief guided written emotional disclosure (WED) intervention resulted in significant reductions in post-traumatic stress disorder (PTSD) symptomology in women, but not men, living with HIV. Levels of 24-hour urinary output of epinephrine (E) and norepinephrine (NE) are shown to be elevated in persons diagnosed with PTSD. The current study tested whether there was an effect for the 4-week WED intervention on 6-month change in urinary E and NE output amongst persons living with HIV.
Fourteen women and 11 men living with HIV randomized to four 30-min expressive writing sessions of either trauma writing or daily events writing in the parent trial were included based upon collection of urine specimens at baseline, 1-, and 6-months after the intervention. Total volume (µg) and concentration (µg/ml) of urinary E and NE were derived from the specimens as study outcomes.
Four repeated measures analyses of covariance (ANCOVA) were performed to evaluate study outcomes using trauma- versus daily-writing as the between-subject factors and collection time point as the within-subject factor, controlling for age and sex. A group x time interaction was observed wherein the trauma writing treatment group showed a significantly greater decrease in total urinary output, F(2, 46) = 4.03, p = .03, and concentration, F(2, 46) = 4.74, p = .01 of epinepherine. Post-hoc analyses revealed the interaction effect for the total, F(2, 22) = 4.82, p = .03, and concentration, F(2, 22) = 7.57, p = .005, of urinary E output over 6-months was significant for women. Interactions were not observed in urinary NE output.
Significant reductions in the total output and concentration of urinary E were found up to 6-months following initiation of a 4-session guided written emotional disclosure intervention. Profiles of sympathoadrenal activity and response to expressive writing differ between men and women living with HIV. Futher research is need to characterize the putative pathways linking sympathoadrenal response to upstream neurobiological function and downstream inflammatory-immune status in women living with HIV and PTSD.
Daily heart rate variability biofeedback training decreases locus coeruleus MRI contrast in younger adults in a randomized clinical trial
2023, International Journal of Psychophysiology
As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast was assessed using turbo spin echo MRI scans, and RNA sequencing was used to assess cAMP-responsive element binding protein (CREB)-regulated gene expression in circulating blood cells, an index of sympathetic nervous system signaling. We found that left LC contrast decreased in younger participants in the experimental group, and across younger participants, decreases in left LC contrast were related to the extent to which participants increased their heart rate oscillations during training. Furthermore, decreases in left LC contrast were associated with decreased expression of CREB-associated gene transcripts. On the contrary, there were no effects of biofeedback on LC contrast among older participants in the experimental group. These findings provide novel evidence that in younger adults, HRV biofeedback involving slow, paced breathing can decrease both LC contrast and sympathetic nervous system signaling.

View all citing articles on Scopus

View full text

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

Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies

Neuroscience

Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor

J. Biol. Chem.

Estradiol increases catecholamine levels in the hypothalamus of ovariectomized rats during the dark-phase

Eur. J. Pharmacol.

Puberty onset of gender differences in rates of depression: a developmental, epidemiologic and neuroendocrine perspective

J. Affect. Disord.

Estrogen increases G protein coupled receptor kinase 2 in the cortex of female rats

Brain Res.

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

J. Neurosci.

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

J. Neurosci.

An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance

Annu. Rev. Neurosci.

The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network

Science

Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men

Mol. Psychiatry

The dorsal locus coeruleus is larger in male than in female Sprague-Dawley rats

Neurosci. Lett.

CRF and CRF receptors: role in stress responsivity and other behaviors

Annu. Rev. Pharmacol. Toxicol.

Sex differences in molecular and cellular substrates of stress

Cell. Mol. Neurobiol.

Cognitive disruptions in stress-related psychiatric disorders: a role for corticotropin releasing factor (CRF)

Horm. Behav.

Sexual dimorphism in locus coeruleus dendritic morphology: a structural basis for sex differences in emotional arousal

Physiol. Behav.

Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology

Mol. Psychiatry

Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression

Mol. Psychiatry

Effects of locus coeruleus activation on electroencephalographic activity in the neocortex and hippocampus

J. Neurosci.

The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes

Brain Res. Brain Res. Rev.

Effects of locus coeruleus inactivation on electroencephalographic activity in neocortex and hippocampus

Neuroscience

A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain

Am. J. Hum. Genet.

Gender differences in trauma and posttraumatic stress disorder

J. Gend. Specif. Med.

Spatial, temporal and numeric analysis of alzheimer changes in the nucleus coeruleus

Neurobiol. Aging

Beta-adrenergic activation and memory for emotional events

Nature

Noradrenergic modulation of cognition: therapeutic implications

J. Psychopharmacol.

Corticotropin releasing factor receptor-mediated stimulation of adenylate cyclase activity in the rat brain

Brain Res.

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain

Am. J. Hum. Genet.

Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain

J. Neurobiol.

Phasic activation of monkey locus ceruleus neurons by simple decisions in a forced-choice task

J. Neurosci.

Effects of pretreatment with corticotropin-releasing factor (CRF) on the electrophysiological responsivity of the locus coeruleus to subsequent CRF challenge

Neuroscience

Reciprocal cross-desensitization of locus coeruleus electrophysiological responsivity to corticotropin-releasing factor and stress

Brain Res.

Long-term regulation of locus ceruleus sensitivity to corticotropin-releasing factor by swim stress

J. Pharmacol. Exp. Ther.

Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor

Neuropsychopharmacology

Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus

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