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- Lundberg, Stina, 1990-
(författare)
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Adolescent behavior : Links to early-life stress and alcohol in male and female rats
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Granholm, Linnea, 1986-
(författare)
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Stress, Drugs and Neuroscience : Neurobiological Effects of Social Stressors and Drug Exposure in Young and Adolescent Rats
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Experiences early in life or during adolescence modulate neuronal networks in the immature brain and consequently lay the foundation for future susceptibility or resilience towards psychiatric disorders. The objective in this thesis is to understand, in part, how the surrounding environment shapes the brain of a young individual. Three types of negative life events were studied, in an animal model, for their effects on the brain reward system (i.e., endogenous opioids and dopamine) and voluntary drug intake. These were: disruption of maternal care, disruption of interaction with peers, and exposure to drugs. Stress, in the form of maternal separation, altered expression of opioid genes in the dorsal striatum and amygdala, and the response to subsequent alcohol intake on these genes was dependent on early life conditions. Basal levels of endogenous opioids were also dependent on how the animals were housed in early adolescence. Short single housing (30 minutes) caused an acute stress response as evidenced by increased serum corticosterone and nociceptin/orphanin FQ in brain areas associated with stress. A prolonged single housing resulted in a marked decrease of Met-Enk-Arg6-Phe7 (i.e., a marker of enkephalins) in several brain areas. The endogenous opioids were also affected by repeated exposure of ethanol during adolescence; ethanol intoxication increased the accumbal levels of Met-Enk-Arg6-Phe7 and decreased those of β-endorphin. Residual effects of the adolescent ethanol exposure were found in Met-Enk-Arg6-Phe7 levels in the amygdala, ventral tegmental area, and substantia nigra. Furthermore, rats exposed to ethanol as adolescents had alterations in the dopamine dynamics in the dorsal striatum. Both endogenous opioids and dopamine are essential in mediating rewarding properties. Alterations of these systems, caused by environmental disturbances and alcohol exposure, presented herein could explain, in part, the increased susceptibility for alcohol- and substance use disorders later in life.
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| 3. |
- Vrettou, Maria, 1988-
(författare)
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Early life experiences and alcohol use in youth : An emerging role of the Vesicular Glutamate Transporters
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Initiation of alcohol consumption usually takes place during adolescence, a period characterized by a plethora of physical and emotional changes. Towards early adulthood, hazardous drinking patterns can emerge and potentially lead to the development of Alcohol Use Disorder (AUD). Both positive and negative experiences during early life can shape brain development and, through interactions with the genetic make-up, can contribute to the vulnerability of an individual to develop AUD. Epigenetic mechanisms, such as DNA methylation, potentially mediate the effect of environmental influences on gene expression, thus serving as the missing link between gene, environment and phenotype. Among various neuroadaptive changes seen in AUD, those within the glutamatergic system appear particularly prominent, mainly in withdrawal and relapse states, but also in stress-related outcomes. The glutamatergic phenotype can be determined by the expression of the Vesicular Glutamate Transporters 1-3 (VGLUT1-3). To date, the relationship between early life experiences, alcohol consumption, and Vgluts/VGLUTs genes (rodents/humans) in the initial stage of alcohol consumption and during the sensitive period of late adolescence/young adulthood has not been investigated.The present thesis, based on three studies on rodents and one on humans, aimed to examine Vglut/VGLUT1-3 correlates of early life experiences and alcohol drinking during youth. The effect of co-exposure to nicotine, because of its high comorbidity with alcohol use, as well as the role of key DNA methylation-regulating genes was also investigated. The main finding showed that individuals exposed to early life stress were more sensitive to the effect of alcohol on Vglut1-3 mRNA expression and DNA methylation, as well as expression of the DNA methylation-regulating genes, in limbic and striatal brain regions, as compared with controls. In an independent sample, prolonged nicotine co-exposure with alcohol during adolescence was associated with higher Vglut2 expression in the ventral tegmental area of young adult rats. Lastly, the single nucleotide polymorphism rs2290045 in VGLUT2 was found to moderate the environmental sensitivity to alcohol-related problems in humans. Carriers of the minor allele (T) displayed differential susceptibility to the environment; increasing quality of parenting was associated with higher and lower alcohol-related problems in the absence and presence of previous maltreatment, respectively.In conclusion, the findings highlight for the first time the role of Vgluts/VGLUTs in early stress-mediated sensitivity towards alcohol consumption and alcohol-related problems during adolescence and young adulthood, and especially a potential Vglut2/VGLUT2-mediated molecular signature behind the interactive mechanisms of these two aversive environmental factors, as well as of nicotine co-exposure.
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