Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders

Introduction Using proton magnetic resonance spectroscopy imaging, the effects of early life stress on nonhuman primate striatal neuronal integrity were examined as reflected by N-acetyl aspartate (NAA) concentrations. NAA measures were interrogated through examining their relationship to previously documented early life stress markers—cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and behavioral timidity. Rodent models of depression exhibit increases in neurotrophic effects in the nucleus accumbens. We hypothesized that rearing under conditions of early life stress (variable foraging demand, VFD) would produce persistent elevations of NAA concentrations (in absolute or ratio form) in ventral striatum/caudate nucleus (VS/CN) with altered correlation to early life stress markers. Methods Eleven bonnet macaque males reared under VFD conditions and seven age-matched control subjects underwent proton magnetic resonance spectroscopy imaging during young adulthood. Voxels were placed over VS/CN to capture nucleus accumbens. Cisternal cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and response to a human intruder had been previously determined. Results VFD-reared monkeys exhibited significantly increased NAA/creatine concentrations in right VS/CN in comparison to normally reared controls, controlling for multiple comparisons. In comparison to controls, VFD cerebrospinal fluid corticotropin-releasing factor concentrations were directly associated with right VS/CN absolute NAA. Left hippocampal volume was inversely associated with left VS/CN NAA/creatine in VFD reared but not in controls. Disruption of a normative inverse correlation between left VS/CN NAA and body mass was noted in VFD. Only non-VFD subjects exhibited a direct relationship between timidity response to an intruder and right VS/CN NAA. Conclusion Early life stress produced persistent increases in VS/CN NAA, which demonstrated specific patterns of association (or lack thereof) to early life stress markers in comparison to non-VFD subjects. The data are broadly consistent with a stable nonhuman primate phenotype of anxiety and mood disorder vulnerability whereby in vivo indicators of neuronal integrity, although reduced in hippocampus, are increased in striatum. The findings may provide a catalyst for further studies in humans and other species regarding a reciprocal hippocampal/nucleus accumbens relationship in affective disorders.

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

Neurobiology of Stress ◽

10.1016/j.ynstr.2017.01.001 ◽

2018 ◽

Vol 8 ◽

pp. 202-210 ◽

Cited By ~ 2

Author(s):

Jeremy D. Coplan ◽

Anna V. Rozenboym ◽

Sasha L. Fulton ◽

Venkatesh Panthangi ◽

Jean Tang ◽

...

Keyword(s):

Anxiety Disorders ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Left Ventricular ◽

Thrifty Phenotype ◽

Thrifty Phenotype Hypothesis ◽

Mood And Anxiety Disorders ◽

And Function ◽

Ventricular Dimension

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Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels

Alcohol ◽

10.1016/j.alcohol.2011.11.003 ◽

2012 ◽

Vol 46 (4) ◽

pp. 371-376 ◽

Cited By ~ 9

Author(s):

Kimberly N. Huggins ◽

Tiffany A. Mathews ◽

Jason L. Locke ◽

Kendall T. Szeliga ◽

David P. Friedman ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Brain Tissue ◽

Life Stress ◽

Early Life ◽

Rhesus Macaques ◽

Early Life Stress ◽

System Activity ◽

Tissue Levels ◽

Serotonin System ◽

Hydroxyindoleacetic Acid

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Evidence for a sensitive period in the effects of early life stress on hippocampal volume

Developmental Science ◽

10.1111/desc.12775 ◽

2018 ◽

Vol 22 (3) ◽

Cited By ~ 15

Author(s):

Kathryn L. Humphreys ◽

Lucy S. King ◽

Matthew D. Sacchet ◽

M. Catalina Camacho ◽

Natalie L. Colich ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Hippocampal Volume ◽

Sensitive Period

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Cerebrospinal Fluid Corticotropin-Releasing Factor and Perceived Early-Life Stress in Depressed Patients and Healthy Control Subjects

Neuropsychopharmacology ◽

10.1038/sj.npp.1300375 ◽

2003 ◽

Vol 29 (4) ◽

pp. 777-784 ◽

Cited By ~ 116

Author(s):

Linda L Carpenter ◽

Audrey R Tyrka ◽

Christopher J McDougle ◽

Robert T Malison ◽

Michael J Owens ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Corticotropin Releasing Factor ◽

Control Subjects ◽

Depressed Patients ◽

Healthy Control

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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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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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Maternal Cerebrospinal Fluid Glutamate in Response to Variable Foraging Demand: Relationship to Cerebrospinal Fluid Serotonin Metabolites in Grown Offspring

Chronic Stress ◽

10.1177/2470547018785625 ◽

2018 ◽

Vol 2 ◽

pp. 247054701878562 ◽

Cited By ~ 1

Author(s):

Jeremy D. Coplan ◽

Nishant K. Gupta ◽

Sarah K. Flynn ◽

Wade J. Reiner ◽

David Gaita ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Anxiety Disorders ◽

Longitudinal Design ◽

Predictor Variable ◽

Corticotropin Releasing Factor ◽

Cross Sectional ◽

Macaque Model ◽

Adolescent Offspring ◽

Mood And Anxiety Disorders ◽

Hydroxyindoleacetic Acid

Background Maternal response to allostatic overload during infant rearing may alter neurobiological measures in grown offspring, potentially increasing susceptibility to mood and anxiety disorders. We examined maternal cerebrospinal fluid (CSF) glutamate response during exposure to variable foraging demand (VFD), a bonnet macaque model of allostatic overload, testing whether activation relative to baseline predicted concomitant CSF elevations of the stress neuropeptide, corticotropin-releasing factor. We investigated whether VFD-induced activation of maternal CSF glutamate affects maternal–infant attachment patterns and offspring CSF 5-hydroxyindoleacetic acid concentrations. Methods Mother–infant dyads were exposed to the “VFD stressor,” a paradigm in which mothers experience 16 weeks of foraging uncertainty while rearing their infant offspring. Through staggering the infant age of VFD onset, both a cross-sectional design and a longitudinal design were used. Maternal CSF glutamate and glutamine concentrations post-VFD exposure were cross-sectionally compared to maternal VFD naive controls. Proportional change in concentrations of maternal glutamate (and glutamine), a longitudinal measure, was evaluated in relation to VFD-induced elevations of CSF corticotropin-releasing factor. The former measure was related to maternal–infant proximity scores obtained during the final phases of VFD exposure. Maternal glutamatergic response to VFD exposure was used as a predictor variable for young adolescent offspring CSF metabolites of serotonin, dopamine, and norepinephrine. Results Following VFD exposure, maternal CSF glutamate concentrations correlated positively with maternal CSF CRF concentrations. Activation relative to baseline of maternal CSF glutamate concentrations following VFD exposure correlated directly with a) increased maternal-infant proximity during the final phases of VFD and b) offspring CSF concentrations of monoamine metabolites including 5-hydroxyindoleacetic acid, which was elevated relative to controls. Conclusions Activation of maternal CSF glutamate in response to VFD-induced allostasis is directly associated with elevations of maternal CSF corticotropin-releasing factor. Maternal CSF glutamate alterations induced by VFD potentially compromise serotonin neurotransmission in grown offspring, conceivably modeling human vulnerability to treatment-resistant mood and anxiety disorders.

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