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.
Highlights
Prenatal stress (PS) is one of the most critical determinants of health and disease (Cottrell and Seckl, 2009)
Ischemia did not significantly change the levels of circulating CORT in STROKE-only and STRESS + STROKE groups, but the effect of stress compared to non-stress groups disappeared
An independent sample t-test revealed a significant increase in the Na/K ratio in stressed animals before ischemia (Stressed, 0.107 ± 0.04 ppm vs. Non-stressed, 0.082 ± 0.007 ppm; t(13) = 4.308, p = 0.007; Figure 1B)
Summary
Prenatal stress (PS) is one of the most critical determinants of health and disease (Cottrell and Seckl, 2009). PS is associated with poor health later in life, including a higher risk of hypertension and cardio- and cerebrovascular disease (Igosheva et al, 2007; van Dijk et al, 2012). Stress has been recognized as a critical variable in stroke risk and recovery (Kirkland et al, 2008; Dunn et al, 2011; Walker et al, 2014). Stress represents a critical regulator of metabolic and cardiovascular function and is the cause of hypertension, the number one risk factor for stroke (Kulkarni et al, 1998). Experimental evidence revealed that PS is associated with poor stroke. PS impedes recovery after ischemic lesion with associated transcriptomic changes (Zucchi et al, 2014)
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