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Adolescent behavior: Links to early-life stress and alcohol in male and female rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adolescence is an important developmental phase with large changes in behavior, physiology and neurobiology, which transform an individual from immature child to independent adult. Due to these changes, adolescence is a sensitive period for exposure to environmental factors such as stress and drug exposure; it is also a common age of onset for alcohol consumption as well as several psychiatric disorders. Despite these factors, less is known about this developmental period than regarding adult individuals. Behavior is regulated by the central nervous system and can be used as a lens to study these processes as well as for examination of associations between individual differences, early-life stress and alcohol. The aim of this thesis was to experimentally examine adolescent behavior and its links to early-life stress and alcohol in adolescent male and female rats. Different behavioral tests were used to profile adolescent animals together with animal models of early-life stress, voluntary alcohol consumption and alcohol exposure. In addition, stress responsiveness after early-life stress and the impact of alcohol exposure on endogenous opioid peptide levels as well as blood alcohol concentrations were examined. The adolescent behavioral profile in the multivariate concentric square field™ (MCSF) was characterized and validated against the elevated plus maze and open field tests. The main finding was subgroups based on individual variation that revealed three distinct behavioral types: Explorers, Shelter seekers and Main type animals. This pattern was replicated in an additional, independent cohort. Early-life stress, modelled by prolonged maternal separation, showed small effects on behavior in the MCSF and on social play behavior. However, an effect on stress responsiveness in males but not females subjected to prolonged maternal separation was discovered. Predisposition for high alcohol consumption did not have a shared behavioral profile among selectively bred rat lines. However, a subgroup of high drinking individuals in an outbred cohort showed behavioral similarities to one of the selectively bred lines. Alcohol exposure showed small, but sex-dependent, effects on behavior and endogenous opioid peptide levels. Together, these studies provide new information about adolescent behavior and associations to early-life stress and alcohol in males and females, relationships not extensively studied in adolescence.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. , p. 97
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 284
Keywords [en]
Adolescence, alcohol exposure, behavior, corticosterone, dynorphin, early life, endogenous opioid peptides, Met-enkephalin-Arg6Phe7 (MEAP), individual differences, multivariate concentric square field (MCSF), phenotyping, radioimmunoassay, selective breeding for alcohol consumption, voluntary alcohol intake
National Category
Neurosciences Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-405313ISBN: 978-91-513-0893-7 (print)OAI: oai:DiVA.org:uu-405313DiVA, id: diva2:1412684
Public defence
2020-04-24, A1:107a, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2020-04-01 Created: 2020-03-06 Last updated: 2020-05-19
List of papers
1. Adolescent Exploratory Strategies and Behavioral Types in the Multivariate Concentric Square Field (TM) Test
Open this publication in new window or tab >>Adolescent Exploratory Strategies and Behavioral Types in the Multivariate Concentric Square Field (TM) Test
2019 (English)In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 13, article id 41Article in journal (Refereed) Published
Abstract [en]

Adolescence is an important developmental phase with extensive changes in behavior due to remodeling of the brain and hormonal systems. Validation of animal behavioral tests in this age group is therefore of importance as differences to adult behavior are often not clarified. The aim of the present study was to investigate adolescent behavior in the multivariate concentric square field (TM) (MCSF) test and its relationship to other common behavioral tests as well as to a literature dataset of adult animals. Sixty adolescent male Wistar rats were tested in the MCSF and one of four reference tests; the elevated plus maze, the open field with or without start box, or the social play behavior test. Additionally, 12 animals were tested twice in the MCSF. When analyzing the first encounter with the MCSF test, a distinct grouping of the individuals into three behavioral types was observed. Approximately 20% of the animals had high levels of activity and an additional 20% had high levels of shelter seeking-behavior, these groups composed the outlying behavioral types named Explorers and Shelter seekers, respectively, which were distinct from the Main type of animals. When tested in the MCSF for a second time, the adolescent animals showed a recollection of the arena as they changed their behavior in relation to the first encounter. When comparing the MCSF performance to the reference tests, a relationship was found between the MCSF and the other behavioral test entailing forced exploration, while no relationship was found between the MCSF and social play. The adolescent behavioral profile was characterized by decreased risk assessment and a different activity profile than adults. In conclusion, the MCSF test is useful for profiling adolescent rats but the behavioral interpretation differs from that of adults due to differences in behavioral manifestation during adolescence and the presence of natural subgroups. Adolescent exploration shows a relationship across tests, but the MCSF gives more information than any of the other behavioral tests based on forced exploration. Further studies into the neurobiology behind the behavioral types and how different manipulations affect the distribution into the behavioral types are of interest.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
behavior, elevated plus maze, open field, phenotyping, risk taking, social play, validation, Wistar rat
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-379899 (URN)10.3389/fnbeh.2019.00041 (DOI)000460350200001 ()30886574 (PubMedID)
Available from: 2019-03-22 Created: 2019-03-22 Last updated: 2020-03-06Bibliographically approved
2. Behavioral profiling in early adolescence and early adulthood of male Wistar rats after short and prolonged maternal separation
Open this publication in new window or tab >>Behavioral profiling in early adolescence and early adulthood of male Wistar rats after short and prolonged maternal separation
2020 (English)In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 14, article id 37Article in journal (Refereed) Published
Abstract [en]

Early-life stress and its possible correlations to genes, environment, and later health outcomes can only be studied retrospectively in humans. Animal models enable the exploration of such connections with prospective, well-controlled study designs. However, with the recent awareness of replicability issues in preclinical research, the reproducibility of results from animal models has been highlighted. The present study aims to reproduce the behavioral effects of maternal separation (MS) previously observed in the multivariate concentric square fieldTM (MCSF) test. A second objective was to replicate the adolescent behavioral profiles previously described in the MCSF test. Male rats, subjected to short or prolonged MS or standard rearing, were subjected to behavioral testing in early adolescence and early adulthood. As seen in previous studies, the behavioral effects of MS in the MCSF were small at both tested time points. When tested in early adolescence, the animals exhibited a similar behavioral profile as previously seen, and the finding of adolescent behavioral types was also reproduced. The distribution of animals into the behavioral types was different than in the initial study, but in a manner consistent with developmental theories, as the current cohort was younger than the previous. Notably, the Shelter seeker behavioral type persisted through development, while the Explorer type did not. The lack of basal behavioral effect after MS is in line with the literature on this MS paradigm; the working hypothesis is that the prolonged MS gives rise to a phenotype predisposed to negative health outcomes but which is not apparent without additional provocation.

National Category
Neurosciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-405312 (URN)10.3389/fnbeh.2020.00037 (DOI)000525587300001 ()32265671 (PubMedID)
Funder
Swedish Research Council, K2012-61X-22090-01-3
Available from: 2020-02-27 Created: 2020-02-27 Last updated: 2020-06-05Bibliographically approved
3. 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, p. 137-144Article 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: 2020-03-06Bibliographically approved
4. Behavioral profiles of adolescent alcohol-preferring/non-preferring (P/NP) and high/low alcohol-drinking (HAD/LAD) rats are dependent on line but not sex
Open this publication in new window or tab >>Behavioral profiles of adolescent alcohol-preferring/non-preferring (P/NP) and high/low alcohol-drinking (HAD/LAD) rats are dependent on line but not sex
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-405308 (URN)
Available from: 2020-02-27 Created: 2020-02-27 Last updated: 2020-03-11Bibliographically approved
5. Adolescents and alcohol – voluntary consumption or passive exposure and links to behavior, endogenous opioids and blood alcohol levels in male and female rats
Open this publication in new window or tab >>Adolescents and alcohol – voluntary consumption or passive exposure and links to behavior, endogenous opioids and blood alcohol levels in male and female rats
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-405304 (URN)
Available from: 2020-02-27 Created: 2020-02-27 Last updated: 2020-03-11Bibliographically approved

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