Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

Abstract

Background: Vascular cognitive impairment and dementia (VCID), which occurs immediately or in delayed fashion in 25-30% of stroke survivors, or secondary to chronic cerebral hypoperfusion, is the second leading cause of dementia following Alzheimers disease. To date, efficacious therapies are unavailable. We have shown previously in mice that repetitive hypoxic preconditioning (RHC) induces a long-lasting resilience to acute stroke (Stowe et al., 2011). More recently, we documented that untreated, first-generation adult progeny of mice exposed to RHC prior to mating are protected from retinal ischemic injury (Harman et al., 2020), consistent with accumulating evidence supporting the concept that long-lasting phenotypes induced epigenetically by intermittent stressors may be heritable. We undertook the present study to test the hypothesis that RHC will induce resilience to VCID, and that such RHC-induced resilience can also be inherited. Methods: Chronic cerebral hypoperfusion (CCH) was induced in C57BL/6J mice secondary to bilateral carotid artery stenosis with microcoils in both the parental (F0) generation, and in their untreated first-generation (F1) offspring. Cohorts of F0 mice were directly exposed to either 8 wks of RHC (1 h of systemic hypoxia 11% oxygen, 3x/week) or normoxia prior to CCH. Cohorts of F1 mice were derived from F0 mice treated with RHC prior to mating, and untreated, normoxic controls that were age-matched at the time of stenosis induction. Demyelination in the corpus callosum of F0 mice was assessed following 3 months of CCH by immunohistochemistry. Mice from both generations were assessed for short-term recognition memory in vivo by novel object preference (NOP) testing following 3 months of CCH, and a month thereafter, ex vivo measurements of CA1 hippocampal long-term potentiation (LTP) were recorded from the same animals as a metric of long-lasting changes in synaptic plasticity. Results: Three months of CCH caused demyelination and concomitant impairments in recognition memory in control mice from both generations. However, these CCH-induced memory impairments were prevented in F0 animals directly treated with RHC, as well as in their untreated adult F1 progeny. Similarly, hippocampal LTP was preserved in the 4-month CCH cohorts of mice directly treated with RHC, and in their untreated offspring with CCH. Conclusions: Our findings demonstrate that RHC or other repetitively-presented, epigenetic-based therapeutics may hold promise for inducing a long-lasting resilience to VCID in treated individuals, and in their first-generation adult progeny.

Intermittent hypoxia conditioning as a potential prevention and treatment strategy for ischemic stroke: Current evidence and future directions

“…Studies have confirmed that 10% of IH is neuroprotective, whereas 6% of IH exacerbates tissue damage, and this different outcome is associated with changes in susceptibility to mitochondrial damage (Jackman et al, 2014). A recent study confirmed for the first time that brief, repeated exposure to systemic hypoxia attenuates hypoperfusioninduced cognitive impairment and that this resistance to dementia is heritable, allowing mice offspring to avoid memory loss even in the presence of persistent cerebral hypoperfusion (Belmonte et al, 2022). Due to the unpredictability of IS, few clinical studies have focused on it, with most studies conducted on animal models.…”

Maternal repetitive hypoxia prior to mating confers epigenetic resilience to memory impairment in male progeny.

“…F0 mice were treated with twenty-four 1-hr exposures of mild-tomoderate systemic hypoxia (RHC) every other day for 8 weeks, as described previously (Belmonte et al, 2022). Untreated controls consisted of age-and sex-matched cages of mice exposed to normal atmospheric oxygen (room air) of equivalent frequency and duration.…”

“…Three age-matched BCAS/disease mouse groups were established; specifically, they included mice born to RHC-treated mothers and fathers (Both-RHC), to RHC-treated mothers (Mo-RHC), and to RHC-treated fathers (Fa-RHC). None of the mice from these latter three groups were designated for sham-BCAS surgery because we previously confirmed in both sexes that, relative to CTL mice, those mice treated with RHC (without BCAS) exhibited normal corpus callosum myelination, hippocampal LTP responses, and recognition memory (Belmonte et al, 2022).…”

“…We recently showed that positive/adaptive central nervous system phenotypes induced in somatic cells of parent (F0) mice by repetitive hypoxic conditioning (RHC) can also be transmitted intergenerationally, as a result of the additional epigenetic changes, this stimulus induces in their germ cells (Belmonte et al, 2022;Harman et al, 2020). Specifically, using a well-established mouse model of vascular cognitive impairment and dementia (VCID) secondary to 3 months of chronic cerebral hypoperfusion (CCH), we showed that adaptive epigenetic responses induced by RHC were recapitulated in the next generation.…”

“…Specifically, using a well-established mouse model of vascular cognitive impairment and dementia (VCID) secondary to 3 months of chronic cerebral hypoperfusion (CCH), we showed that adaptive epigenetic responses induced by RHC were recapitulated in the next generation. The responses were manifested functionally in hippocampal slices as a retention in long-term potentiation (LTP), an electrophysiological substrate of memory formation and synaptic plasticity, and in conscious mice as a resilience to recognition memory impairment (Belmonte et al, 2022). Herein, we undertook studies using the latter neurocognitive endpoint to determine whether this dementia resilience in first-generation (F1) mice results from RHC-induced changes in the germline cells of F0 males, F0 females, or both.…”