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

Abstract

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.

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

“…After 3 months of CCH or normal cerebral perfusion, recognition memory was assessed in all F1 groups by the novel object recognition (NOR) test (Lueptow, 2017), as described previously (Belmonte et al, 2022). In brief, on the day before the test, mice were individually habituated for 15 min to an empty, dimly lit, black Plexiglass box with a white floor (20 × 20 × 20 cm).…”

“…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).…”

“…BCAS was performed aseptically, as described previously (Belmonte et al, 2022). In brief, mice were anesthetized with ketamine (87 mg/kg, i.p.)…”

“…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.…”

“…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.…”