Evidence for Ancestral Programming of Resilience in a Two-Hit Stress Model

Abstract

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) may accumulate across generations and alter stress vulnerability and resilience. Here, we report in female rats that a family history of recurrent ancestral PS facilitates certain aspects of movement performance, and that these benefits are abolished by the experience of a second hit, induced by a silent ischemia during adulthood. Female F4-generation rats with and without a family history of cumulative multigenerational PS (MPS) were tested for skilled motor function before and after the induction of a minor ischemic insult by endothelin-1 infusion into the primary motor cortex. MPS resulted in improved skilled motor abilities and blunted hypothalamic-pituitary-adrenal (HPA) axis function compared to non-stressed rats. Deep sequencing revealed downregulation of miR-708 in MPS rats along with upregulation of its predicted target genes Mapk10 and Rasd2. Through miR-708 stress may regulate mitogen-activated protein kinase (MAPK) pathway activity. Hair trace elemental analysis revealed an increased Na/K ratio, which suggests a chronic shift in adrenal gland function. The ischemic lesion activated the HPA axis in MPS rats only; the lesion, however, abolished the advantage of MPS in skilled reaching. The findings indicate that MPS generates adaptive flexibility in movement, which is challenged by a second stressor, such as a neuropathological condition. Thus, a second “hit” by a stressor may limit behavioral flexibility and neural plasticity associated with ancestral stress.

Non-diagnostic symptoms in a mouse model of autism in relation to neuroanatomy: the BTBR strain reinvestigated

“…The volume averages were calculated by dividing the sum of measures obtained from each brain by the total number of sections (shrunk brain area in mm 2 ). The approximate volume of the cortex and hippocampus (HPC; shrunk volume in mm 3 ) was determined by multiplying the total area in mm 2 by both the thickness of each slice (40 μm) and the sampling interval (5) 34 . The hippocampal volume (B6, n = 7; BTBR, n = 8) in each mouse was estimated using a set of four cross sections of the dHPC area, from ~−1.06 to ~−2.06 mm relative to bregma.…”

Ancestral stress programs sex-specific biological aging trajectories and non-communicable disease risk

“…Experimental studies revealed that multigenerational prenatal stress (MPS) in particular is more potent in programming the stress response than early life stress [15,26], especially in male offspring. The recurrent gestational challenge in MPS models was shown to impair fine motor function, alter neuromorphology and induce hemispheric dominance shifts in males [3,16], while improving fine function and promoting resilience in females [17]. Thus, MPS models may offer unique insights into evolutionary mechanisms of sex-dependent adaptation and resilience.…”

“…Thus, MPS models may offer unique insights into evolutionary mechanisms of sex-dependent adaptation and resilience. Research has shown that ancestral biological memories of adverse experiences are linked to epigenetic modification, such as DNA methylation [30,33,34], histone modification [35][36][37] and miRNA expression [17,26,[30][31][32]. Notably, the consequences of ancestral stress become particularly visible during early development and old age [16].…”

“…F4 generation male and female offspring were derived from two lineages bred under standardized conditions: multigenerational prenatal stress (MPS) and non-stress yoked CONTROL. Prenatal stress was induced by subjecting pregnant dams to semi-random daily 5 min swim and 20 min restraint stress in a Plexiglas cylinder from gestational days 12-18 [3,17,24,26,93].…”

“…The developmental origins of health and disease (DOHaD) hypothesis postulates that many common NCDs originate in utero by re-programming fetal physiological and metabolic responses with lifelong consequences on organ and tissue function [8]. Animal and clinical studies demonstrate that an adverse prenatal environment exacerbates hypothalamic-pituitary-adrenal (HPA) axis responsiveness; heightens risk for abnormal heart and kidney morphology and disease; increases blood pressure, cholesterol, insulin, and obesity; impairs mental health trajectories; and reduces lifespan [9][10][11][12][13][14][15][16][17].…”