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Reversing Behavioral, Neuroanatomical, and Germline Influences of Intergenerational Stress.

ABSTRACT: BACKGROUND:Stressors affect populations exposed to them as well as offspring. Strategies preventing the intergenerational propagation of effects of stress would benefit public health. Olfactory cue-based fear conditioning provides a framework to address this issue. METHODS:We 1) exposed adult male mice to an odor, acetophenone (Ace) or Lyral (parental generation [F0]-Exposed), 2) trained mice to associate these odors with mild foot shocks (F0-Trained), and 3) trained mice to associate these odors with mild foot shocks and then extinguished their fear toward these odors with odor-only presentations (F0-Extinguished). We then examined sensitivity of future generation (F1) offspring to these odors, expression of M71 odorant (Ace-responsive) and MOR23 odorant (Lyral-responsive) receptor-expressing cell populations in F1 offspring, and DNA methylation at genes encoding the Ace- (Olfr151, Olfr160) and Lyral- (Olfr16) responsive receptors in F0 sperm. RESULTS:Extinguishing fear toward Ace or Lyral of F0 male mice (F0-Extinguished) that had been fear conditioned with Ace or Lyral, respectively, results in F1-Extinguished offspring that do not demonstrate behavioral sensitivity to Ace or Lyral, respectively, and do not have enhanced representation for M71 or MOR23 odorant receptors in the olfactory system, as is observed in F1-Trained-Ace or F1-Trained-Lyral cohorts, respectively. The promoters of genes encoding Olfr151 and Olfr160 receptors are less methylated in F0-Trained-Ace sperm compared with F0-Exposed-Ace sperm. The Olfr16 promoter is less methylated in F0-Trained-Lyral sperm compared with F0-Exposed-Lyral sperm, and F0-Extinguished-Lyral sperm have methylation levels comparable to F0-Exposed-Lyral sperm. CONCLUSIONS:Our study demonstrates the potential of using extinction-based behavioral strategies to reverse influences of parental stress in offspring and in the parental germline.

SUBMITTER: Aoued HS

PROVIDER: S-EPMC6326876 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Reversing Behavioral, Neuroanatomical, and Germline Influences of Intergenerational Stress.

Aoued Hadj S HS Sannigrahi Soma S Doshi Nandini N Morrison Filomene G FG Linsenbaum Hannah H Hunter Sarah C SC Walum Hasse H Baman Justin J Yao Bing B Jin Peng P Ressler Kerry J KJ Dias Brian G BG

Biological psychiatry 20180827 3

<h4>Background</h4>Stressors affect populations exposed to them as well as offspring. Strategies preventing the intergenerational propagation of effects of stress would benefit public health. Olfactory cue-based fear conditioning provides a framework to address this issue.<h4>Methods</h4>We 1) exposed adult male mice to an odor, acetophenone (Ace) or Lyral (parental generation [F0]-Exposed), 2) trained mice to associate these odors with mild foot shocks (F0-Trained), and 3) trained mice to assoc ...[more]

PMID: 30292395

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Project description:ObjectiveThe paraventricular nucleus of hypothalamus (PVN), an integrative center in the brain, orchestrates a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and test their physiological functions beyond feeding.MethodsUsing a combination of viral tools, we mapped PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding.ResultsWe found that PVNMC4R+ neurons innervate many different brain regions that are known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure, and brown adipose tissue temperature. These physiological changes accompanied acute transient hyperactivity followed by hypoactivity and resting-like behavior.ConclusionsOur results elucidate the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermoregulation, cardiovascular function, and biphasic behavioral activation.

Dataset Information

Reversing Behavioral, Neuroanatomical, and Germline Influences of Intergenerational Stress.

Publications

Reversing Behavioral, Neuroanatomical, and Germline Influences of Intergenerational Stress.

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