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Examining Female Resilience to Early Environmental Influences: Short- and long-term consequences on behaviour, HPA axis activity and alcohol intake after prolonged maternal separation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neurofarmakologi, bereoende och beteende)
2017 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Early-life experiences are an important factor influencing further development of the individual. Adverse experiences early in life, such as various kinds of abuse or neglect, are types of early-life stress that can adversely affect an individuals health, as well as contribute to the development of an array of disorders later in life. Most prominent is the increased risk for psychiatric disorders, primarily depression, anxiety-related and substance use disorders. Many of the implicated disorders also exhibit sex-dependent differences in prevalence and severity. Thus, it is important to consider sex-dependent effects when modeling early-life stress and its consequences. A common animal model for early-life stress is prolonged maternal separation (MS). MS is an umbrella term for different manipulations of the early environment of rodent pups. In this thesis, a prolonged MS condition with separation of rat litters from their dams for six hours per day during the first three weeks of life (MS360) was used. In male offspring MS360 have been associated with early-life stress and negative effects apparent during both adolescence and adulthood. The literature regarding female offspring is not as substantial as for the males, but it seems that females’ exhibit less pronounced or no effect after prolonged MS independent of separation time. In addition, the studies that have examined female offspring have done so in adulthood and thus, short-term consequences of prolonged MS possibly present during adolescence have not been investigated. The aim of this thesis is to provide a broad investigation into the consequences of prolonged MS in female offspring, in both adolescence and adulthood. As stated above, MS360 was used as the adverse rearing condition in this thesis. As control, daily short MS (15 min; MS15) was used; this ensured that all animals were handled equally, except for the length of separation. Any detected differences are thus due to the length of separation only. Three categories of assessments were used to evaluate short- and long-term consequences: 1) hypothalamus-pituitary-adrenal (HPA) axis assessments, 2) behavioral assessments and 3) assessment of voluntary alcohol consumption. HPA axis reactivity was assessed in adolescent and adult offspring by blood sampling before and after challenge. HPA activity was also evaluated after long-term alcohol consumption by measurement of the fecal corticosterone content. Behavior was assessed in adolescence by registration of social play behavior and in adulthood by generation of behavioral profiles in the multivariate concentric square fieldTM (MCSF). Alcohol consumption was evaluated using the modified intermittent alcohol access schedule with the two- (20% alcohol) and three- bottle (5% and 20% alcohol) free-choice paradigms. Female offspring did not differ depending on rearing condition in HPA reactivity in adolescence or adulthood. However, after the long-term alcohol intake, MS360 females had increased levels of corticosterone in their feces compared to MS15 females. No difference was detected in adolescent social play among female offspring and only a minor alteration was detected in the adult behavioral profile, where MS360 females had increased risk assessment compared to MS15 females. No effect of rearing condition was seen during the two-bottle choice paradigm of alcohol intake, while whole- group differences over time were discovered. Alcohol intake and preference were highest the first week of access and directly after a two-week deprivation period, apart from those time-points, intake and preference were maintained on a stable level. In the three-bottle choice, an interaction with rearing condition was revealed for the total alcohol preference, however this only translated to a minor group-dependent difference. In conclusion, females reared under a prolonged MS paradigm exhibited no or only minor basal changes in HPA axis reactivity, behavior and alcohol consumption. However, after long-term alcohol intake females subjected to prolonged MS had increased corticosterone excretion into feces. That differences only emerge after long-term perturbation can be a sign that females have higher buffering capabilities than males after early-life adversity, as modeled through prolonged MS, and thus require additional challenges before consequences become apparent. This thesis highlights the importance of considering sex when studying the impact of early-life stress, and that the choice of animal model needs to be considered carefully in relation to the research question posed.

Place, publisher, year, edition, pages
Uppsala: Uppsala University, 2017.
Series
Faculty of Pharmacy, Uppsala University Licentiate Theses, 49
Keyword [en]
Adolescence, Adulthood, Corticosterone, Early-life stress, Handling, Maternal deprivation, Multivariate concentric square field, MCSF, Sex differences, Social play behavior, Stress reactivity, Supplier differences
National Category
Neurosciences Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-322550OAI: oai:DiVA.org:uu-322550DiVA: diva2:1098630
Presentation
2017-06-12, BMC, B7:113, Husargatan 3, Uppsala, 13:15 (English)
Supervisors
Available from: 2017-06-01 Created: 2017-05-24 Last updated: 2017-06-01Bibliographically approved
List of papers
1. Altered corticosterone levels and social play behavior after prolonged maternal separation in adolescent male but not female Wistar rats
Open this publication in new window or tab >>Altered corticosterone levels and social play behavior after prolonged maternal separation in adolescent male but not female Wistar rats
2017 (English)In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 87, 137-144 p.Article in journal (Refereed) Published
Abstract [en]

Early-life socio-environmental factors are crucial for normal developmental processes; adverse experiences early in life can therefore lead to detrimental effects in several physiological systems. The aim of this study was to examine short-term effects of early adverse experiences in a maternal separation (MS) rodent model. In this study two separation conditions were used: daily 15-(MS15) or 360-min (MS360) separation of the litter from the dam during postnatal day 1-21. In early adolescence, male and female offspring were subjected to a single-isolation procedure with analysis of corticosterone levels prior to and after isolation. In addition, social play behavior was assessed during mid-adolescence. There was a clear difference between male and female offspring in both tests performed. There was no difference in corticosterone levels between the female MS groups, whereas MS360 males showed higher baseline and recovery corticosterone levels than MS15 males. The amount of pinning, a specific social play behavior, was affected by rearing with MS360 males having a higher frequency than MS15 males, while there was no difference between the female MS groups. The observation that males but not females are affected by MS360 has previously been reported for adult animals, and herein we show that this difference is present already in adolescence. Changes in corticosterone levels and social behavior following early-life adversity have been associated with adult behavioral alterations, and our results confirm that these changes emerge already within adolescence.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-316957 (URN)10.1016/j.yhbeh.2016.11.016 (DOI)000392905500016 ()27884596 (PubMedID)
Funder
Swedish Research Council, K2012-61 x-22090-01-3
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-05-24Bibliographically approved
2. Few long-term consequences after prolonged maternal separation in female Wistar rats
Open this publication in new window or tab >>Few long-term consequences after prolonged maternal separation in female Wistar rats
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Environmental factors during the early-life period are known to have long-term consequences for the adult phenotype. An intimate interplay between genes and environment shape the individual and may affect vulnerability for psychopathology in a sex-dependent manner. A rodent maternal separation model was here used to study the long-term effects of different early-life rearing conditions on adult behavior, HPA axis activity and long-term voluntary alcohol intake. Litters were subjected to 15 (MS15) or 360 min (MS360) of daily maternal separation during postnatal day 1–21. In adulthood, the behavioral profiles were investigated using the multivariate concentric square field™ (MCSF) test or examined for HPA axis reactivity by cat-odor exposure with subsequent characterization of voluntary alcohol intake and associated changes in HPA axis activity. Adult female offspring showed mostly no, or only minor, effects of MS360 on behavior, HPA axis reactivity and long-term alcohol intake. Instead, more pronounced effects were found dependent on changes in the female’s natural hormonal cycle or by the choice of animal supplier. However, changes were revealed in corticosterone load after long-term alcohol access, as females subjected to MS360 had higher concentrations of fecal corticosterone. The present findings are in line with and expand on previous studies on the long-term effects of maternal separation and the sex-dependent effects, with regard to behavior and voluntary alcohol intake. Why female rats show increased resilience compared to males using the present experimental protocol for maternal separation remains to be further investigated.

Keyword
Alcohol intake, behavior, estrus cycle, gonadal hormone, handling, HPA axis reactivity, maternal deprivation, multivariate concentric square field test, MCSF, resilience, sex differences, stress reactivity, supplier differences
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-322548 (URN)
Funder
Swedish Research Council, K2012-61-22090-01-3, K2005-04X-12588-08AThe Swedish Brain FoundationAFA Insurance
Available from: 2017-05-24 Created: 2017-05-24 Last updated: 2017-05-24

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