Sexually Dimorphic Responses of the Brain Norepinephrine System to Stress and Corticotropin-Releasing Factor

Curtis, Andre L.; Bethea, Thelma; Valentino, Rita J.

doi:10.1038/sj.npp.1300875

Cited by 193 publications

(220 citation statements)

References 49 publications

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“…Therefore, it is likely that other peptide hormones or neurotransmitter systems -which respond specifically to the swim stress challenge -are involved in the strong and rapid regulation of Fos, Per1 and Sgk1. Possible neurotransmitter systems involved could be norepinephrine and serotonin, both of which are very strongly increased after cold swim stress (Gotoh et al, 1998;Linthorst et al, 2008), show sex-specific responses to stressful stimuli (Curtis et al, 2006;Pitychoutis et al, 2012), and can stimulate Fos expression (Castro et al, 2003;Gubits et al, 1989). In addition, glutamate may also be involved in the regulation of stress-induced gene expression, as NMDA-receptor antagonists have been shown to block the stress-induced increase in Fos expression in the hippocampus (Bozas et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal gene expression induced by cold swim stress depends on sex and handling

Bohacek

Manuella

Roszkowski

et al. 2015

Psychoneuroendocrinology

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Summary: Stress-related disorders such as PTSD and depression are more prevalent in women than men. One reason for such discordance may be that brain regions involved in stress responses are more sensitive to stress in females. Here, we compared the effects of acute stress on gene transcription in the hippocampus of female and male mice, and also examined the involvement of two key stress-related hormones, corticosterone and corticotropin releasing hormone (Crh). Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), we measured gene expression of Fos, Per1 and Sgk1 45 min after exposure to brief cold swim stress. Stress induced a stronger increase in Fos and Per1 expression in females than males. The handling control procedure increased Fos in both sexes, but occluded the effects of stress in males. Further, handling increased Per1 only in males. Sgk1 was insensitive to handling, and increased in response to stress similarly in males and females. The transcriptional changes observed after swim stress were not mimicked by corticosterone injections, and the stress-induced increase in Fos, Per1 and Sgk1 could neither be prevented by pharmacologically blocking glucocorticoid receptor (GR) nor by blocking Crh receptor 1 (Crhr1) before stress exposure. Finally, we demonstrate that the effects are stressor-specific, as the expression of target genes could not be increased by brief restraint stress in either sex. In summary, we find strong effects of acute swim stress on hippocampal gene expression, complex interactions between handling and sex, and a remarkably unique response pattern for each gene. Overall, females respond to a cold swim challenge with stronger hippocampal gene transcription than males, independent of two classic mediators of the stress response, corticosterone and Crh. These findings may have important implications for understanding the higher vulnerability of women to certain stress-related neuropsychiatric diseases. In summary, we find strong effects of acute swim stress on hippocampal gene expression, complex interactions between handling and sex, and a remarkably unique response pattern for each gene. Overall, females respond to a cold swim challenge with stronger hippocampal gene transcription than males, independent of two classic mediators of the stress response, corticosterone and Crh. These findings may have important implications for understanding the higher vulnerability of women to certain stress-related neuropsychiatric diseases.

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Section: Discussionmentioning

confidence: 99%

Hippocampal gene expression induced by cold swim stress depends on sex and handling

Bohacek

Manuella

Roszkowski

et al. 2015

Psychoneuroendocrinology

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“…Given the very robust overexpression of the transgene (Figure 1a and b), we do not expect that the behavioral sex differences are due to differences in expression of the CRF transgene itself, but are instead due to sex differences in the endogenous CRF signaling pathways in response to high CRF since females exhibit altered cellular responses to CRF signaling (Bangasser et al, 2013). Locus coeruleus neurons of female rats are more sensitive to CRF resulting in heightened noradrenergic reactivity during stress or in conditions of CRF overexpression, likely due to their limited ability to desensitize CRFR1 receptors (Bangasser et al, 2010;Bangasser et al, 2013;Curtis et al, 2006). This mechanism may partly explain why women show higher incidence of stress-related affective and anxiety disorders compared to men and why CRFOE appeared to result in more behavioral changes in females compared to males (Koenen and Widom, 2009).…”

Section: Discussionmentioning

confidence: 99%

Forebrain-Specific CRF Overproduction During Development is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

Tóth

Gresack

Bangasser

et al. 2013

Neuropsychopharmacol

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Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure.

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“…For instance, sexes differ in CRH receptor and Fkbp5 expression during early development, particularly following early-life stress (Bourke et al, 2013;Weathington et al, 2014). Moreover, enhanced CRH neurotransmission during early-life induces sex-specific alterations in monoaminergic systems (Curtis et al, 2006;Howerton et al, 2014;McEuen et al, 2009). The sex-dependent effects of predator stress in the present study may also be due to the reduced ability of females to desensitize CRH receptors (Bangasser et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOE dev ) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOE dev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOE dev exposed and unexposed mice were examined 7 days after predator stress. CRHOE dev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOE dev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOE dev , males developed significant avoidance only when exposed to both CRHOE dev and stress. Quantitative real-time-PCR analysis indicated that CRHOE dev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOE dev did not. Similar to CRHOE dev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOE dev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.

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Sexually Dimorphic Responses of the Brain Norepinephrine System to Stress and Corticotropin-Releasing Factor

Cited by 193 publications

References 49 publications

Hippocampal gene expression induced by cold swim stress depends on sex and handling

Hippocampal gene expression induced by cold swim stress depends on sex and handling

Forebrain-Specific CRF Overproduction During Development is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

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