Epigenetic conditioning induces intergenerational resilience to dementia in a mouse model of vascular cognitive impairment.

INTRODUCTION: Epigenetic stimuli induce beneficial or detrimental changes in gene expression, and consequently, phenotype. Some of these phenotypes can manifest across the lifespan-and even in subsequent generations. Here, we used a mouse model of vascular cognitive impairment and dementia (VCID) to determine whether epigenetically induced resilience to specific dementia-related phenotypes is heritable by first-generation progeny. METHODS: Our systemic epigenetic therapy consisted of 2 months of repetitive hypoxic "conditioning" (RHC) prior to chronic cerebral hypoperfusion in adult C57BL/6J mice. Resultant changes in object recognition memory and hippocampal long-term potentiation (LTP) were assessed 3 and 4 months later, respectively. RESULTS: Hypoperfusion-induced memory/plasticity deficits were abrogated by RHC. Moreover, similarly robust dementia resilience was documented in untreated cerebral hypoperfused animals derived from RHC-treated parents. CONCLUSIONS: Our results in experimental VCID underscore the efficacy of epigenetics-based treatments to prevent memory loss, and demonstrate for the first time the heritability of an induced resilience to dementia.

Differential regulation of cerebral microvascular transcription by single and repetitive hypoxic conditioning.

Systemic conditioning therapeutics afford brain protection at all levels of organization, occurring autonomously for neurons, glia, vascular smooth muscle, and endothelium, which are mediated systemically for the adaptive and innate immune system. The present study was undertaken to examine acute (3 h) and delayed (2 days) gene expression changes in mouse cerebral microvessels following single hypoxic conditioning (HX1) and repetitive hypoxic conditioning (HX9), the latter for which we showed previously to extend focal stroke tolerance from days to months. Microarray (Illumina) analyses were performed on microvessel-enriched fractions of adult mouse brain obtained from the following five groups (naïve; HX1-3h; HX1-2days; HX9-3h; HX9-2days). Differentially expressed genes were analyzed bioinformatically using Ingenuity Pathway Analysis software, with qPCR validating selected up- and down-regulated genes. As expected, some differentially expressed genes were common to more than one treatment or time point, whereas others were unique to treatment or time point. Bioinformatic analyses provided insights into acute (3h) inflammatory and immune signaling pathways that may be differentially activated by HX1 and HX9, with anti-inflammatory and trophic pathways coincident with the ischemia-tolerant phenotype two days after HX1. Interestingly, two days after HX9, microvessels were transcriptionally silent, with only five genes remaining differentially expressed relative to naïve mice. Our microarray findings and bioinformatic analyses suggest that cerebral microvessels from HX1-treated mice exhibit early activation of immune system signaling that is largely suppressed in microvessels from HX9-treated mice. These and other differences between these responses require further study, including at the proteomic level, and with pharmacologic and genetic experiments designed to reveal causality, to reveal further insights into the mechanisms underlying long-lasting stroke tolerance.

Remote Limb Ischemic Conditioning at Two Cuff Inflation Pressures Yields Learning Enhancements in Healthy Adults.

The authors tested whether 2 doses of remote limb ischemic conditioning (RLIC), induced via blood pressure cuff inflation, enhanced motor and cognitive learning to an equal extent, and explored a panel of blood biomarkers of RLIC. Thirty-two young adults were randomized to 3 groups and underwent a 7-day protocol of RLIC/sham followed by motor and cognitive training, with follow-up. Both RLIC groups had greater motor learning and a trend toward greater cognitive learning compared with the sham group. RLIC at the lower inflation pressure was as effective as RLIC with the higher inflation pressure. No significant candidate blood biomarkers were found. RLIC could be a well-tolerated method to enhance learning and improve rehabilitation outcomes in people with neurological conditions.

Remote limb ischemic conditioning enhances motor learning in healthy humans.

Brief bouts of sublethal ischemia have been shown to protect exposed tissue (ischemic conditioning) and tissues at remote sites (remote ischemic conditioning) against subsequent ischemic challenges. Given that the mechanisms of this protective phenomenon are multifactorial and epigenetic, we postulated that remote limb ischemic conditioning (RLIC) might enhance mechanisms responsible for neural plasticity, and thereby facilitate learning. Specifically, we hypothesized that conditioning of the nervous system with RLIC, achieved through brief repetitive limb ischemia prior to training, would facilitate the neurophysiological processes of learning, thus making training more effective and more long-lasting. Eighteen healthy adults participated in this study; nine were randomly allocated to RLIC and nine to sham conditioning. All subjects underwent seven consecutive weekday sessions and 2-wk and 4-wk follow-up sessions. We found that RLIC resulted in significantly greater motor learning and longer retention of motor performance gains in healthy adults. Changes in motor performance do not appear to be due to a generalized increase in muscle activation or muscle strength and were not associated with changes in serum brain-derived neurotrophic factor (BDNF) concentration. Of note, RLIC did not enhance cognitive learning on a hippocampus-dependent task. While future research is needed to establish optimal conditioning and training parameters, this inexpensive, clinically feasible paradigm might ultimately be implemented to enhance motor learning in individuals undergoing neuromuscular rehabilitation for brain injury and other pathological conditions.

Poised for success: implementation of sound conditioning strategies to promote endogenous protective responses to stroke in patients.

The following perspective represents our summary of questions, ideas, concerns, and recommendations expressed by speakers and discussants at the second Biennial Translational Preconditioning Workshop held in Miami in December 2011.