Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

Touma, Chadi; Fenzl, Thomas; Ruschel, Jörg; Palme, Rupert; Holsboer, Florian; Kimura, Mayumi; Landgraf, Rainer

doi:10.1371/journal.pone.0004325

Cited by 72 publications

(69 citation statements)

References 73 publications

(144 reference statements)

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“…50 Even in the absence of elevated HPA activity, however, it is noteworthy that CRH-COE hom -Nes and -Cam mice display increased spontaneous REM sleep as most other animal models of depression do. [51][52][53][54][55] It has been always difficult to dissociate the effects of each separate HPA hormone on sleep and to offer a mechanism how depression or stress promotes REM sleep. Exogenous administration of an unphysiologically high CRH dose triggers hyperarousal, leaving it unclear by which mechanism REM sleep is suppressed.…”

Section: Discussionmentioning

confidence: 99%

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

Kimura

Müller-Preuß

et al. 2009

Mol Psychiatry

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Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion.

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Section: Discussionmentioning

confidence: 99%

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

Kimura

Müller-Preuß

et al. 2009

Mol Psychiatry

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“…120,125,126 Similarly, the distinct stress reactivity mouse model in reference to the HPA axis that shows high stress reactivity, spends time in more REM sleep than the other lines with intermediate or low stress reactivity. 127,128 The amount of non-REM sleep is indistinguishable between these three separate breeding lines selected for high (HR), intermediate (IR), or low (LR) corticosterone increases in response to stressors. However, the high stress reactivity line shows lower SWA during non-REM sleep, whereas the theta power in the LR line is lower than the others across all vigilance states.…”

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confidence: 99%

Sleep electroencephalography as a biomarker in depression

Steiger¹,

Pawlowski²,

Kimura³

2015

CPT

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Abstract:The sleep electroencephalogram (EEG) provides biomarkers of depression, which may help with diagnosis, prediction of therapy response, and prognosis in the treatment of depression. In patients with depression, characteristic sleep EEG changes include impaired sleep continuity, disinhibition of rapid-eye-movement (REM) sleep, and impaired non-REM sleep. Most antidepressants suppress REM sleep in depressed patients, healthy volunteers, and in animal models. REM suppression appears to be an important, but not an absolute requirement, for antidepressive effects of a substance. Enhanced REM density, a measure for frequency of REM, characterizes high-risk probands for affective disorders. REM-sleep changes were also found in animal models of depression. Sleep-EEG variables were shown to predict the response to treatment with antidepressants. Furthermore, certain clusters of sleep EEG variables predicted the course of the disorder for several years. Some of the predicted sleep EEG markers appear to be related to hypothalamic-pituitary-adrenal system activity.

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“…Animals were between 3 and 5 months of age during the experiments. All experiments were performed during the trough of the circadian rhythm of GC secretion (between 0900 and 1200 h, Touma et al (2009)) and the order of testing was counterbalanced across the different breeding lines. At least 10 days before the experiments, the animals were housed singly in transparent polycarbonate cages (standard Makrolon cages type II, Bayer MaterialScience GmbH, Darmstadt, Germany; 23!16!14 cm).…”

Section: Animals and Housing Conditionsmentioning

confidence: 99%

Corticosteroid-binding globulin contributes to the neuroendocrine phenotype of mice selected for extremes in stress reactivity

Mattos¹,

Heinzmann²,

Norkowski³

et al. 2013

Journal of Endocrinology

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Increasing evidence indicates an important role of steroid-binding proteins in endocrine functions, including hypothalamic-pituitary-adrenal (HPA) axis activity and regulation, as they influence bioavailability, local delivery, and cellular signal transduction of steroid hormones. In the plasma, glucocorticoids (GCs) are mainly bound to the corticosteroidbinding globulin (CBG) and to a lesser extend to albumin. Plasma CBG levels are therefore involved in the adaptive stress response, as they determine the concentration of free, biologically active GCs. In this study, we investigated whether male mice with a genetic predisposition for high-reactivity (HR), intermediate-reactivity (IR), or low-reactivity (LR) stress-induced corticosterone (CORT) secretion present different levels of free CORT and CORT-binding proteins, basally and in response to stressors of different intensity. Our results suggest a fine control interaction between plasma CBG expression and stress-induced CORT release. Although plasma CBG levels, and therefore CBG binding capacity, were higher in HR animals, CORT secretion overloaded the CBG buffering function in response to stressors, resulting in clearly higher free CORT levels in HR compared with IR and LR mice (HROIROLR), resembling the pattern of total CORT increase in all three lines. Both stressors, restraint or forced swimming, did not evoke fast CBG release from the liver into the bloodstream and therefore CBG binding capacity was not altered in our three mouse lines. Thus, we confirm CBG functions in maintaining a dynamic equilibrium between CBG-bound and unbound CORT, but could not verify its role in delaying the rise of plasma free CORT immediately after stress exposure.

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Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

Cited by 72 publications

References 73 publications

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

Sleep electroencephalography as a biomarker in depression

Corticosteroid-binding globulin contributes to the neuroendocrine phenotype of mice selected for extremes in stress reactivity

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