Sleep Disturbances in PTSD

Stress-induced alterations in sleep have been linked to the development of post-traumatic stress disorder (PTSD) and sleep complaints and disturbances in arousal are continuing symptoms in patients. PTSD-related changes in sleep have not been fully characterized but involve persistent disturbances in both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). PTSD is considered a disorder of the fear circuitry, which includes the amygdala, dorsal anterior cingulate, hippocampus, and ventromedial prefrontal cortex. Currently, several animal models are used to examine the underlying neurobiology of PTSD; however, sleep has been characterized in only a limited number of models. Intense conditioned fear training, which may best model PTSD in rodents, can produce reductions in REMS as well as alterations in NREMS that may vary with mouse and rat strains. The amygdala, a central region in current concepts of PTSD, plays significant roles in regulating the stress response and changes in stress-induced alterations in arousal and sleep. This chapter reviews sleep-related findings in patients with PTSD and in animal experimental paradigms currently utilized to model the disorder, as well as the neurobiology that has been linked to disturbed sleep in PTSD. It will also discuss the impact of PTSD treatments on sleep disturbances

Controllable and Uncontrollable Stress Differentially Impact Fear Conditioned Alterations in Sleep and Neuroimmune Signaling in Mice

Stress induces neuroinflammation and disrupts sleep, which together can promote a number of stress-related disorders. Fear memories associated with stress can resurface and reproduce symptoms. Our previous studies have demonstrated sleep outcomes can be modified by stressor controllability following stress and fear memory recall. However, it is unknown how stressor controllability alters neuroinflammatory signaling and its association with sleep following fear memory recall. Mice were implanted with telemetry transmitters and experienced escapable or inescapable footshock and then were re-exposed to the shuttlebox context one week later. Gene expression was assessed with Nanostring® panels using RNA extracted from the basolateral amygdala and hippocampus. Freezing and temperature were examined as behavioral measures of fear. Increased sleep after escapable stress was associated with a down-regulation in neuro-inflammatory and neuro-degenerative related genes, while decreased sleep after inescapable stress was associated with an up-regulation in these genes. Behavioral measures of fear were virtually identical. Sleep and neuroimmune responses appear to be integrated during fear conditioning and reproduced by fear memory recall. The established roles of disrupted sleep and neuroinflammation in stress-related disorders indicate that these differences may serve as informative indices of how fear memory can lead to psychopathology

The Basolateral Amygdala Mediates the Role of Rapid Eye Movement Sleep in Integrating Fear Memory Responses

The basolateral amygdala (BLA) mediates the effects of stress and fear on rapid eye movement sleep (REM) and on REM-related theta (θ) oscillatory activity in the electroencephalograph (EEG), which is implicated in fear memory consolidation. We used optogenetics to assess the potential role of BLA glutamate neurons (BLAGlu) in regulating behavioral, stress and sleep indices of fear memory, and their relationship to altered θ. An excitatory optogenetic construct targeting glutamatergic cells (AAV-CaMKIIα-hChR2-eYFP) was injected into the BLA of mice. Telemetry was used for real-time monitoring of EEG, activity, and body temperature to determine sleep states and stress-induced hyperthermia (SIH). For 3 h following shock training (ST: 20 footshocks, 0.5 mA, 0.5 s, 1 min interval), BLA was optogenetically stimulated only during REM (REM + L) or NREM (NREM + L). Mice were then re-exposed to the fear context at 24 h, 48 h, and 1 week after ST and assessed for behavior, SIH, sleep and θ activity. Control mice were infected with a construct without ChR2 (eYFP) and studied under the same conditions. REM + L significantly reduced freezing and facilitated immediate recovery of REM tested at 24 h and 48 h post-ST during contextual re-exposures, whereas NREM + L had no significant effect. REM + L significantly reduced post-ST REM-θ, but attenuated REM-θ reductions at 24 h compared to those found in NREM + L and control mice. Fear-conditioned SIH persisted regardless of treatment. The results demonstrate that BLAGlu activity during post-ST REM mediates the integration of behavioral and sleep indices of fear memory by processes that are associated with θ oscillations within the amygdalo-hippocampal pathway. They also demonstrate that fear memories can remain stressful (as indicated by SIH) even when fear conditioned behavior (freezing) and changes in sleep are attenuated

MicroRNAs in Basolateral Amygdala Associated with Stress and Fear Memories Regulate Rapid Eye Movement Sleep in Rats

Stress-related sleep disturbances are distressing clinical symptoms in posttraumatic stress disorder patients. Intensely stressful events and their memories change rapid eye movement (REM) sleep in animal models. REM sleep varies with individual differences of stress resilience or vulnerability. The basolateral amygdala (BLA) is a primary mediator of the effects of stress and fear memories on sleep. However, the molecular mechanisms in BLA regulating the effects of fear conditioning, shock training (ST) and context re-exposure (CTX) on REM sleep are not well known. MicroRNAs (miRNAs) are small, non-coding RNAs and posttranscriptional gene regulators of diverse biological processes. The aim of this study is to investigate ST- and CTX-altered miRNAs in the BLA of resilience and vulnerable animals and on REM sleep regulation. MiRNAs expression profiles in BLA were generated following ST and CTX using the Taqman Low Density rodent microRNA array. The altered BLA miRNAs expression and REM sleep reduction observed in ST and CTX vulnerable animals. AntagomiR-221 microinjection into BLA for one of the upregulated miRNAs, miR-221 in BLA, attenuated the REM sleep reduction. This study suggests that miRNAs in the BLA may play a significant role in mediating the effects of stress and fear memories on REM sleep

Differential Effect of Light and Dark Period Sleep Fragmentation on Composition of Gut Microbiome and Inflammation in Mice

Bi-directional interactions amongst the gut microbiota, immune system, and brain function are thought to be critical mediators of health and disease. The role sleep plays in mediating these interactions is not known. We assessed the effects of sleep fragmentation (SF) on the microbiota–gut–brain axis. Male C57BL/6NCrl mice (4 to 5 per cage, fed standard lab chow) experienced SF via mechanical stimulation at 2 min intervals during the light (SF) and dark (DD, dark disturbances) periods. Home cage (HC) controls were undisturbed. After 10 days, fecal samples were collected at light onset, midday, light offset, and midnight. Samples were also collected after 10 days without SF. Subsequently, the mice were randomized across groups and allowed 20 additional days of recovery followed by 10 days of SF or DD. To assess effects on the microbiota, 16S rRNA sequencing was used, and mesenteric lymph nodes (MLNs) and cortex and medial prefrontal cortex were analyzed using cytokine arrays. SF and DD produced significant alterations in the microbiota compared to HC, and DD had greater impact than SF on some organisms. SF produced marked suppression in MLNs of chemokines that regulate inflammation (CCL3, CCL4 and their receptor CCR5) and maintain the immune mucosal barrier (Cxcl13) at the same time that cortical cytokines (IL-33) indicated neuroinflammation. DD effects on immune responses were similar to HC. These data suggest that SF alters the microbiome and suppresses mucosal immunity at the same time that mediators of brain inflammation are upregulated. The translational implications for potential application to clinical care are compelling

Sleep Disturbance Alters Cocaine-Induced Locomotor Activity: Involvement of Striatal Neuroimmune and Dopamine Signaling

Sleep disorders have high comorbidity with drug addiction and function as major risk factors for developing drug addiction. Recent studies have indicated that both sleep disturbance (SD) and abused drugs could activate microglia, and that increased neuroinflammation plays a critical role in the pathogenesis of both diseases. Whether microglia are involved in the contribution of chronic SDs to drug addiction has never been explored. In this study, we employed a mouse model of sleep fragmentation (SF) with cocaine treatment and examined their locomotor activities, as well as neuroinflammation levels and dopamine signaling in the striatum, to assess their interaction. We also included mice with, or without, SF that underwent cocaine withdrawal and challenge. Our results showed that SF significantly blunted cocaine-induced locomotor stimulation while having marginal effects on locomotor activity of mice with saline injections. Meanwhile, SF modulated the effects of cocaine on neuroimmune signaling in the striatum and in ex vivo isolated microglia. We did not observe differences in dopamine signaling in the striatum among treatment groups. In mice exposed to cocaine and later withdrawal, SF reduced locomotor sensitivity and also modulated neuroimmune and dopamine signaling in the striatum. Taken together, our results suggested that SF was capable of blunting cocaine-induced psychoactive effects through modulating neuroimmune and dopamine signaling. We hypothesize that SF could affect neuroimmune and dopamine signaling in the brain reward circuitry, which might mediate the linkage between sleep disorders and drug addiction