PLoS ONE 9(3): e92130. doi:10.1371/journal.pone.0092130

Lifetime Stress Cumulatively Programs Brain Transcriptome and Impedes Stroke Recovery: Benefit of Sensory Stimulation

Fabiola C. R. Zucchi1,2, Youli Yao1,3, Yaroslav Ilnytskyy3, Jerrah C. Robbins1, Nasrin Soltanpour1, Igor Kovalchuk3, Olga Kovalchuk3, Gerlinde A. S. Metz1

Corresponding author:

1 Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada, 2 Department of Physiological Sciences, University of Brasilia (UnB), Brasilia, DF, Brazil, 3 Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada



Prenatal stress represents a critical variable affecting lifetime health trajectories, metabolic and vascular functions. Beneficial experiences may attenuate the effects of prenatal stress and its programming of health outcomes in later life. Here we investigated in a rat model (1) if prenatal stress modulates recovery following cortical ischemia in adulthood; (2) if a second hit by adult stress exacerbates stress responses and ischemic damage; and (3) if tactile stimulation (TS) attenuates the cumulative effects of prenatal and adult stress. Prenatally stressed and non-stressed adult male rats underwent focal ischemic motor cortex lesion and were tested in skilled reaching and skilled walking tasks. Two groups of rats experienced recurrent restraint stress in adulthood and one of these groups also underwent daily TS therapy. Animals that experienced both prenatal and adult stress displayed the most severe motor disabilities after lesion. By contrast, TS promoted recovery from ischemic lesion and reduced stress sensitivity. The data also showed that cumulative effects of adverse and beneficial lifespan experiences interact with disease outcomes and brain plasticity through the modulation of gene expression. Microarray analysis of the lesion motor cortex revealed that cumulative lifetime stresses interact with genes related to growth factors and transcription factors, which were not affected by prenatal stress or lesion alone. TS mitigated the consequences of prenatal and adult stress, suggesting a critical role in activity-dependent motor cortical reorganization after ischemic lesion. These findings suggest that beneficial experiences later in life can moderate adverse consequences of early programming and improve lifetime health trajectories.

PMID: 24651125



Given the positive association between hypertension and stroke risk, programming of the stress response by early experiences may critically influence stroke risk and outcome in adulthood. Although the early environment sets the stage for adult health outcomes, experience throughout the life span may modify the imprints of perinatal programming. Accordingly, elevated hypothalamic-pituitary-adrenal (HPA) axis activation by stress in adulthood has been shown to diminish motor recovery after ischemic lesion in a rat model and synergistically impair outcomes in aged rats. By contrast, experiential therapies have been shown to effectively promote recovery from stroke, including environmental enrichment and tactile stimulation (TS) and its equivalent in humans, massage or touch therapy. TS may mitigate excessive HPA axis activity, reduce stress sensitivity, and improve immune functions.

Here we investigated the influence of prenatal stress on focal ischemia outcomes and the benefit of TS in a rat model of stroke. We hypothesized that enriching the environment with TS may reduce the effects of adverse perinatal experience in healthy animals, and facilitate recovery from ischemic cortical damage in adulthood. We show that prenatal stress programs the adult stress response and compromises behavioural and structural recovery from ischemic brain damage in association with differential gene expression profiles. We also show that cumulative effects of stressful experiences throughout prenatal and postnatal periods affect the transcription of genes related to central pathways of neuronal survival and plasticity. Lastly, we show that TS counteracts the detrimental effects of chronic stress across prenatal and postnatal periods and facilitates recovery from ischemic brain injury through altered gene expression and enhanced motor recovery. Thus, this study demonstrates a link between perinatal programming by adverse environment and cerebrovascular health later in life. The transcriptomic changes found here are arguably associated with epigenetic regulation that alters disease outcomes, such as stroke. Even short periods of stress in adulthood induce miRNA-mediated transcriptomic programming of the motor system. Such epigenetic processes linked to prenatal stress may influence brain development and stress response with lifetime consequences on behaviour.

The importance of this study: This study suggests that stress during pregnancy may occur during a critical phase of fetal sensorimotor and stress response programming to affect motor function and neurological outcomes following focal ischemic infarct later in life. By contrast, enriched multimodal experiences, such as TS or touch therapy, may effectively intervene and offset the consequences of early life stress.



Figure 1. Experimental design. Time-course of procedures. Adult male offspring was pre-trained and tested in a pellet reaching task and skilled walking. Blood samples were collected three times for corticosterone assessments. Adulthood stress and TS were induced for four weeks starting one week pre-lesion. Transcriptomic analyses were performed after behavioural testing was completed. doi:10.1371/journal.pone.0092130.g001




Figure 2. A, Tactile stimulation (TS) restored forelimb function after ischemic lesion. Reaching success in the single pellet reaching task. Sequence of video frames depicting grasp and supination 1 components (qualitative assessment of reaching components). Note that the ischemic lesion reduced quantitative (success) and qualitative aspects of skilled reaching. Cumulative effects of prenatal and adult stress further reduced skilled reaching ability. TS promoted reaching success and movement ability. B, Cumulative stress and TS differentially altered motor cortex gene expression. Microarrays of motor cortex gene expression after prenatal stress, cumulative prenatal and adult stress, ischemic lesion, and TS. C, TS offset effects of cumulative stress in skilled walking ability. Walking time and score. Photograph in (C) shows a rat performing the ladder rung walking task. Prenatal stress prolonged the time to cross the ladder at baseline and post-lesion periods. Cumulative stress exaggerated the effects of ischemia in limb placement and inter-limb coordination. TS improved time measurements and scores. Asterisks indicate significances: *p,0.05, **p,0.01, ***p,0.001. doi:10.1371/journal.pone.0092130.g001



  1. Yao Y, Robinson AM,Zucchi FCR, Robbins JC, Babenko O, Kovalchuk O, Kovalchuk I, Olson DM, Metz GA. Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes. BMC Med (2014) Aug 7;12:121. doi: 10.1186/s12916-014-0121-6.
  2. Zucchi FCR, Yao Y, Ilnytskyy Y, Robbins JC, Soltanpour N, Kovalchuk I, Kovalchuk O, Metz GA. Lifetime stress cumulatively programs brain transcriptome and impedes stroke recovery: benefit of sensory stimulation. PLoS One (2014) Mar 20;9(3):e92130. doi: 10.1371/journal.pone.0092130. eCollection 2014.
  3. Zucchi FCR, Yao Y, Ward ID, Ilnytskyy Y, Olson DM, Benzies K, Kovalchuk I, Kovalchuk O, Metz GA. Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. PLoS ONE (2013) 8(2):e56967. doi: 10.1371/journal.pone.0056967.
  4. Ward ID, Zucchi FCR, Robbins J, Falkenberg EA, Olson DM, Benzies K, Metz GA. Transgenerational programming of maternal behaviour by prenatal stress. BMC Pregnancy and Childbirth (2013) 13(Suppl 1):S9
  5. Zucchi FCR, Yao Y, Metz GA. The Secret Language of Destiny: Stress Imprinting and Transgenerational Origins of Disease. Front Gene (2012) 3:96. doi: 10.3389/fgene.2012.00096



This research was supported by Alberta Innovates – Health Solutions (AI-HS; FZ and GM), Preterm Birth and Healthy Outcomes funded by the AI-HS Interdisciplinary Team Grant #200700595 (GM), Hotchkiss Brain Institute (FZ), Norlien Foundation (FZ), the Canadian Institutes of Health Research (GM), and the Natural Sciences and Engineering Research Council of Canada (GM). GM is a Senior Scholar of Alberta Innovates-Health Solutions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Competing Interests

The authors have declared that no competing interests exist.



The authors thank Erin Falkenberg, Danyel Oliveira, Majken Villiger and Norah-Faye Matthies for assistance with the experiments.


Author Contributions

Conceived and designed the experiments: FZ GM. Performed the experiments: FZ YY JR NS. Analyzed the data: FZ YY YI. Contributed reagents/materials/analysis tools: IK OK GM. Wrote the paper: FZ IK OK GM.



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