Alisa S. Elliott

Epidemiological studies show a positive association between adequate sleep and good health. Further, disrupted sleep may increase the risk for CNS diseases, such as stroke and Alzheimer’s disease. However, there has been limited progress in determining how sleep is linked to brain health or how sleep disruption may increase susceptibility to brain insult and disease. Animal studies can aid in understanding these links. In reviewing the animal literature related to the effects of sleep disruption on the brain, we found most of the work was directed toward investigating and characterizing the role of various brain areas or structures in initiating and regulating sleep. In contrast, limited effort has been directed towards understanding how sleep disruption alters the brain’s health or susceptibility to insult. We also note many current studies have determined the changes in the brain following compromised sleep by examining, for example, the brain transcriptome or to a more limited extent the proteome. However, these studies have utilized almost exclusively total sleep deprivation (e.g., 24 out of 24 hours) paradigms or single short periods of limited acute sleep deprivation (e.g., 3 out of 24 hours). While such strategies are beneficial in understanding how sleep is controlled, they may not have much translational value for determining links between sleep and brain health or for determining how sleep disruption may increase brain susceptibility to insult. Surprisingly, few studies have determined how the duration and recurrence of sleep deprivation influence the effects seen after sleep deprivation. Our aim in this review was to identify relevant rodent studies from 1980 through 2012 and analyze those that use varying durations of sleep deprivation or restriction in their effort to evaluate the effects of sleep deprivation on the brain transcriptome and to a more limited extent the proteome. We examined how differences in the duration of sleep deprivation affect gene and protein expression to better understand the full consequences of repeated sleep disruption on the brain. Future research needs to consider and emphasize how the type and extent of the sleep deprivation exposure impacts the conclusions reached concerning the influence of sleep disruption on the brain. We identified relevant studies between 1980 and 2012 by searching the electronic databases of PubMed, Medline (Ovid), Embase (Ovid), and Web of Science using the terms “sleep” AND “disrupt”, “deprivation”, “restrict”, “fragment”, “loss”, “disturb”, “disorder”, “dysfunction”, “brain”, “cortex”, striatum”, hypothalamus”, “hippocampus”, “gene”, “protein”, “genomics”, “proteomics”, “polymerase chain reaction”, “pcr”, “microarray”, “molecular”, “rodent” “rat”, “rats”, “mouse”, “mice”. All searches were limited to rodent studies in English and the reference lists of retrieved articles were searched for additional pertinent studies.

The translation of neuroprotective agents for ischemic stroke from bench-to-bedside has largely failed to produce improved treatments since the development of tissue plasminogen activator (tPA). One possible reason for lack of translation is the failure to acknowledge the greatest risk factor for stroke, age, and other common comorbidities such as hypertension, obesity, and diabetes that are associated with stroke. In this review, we highlight both mechanisms of studying these factors and results of those that have been addressed. We also discuss the potential role of other lifestyle factors associated with an increased stroke risk such as sleep fragmentation and/or deprivation. Furthermore, many proposed therapeutic agents have targeted molecular mechanisms occurring soon after the onset of ischemia despite data indicating delayed patient presentation following ischemic stroke. Modulating inflammation has been identified as a promising therapeutic avenue consistent with preliminary success of ongoing clinical trials for anti-inflammatory compounds such as minocycline. We review the role of inflammation in stroke and in particular, the role of inflammatory cell recruitment and macrophage phenotype in the inflammatory process. Emerging evidence indicates an increasing role of neuro-immune crosstalk, which has led to increased interest in identification of peripheral biomarkers indicative of neural injury. It is our hope that identification and investigation of factors influencing stroke pathophysiology may lead to improved therapeutics.