Effects of corticotropin releasing factor (CRF) on sleep and temperature following predictable controllable and uncontrollable stress in mice.

Laurie L Wellman,Larry D Sanford,Linghui Yang

doi:10.3389/fnins.2015.00258

Abstract

Corticotropin releasing factor (CRF) is a major mediator of central nervous system responses to stressors, including alterations in wakefulness and sleep. However, its role in mediating stress-induced alterations in sleep has not been fully delineated. In this study, we assessed the role of CRF and the non-specific CRF antagonist, astressin (AST), in regulating changes in sleep produced by signaled, escapable shock (SES) and signaled inescapable shock (SIS), two stressors that can increase or decrease sleep, respectively. Male BALB/cJ mice were surgically implanted with transmitters (DataSciences ETA10-F20) for recording EEG, activity and core body temperature by telemetry and a cannula for intracerebroventricular (ICV) microinjections. After baseline (Base) sleep recording, mice were presented tones (90 dB, 2 kHz) that started 5.0 s prior to and co-terminated with footshock (0.5 mA; 5.0 s maximum duration). SES mice (n = 9) always received shock but could terminate it by moving to the non-occupied chamber in a shuttlebox. Yoked SIS mice (n = 9) were treated identically, but could not alter shock duration. Training with SES or SIS was conducted over 2 days to stabilize responses. Afterwards, the mice received saline, CRF [0.4 μg (0.42 mM) or AST (1.0 μg (1.4 mM)] prior to SES or SIS. Sleep was analyzed over 20 h post-stress recordings. After administration of saline, REM was significantly greater in SES mice than in SIS mice whereas after CRF or AST, REM was similar in both groups. Total 20 h NREM did not vary across condition or group. However, after administration of saline and CRF, NREM episode duration was significantly decreased, and NREM episode number significantly increased, in SIS mice compared to SES animals. SES and SIS mice showed similar stress induced hyperthermia (SIH) across all conditions. These data demonstrate that CRF can mediate stress-induced changes in sleep independently of SIH, an index of hypothalamic-pituitary-adrenal axis activation.

Highlights

Corticotropin releasing factor (CRF) is a major mediator of central nervous system responses to stressors (Koob and Bloom, 1985; Heinrichs et al, 1995; Koob, 1999; Koob and Heinrichs, 1999; Bakshi and Kalin, 2000; Deussing and Wurst, 2005) including alterations in wakefulness and sleep (González and Valatx, 1998; Chang and Opp, 2002)
Administration of either CRF or AST reduced or eliminated the differences normally seen between mice trained with SES and SIS, i.e., CRF reduced rapid eye movement sleep (REM) in the SES mice to levels seen in the SIS mice and AST attenuated the reduction in REM in the SIS mice to levels that were not significantly different from those in the SES mice
REM was reduced on the CRF Treatment Day compared to Base, handling control (HC), and AST (Table 1), but there were no significant differences between groups

Summary

Introduction

Corticotropin releasing factor (CRF) is a major mediator of central nervous system responses to stressors (Koob and Bloom, 1985; Heinrichs et al, 1995; Koob, 1999; Koob and Heinrichs, 1999; Bakshi and Kalin, 2000; Deussing and Wurst, 2005) including alterations in wakefulness and sleep (González and Valatx, 1998; Chang and Opp, 2002). There have been few studies examining the role of CRF in regulating stressinduced alterations in sleep, and these have yielded conflicting data. This is exemplified with the work on restraint stress and sleep. González and Valatx (1997) reported that the ICV administration of the broad CRF antagonist, αHelCRF (αhelical CRF9-41), prior to restraint stress at the beginning of the dark period prevented the subsequent increase in REM that can occur after restraint (e.g., Rampin et al, 1991; Bonnet et al, 1997; Meerlo et al, 2001), but did not alter spontaneous REM, NREM, or wakefulness in non-stressed animals. CRF antagonists administered during sleep deprivation reduce recovery REM in rats (González and Valatx, 1998) and mice (Kimura et al, 2010) whereas the repeated administration of CRF during the actual recovery period blocked the increase in REM in sleep-deprived humans (Schüssler et al, 2006)

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