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. 2012 Oct;37(11):2388-404.
doi: 10.1038/npp.2012.94. Epub 2012 Jun 20.

Post-exposure sleep deprivation facilitates correctly timed interactions between glucocorticoid and adrenergic systems, which attenuate traumatic stress responses

Shlomi Cohen  1 , Nitsan Kozlovsky, Michael A Matar, Zeev Kaplan, Joseph Zohar, Hagit Cohen
Affiliations

Post-exposure sleep deprivation facilitates correctly timed interactions between glucocorticoid and adrenergic systems, which attenuate traumatic stress responses

Shlomi Cohen et al. Neuropsychopharmacology. 2012 Oct.

Abstract

Reliable evidence supports the role of sleep in learning and memory processes. In rodents, sleep deprivation (SD) negatively affects consolidation of hippocampus-dependent memories. As memory is integral to post-traumatic stress symptoms, the effects of post-exposure SD on various aspect of the response to stress in a controlled, prospective animal model of post-traumatic stress disorder (PTSD) were evaluated. Rats were deprived of sleep for 6 h throughout the first resting phase after predator scent stress exposure. Behaviors in the elevated plus-maze and acoustic startle response tests were assessed 7 days later, and served for classification into behavioral response groups. Freezing response to a trauma reminder was assessed on day 8. Urine samples were collected daily for corticosterone levels, and heart rate (HR) was also measured. Finally, the impact of manipulating the hypothalamus-pituitary-adrenal axis and adrenergic activity before SD was assessed. Mifepristone (MIFE) and epinephrine (EPI) were administered systemically 10-min post-stress exposure and behavioral responses and response to trauma reminder were measured on days 7-8. Hippocampal expression of glucocorticoid receptors (GRs) and morphological assessment of arborization and dendritic spines were subsequently evaluated. Post-exposure SD effectively ameliorated long-term, stress-induced, PTSD-like behavioral disruptions, reduced trauma reminder freezing responses, and decreased hippocampal expression of GR compared with exposed-untreated controls. Although urine corticosterone levels were significantly elevated 1 h after SD and the HR was attenuated, antagonizing GRs with MIFE or stimulation of adrenergic activity with EPI effectively abolished the effect of SD. MIFE- and EPI-treated animals clearly demonstrated significantly lower total dendritic length, fewer branches and lower spine density along dentate gyrus dendrites with increased levels of GR expression 8 days after exposure, as compared with exposed-SD animals. Intentional prevention of sleep in the early aftermath of stress exposure may well be beneficial in attenuating traumatic stress-related sequelae. Post-exposure SD may disrupt the consolidation of aversive or fearful memories by facilitating correctly timed interactions between glucocorticoid and adrenergic systems.

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Figures

Figure 1
Figure 1
The cut-off behavioral criteria (CBC) algorithm: in order to approximate the approach to understanding animal behavioral models more closely to contemporary clinical conceptions of PTSD, we use an approach that enables the classification of study animals into groups according to degree of response to the stressor, that is, the degree to which individual behavior is altered or disrupted. In order to achieve this, behavioral criteria were defined and then complemented by the definition of cut-off criteria reflecting severity of response; this parallels inclusion and exclusion criteria applied in clinical research. The procedure requires the following steps: (a) verification of global effect: the data must demonstrate that the stressor had a significant effect on the overall behavior of exposed vs unexposed populations at the time of assessment. (b) Application of the CBC's to the data: in order to maximize the resolution and minimize false positives, extreme responses to both elevated plus-maze (EPM) and acoustic startle response (ASR) paradigms, performed in sequence, were required for ‘inclusion' into the EBR group, whereas a negligible degree of response to both was required for inclusion in the MBR group.
Figure 2
Figure 2
Effect of post-exposure SD on relative prevalence rates according to CBC classification: top line: the behavioral procedure used for the unexposed and PSS-exposed rats. Vertical arrow represents total SD procedure. Post-exposure SD reduced the prevalence of PTSD-like behavioral responses (EBR) (a) relative to the exposed-untreated group and concomitantly increased the prevalence of minimal behavioral responders (b). No differences were observed in the prevalence of PBRs (c). CON, unexposed control; EBR, extreme behavioral response; MBR, minimal behavioral response; PBR, partial behavioral response; PSS, predator scent stress; SD, sleep deprivation.
Figure 3
Figure 3
Effect of post-exposure SD on urine corticosterone levels: post-exposure SD, 1 h after the end of the real or sham stress, caused urine corticosterone levels (a) to increase in a rapid spike, followed by a rapid decline within the next 12 h, in both the stress-exposed and -unexposed groups. (b) The area under the curve. All data represent group mean±SEM. CON, unexposed control; PSS, predator scent stress; SD, sleep deprivation.
Figure 4
Figure 4
Effect of post-exposure SD on HR: (a) HR (bpm) in exposed-untreated rats (N=12) and exposed rats treated with SD (N=10). (b) HR profile in telemetry-instrumented rats. Post-exposure SD abolished the PSS-induced tachycardia. All data represent group mean±SEM. bpm, beat per minute; CON, unexposed control; HR, heart rate; PSS, predator scent stress; SD, sleep deprivation.
Figure 5
Figure 5
Effect of post-exposure SD on GR immunoreactivity in the hippocampus: top line: the behavioral procedure used for the unexposed and PSS-exposed rats. Vertical arrow represents total SD procedure. The quantitative analysis of GR immunostaining in the hippocampus subregions CA1 (a), and DG (b) of unexposed-untreated rats (N=8), unexposed rats treated with SD (N=8), exposed-untreated rats (N=8) and exposed rats treated with SD (N=6). On the right are representative photographs of GR immunoreactivity for each area. Photographs were acquired at × 20 (scale bar, 100 μm) and × 40 magnification (scale bar, 50 μm). The cells in red were GR positive. All data represent group mean±SEM. CA1, cornu ammonis 1; CON, unexposed control; DG, dentate gyrus; PSS, predator scent stress; SD, sleep deprivation. The color reproduction of this figure is available on the Neuropyschopharmacology journal online.
Figure 6
Figure 6
Effect of post-exposure SD on dendritic morphology in the dentate gyrus granule cells: top line: the behavioral procedure used for the unexposed and PSS-exposed rats. Vertical arrow represents total SD procedure. (a) Sholl-analysis for intersections per 25-μm radial unit distance from unexposed-untreated controls (N=7), unexposed rats treated with SD (N=8), exposed-untreated rats (N=8) or exposed rats treated with SD (N=8). Inset—the AUC, representing distance from soma. (b) Quantitative analysis of total dendritic length (μm) of dentate gyrus granule cells from the suprapyramidal blade. (c) Computer-generated plots of reconstructions and photomicrographs of the dendritic tree from granule cells. (d) Quantification of overall spine density per 10 μm of dendritic granule cells. (e) Photomicrographs showing representative Golgi–Cox-impregnated dendritic spines. Neurons from exposed animals treated with SD had significantly more dendritic intersections within each sphere at Sholl radii 10–85 μm than did neurons from the exposed-untreated group. Moreover, exposed animals treated with SD exhibited significantly greater total dendritic length as compared with exposed-untreated animals. The spine density along the dentate granule cells was significantly increased in exposed animals treated with SD as compared with exposed-untreated animals. Results displayed as mean±SEM. CON, unexposed control; PSS, predator scent stress; SD, sleep deprivation.
Figure 7
Figure 7
Effects of MIFE and EPI administration post-exposure and pre-SD on relative prevalence rates according to CBC classification: top line: the behavioral procedure used for the unexposed and PSS-exposed rats. Vertical arrow represents total SD procedure. Administration of MIFE or EPI post-exposure and pre-SD increased the prevalence of PTSD-like behavioral responses (EBR) (a) relative to the vehicle treatment group and concomitantly decreased the prevalence of minimal behavioral responders (b). No differences were observed in the prevalence of PBRs (c). CON, unexposed control; EBR, extreme behavioral response; EPI, epinephrine; MBR, minimal behavioral response; MIFE, mifepristone; PBR, partial behavioral response; PSS, predator scent stress; SD, sleep deprivation.
Figure 8
Figure 8
Effects of MIFE and EPI administration post-exposure and pre-SD on GR immunoreactivity in the hippocampus: top line: the behavioral procedure used for the unexposed and PSS-exposed rats. Vertical arrow represents total SD procedure. The quantitative analysis of GR immunostaining in the hippocampus subregions CA1 (a), and DG (b) of exposed rats treated with vehicle (N=4), exposed-vehicle rats treated with SD (N=4), exposed–SD rats treated with MIFE (N=4) or exposed-SD rats treated with EPI (N=3). On the right are representative photographs of GR immunoreactivity for each area. Photographs were acquired at × 20 (Scale bar, 100 μm) and × 40 magnification (Scale bar, 50 μm). The cells in red were GR positive. All data represent group mean±SEM. CA1, cornu ammonis 1; CON, unexposed control; DG, dentate gyrus; EPI, epinephrine; MIFE, mifepristone; PSS, predator scent stress; SD, sleep deprivation. The color reproduction of this figure is available on the Neuropyschopharmacology journal online.
Figure 9
Figure 9
Effects of MIFE and EPI administration post-exposure and pre-SD on dendritic morphology in the DG granule cells: top line: the behavioral procedure used for the unexposed and PSS-exposed rats. Vertical arrow represents total SD procedure. (a) Sholl-analysis for intersections per 25-μm radial unit distance from exposed rats treated with vehicle (N=4), exposed-vehicle rats treated with SD (N=4), exposed-SD rats treated with MIFE (N=4) or exposed-SD rats treated with EPI (N=3). Inset—the AUC, representing distance from soma. (b) Quantitative analysis of total dendritic length (μm) of DG granule cells from the suprapyramidal blade. (c) Computer-generated plots of reconstructions and photomicrographs of the dendritic tree from granule cells. (d) Quantification of overall spine density per 10 μm of dendritic granule cells. (e) Photomicrographs showing representative Golgi–Cox-impregnated dendritic spines. Neurons from exposed animals treated with SD had significantly more dendritic intersections within each sphere at Sholl radii 35–60 μm than did neurons from the exposed-SD group treated with MIFE or EPI. Moreover, exposed animals treated with SD exhibited significantly greater total dendritic length as compared with exposed-SD animals treated with MIFE or EPI. The spine density along the dentate granule cells was significantly increased in exposed animals treated with SD as compared with exposed-SD animals treated with MIFE or EPI. Results displayed as mean±SEM. CON, unexposed control; EPI, epinephrine; MIFE, mifepristone; PSS, predator scent stress; SD, sleep deprivation. *p<0.05 vs PSS-Vehicle, PSS-SD-Mif, PSS-SD-Epi; #p<0.05 vs PSS-SD-Mif, PSS-SD-Epi.
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