Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol

Abstract Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain’s transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

Download Full-text

P.220 FKBP51 loss in glutamatergic forebrain neurons and early life stress exposure shape anxiety and cognition in female mice

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2019.12.046 ◽

2020 ◽

Vol 31 ◽

pp. S33-S34

Author(s):

L. Van Doeselaar ◽

C. Engelhardt ◽

J. Bordes ◽

L. Brix ◽

J. Deussing ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Stress Exposure ◽

Female Mice ◽

Forebrain Neurons

Download Full-text

Enhancement of nerve-injury-induced thermal and mechanical hypersensitivity in adult male and female mice following early life stress

Life Sciences ◽

10.1016/j.lfs.2014.11.012 ◽

2015 ◽

Vol 121 ◽

pp. 28-34 ◽

Cited By ~ 17

Author(s):

Takashi Nishinaka ◽

Kazuo Nakamoto ◽

Shogo Tokuyama

Keyword(s):

Nerve Injury ◽

Adult Male ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Male And Female ◽

Mechanical Hypersensitivity ◽

Female Mice

Download Full-text

Early life stress increases preadipocyte number and early markers of differentiation in female mice fed a high fat diet

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.06111 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Jaqueline R. Leachman ◽

Eva Gatineau ◽

Madhur Agarwal ◽

Carolina Dalmasso ◽

Xiu Xu ◽

...

Keyword(s):

High Fat Diet ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

High Fat ◽

Female Mice ◽

Early Markers

Download Full-text

Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

10.1101/624353 ◽

2019 ◽

Author(s):

Catherine Jensen Peña ◽

Milo Smith ◽

Aarthi Ramakrishnan ◽

Hannah M. Cates ◽

Rosemary C. Bagot ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Cortical Plasticity ◽

Early Life Stress ◽

Stress Sensitivity ◽

Sensitive Period ◽

Male And Female ◽

Reward Circuitry ◽

Female Mice ◽

Increase Risk

ABSTRACTAbuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain’s transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

Download Full-text

MeCP2 haplodeficiency and early-life stress interaction on anxiety-like behavior in adolescent female mice

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09409-7 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

María Abellán-Álvaro ◽

Oliver Stork ◽

Carmen Agustín-Pavón ◽

Mónica Santos

Keyword(s):

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Hypothalamic Nucleus ◽

Corticotropin Releasing Hormone ◽

Wild Type ◽

Releasing Hormone ◽

Complex Disorders ◽

Female Mice

Abstract Background Early-life stress can leave persistent epigenetic marks that may modulate vulnerability to psychiatric conditions later in life, including anxiety, depression and stress-related disorders. These are complex disorders with both environmental and genetic influences contributing to their etiology. Methyl-CpG Binding Protein 2 (MeCP2) has been attributed a key role in the control of neuronal activity-dependent gene expression and is a master regulator of experience-dependent epigenetic programming. Moreover, mutations in the MECP2 gene are the primary cause of Rett syndrome and, to a lesser extent, of a range of other major neurodevelopmental disorders. Here, we aim to study the interaction of MeCP2 with early-life stress in variables known to be affected by this environmental manipulation, namely anxiety-like behavior and activity of the underlying neural circuits. Methods Using Mecp2 heterozygous and wild-type female mice we investigated the effects of the interaction of Mecp2 haplodeficiency with maternal separation later in life, by assessing anxiety-related behaviors and measuring concomitant c-FOS expression in stress- and anxiety-related brain regions of adolescent females. Moreover, arginine vasopressin and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus were analyzed for neuronal activation. Results In wild-type mice, maternal separation caused a reduction in anxiety-like behavior and in the activation of the hypothalamic paraventricular nucleus, specifically in corticotropin-releasing hormone-positive cells, after the elevated plus maze. This effect of maternal separation was not observed in Mecp2 heterozygous females that per se show decreased anxiety-like behavior and concomitant decreased paraventricular nuclei activation. Conclusions Our data supports that MeCP2 is an essential component of HPA axis reprogramming and underlies the differential response to anxiogenic situations later in life.

Download Full-text

Exacerbated obesogenic response in female mice exposed to early life stress is linked to fat depot-specific upregulation of leptin protein expression

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00243.2020 ◽

2020 ◽

Vol 319 (5) ◽

pp. E852-E862

Author(s):

Jacqueline R. Leachman ◽

Mathew D. Rea ◽

Dianne M. Cohn ◽

Xiu Xu ◽

Yvonne N. Fondufe-Mittendorf ◽

...

Keyword(s):

Protein Expression ◽

Fat Mass ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Disease Risk ◽

Early Life Stress ◽

Female Mice ◽

Fat Depot ◽

Leptin Expression

Early life stress (ELS) is an independent risk factor for increased BMI and cardiometabolic disease risk later in life. We have previously shown that a mouse model of ELS, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. Therefore, the aim of this study was to investigate 1) whether the short- and long-term effects of HF on leptin expression are influenced by MSEW in a sex-specific manner and 2) the potential epigenetic mechanisms underlying the MSEW-induced changes in leptin expression. After 1 wk of HF, both MSEW male and female mice displayed increased fat mass compared with controls ( P < 0.05). However, only MSEW female mice showed elevated leptin mRNA expression in gonadal white adipose tissue (gWAT; P < 0.05). After 12 wk of HF, fat mass remained increased only in female mice ( P < 0.05). Moreover, plasma leptin and both leptin mRNA and protein expression in gWAT were augmented in MSEW female mice compered to controls ( P < 0.05), but not in MSEW male mice. This association was not present in subcutaneous WAT. Furthermore, among 16 CpG sites in the leptin promoter, we identified three hypomethylated sites in tissue from HF-fed MSEW female mice compared with controls (3, 15, and 16, P < 0.05). These hypomethylated sites showed greater binding of key adipogenic factors such as PPARγ ( P < 0.05). Taken together, our study reveals that MSEW superimposed to HF increases leptin protein expression in a sex- and fat depot-specific fashion. Our data suggest that the mechanism by which MSEW increases leptin expression could be epigenetic.

Download Full-text