, Volume 17, Issue 1, pp 5–13 | Cite as

Sex differences in stress responses: a critical role for corticotropin-releasing factor

  • Debra A. BangasserEmail author
  • Kimberly R. Wiersielis
Review Article


Rates of post-traumatic stress disorder, panic disorder, and major depression are higher in women than in men. Another shared feature of these disorders is that dysregulation of the stress neuropeptide, corticotropin-releasing factor (CRF), is thought to contribute to their pathophysiology. Therefore, sex differences in responses to CRF could contribute to this sex bias in disease prevalence. Here, we review emerging data from non-human animal models that reveal extensive sex differences in CRF functions ranging from its presynaptic regulation to its postsynaptic efficacy. Specifically, detailed are sex differences in the regulation of CRF-containing neurons and the amount of CRF that they produce. We also describe sex differences in CRF receptor expression, distribution, trafficking, and signaling. Finally, we highlight sex differences in the processes that mitigate the effects of CRF. In most cases, the identified sex differences can lead to increased stress sensitivity in females. Thus, the relevance of these differences for the increased risk of depression and anxiety disorders in women compared to men is also discussed.


Anxiety Arousal Attention Corticotropin-releasing hormone Depression Post-traumatic stress disorder Sexual dimorphism 


Psychiatric disorders, such as post-traumatic stress disorder (PTSD), panic disorder, and major depression, affect many individuals worldwide [1, 2, 3]. These disorders are considered stress-related because stressful life events are associated with their onset and severity [4, 5, 6, 7]. Indeed, risk for developing panic disorder and depression is related to the number of life stressors the patient experiences [4, 5, 8]. PTSD is, by definition, preceded by exposure to a traumatic event [9]. In addition to sharing stress as an etiological factor, these disorders are also sex-biased, being more common in women than in men [10, 11, 12, 13]. This sex bias is observed across cultures [14, 15, 16], suggesting that sociocultural factors cannot fully explain sex differences in disease prevalence. New research from non-human animal studies is revealing biological factors that can increase female vulnerability to stress and stress-related pathology [17, 18]. Here, we focus on sex differences in the stress neuropeptide, corticotropin-releasing factor (CRF), and highlight a multitude of CRF-driven mechanisms that can alter responses to stress in males versus females and potentially contribute to the higher rates of stress-related psychiatric disorders in women.

During a stressful event, CRF activates the hypothalamic-pituitary-adrenal (HPA) axis when its release from the paraventricular nucleus (PVN) of the hypothalamus causes the anterior pituitary to stimulate the secretion of adrenocorticotropic hormone (ACTH). ACTH, in turn, acts on the adrenal cortex to produce glucocorticoids (e.g., cortisol in primates and corticosterone in many rodent species). Glucocorticoids mobilize energy stores through glucose metabolism while suppressing the immune system and reproduction [19, 20, 21]. Glucocorticoids then act on the PVN and pituitary to terminate the HPA axis response [22, 23]. Along with initiating this endocrine limb of the stress response, CRF acts centrally via CRF1 and CRF2 receptors in brain stem and forebrain regions to initiate autonomic, behavioral, and cognitive responses to stress [24, 25, 26]. Activation of these responses by CRF in the short term facilitates coping with environmental challenges. However, inappropriate or persistent release of CRF is linked to pathology. In fact, individuals with PTSD and depression show elevated levels of CRF in cerebrospinal fluid (CSF), with successful treatment being able to reduce these high CRF levels [27, 28, 29, 30]. CRF levels in CSF are thought to reflect extrahypothalamic release of CRF and do not correlate well with plasma cortisol levels [31], which may explain why elevated CRF in CSF is found in patients with both PTSD and depression, conditions associated with low and high levels of cortisol, respectively [32, 33]. In addition to changes in CSF measures of CRF, alterations in CRF and CRF1 receptor binding are also observed in the brains of patients with PTSD and depression [27, 34, 35, 36]. Additionally, genomic studies have identified single-nucleotide polymorphisms on the genes for CRF and the CRF1 receptor that are linked to the development and/or severity of PTSD, panic disorder, and depression [37, 38, 39, 40]. These studies implicate CRF dysregulation as an etiological contributor to several psychiatric diseases. Given that these disorders occur more frequently in women than in men, sex differences in CRF function could contribute to sex-biased psychopathology.

Historically, female rodents have been excluded from most basic neuroscience studies, including those investigating stress responses [41]. One reason for this underrepresentation of females is that studying female rodents has been considered challenging because of their short estrous cycle and the fact that ovarian hormones can induce neuronal plasticity (e.g., [42, 43]). However, recent studies have demonstrated that data from female rodents are no more variable than data from male rodents [44, 45]. Thus, although cycle effects are important to consider, excluding female subjects due to concerns about increased variability is not a valid approach. Instead, comparing males to females can, in some cases, reveal risk factors for disease. Here, we detail how incorporating female rodents into studies examining CRF function is revealing important clinically relevant sex differences.

Sex differences in CRF-mediated responses to stress

Stressful events activate CRF-producing neurons in several brain regions and there is evidence for sex differences in this activation. For example, acute restraint stress activates more CRF neurons in regions of the hypothalamus and bed nucleus of the stria terminalis (BNST) in adult female than in male rats [46]. The downstream effects of stressor exposure on CRF function are also different in males and females. Specifically, in adult mice, females are more sensitive to a chronic variable stress manipulation and this increased sensitivity is linked to epigenetic regulation of the CRF signaling pathway in the nucleus accumbens [47]. In contrast to the effects of stress in adulthood, maternal stress early in gestation increases stress responsivity only in male offspring, an effect that is associated with epigenetic modifications to the CRF gene [48]. Certainly, more studies including females are needed. Yet collectively, these results indicate that stressor exposure can initiate sex-specific responses via regulation of CRF, and these effects differ between the sexes depending on the developmental time point.

Other research has focused on sex differences in the effect of CRF administration or CRF overexpression on anxiety-related behaviors. Initial studies evaluating the effects of CRF on behavior used male rodents and found that central administration of CRF in males evokes anxiety-related behaviors, including burying (a defensive behavior), headshakes (an arousal-related behavior), and grooming (a self-directed behavior thought to be soothing) [37, 49, 50]. We extended this work to examine CRF-evoked behaviors in both male and female rats. CRF increased all of these behaviors in both sexes, but females groomed more than males [51]. Females groomed the most when CRF was administered at the stage of their estrous cycle when ovarian hormones were highest, suggesting that these ovarian hormones potentiate the effect of CRF on grooming [51]. Finally, this sex difference in grooming was associated with ovarian hormone regulation of CRF-activated functional connectivity networks, highlighting a mechanism by which sex differences in the effects of CRF can be established at the network level [51, 52].

CRF-overexpressing (CRF-OE) mice have been used to demonstrate sex differences in the developmental effects of CRF hypersecretion. Specifically, mice with forebrain CRF overexpression during development displayed anxiety-related behavior in adulthood, an effect that was particularly pronounced in females [53]. When given a second stressor in adulthood (exposure to predator odor), only male mice with CRF overexpression early in development displayed avoidance [54]. One caveat to this result is that predator odor induced high levels of avoidance in females, regardless of a history of CRF overexpression [54]. Collectively, these studies suggest that under some circumstances, CRF increases anxiety-like behavior more in females than in males. Nevertheless, males are not unaffected by CRF and in fact may be more sensitive to a second stress hit after exposure to high levels of CRF early in development.

CRF can alter cognitive processes [55, 56, 57, 58, 59]. Although most of the research has focused on males (reviewed in [57]), our laboratory assessed in both sexes the effect of central CRF administration on attention. We specifically tested sustained attention, which is the ability to continuously monitor situations for intermittent and unpredictable events [60]. CRF dose-dependently impaired sustained attention in both male and female rats. However, the effect of CRF on sustained attention in females was dependent on the estrous cycle [60]. When females were in diestrus, where ovarian hormones are low, CRF profoundly disrupted attention. However, when females were in cycle phases characterized by elevated levels of ovarian hormones, CRF had no effect on attention [60]. Thus, in this example, ovarian hormones are hypothesized to be protective against the negative impact of CRF on attention. Whether CRF regulates other cognitive processes differently in male versus female rats warrants further study.

Studies on sex differences in the effects of CRF administration in non-human primates and humans have focused on CRF’s regulation of the HPA axis. Specifically, an intravenous CRF challenge increases cortisol levels more in female than male rhesus monkeys and common marmosets [61, 62]. This sex difference is linked to dihydrotestosterone, which reduces CRF-stimulated cortisol release in male monkeys [63]. Although these findings suggest sex differences in CRF sensitivity, the CRF challenge in marmosets did not increase ACTH levels more in females than males, suggesting sex differences in the adrenal response to ACTH in this species [62]. In healthy humans, an intravenous CRF challenge increases ACTH levels more in women than men, suggesting heightened sensitivity to CRF in women [64]. These studies do provide evidence that, in primates, the HPA axis of females is more sensitive than that of males to the effects of CRF. Whether sex differences in CRF sensitivity are also present in regions that regulate anxiety and cognition remains to be determined in primates.

Sex differences in CRF receptors

As noted, CRF can differentially alter behavior in males versus females. The fact that behaviors change following the administration of CRF indicates that sex differences are mediated by postsynaptic processes. Indeed, there is evidence for sex differences in CRF receptor density, expression, distribution, trafficking, and signaling in certain brain regions (Fig. 1). Evidence for sex differences in CRF receptors first comes from binding studies. Specifically, CRF1 receptor binding in regions of the amygdala and cortex is higher in adult female rats, while CRF2 receptor binding is higher in regions of the amygdala and hypothalamus in male rats [65, 66]. Interestingly, many of these changes in binding emerge following puberty, implicating pubertal hormone surges in these sex differences [65, 66].
Fig. 1

Depiction of sex differences in CRF receptors. CRF receptors are in green and CRF is in blue. a Sex difference in CRF receptor expression. b Sex difference in the localization of CRF receptors on different cell types. c Sex difference in CRF receptor trafficking. d Sex difference in CRF receptor coupling and signaling. β, β-arrestin2; PKA, protein kinase A

Sex differences in receptor binding can be driven by changes in receptor number. Although the regions in the binding study were not directly assessed for sex differences in receptor levels, the dorsal raphe (DR) has been. In the dorsal and ventrolateral portions of the DR, CRF1 receptor expression is increased in female compared to male rats, while in the ventrolateral DR, CRF2 receptor expression is also higher in females than males (Fig. 1a) [67]. Unlike in rats, sex differences in CRF1 receptor expression are not found in the DR of mice, but there are sex differences in CRF1 receptor distribution [68]. Specifically, the CRF1 receptor co-localizes with DR parvalbumin neurons more in male than in female mice (Fig. 1b) [68]. Given that the levels of CRF1 receptor mRNA are comparable in both sexes [68], CRF1 receptors must co-localize with a cell type different from parvalbumin neurons in females, but the identity of that cell type remains unknown. Sex differences in the types of neurons preferentially regulated by CRF could lead to different behaviors. In fact, this sex difference in CRF1 receptor distribution is associated with increased anxiety in males following local administration of CRF into the DR [68]. Sex differences in the distribution of CRF receptors are also found in hippocampal CA1 dendrites [69]. In CA1, female rats have more CRF receptors in delta opioid receptor-containing dendrites than males [69]. These structural sex differences could lead to sex differences in interactions between CRF and endogenous opioids.

In addition to sex differences in CRF receptor distribution in different types of neurons, we identified sex differences in CRF1 receptor localization within neurons in the locus coeruleus (LC)-arousal center. During a stressful event, CRF is released into the LC where it binds to CRF1 receptors [70, 71, 72]. This receptor activation causes LC neurons to increase their firing rate, thereby releasing norepinephrine into the forebrain to increase arousal [70, 71, 72, 73]. Typically, activation of this circuit increases alertness to facilitate responding to stressors. However, overactivation of the circuit can lead to the dysregulated state of hyperarousal, which is characterized by restlessness, lack of concentration, and disrupted sleep [74, 75]. One cellular mechanism that compensates for excessive CRF release is receptor internalization. During internalization, β-arrestin2 binds to the CRF1 receptor, initiating its trafficking from the plasma membrane to the cytosol where the receptor can no longer be activated [76, 77, 78, 79, 80]. In male rats, acute swim stressor exposure causes β-arrestin2 to bind to the CRF1 receptor, an effect accompanied by CRF1 receptor internalization in LC dendrites [81, 82]. However, β-arrestin2 binding and internalization are not observed following exposure to swim stress in female rats [82]. Further, studies in CRF-OE mice with overexpression throughout their lifespan revealed a similar pattern of CRF1 receptor internalization in LC dendrites of males, but not females (Fig. 1c) [83]. This lack of internalization in females may render their LC neurons more sensitive to conditions of excessive CRF release. In fact, LC neurons of CRF-OE females fire three times faster than those of males [83], an effect that would lead to increased arousal in CRF-OE females.

CRF1 receptors also activate different intracellular signaling pathways in male and female rodents [84, 85]. CRF1 receptors are G protein-coupled receptors that preferentially bind Gs to activate the cAMP-PKA signaling pathway [77, 86, 87, 88]. CRF1 receptors are more highly coupled to Gs in females than males [82]. Accordingly, overexpression of CRF induces greater cAMP-PKA signaling in female than in male mice [84, 85]. In the LC, this increased CRF1 receptor signaling through the cAMP-PKA pathway in females is associated with increased sensitivity to CRF [84]. Thus, a stressful event could increase arousal more in females than males because female CRF1 receptors signal more through the cAMP-PKA pathway that activates LC neurons.

Interestingly, male CRF1 receptors may preferentially signal through a different pathway. As mentioned above, their CRF1 receptors more readily bind β-arrestin2 than those of females [82]. In addition to initiating internalization, β-arrestin2 also can activate signaling cascades that are often distinct from pathways activated by G proteins [89, 90, 91]. Using a phosphoproteomic approach in CRF-OE mice, we found increased phosphorylation of β-arrestin2-mediated signaling pathways (e.g., Rho signaling) in CRF-OE male mice [85]. Collectively, these results suggest a model of sex-biased CRF1 receptor signaling, such that this receptor signals more through β-arrestin2-mediated pathways in males and more through Gs-mediated pathways in females (Fig. 1d) [92, 93, 94]. Different signaling pathways induce distinct cellular consequences, leading to different physiological responses, some of which may increase the risk for certain types of pathology. Therefore, sex differences in signaling could bias males versus females towards different diseases. In fact, an unexpected finding from our phosphoproteomic studies was that overexpression of CRF increased the phosphorylation of proteins in Alzheimer’s disease pathways more in female than male mice [85]. Using a mouse model of Alzheimer’s disease pathology, we found that CRF overexpression increased amyloid plaque formation to a greater degree in females than males [85]. Taken together, these results suggest that sex-biased CRF receptor signaling is an important, yet underexplored, mechanism by which sex differences in risk factors for diseases ranging from psychiatric to neurodegenerative are established.

Sex differences in CRF expression and the regulation of CRF effects

Sex differences in CRF levels are also found in certain brain regions. CRF expression in the PVN has been found to be higher in female than male rodents in some [95, 96, 97] but not all studies [98]. Given that CRF in this region initiates the HPA axis, increased CRF expression in the PVN of females may explain why levels of corticosterone are higher in female than male rodents [99, 100]. The sex difference in hypothalamic CRF is linked to ovarian hormones in females, as levels of CRF are highest at the phases of the estrous cycle characterized by high ovarian hormones [96]. Evidence that this effect is driven by estradiol comes from a study in rhesus monkeys in which estradiol treatment of ovariectomized females increased CRF expression in the PVN [101]. Outside of the PVN, increased CRF expression has been reported by some to be elevated in the central nucleus of the amygdala in female relative to male rats [95], although this sex difference is not always observed [96]. Similarly, CRF immunoreactivity is stronger in female than male rats in the fusiform, but not in the oval nucleus of the BNST [98].

Excess CRF expression in females was recently associated with increased anxiety [102]. Li and colleagues (2016) found that oxytocin interneurons in the medial prefrontal cortex of both male and female mice release CRF-binding protein (CRFBP), which binds free CRF reducing its bioavailability, thereby inhibiting CRF’s effect on its receptors [103]. Despite the release of CRFBP in both sexes, oxytocin interneurons mitigated the anxiogenic effect of CRF only in males [102]. The lack of an effect in females was attributed to their higher levels of CRF expression, which are thought to exceed the capacity of CRFBPs to prevent CRF from inducing anxiety [102]. Interestingly, in the pituitary, CRFBP expression is higher in females than in males, perhaps to compensate, at least in part, for higher levels of CRF in the PVN [95, 96, 97, 104]. When considered together, these studies point to sex differences in CRF expression and CRFBP efficacy as potential contributors to sex differences in stress responses.

CRFBP is one mechanism for reducing the effect of CRF. However, there are other processes involved in CRF regulation, and new research has found a sex difference in another such mechanism. As noted, CRF activates LC neurons and females are more sensitive to this effect [82, 105]. This LC activation is tempered by the release of endogenous opioids that bind to μ-opioid receptors (MORs) [106, 107]. The ability of a MOR agonist to reduce CRF activation of LC neurons was greater in male compared to female rats [108]. This sex difference was linked to decreased female MOR expression in the LC [108]. These findings indicate that during stress, the ability of endogenous opioids to promote the recovery of the LC arousal circuit is decreased in females. When considered with the aforementioned sex differences in CRF1 receptors that render female LC neurons more sensitive to CRF, these findings indicate that arousal in females is more responsive to stress and less quick to subside after stressor exposure, which would predispose females to hyperarousal. If similar mechanisms are found in humans, it may explain why women are more likely to suffer from disorders with hyperarousal features, such as PTSD and depression.

In addition to sex differences in mechanisms that regulate the downstream consequences of CRF, there is emerging evidence for sex differences in the receptors that regulate neurons that produce CRF. CRF neurons express NMDA receptors, suggesting glutamatergic regulation of these cells [109]. Knocking out Grin1 subunits of the NMDA receptor results in a loss of NMDA function, and mice genetically modified so that Grin1 is deleted specifically from their CRF-containing neurons have been produced [110, 111, 112]. These mice display increased fear expression and social withdrawal if they are male [111, 112]. However, female mice are unaffected by this loss of NMDA receptor function in CRF neurons [111]. Thus, glutamatergic regulation of CRF neurons via NMDA receptors appears sex-specific. Given that the receptor subtype(s) on CRF neurons that mediate these stress-related behaviors in females remains unknown, certainly, further investigation into sex differences in the afferent control of CRF neurons is required.


CRF function has mostly been characterized in male subjects, but when females are included, studies reveal several important sex differences. First, CRF-producing neurons are regulated by different types of receptors [111]. Moreover, within CRF neurons, expression of CRF is reported to be higher in females than males in some brain regions, an effect that can overcome the ability of CRFBP to buffer the effects of CRF on anxiety in females [102]. Further, at the receptor level, there are sex differences in receptor expression, distribution, trafficking, and signaling, and many, but not all, of these sex differences have been linked to increased female CRF sensitivity [67, 68, 82, 83, 85]. Finally, there are sex differences in the processes that regulate CRF’s effects, such as increased CRFBP in the pituitary of females [104] and reduced MOR regulation of CRF-induced neuronal activation in females [108]. Most of these sex differences translate into enhanced CRF efficacy in females and may help explain why women are more likely to suffer from disorders characterized by CRF dysregulation, including PTSD, panic disorder, and major depression [10, 11, 12, 13].

How these sex differences in CRF function are established remains largely unknown. There is evidence that, in some cases, circulating ovarian hormones play a role [51, 60, 96, 113, 114]. These hormones may directly regulate the expression of CRF because its promotor contains putative estrogen response elements [115]. Membrane estrogen receptors that initiate intracellular signaling cascades also can regulate CRF neurons. For example, estradiol increases the excitability of CRF neurons in the PVN via the activation of the putative Gq-coupled membrane estrogen receptor [116]. The effect of CRF on postsynaptic neurons can also be regulated by membrane estrogen receptors, such as the G protein-coupled estrogen receptor 1 (GPER1), which can form a heterodimer with CRF receptors [117]. Although the cellular consequences of this interaction remain unknown [117], this receptor heterodimerization likely alters intracellular signaling. It is important to note, however, that not all sex differences are regulated by circulating ovarian hormones. For example, sex differences in CRF1 receptor function in the LC are still apparent in rats gonadectomized in adulthood [82, 105]. This result indicates that circulating hormones do not play a role, but rather that this receptor sex difference results from organizational effects of hormonal surges in development or the different complement of genes on sex chromosomes. In fact, not only can circulating levels of estradiol regulate CRF in the hypothalamus [101], but perinatal estradiol exposure masculinizes adult hypothalamic CRF gene expression [118, 119]. This result highlights how organizational effects of gonadal hormones can lead to the sexual differentiation of CRF circuits. As more sex differences are identified in the effects of CRF, additional studies will be needed to determine the factors that establish sex differences in CRF function.

In conclusion, the field is just beginning to include female subjects and already sex differences have been found in almost every aspect of CRF function. Not only can many of these sex differences increase female vulnerability to certain disorders, but they suggest that pharmacotherapies targeting aspects of CRF function may work differently in men and women. More broadly speaking, it seems unlikely that the CRF system is unique in its sexual differentiation because CRF and CRF receptors are similar to other neuropeptides and receptors. It is therefore likely that as more investigators compare male and female brains, extensive sex differences beyond the CRF system will be reported, thereby shedding light on a multitude of mechanisms that can bias males and females towards different pathologies.

Grant support

This work was supported by NSF CAREER grant IOS-1552416 to D.A.B.


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Murray CJL, Lopez AD (1996) Evidence-based health policy—lessons from the global burden of disease study. Science 274:740–743PubMedCrossRefGoogle Scholar
  2. 2.
    Lopez AD, Murray CC (1998) The global burden of disease, 1990-2020. Nat Med 4:1241–1243PubMedCrossRefGoogle Scholar
  3. 3.
    Kessler RC, Aguilar-Gaxiola S, Alonso J et al (2009) The global burden of mental disorders: an update from the WHO World Mental Health (WMH) Surveys. Epidemiol Psichiatr Soc 18:23–33PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Faravelli C (1985) Life events preceding the onset of panic disorder. J Affect Disord 9:103–105PubMedCrossRefGoogle Scholar
  5. 5.
    Kendler KS, Kessler RC, Walters EE et al (1995) Stressful life events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry 152:833–842PubMedCrossRefGoogle Scholar
  6. 6.
    Melchior M, Caspi A, Milne BJ, Danese A, Poulton R, Moffitt TE (2007) Work stress precipitates depression and anxiety in young, working women and men. Psychol Med 37:1119–1129PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Breslau N (2009) The epidemiology of trauma, PTSD, and other posttrauma disorders. Trauma Violence Abuse 10:198–210PubMedCrossRefGoogle Scholar
  8. 8.
    Kendler KS, Hettema JM, Butera F, Gardner CO, Prescott CA (2003) Life event dimensions of loss, humiliation, entrapment, and danger in the prediction of onsets of major depression and generalized anxiety. Arch Gen Psychiatry 60:789–796PubMedCrossRefGoogle Scholar
  9. 9.
    American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Publishing, Washington, D.C.CrossRefGoogle Scholar
  10. 10.
    Sheikh JI, Leskin GA, Klein DF (2002) Gender differences in panic disorder: findings from the National Comorbidity Survey. Am J Psychiatry 159:55–58PubMedCrossRefGoogle Scholar
  11. 11.
    Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU (2012) Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res 21:169–184PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Breslau N (2002) Gender differences in trauma and posttraumatic stress disorder. J Gend Specif Med 5:34–40PubMedGoogle Scholar
  13. 13.
    Tolin DF, Foa EB (2006) Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research. Psychol Bull 132:959–992PubMedCrossRefGoogle Scholar
  14. 14.
    Weissman MM, Bland R, Joyce PR, Newman S, Wells JE, Wittchen HU (1993) Sex differences in rates of depression: cross-national perspectives. J Affect Disord 29:77–84PubMedCrossRefGoogle Scholar
  15. 15.
    Seeman MV (1997) Psychopathology in women and men: focus on female hormones. Am J Psychiatry 154:1641–1647PubMedCrossRefGoogle Scholar
  16. 16.
    Seedat S, Scott K, Angermeyer MC et al (2009) Cross-national associations between gender and mental disorders in the world health organization world mental health surveys. Arch Gen Psychiatry 66:785–795PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Bangasser DA, Valentino RJ (2014) Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front Neuroendocrinol 35:303–319PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bangasser DA, Wicks B (2017) Sex-specific mechanisms for responding to stress. J Neurosci Res 95:75–82PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Munck A, Guyre PM, Holbrook NJ (1984) Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5:25–44PubMedCrossRefGoogle Scholar
  20. 20.
    McEwen BS, Seeman T (1999) Protective and damaging effects of mediators of stress. Elaborating and testing the concepts of allostasis and allostatic load. Ann N Y Acad Sci 896:30–47PubMedCrossRefGoogle Scholar
  21. 21.
    Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397PubMedCrossRefGoogle Scholar
  22. 22.
    De Kloet ER, Reul JM (1987) Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems. Psychoneuroendocrinology 12:83–105PubMedCrossRefGoogle Scholar
  23. 23.
    Dallman MF, Akana SF, Scribner KA et al (1992) Stress, feedback and facilitation in the hypothalamo-pituitary-adrenal axis. J Neuroendocrinol 4:517–526PubMedCrossRefGoogle Scholar
  24. 24.
    Owens MJ, Nemeroff CB (1991) Physiology and pharmacology of corticotropin-releasing factor. Pharmacol Rev 43:425–473PubMedGoogle Scholar
  25. 25.
    Valentino RJ, Commons KG (2005) Peptides that fine-tune the serotonin system. Neuropeptides 39:1–8PubMedCrossRefGoogle Scholar
  26. 26.
    Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557PubMedCrossRefGoogle Scholar
  27. 27.
    Bremner JD, Licinio J, Darnell A et al (1997) Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154:624–629PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Nemeroff CB (1996) The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry 1:336–342PubMedGoogle Scholar
  29. 29.
    Heuser I, Bissette G, Dettling M et al (1998) Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment. Depress Anxiety 8:71–79PubMedCrossRefGoogle Scholar
  30. 30.
    De Bellis MD, Gold PW, Geracioti TD Jr, Listwak SJ, Kling MA (1993) Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am J Psychiatry 150:656–657PubMedCrossRefGoogle Scholar
  31. 31.
    Baker DG, West SA, Nicholson WE et al (1999) Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 156:585–588PubMedGoogle Scholar
  32. 32.
    Yehuda R, Southwick SM, Nussbaum G, Wahby V, Giller EL Jr, Mason JW (1990) Low urinary cortisol excretion in patients with posttraumatic stress disorder. J Nerv Ment Dis 178:366–369PubMedCrossRefGoogle Scholar
  33. 33.
    Holsboer F (2001) Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 62:77–91PubMedCrossRefGoogle Scholar
  34. 34.
    Wang SS, Kamphuis W, Huitinga I, Zhou JN, Swaab DF (2008) Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. Mol Psychiatry 13(786–799):741CrossRefGoogle Scholar
  35. 35.
    Austin MC, Janosky JE, Murphy HA (2003) Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men. Mol Psychiatry 8:324–332PubMedCrossRefGoogle Scholar
  36. 36.
    Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF (1994) Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60:436–444PubMedCrossRefGoogle Scholar
  37. 37.
    Sherman JE, Kalin NH (1987) The effects of ICV-CRH on novelty-induced behavior. Pharmacol Biochem Behav 26:699–703PubMedCrossRefGoogle Scholar
  38. 38.
    Smoller JW, Rosenbaum JF, Biederman J et al (2003) Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition. Biol Psychol 54:1376–1381CrossRefGoogle Scholar
  39. 39.
    Amstadter AB, Nugent NR, Yang BZ et al (2011) Corticotrophin-releasing hormone type 1 receptor gene (CRHR1) variants predict posttraumatic stress disorder onset and course in pediatric injury patients. Dis Markers 30:89–99PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Liu Z, Zhu F, Wang G et al (2006) Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci Lett 404:358–362PubMedCrossRefGoogle Scholar
  41. 41.
    Beery AK, Zucker I (2011) Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35:565–572PubMedCrossRefGoogle Scholar
  42. 42.
    Woolley CS, Gould E, Frankfurt M, McEwen BS (1990) Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 10:4035–4039PubMedCrossRefGoogle Scholar
  43. 43.
    Shors TJ, Chua C, Falduto J (2001) Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J Neurosci 21:6292–6297PubMedCrossRefGoogle Scholar
  44. 44.
    Becker JB, Prendergast BJ, Liang JW (2016) Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol Sex Differ 7:34PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Prendergast BJ, Onishi KG, Zucker I (2014) Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev 40:1–5PubMedCrossRefGoogle Scholar
  46. 46.
    Babb JA, Masini CV, Day HE, Campeau S (2013) Sex differences in activated corticotropin-releasing factor neurons within stress-related neurocircuitry and hypothalamic-pituitary-adrenocortical axis hormones following restraint in rats. Neuroscience 234:40–52PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hodes GE, Pfau ML, Purushothaman I et al (2015) Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci 35:16362–16376PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Mueller BR, Bale TL (2008) Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 28:9055–9065PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Howard O, Carr GV, Hill TE, Valentino RJ, Lucki I (2008) Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats. Psychopharmacology 199:569–582PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Gargiulo PA, Donoso AO (1996) Distinct grooming patterns induced by intracerebroventricular injection of CRH, TRH and LHRH in male rats. Braz J Med Biol Res 29:375–379PubMedGoogle Scholar
  51. 51.
    Wiersielis KR, Wicks B, Simko H et al (2016) Sex differences in corticotropin releasing factor-evoked behavior and activated networks. Psychoneuroendocrinology 73:204–216PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Salvatore M, Wiersielis KR, Luz S, Waxler D, Bhatnagar S, Bangasser DA (2017) Sex differences in circuits activated by corticotropin releasing factor in rats. Horm Behav.
  53. 53.
    Toth M, Gresack JE, Bangasser DA et al (2014) Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice. Neuropsychopharmacology 39:1409–1419PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Toth M, Flandreau EI, Deslauriers J et al (2016) Overexpression of forebrain CRH during early life increases trauma susceptibility in adulthood. Neuropsychopharmacology 41:1681–1690PubMedCrossRefGoogle Scholar
  55. 55.
    Snyder K, Wang WW, Han R, McFadden K, Valentino RJ (2012) Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility. Neuropsychopharmacology 37:520–530PubMedCrossRefGoogle Scholar
  56. 56.
    Van’t Veer A, Yano JM, Carroll FI, Cohen BM, Carlezon WA (2012) Corticotropin-releasing factor (CRF)-induced disruption of attention in rats is blocked by the kappa-opioid receptor antagonist JDTic. Neuropsychopharmacology 37:2809–2816CrossRefGoogle Scholar
  57. 57.
    Bangasser DA, Kawasumi Y (2015) Cognitive disruptions in stress-related psychiatric disorders: a role for corticotropin releasing factor (CRF). Horm Behav 76:125–135PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Hupalo S, Berridge CW (2016) Working memory impairing actions of corticotropin-releasing factor (CRF) neurotransmission in the prefrontal cortex. Neuropsychopharmacology 41:2733–2740PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Isogawa K, Bush DE, Ledoux JE (2012) Contrasting effects of pretraining, posttraining, and pretesting infusions of corticotropin-releasing factor into the lateral amygdala: attenuation of fear memory formation but facilitation of its expression. Biol Psychol 73:353–359CrossRefGoogle Scholar
  60. 60.
    Cole RD, Kawasumi Y, Parikh V, Bangasser DA (2016) Corticotropin releasing factor impairs sustained attention in male and female rats. Behav Brain Res 296:30–34PubMedCrossRefGoogle Scholar
  61. 61.
    Sanchez MM, McCormack K, Grand AP, Fulks R, Graff A, Maestripieri D (2010) Effects of sex and early maternal abuse on adrenocorticotropin hormone and cortisol responses to the corticotropin-releasing hormone challenge during the first 3 years of life in group-living rhesus monkeys. Dev Psychopathol 22:45–53PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Johnson EO, Kamilaris TC, Carter CS, Calogero AE, Gold PW, Chrousos GP (1996) The biobehavioral consequences of psychogenic stress in a small, social primate (Callithrix jacchus jacchus). Biol Psychol 40:317–337CrossRefGoogle Scholar
  63. 63.
    Toufexis DJ, Wilson ME (2012) Dihydrotestosterone differentially modulates the cortisol response of the hypothalamic–pituitary–adrenal axis in male and female rhesus macaques, and restores circadian secretion of cortisol in females. Brain Res 1429:43–51PubMedCrossRefGoogle Scholar
  64. 64.
    Gallucci WT, Baum A, Laue L et al (1993) Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis. Health Psychol 12:420–425PubMedCrossRefGoogle Scholar
  65. 65.
    Weathington JM, Cooke BM (2012) Corticotropin-releasing factor receptor binding in the amygdala changes across puberty in a sex-specific manner. Endocrinology 153:5701–5705PubMedCrossRefGoogle Scholar
  66. 66.
    Weathington JM, Hamki A, Cooke BM (2014) Sex- and region-specific pubertal maturation of the corticotropin-releasing factor receptor system in the rat. J Comp Neurol 522:1284–1298PubMedCrossRefGoogle Scholar
  67. 67.
    Lukkes JL, Norman KJ, Meda S, Andersen SL (2016) Sex differences in the ontogeny of CRF receptors during adolescent development in the dorsal raphe nucleus and ventral tegmental area. Synapse 70:125–132PubMedCrossRefGoogle Scholar
  68. 68.
    Howerton AR, Roland AV, Fluharty JM et al (2014) Sex differences in corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity. Biol Psychol 75:873–883CrossRefGoogle Scholar
  69. 69.
    Williams TJ, Akama KT, Knudsen MG, McEwen BS, Milner TA (2011) Ovarian hormones influence corticotropin releasing factor receptor colocalization with delta opioid receptors in CA1 pyramidal cell dendrites. Exp Neurol 230:186–196PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Page ME, Berridge CW, Foote SL, Valentino RJ (1993) Corticotropin-releasing factor in the locus coeruleus mediates EEG activation associated with hypotensive stress. Neurosci Lett 164:81–84PubMedCrossRefGoogle Scholar
  71. 71.
    Valentino RJ, Curtis AL, Page ME, Pavcovich LA, Florin-Lechner SM (1997) Activation of the locus ceruleus brain noradrenergic system during stress: circuitry, consequences, and regulation. Adv Pharmacol 42:781–784CrossRefGoogle Scholar
  72. 72.
    Curtis AL, Valentino RJ (1994) Corticotropin-releasing factor neurotransmission in locus coeruleus: a possible site of antidepressant action. Brain Res Bull 35:581–587PubMedCrossRefGoogle Scholar
  73. 73.
    Curtis AL, Lechner SM, Pavcovich LA, Valentino RJ (1997) 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 281:163–172PubMedGoogle Scholar
  74. 74.
    Gold PW, Chrousos GP (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7:254–275PubMedCrossRefGoogle Scholar
  75. 75.
    Bangasser DA, Valentino RJ (2012) Sex differences in molecular and cellular substrates of stress. Cell Mol Neurobiol 32:709–723PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Hauger RL, Smith RD, Braun S, Dautzenberg FM, Catt KJ (2000) Rapid agonist-induced phosphorylation of the human CRF receptor, type 1: a potential mechanism for homologous desensitization. Biochem Biophys Res Commun 268:572–576PubMedCrossRefGoogle Scholar
  77. 77.
    Hauger RL, Risbrough V, Oakley RH, Olivares-Reyes JA, Dautzenberg FM (2009) Role of CRF receptor signaling in stress vulnerability, anxiety, and depression. Ann N Y Acad Sci 1179:120–143PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Reyes BA, Fox K, Valentino RJ, Van Bockstaele EJ (2006) Agonist-induced internalization of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Eur J Neurosci 23:2991–2998PubMedCrossRefGoogle Scholar
  79. 79.
    Holmes KD, Babwah AV, Dale LB, Poulter MO, Ferguson SS (2006) Differential regulation of corticotropin releasing factor 1alpha receptor endocytosis and trafficking by beta-arrestins and Rab GTPases. J Neurochem 96:934–949PubMedCrossRefGoogle Scholar
  80. 80.
    Oakley RH, Olivares-Reyes JA, Hudson CC, Flores-Vega F, Dautzenberg FM, Hauger RL (2007) Carboxyl-terminal and intracellular loop sites for CRF1 receptor phosphorylation and beta-arrestin-2 recruitment: a mechanism regulating stress and anxiety responses. Am J Physiol Regul Integr Comp Physiol 293:R209–R222PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Reyes BA, Valentino RJ, Van Bockstaele EJ (2008) Stress-induced intracellular trafficking of corticotropin-releasing factor receptors in rat locus coeruleus neurons. Endocrinology 149:122–130PubMedCrossRefGoogle Scholar
  82. 82.
    Bangasser DA, Curtis A, Reyes BA et al (2010) Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry 15(877):896–904CrossRefGoogle Scholar
  83. 83.
    Bangasser DA, Reyes BA, Piel D et al (2013) Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression. Mol Psychiatry 18:166–173PubMedCrossRefGoogle Scholar
  84. 84.
    Bangasser DA, Shors TJ (2010) Critical brain circuits at the intersection between stress and learning. Neurosci Biobehav Rev 34:1223–1233PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Bangasser DA, Dong H, Carroll J et al (2016) Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer’s disease-related signaling. Mol Psychiatry 22(8):1126–1133PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Grammatopoulos DK, Randeva HS, Levine MA, Kanellopoulou KA, Hillhouse EW (2001) Rat cerebral cortex corticotropin-releasing hormone receptors: evidence for receptor coupling to multiple G-proteins. J Neurochem 76:509–519PubMedCrossRefGoogle Scholar
  87. 87.
    Blank T, Nijholt I, Grammatopoulos DK, Randeva HS, Hillhouse EW, Spiess J (2003) Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning. J Neurosci 23:700–707PubMedCrossRefGoogle Scholar
  88. 88.
    Battaglia G, Webster EL, De Souza EB (1987) Characterization of corticotropin-releasing factor receptor-mediated adenylate cyclase activity in the rat central nervous system. Synapse 1:572–581PubMedCrossRefGoogle Scholar
  89. 89.
    Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517PubMedCrossRefGoogle Scholar
  90. 90.
    DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK (2007) Beta-arrestins and cell signaling. Annu Rev Physiol 69:483–510PubMedCrossRefGoogle Scholar
  91. 91.
    Violin JD, Lefkowitz RJ (2007) Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci 28:416–422PubMedCrossRefGoogle Scholar
  92. 92.
    Valentino RJ, Bangasser D, Van Bockstaele EJ (2013) Sex-biased stress signaling: the corticotropin-releasing factor receptor as a model. Mol Pharmacol 83:737–745PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Valentino RJ, Van Bockstaele E, Bangasser D (2013) Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends Pharmacol Sci 34:437–444PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Valentino RJ, Bangasser DA (2016) Sex-biased cellular signaling: molecular basis for sex differences in neuropsychiatric diseases. Dialogues Clin Neurosci 18:385–393PubMedPubMedCentralGoogle Scholar
  95. 95.
    Iwasaki-Sekino A, Mano-Otagiri A, Ohata H, Yamauchi N, Shibasaki T (2009) Gender differences in corticotropin and corticosterone secretion and corticotropin-releasing factor mRNA expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala in response to footshock stress or psychological stress in rats. Psychoneuroendocrinology 34:226–237PubMedCrossRefGoogle Scholar
  96. 96.
    Viau V, Bingham B, Davis J, Lee P, Wong M (2005) Gender and puberty interact on the stress-induced activation of parvocellular neurosecretory neurons and corticotropin-releasing hormone messenger ribonucleic acid expression in the rat. Endocrinology 146:137–146PubMedCrossRefGoogle Scholar
  97. 97.
    Dunčko R, Kiss A, Škultétyová I, Rusnák M, Ježová D (2001) Corticotropin-releasing hormone mRNA levels in response to chronic mild stress rise in male but not in female rats while tyrosine hydroxylase mRNA levels decrease in both sexes. Psychoneuroendocrinology 26:77–89PubMedCrossRefGoogle Scholar
  98. 98.
    Sterrenburg L, Gaszner B, Boerrigter J et al (2012) Sex-dependent and differential responses to acute restraint stress of corticotropin-releasing factor-producing neurons in the rat paraventricular nucleus, central amygdala, and bed nucleus of the stria terminalis. J Neurosci Res 90:179–192PubMedCrossRefGoogle Scholar
  99. 99.
    Kitay JI (1961) Sex differences in adrenal cortical secretion in the rat. Endocrinology 68:818–824PubMedCrossRefGoogle Scholar
  100. 100.
    Critchlow V, Liebelt RA, Bar-Sela M, Mountcastle W, Lipscomb HS (1963) Sex difference in resting pituitary-adrenal function in the rat. Am J Phys 205:807–815Google Scholar
  101. 101.
    Roy BN, Reid RL, Van Vugt DA (1999) The effects of estrogen and progesterone on corticotropin-releasing hormone and arginine vasopressin messenger ribonucleic acid levels in the paraventricular nucleus and supraoptic nucleus of the rhesus monkey. Endocrinology 140:2191–2198PubMedCrossRefGoogle Scholar
  102. 102.
    Li K, Nakajima M, Ibañez-Tallon I, Heintz N (2016) A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell 167:60–72.e11PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Eede FVD, Broeckhoven CV, Claes SJ (2005) Corticotropin-releasing factor-binding protein, stress and major depression. Ageing Res Rev 4:213–239CrossRefGoogle Scholar
  104. 104.
    Speert DB, McClennen SJ, Seasholtz AF (2002) Sexually dimorphic expression of corticotropin-releasing hormone-binding protein in the mouse pituitary. Endocrinology 143:4730–4741PubMedCrossRefGoogle Scholar
  105. 105.
    Curtis AL, Bethea T, Valentino RJ (2006) Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor. Neuropsychopharmacology 31:544–554PubMedCrossRefGoogle Scholar
  106. 106.
    Abercrombie ED, Jacobs BL (1988) Systemic naloxone administration potentiates locus coeruleus noradrenergic neuronal activity under stressful but not non-stressful conditions. Brain Res 441:362–366PubMedCrossRefGoogle Scholar
  107. 107.
    Valentino RJ, Wehby RG (1989) Locus ceruleus discharge characteristics of morphine-dependent rats: effects of naltrexone. Brain Res 488:126–134PubMedCrossRefGoogle Scholar
  108. 108.
    Guajardo HM, Snyder K, Ho A, Valentino RJ (2017) Sex differences in μ-opioid receptor regulation of the rat locus coeruleus and their cognitive consequences. Neuropsychopharmacology 42:1295–1304PubMedCrossRefGoogle Scholar
  109. 109.
    Beckerman MA, Van Kempen TA, Justice NJ, Milner TA, Glass MJ (2013) Corticotropin-releasing factor in the mouse central nucleus of the amygdala: ultrastructural distribution in NMDA-NR1 receptor subunit expressing neurons as well as projection neurons to the bed nucleus of the stria terminalis. Exp Neurol 239:120–132PubMedCrossRefGoogle Scholar
  110. 110.
    Monyer H, Sprengel R, Schoepfer R et al (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217–1221PubMedCrossRefGoogle Scholar
  111. 111.
    Gilman TL, DaMert JP, Meduri JD, Jasnow AM (2015) Grin1 deletion in CRF neurons sex-dependently enhances fear, sociability, and social stress responsivity. Psychoneuroendocrinology 58:33–45PubMedCrossRefGoogle Scholar
  112. 112.
    Gafford G, Jasnow AM, Ressler KJ (2014) Grin1 receptor deletion within CRF neurons enhances fear memory. PLoS One 9:e111009PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Carey MP, Deterd CH, de Koning J, Helmerhorst F, De Kloet ER (1995) The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female rat. J Endocrinol 144:311–321PubMedCrossRefGoogle Scholar
  114. 114.
    Atkinson HC, Waddell BJ (1997) Circadian variation in basal plasma corticosterone and adrenocorticotropin in the rat: sexual dimorphism and changes across the estrous cycle. Endocrinology 138:3842–3848PubMedCrossRefGoogle Scholar
  115. 115.
    Vamvakopoulos NC, Chrousos GP (1993) Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction. J Clin Invest 92:1896–1902PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Hu P, Liu J, Yasrebi A et al (2016) Gq protein-coupled membrane-initiated estrogen signaling rapidly excites corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus in female mice. Endocrinology 157:3604–3620PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Akama KT, Thompson LI, Milner TA, McEwen BS (2013) Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines. J Biol Chem 288:6438–6450PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Patchev VK, Hayashi S, Orikasa C, Almeida OF (1995) Implications of estrogen-dependent brain organization for gender differences in hypothalamo-pituitary-adrenal regulation. FASEB J 9:419PubMedCrossRefGoogle Scholar
  119. 119.
    Patchev VK, Hayashi S, Orikasa C, Almeida OF (1999) Ontogeny of gender-specific responsiveness to stress and glucocorticoids in the rat and its determination by the neonatal gonadal steroid environment. Stress 3:41–54PubMedCrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2018

Authors and Affiliations

  1. 1.Department of Psychology and Neuroscience ProgramTemple UniversityPhiladelphiaUSA

Personalised recommendations