Repeated Exposure to Conditioned Fear Stress Increases Anxiety and Delays Sleep Recovery Following Exposure to an Acute Traumatic Stressor

Abstract

Repeated stressor exposure can sensitize physiological responses to novel stressors and facilitate the development of stress-related psychiatric disorders including anxiety. Disruptions in diurnal rhythms of sleep–wake behavior accompany stress-related psychiatric disorders and could contribute to their development. Complex stressors that include fear-eliciting stimuli can be a component of repeated stress experienced by human beings, but whether exposure to repeated fear can prime the development of anxiety and sleep disturbances is unknown. In the current study, adult male F344 rats were exposed to either control conditions or repeated contextual fear conditioning for 22 days followed by exposure to no, mild (10), or severe (100) acute uncontrollable tail shock stress. Exposure to acute stress produced anxiety-like behavior as measured by a reduction in juvenile social exploration and exaggerated shock-elicited freezing in a novel context. Prior exposure to repeated fear enhanced anxiety-like behavior as measured by shock-elicited freezing, but did not alter social exploratory behavior. The potentiation of anxiety produced by prior repeated fear was temporary; exaggerated fear was present 1 day but not 4 days following acute stress. Interestingly, exposure to acute stress reduced rapid eye movement (REM) and non-REM (NREM) sleep during the hours immediately following acute stress. This initial reduction in sleep was followed by robust REM rebound and diurnal rhythm flattening of sleep/wake behavior. Prior repeated fear extended the acute stress-induced REM and NREM sleep loss, impaired REM rebound, and prolonged the flattening of the diurnal rhythm of NREM sleep following acute stressor exposure. These data suggest that impaired recovery of sleep/wake behavior following acute stress could contribute to the mechanisms by which a history of prior repeated stress increases vulnerability to subsequent novel stressors and stress-related disorders.

Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity

“…Rats eating test diet, compared to control diet, had increased time spent in REM sleep following stressor exposure or REM rebound. REM rebound is a well-characterized consequence of intense stressor exposure (Suchecki et al, 2012; Greenwood et al, 2014; Thompson et al, 2016) and is believed to be beneficial because it is associated with a reduced risk for developing post-traumatic stress disorder (Mellman et al, 2007). Consistent with the idea that prebiotics may be stress protective; several reports also suggest that individual prebiotics can reduce stress-evoked GI distress.…”

“…For example, experiencing work-related stressors (Akerstedt et al, 2002), having low social support (Mellman and Hipolito, 2006), or exposure to trauma/combat (Mellman et al, 1995, 2007; Rothbaum and Foa, 2002; Capaldi et al, 2011) can all disrupt sleep and the sleep/wake cycle. Preclinical studies testing a variety of animal models of stress in early life or adulthood also report similar outcomes on sleep and the sleep/wake cycle (Madan et al, 2008; Pawlyk et al, 2008; McClung, 2011; Yang et al, 2011; Greenwood et al, 2014; Thompson et al, 2016). …”

“…The F40-EET biotelemetry transmitters (Data Sciences International, St.Paul, MN, USA) were implanted into animals as previously described (Thompson et al, 2012, 2013, 2014, 2016; Greenwood et al, 2014). Briefly, animals were fully anesthetized and unresponsive following ketamine (i.p.…”

“…On PND 87, half of the rats were exposed to 100 inescapable tail shocks which is known to induce depression/anxiety-like behavior, to substantially increase corticosterone, and to disrupt diurnal physiology/sleep as previously described (Greenwood et al, 2005, 2014; Thompson et al, 2013, 2014, 2016; Speaker et al, 2014). Inescapable tail shock can produce clear impacts on the dependent measures we examined in this experiment (i.e., both sleep and the gut microbiota).…”

The basolateral amygdala can mediate the effects of fear memory on sleep independently of fear behavior and the peripheral stress response

“…Recent work (Wellman et al, 2016) and the current study also demonstrate that individual outbred rats can show either decreases or increases in REM in response to IS, also without differences in freezing or SIH. Thus, while several studies have demonstrated that sleep may play a role in the consolidation of contextual fear memory associated with brief or mild fearful experiences (e.g., Graves, Heller, Pack, and Abel, 2003; Greenwood, Thompson, Opp, and Fleshner, 2014; Hagewoud, Bultsma, Barf, Koolhaas, and Meerlo, 2011; Hellman and Abel, 2007; Kumar and Jha, 2012; Menz, Rihm, and Büchel, 2016; Menz, Rihm, Salari, Born, Kalisch, Pape, Marshall, and Buchel, 2013; Rossi, Tiba, Moreira, Ferreira, Oliveira, and Suchecki, 2014; Silvestri, 2005; for recent review see Havekes, Meerlo, and Abel, 2015), there is no evidence that REM sleep is necessary for the formation of contextual fear memory associated with relatively intense stressful experiences. Interestingly, we found no correlation between freezing and either REM or NREM sleep.…”