Prereproductive Stress to Female Rats Alters Corticotropin Releasing Factor Type 1 Expression in Ova and Behavior and Brain Corticotropin Releasing Factor Type 1 Expression in Offspring

doi:10.1016/j.biopsych.2013.04.014

Biological Psychiatry

Volume 74, Issue 9, 1 November 2013, Pages 680-687

https://doi.org/10.1016/j.biopsych.2013.04.014 Get rights and content

Background

Human and animal studies indicate that vulnerability to stress may be heritable and that changes in germline may mediate some transgenerational effects. Corticotropin releasing factor type 1 (CRF1) is a key component in the stress response. We investigated changes in CRF1 expression in brain and ova of stressed female rats and in the brain of their neonate and adult offspring. Behavioral changes in adulthood were also assessed.

Methods

Adult female rats underwent chronic unpredictable stress. We extracted mature oocytes and brain regions from a subset of rats and mated the rest 2 weeks following the stress procedure. CRF1 expression was assessed using quantitative reverse-transcription polymerase chain reaction. Tests of anxiety and aversive learning were used to examine behavior of offspring in adulthood.

Results

We show that chronic unpredictable stress leads to an increase in CRF1 messenger RNA expression in frontal cortex and mature oocytes. Neonatal offspring of stressed female rats show an increase in brain CRF1 expression. In adulthood, offspring of stressed female rats show sex differences in both CRF1 messenger RNA expression and behavior. Moreover, CRF1 expression patterns in frontal cortex of female offspring depend upon both maternal and individual adverse experience.

Conclusions

Our findings demonstrate that stress affects CRF1 expression in brain but also in ova, pointing to a possible mechanism of transgenerational transmission. In offspring, stress-induced changes are evident at birth and are thus unlikely to result from altered maternal nurturance. Finally, brain CRF1 expression in offspring depends upon gender and upon maternal and individual exposure to adverse environment.

Section snippets

Animals

Female Sprague-Dawley rats bred at the University of Haifa were maintained with minimal stress as previously described (12) (Supplement 1). The study was approved by the University of Haifa Committee on Animal Experimentation (197/10, 215/11).

Procedure

The detailed procedure is provided in Supplement 1. Briefly, adult female rats were randomly divided into two groups (Figure 1). Female rats (postnatal day [P]45–54) in the PRS group underwent chronic unpredictable stress 26, 27, and female rats from the

CRF1 mRNA Expression in Mature Oocytes of Stressed Female Rats

To determine CRF1 mRNA expression in oocytes after chronic unpredictable stress, we performed quantitative RT-PCR on RNA extracted from mature oocytes successfully harvested from control and stressed adult female rats. No differences in the number of oocytes from stressed and control female rats were observed (t test, p > .1). As can be seen in Figure 2A, stress led to an 18.5-fold increase in the expression of CRF1 mRNA in oocytes (t test, p < .05).

CRF1 mRNA Expression in Brain of Stressed Female Rats

We compared CRF1 mRNA expression in amygdala,

Discussion

We show that chronic unpredictable stress to virgin female rats 2 weeks before reproduction (PRS) leads to a mild increase in CRF1 mRNA expression in their frontal cortex and a dramatic increase in CRF1 mRNA in their ova. Their offspring (O-PRS) show several effects at birth, including an increase in brain CRF1 expression. In adulthood, O-PRS rats show sex-specific behavioral abnormalities in anxiety and fear learning tests and experience-dependent abnormalities in CRF1 expression in frontal

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Chronic parental stress impacts offspring functioning throughout life. Chronic variable stress prior to conception impairs offspring development in terms of behavior, neuroanatomy, and neurobiology. Previously, our lab demonstrated that even a consistent stressor experienced by the sire or the dam shapes offspring development beginning in early life. Here, we show how consistent maternal stress prior to conception influences the brain and behavior of offspring in adolescence and adulthood. Female Long-Evans rats were exposed to elevated platform stress twice daily for 27 consecutive days immediately prior to mating with non-stressed males. Male and female offspring were assessed in the open field and elevated plus maze in adolescence, and open field, elevated plus maze, Whishaw tray reaching, and Morris water task in adulthood. Offspring were then euthanized, and their brains were stained with Golgi-Cox solution and then examined for dendritic spine density and hippocampal volume. Major findings include deficits in spatial memory, decreased medial prefrontal cortex spine density, and reduced right dorsal hippocampal volume in male offspring only. This work illustrates that the effects of consistent maternal stress prior to conception are lifelong and highly sexually dimorphic.
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Archival ReportPrereproductive Stress to Female Rats Alters Corticotropin Releasing Factor Type 1 Expression in Ova and Behavior and Brain Corticotropin Releasing Factor Type 1 Expression in Offspring

Background

Methods

Results

Conclusions

Section snippets

Animals

Procedure

CRF1 mRNA Expression in Mature Oocytes of Stressed Female Rats

CRF1 mRNA Expression in Brain of Stressed Female Rats

Discussion

Front Neuroendocrinol

Biol Psychiatry

Neurosci Biobehav Rev

Neurosci Lett

Biol Psychiatry

Biol Psychiatry

Peptides

J Reprod Immunol

Biol Psychiatry

Biol Psychiatry

Brain Res

Neurosci Biobehav Rev

J Neurosci Methods

Exp Neurol

BMC Neurosci

Physiol Behav

Brain Res

J Pharmacol Methods

Eur J Pharmacol

Horm Behav

Behav Brain Res

Neurosci Biobehav Rev

Behav Brain Res

Transmission of response to trauma? Second-generation Holocaust survivors' reaction to cancer

Am J Psychiatry

Transgenerational transmission of cortisol and PTSD risk

Prog Brain Res

Archival Report
Prereproductive Stress to Female Rats Alters Corticotropin Releasing Factor Type 1 Expression in Ova and Behavior and Brain Corticotropin Releasing Factor Type 1 Expression in Offspring