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

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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Effects of essential oil from Chamaecyparis obtusa on cytokine genes in the hippocampus of maternal separation rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0224 ◽

2014 ◽

Vol 92 (2) ◽

pp. 95-101 ◽

Cited By ~ 10

Author(s):

Hae Jeong Park ◽

Su Kang Kim ◽

Won Sub Kang ◽

Jong-Min Woo ◽

Jong Woo Kim

Keyword(s):

Essential Oil ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Elevated Plus Maze ◽

Early Life Stress ◽

Chamaecyparis Obtusa ◽

Gene Expressions ◽

Cytokine Genes ◽

Plus Maze

We investigated the effects of an essential oil from Chamaecyparis obtusa (EOCO) on early life stress, using maternal separation (MS) rats and a microarray method to analyze the changes in gene expressions caused by EOCO in the hippocampus of MS rats. Rats in the MS groups were separated from their respective mothers from postnatal day (pnd) 14 to 28. Rats in the EOCO-treated groups were exposed to EOCO for 1 or 2 h by inhalation from pnd 21 to 28. The EOCO-treated MS rats showed decreased anxiety-related behaviors compared with the untreated MS rats in the elevated plus-maze (EPM) test. In the microarray analysis, we found that EOCO downregulated the expressions of cytokine genes such as Ccl2, Il6, Cxcl10, Ccl19, and Il1rl in the hippocampus of MS rats, and also confirmed that using reverse transcriptase – PCR. In particular, the expressions of Ccl2 and Il6 were predominantly decreased by EOCO in the hippocampus of MS rats. Interestingly, protein expression was also reduced by EOCO in MS rats. These results indicate that EOCO decreases MS-induced anxiety-related behaviors, and modulates cytokines, particularly Ccl2 and Il6, in the hippocampus of MS rats.

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Long-term aberrations to cerebellar endocannabinoids induced by early-life stress

10.1101/830901 ◽

2019 ◽

Cited By ~ 1

Author(s):

Alexandra B. Moussa-Tooks ◽

Eric Larson ◽

Alex F. Gimeno ◽

Emma Leishman ◽

Lisa A. Bartolomeo ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Cannabinoid Receptors ◽

Early Life Stress ◽

Future Research ◽

Developmental Stress ◽

Specific Effects ◽

Effects Of Stress ◽

Arachidonoyl Glycerol

AbstractStudies of early-life stress traditionally focus on glucocorticoid signaling as a modulator of neurodevelopmental risk, but emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling. Existing studies on stress-induced endocannabinoid dysregulation have focused on changes to cerebrum that are temporally proximal to stressors, but little is known about temporally distal effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Further, sex-specific effects of stress on cerebellar endocannabinoid tone are understudied. Following a naturalistic rodent model of early-life stress, limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids and related lipids and mRNA were assessed, and behavioral performance was evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar deep nuclei in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Transcriptomics for cerebellar interpositus nucleus revealed substantial sex effects, with minimal effects of stress. Stress did impair novel object recognition in both sexes and social preference in females. Taken together, the cerebellar endocannabinoids system exhibits robust sex-specific differences, malleable through early-life stress and perhaps also contributing to sexual differentiation of the brain. The current study may foster future research into stress as a risk factor for cerebellar-related dysfunctions.

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Impact of early life stress on alcohol consumption and on the short- and long-term responses to alcohol in adolescent female rats

Behavioural Brain Research ◽

10.1016/j.bbr.2011.02.033 ◽

2011 ◽

Vol 221 (1) ◽

pp. 43-49 ◽

Cited By ~ 18

Author(s):

V. Van Waes ◽

M. Darnaudéry ◽

J. Marrocco ◽

S.H. Gruber ◽

E. Talavera ◽

...

Keyword(s):

Alcohol Consumption ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Female Rats ◽

Adolescent Female ◽

Short And Long Term

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Inhibition of Fatty Acid Amide Hydrolase (FAAH) During Adolescence and Exposure to Early Life Stress may Exacerbate Depression-like Behaviors in Male and Female Rats

Neuroscience ◽

10.1016/j.neuroscience.2020.12.022 ◽

2021 ◽

Vol 455 ◽

pp. 89-106

Author(s):

Shirley Alteba ◽

Anna Portugalov ◽

Cecilia J. Hillard ◽

Irit Akirav

Keyword(s):

Life Stress ◽

Early Life ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Early Life Stress ◽

Female Rats ◽

Male And Female ◽

Male And Female Rats ◽

Amide Hydrolase ◽

Fatty Acid Amide

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Early-Life Stress Modulates Gut Microbiota and Peripheral and Central Inflammation in a Sex-Dependent Manner

International Journal of Molecular Sciences ◽

10.3390/ijms22041899 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1899 ◽

Cited By ~ 1

Author(s):

Hae Jeong Park ◽

Sang A. Kim ◽

Won Sub Kang ◽

Jong Woo Kim

Keyword(s):

Gut Microbiota ◽

Relative Abundance ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Female Rats ◽

Rrna Gene ◽

Dependent Manner ◽

Male And Female Rats

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1–21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1β) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1β and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.

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The effects of early‐life stress on dopamine system function in adolescent female rats

International Journal of Developmental Neuroscience ◽

10.1016/j.ijdevneu.2017.01.001 ◽

2017 ◽

Vol 57 (1) ◽

pp. 24-33 ◽

Cited By ~ 15

Author(s):

Iwona Majcher‐Maślanka ◽

Anna Solarz ◽

Krzysztof Wędzony ◽

Agnieszka Chocyk

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Female Rats ◽

Adolescent Female ◽

System Function ◽

Dopamine System

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Long term effects of early life stress on HPA circuit in rodent models

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2020.111125 ◽

2021 ◽

Vol 521 ◽

pp. 111125

Author(s):

Lucy Babicola ◽

Rossella Ventura ◽

Sebastian Luca D'Addario ◽

Donald Ielpo ◽

Diego Andolina ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Rodent Models ◽

Long Term Effects

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IMPACT OF EARLY LIFE STRESS ON ANTI-DEPRESSANT SENSITIVITY

Ulyanovsk Medico-biological Journal ◽

10.34014/2227-1848-2021-1-123-132 ◽

2021 ◽

pp. 123-132

Author(s):

V.A. Vokina

Keyword(s):

Open Field ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Anxiety Level ◽

Male Rats ◽

Porsolt Test ◽

The Impact ◽

Sexually Mature

Long-term consequences of impaired perinatal development are very significant. They appear during the neonatal period and in the first years of life, and persist during ontogenesis. There is little data on the impact of any prenatal factors on the sensitivity of a sexually mature organism to medications. The aim of the study is to assess the impact of early life stress on the development of individual antidepressant sensitivity. Materials and Methods. The authors conducted the experiments on sexually mature outbred male rats. To simulate the early life stress, a standard protocol was used. From the 2nd to 15th days of the postnatal period the pup rats were separated from their mother for 3 hours and kept in an incubator. The open-field test, Porsolt test and Sucrose consumption test were used to determine rat’s anxiety level as well as motor, orientation and exploratory activity at puberty. Then, for 14 days, the rats were intragastrically administered with a fluoxetine solution (10 mg/kg/daily), followed by their full examination. Statistical analysis of results was performed using the Mann-Whitney U-test to compare unrelated groups and Wilcoxon's test to compare related groups. Results. Fluoxetine did not have a pronounced antidepressant effect in animals that survived the early life stress. Such animals demonstrated passive floating during the Porsolt test, without any changes in immobility time. When testing in an open field, a sharp increase in the number of freezing behavior was observed, which was an indicator of an increased anxiety level in animals. Conclusion. The results obtained indicate that the long-term effects of neonatal stress may be associated with a change in antidepressant sensitivity or an increase in development of unwanted adverse reactions. Keywords: early life stress, depression, antidepressants, fluoxetine, rats. Отдаленные последствия нарушения перинатального развития весьма значительны и не только проявляются в период новорожденности и в первые годы жизни, но и сохраняются в период онтогенеза. Данные о влиянии каких-либо пренатальных факторов на чувствительность половозрелого организма к действию лекарственных веществ в доступной литературе представлены незначительно. Цель исследования – оценить роль стресса раннего периода жизни в формировании индивидуальной чувствительности к действию антидепрессантов. Материалы и методы. Эксперименты проведены на половозрелых беспородных крысах-самцах. Для моделирования стресса раннего периода жизни использовали стандартный протокол, подразумевающий отделение детенышей от матери со 2-го по 15-й дни постнатального периода на 3 ч в условиях инкубатора. В половозрелом возрасте проводили оценку уровня тревожности, двигательной и ориентировочно-исследовательской активности крыс в условиях теста открытого поля, теста Порсолта и теста «Потребление раствора сахарозы». Затем в течение 14 дней крысам внутрижелудочно вводили раствор флуоксетина (10 мг/кг/сут), после чего обследование повторяли в том же объеме. Статистический анализ результатов исследования проводили с использованием U-критерия Манна–Уитни для сравнения несвязанных групп и критерия Вилкоксона для сравнения связанных групп. Результаты. У животных, переживших стресс раннего периода жизни, флуоксетин не оказывал выраженного антидепрессантного действия. У данных животных в тесте Порсолта преобладало пассивное плавание, без изменения длительности иммобильности. При тестировании в открытом поле наблюдалось резкое повышение числа актов фризинга, что является показателем повышенного уровня тревожности у животных. Выводы. Полученные результаты свидетельствуют о том, что отдаленные последствия неонатального стресса могут быть связанны с изменением чувствительности к действию антидепрессантов или повышением риска развития нежелательных побочных реакций. Ключевые слова: стресс раннего периода жизни, депрессия, антидепрессанты, флуоксетин, крысы.

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