Ancestral Stress Alters Lifetime Mental Health Trajectories and Cortical Neuromorphology via Epigenetic Regulation

Abstract

Experiences during early development are powerful determinants of lifetime mental health. Here we investigated if ancestral stress regulates the brain’s epigenetic memory to alter neuromorphology and emotionality in the remote F4 progeny. Pregnant female rat dams of the parental F0 generation were exposed to stress on gestational days 12–18. To generate a transgenerational stress lineage, their pregnant daughters (F1), grand-daughters (F2) and great-grand-daughters (F3) remained undisturbed. To generate a multigenerational stress lineage, pregnant dams of each generation (F1–F3) were stressed. A lineage of non-stress controls (F0–F3) was also produced. Multigenerational stress exceeded the impact of transgenerational stress by increasing anxiety-like behaviours and stress response in young and middle-aged F4 males but not females. Functional changes were accompanied by reduced spine density in the male medial prefrontal cortex with opposite effects in the orbital frontal cortex. Ancestral stress regulated cortical miR-221 and miR-26 expression and their target genes, thus downregulating ntrk2 and map1a genes in males while downregulating crh and upregulating map1a genes in females. These miRNA-dependent pathways are candidates for developmental programming of lifetime mental health. Thus, multigenerational stress in particular determines sexually dimorphic predisposition to stress vulnerability and generates a phenotype resembling symptoms of post-traumatic stress disorder.

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

“…Hence, MPS in males may blunt basal HPA axis activity thus compromising adaptive stress response at particularly vulnerable times in life [93]. Accordingly, we demonstrated previously that MPS upregulates cortical chr gene expression in adult males, but not in females [26]. These findings suggest a characteristic agedependent profile of stress markers to be considered in the prediction and diagnosis of stress-related NCDs.…”

“…The biological signatures linked to early life adversity are also transmitted across generations. Natural disaster and nutritional birth cohorts [18][19][20][21] as well as experimental studies [3,[22][23][24][25][26][27][28][29] have demonstrated that remote ancestral adverse experiences increase the risk of metabolic, cardiac and renal disease, and mental illness with a sex-specific bias. These adverse health outcomes are linked to epigenetic regulation, including altered microRNA (miRNA) expression [30][31][32].…”

“…These adverse health outcomes are linked to epigenetic regulation, including altered microRNA (miRNA) expression [30][31][32]. 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. 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].…”

“…From a subset of male and female young (6 months, n=12) and aged (18 months, n=12) animals (3 per group) frontal cortex tissue was collected for epigenetic profiling (miRNA and mRNA). Whole tissue deep sequencing revealed that nine cortical miRNAs were differentially regulated by MPS: 1) miR-150-5p, miR-181a-5p and miR-181c-5p that influence immune function through B and T cell regulation [46,47]; 2) miR-34a-5p, miR-34c-5p, and miR-124-3p involved in HPA axis response, synaptic plasticity and mental health [26,[48][49][50]; 3) miR-29a-3p and miR-29b-3p that regulate DNA methylation and resilience [51]; 4) the senescence/longevity biomarker miR-21-5p ([52]; Figure 5).…”