Reduced left ventricular dimension and function following early life stress: A thrifty phenotype hypothesis engendering risk for mood and anxiety disorders

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

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Environmental enrichment rescues survival and function of adult-born neurons following early life stress

Molecular Psychiatry ◽

10.1038/s41380-020-0718-4 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lowenna Rule ◽

Jessica Yang ◽

Holly Watkin ◽

Jeremy Hall ◽

Nichola Marie Brydges

Keyword(s):

Life Stress ◽

Early Life ◽

Environmental Enrichment ◽

Early Life Stress ◽

Adult Born Neurons ◽

And Function

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S.01.02 The interplay between early-life stress and neuroinflammation on structure and function of the brain throughout life

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2018.11.915 ◽

2019 ◽

Vol 29 ◽

pp. S4-S5

Author(s):

A. Korosi

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Structure And Function ◽

And Function ◽

The Brain

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The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2014.00103 ◽

2015 ◽

Vol 7 ◽

Cited By ~ 23

Author(s):

Lianne Hoeijmakers ◽

Paul J. Lucassen ◽

Aniko Korosi

Keyword(s):

Immune Activation ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Structure And Function ◽

And Function ◽

Hippocampal Structure

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Sex and Estrous Cycle Effects on Anxiety- and Depression-related Phenotypes in Two-hit Developmental Stress Model

10.1101/530311 ◽

2019 ◽

Author(s):

Ivana Jaric ◽

Devin Rocks ◽

Heining Cham ◽

Alice Herchek ◽

Marija Kundakovic

Keyword(s):

Anxiety Disorders ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Anxiety And Depression ◽

Synergistic Activity ◽

Stress Model ◽

Depression And Anxiety ◽

Developmental Stress ◽

Behavioral Phenotypes

Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology. To examine potential developmental mechanisms driving sex disparity in risk for anxiety and depression, we established a two-hit developmental stress model including maternal separation in early life followed by social isolation in adolescence. Our study shows complex interactions between early-life and adolescent stress, between stress and sex, and between stress and female estrogen status in shaping behavioral phenotypes of adult animals. In general, increased locomotor activity and body weight reduction were the only two phenotypes where two stressors showed synergistic activity. In terms of anxiety- and depression-related phenotypes, single exposure to early-life stress had the most significant impact and was female-specific. We show that early-life stress disrupts the protective role of estrogen in females, and promotes female vulnerability to anxiety- and depression-related phenotypes associated with the low-estrogenic state. We found plausible transcriptional and epigenetic alterations in psychiatric risk genes, Nr3c1 and Cacna1c, that likely contributed to the stress-induced behavioral effects. In addition, two general transcriptional regulators, Egr1 and Dnmt1, were found to be dysregulated in maternally-separated females and in animals exposed to both stressors, respectively, providing insights into possible transcriptional mechanisms that underlie behavioral phenotypes. Our findings provide a novel insight into developmental risk factors and biological mechanisms driving sex differences in depression and anxiety disorders, facilitating the search for more effective, sex-specific treatments for these disorders.

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Stress and the Brain

The Oxford Handbook of Stress and Mental Health ◽

10.1093/oxfordhb/9780190681777.013.20 ◽

2018 ◽

pp. 434-462

Author(s):

Deanna M. Barch ◽

David Pagliaccio

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Life Stress ◽

Early Life ◽

Diffusion Imaging ◽

Early Life Stress ◽

Resting State Functional Connectivity ◽

Major Depressive ◽

Brain Structure And Function ◽

And Function

This chapter reviews associations between early life stress and brain structure and function as assessed by structural and functional magnetic resonance imaging. Particularly, this chapter focuses on structural associations in children and adults and the regional overlap with neural alterations observed in major depressive disorder, though we also more briefly cover diffusion imaging, task-based imaging, and resting-state functional connectivity. Major depressive disorder is highlighted given that early life stress is a critical risk factor for depression and the neural alterations observed with stress and depression may serve as key mediating factors of this association. A brief methodological overview is provided for each neuroimaging domain as well as a discussion of limitations and future directions for this field.

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3004 Effects of Early Life Stress on Adult Behavioral and Neural Outcomes in Rats

Journal of Clinical and Translational Science ◽

10.1017/cts.2019.26 ◽

2019 ◽

Vol 3 (s1) ◽

pp. 9-10

Author(s):

Alexandra Moussa-Tooks ◽

Ken Mackie ◽

John Green ◽

Lisa Bartolomeo ◽

Alex Gimeno ◽

...

Keyword(s):

Anxiety Disorders ◽

Life Stress ◽

Early Life ◽

Cannabinoid Receptors ◽

Social Preference ◽

Elevated Plus Maze ◽

Early Life Stress ◽

Female Rats ◽

Plus Maze

OBJECTIVES/SPECIFIC AIMS: Early life stress is known to greatly impact neurodevelopment during critical periods, conferring risk for various psychopathologies, including the onset and exacerbation of schizophrenia and anxiety disorders. The endocannabinoid system is highly integrated into the stress response and may be one means by which early life stress produces such deleterious effects. Using a naturalistic, ecologically valid animal model, this study explored interactions between the stress response and endocannabinoid systems within the cerebellum, a region dense with the CB1 endocannabinoid receptors and shown to be susceptible to stress. METHODS/STUDY POPULATION: This study explored behavioral and neural impacts of early life stress in Long-Evans rats reared with or without limited access to bedding material during postnatal day (PND) 2-9. Corticosterone (CORT) levels were measured at PND8 and 70. During PND50-70, rats were assessed on Novel Object Recognition to test memory, Rotarod to evaluate cerebellar integrity, Elevated Plus Maze to assay anxiety, Social Preference, and Eyeblink Conditioning, a cerebellar-dependent and endocannabinoid-mediated task. Lipid analysis was performed on PND70 tissue samples of cerebellar interpositus (IP) nucleus via high-performance liquid chromatography and tandem mass spectrometry. RESULTS/ANTICIPATED RESULTS: Both male and female rats experiencing early life stress exhibited significantly impaired recognition memory (N = 16-20/group). Female rats having undergone stress exhibited decreased social preference compared to normally reared females (N = 11/group). Stressed males showed facilitated eyblink conditioning compared to normally reared males (N = 7-9/group). There were no group differences in rotarod or elevated plus maze performance or CORT levels at PND8 or 70 across rearing groups. At PND70, male rats experiencing early life stress exhibited a significant decrease in 2-arachidonoyl glycerol (2-AG) and arachidonic acid levels in the IP nucleus compared to normally reared males (N = 8-9/group). Compared to normally reared females, those experiencing early life stress exhibited a significant increase in prostaglandin E2 levels in the IP nucleus (N = 6-7/group). DISCUSSION/SIGNIFICANCE OF IMPACT: Early life stress, induced by limited bedding, resulted in sex-specific behavioral and lipid impairments. Results suggest that stress causes long-term alterations in endocannabinoid dynamics in males in the cerebellar IP nucleus and sex-related lipids in female cerebellum. These changes may contribute to observed long-term behavioral aberrations. Moreover, findings suggest these behavioral changes may be the result of negative-feedback dysfunction (as evidenced by decreased endocannabinoids in males) or increased neural inflammation or proliferation (as evidenced by increased prostaglandins in females). Future analysis will quantify mRNA and protein for cannabinoid receptors to better characterize aberrations to this system. Moreover, other neural regions dense with cannabinoid receptors (i.e., PFC, hippocampus) will be investigated. This work provides a basis for understanding stress impacts on the development of cognitive deficits observed in psychotic and anxiety disorders. Specifically, facilitation of eyblink conditioning complements research in humans with anxiety disorders. Broadly, understanding stress-related endocannabinoid dysregulation may provide insights into risks for, and the development of, psychopathology and uncover novel therapeutic targets with high translational power.

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Long-Term Decreases in the Expression of Calcineurin and GABAA Receptors Induced by Early Maternal Separation Are Associated with Increased Anxiety-Like Behavior in Adult Male Rats

Developmental Neuroscience ◽

10.1159/000512221 ◽

2020 ◽

pp. 1-10

Author(s):

Maryam Mahmoodkhani ◽

Maedeh Ghasemi ◽

Leila Derafshpour ◽

Mohammad Amini ◽

Nasrin Mehranfard

Keyword(s):

Anxiety Disorders ◽

Glutamate Receptors ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Central Area ◽

Early Life Stress ◽

Brain Regions ◽

Male Rats ◽

Lower Percentage

Introduction: Early life stress is a well-described risk factor of anxiety disorders in adulthood. Dysfunction in GABA/glutamate receptors and their functional regulator, calcineurin, is linked to anxiety disorders. Here, we investigated the effect of early life stress, such as repeated maternal separation (MS; 3 h per day from postnatal day [P] 2 to 11), on changes in the expression of calcineurin as well as the ionotropic glutamatergic and GABAergic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and GABAA receptors in the hippocampus and prefrontal cortex (PFC) of adolescent (P35) and adult (P62) male Wistar rats and their correlations with anxiety-like behavior in adulthood. Methods: The protein levels were assessed by Western blot analysis. Anxiety-like behavior was measured in the elevated plus maze (EPM) and open field (OF) tests. Results: MS induced a regional transient decrease of glutamate receptors expression at P35, with decreased NMDA and AMPA receptor levels, respectively, in the hippocampus and PFC, suggesting a possible decrease in excitatory synaptic strength. In contrast to glutamate receptors, MS had long-lasting influence on GABAA receptor and calcineurin levels, with reduced expression of GABAA receptor and calcineurin in both brain regions at P35 that continued into adulthood. These results were accompanied by increased anxiety behavior in adulthood, shown by lower percentage of number of total entries and time spent in the open arms of the EPM, and by lower time spent and number of entries in the OF central area. Conclusions: Together, our study suggests that GABAA receptors via calcineurin-dependent signaling pathways may play an important role in the expression of stress-induced anxiety-like behavior.

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