On regulation of hippocampal neurogenesis : roles of ethanol intake, physical activity and environment

The addiction research field struggles with the question of how long-term memories associated with addictions, which are likely to have a role in the relapse phenomenon, are formed. The work in this thesis has focused on structural adaptations and changes in plasticity genes in hippocampus, formed by both naturally awarding and drug-induced reward-seeking behaviors. Changes in the hippocampal neural network are further investigated in relation to social and environmental interactions. Specifically, analysis of formation, migration and differentiation of new cells, primarily neurons, in the dentate gyrus of hippocampus was performed. Mice and rats were studied in two putatively reward-generating behaviors, the two-bottle free-choice model of ethanol consumption, and voluntary wheel-running. Animals were also exposed to different environmental conditions, standard and enhanced, and altered social contacts.

Papers I and II describe effects of ethanol on hippocampal neurogenesis. Mice offered 10% ethanol in one of the two bottles in the free-choice model for short or long periods consumed ≈ 6 g ethanol/kg/day. These mice displayed increased cell proliferation and neurogenesis in the dentate gyrus. However, rats offered a lower ethanol concentration (5% v/v) consumed less ethanol (1.8 g/kg/day). Interestingly, this level of ethanol intake did not affect cell proliferation and neurogensis. When rats voluntarily consuming ethanol were subjected to repeated irregular withdrawal phases, ethanol intake decreased and they gained 30% in weight compared to continuously drinking animals or water-consuming controls. These animals also had decreased hippocampal neurogenesis. An irregular, and for the animals unpredictable and thus hypothetically stressful ethanol intake also decreased expression of the Nogo-receptor in hippocampus, while constant ethanol exposure did not. In conclusion, constant low ethanol intake does not affect hippocampal neurogenesis, while an irregular, presumably stressful intake does. Hypothetically, the increased number of new neurons detected after high ethanol intake could be involved in the formation of ethanol-associated memories, and ultimately in cue-induced relapse.

Papers III-VI address the effects of wheel running on cell proliferation, cell survival and neurogenesis and on plasticity genes in hippocampus. The adaptations found in hippocampus varied with running periods, social contacts and environment. In summary, long-term running increased neurogenesis in hippocampus whereas intermittent access to the running wheels did not induce any changes in hippocampal cell survival. Intermittent housing in enhanced environments, however, increased survival of newly formed cells compared to standard cage conditions. Cell proliferation in the dentate gyrus was increased more after 1 week than 4 weeks of running. In addition, the Nogo-receptor was found to be down-regulated at one week but not after four weeks of running. BDNF mRNA levels were increased after both one and four weeks of running. This suggests that the time frame for learning a new motor skill or to learn to appreciate the rewarding properties of a motor behavior, in this case the running in running-wheels, is associated with the highest hippocampal cell proliferation and the lowest levels of the Nogo-receptor. In support of this hypothesis that the Nogo receptor is always down-regulated in situations of long-term learning, it was found that Nogo-receptor overexpressing mice did not learn to develop an excessive running behavior during a five-week trial period.

Taken together, both natural and drug-induced reward-generating behaviors induce changes of hippocampal neurogenesis and transcription of plasticity associated genes. These adaptations are likely to be linked to associative and motor learning of the two behaviors and can therefore function as key elements in the establishment of addictions and in relapse.

List of scientific papers

I. Aberg E, Hofstetter CP, Olson L, Brené S (2005). "Moderate ethanol consumption increases hippocampal cell proliferation and neurogenesis in the adult mouse." Int J Neuropsychopharmacol 8(4): 557-67
https://pubmed.ncbi.nlm.nih.gov/16202182

II. Åberg E, Brene S (2007). "Ethanol consumption with unpredictable withdrawal episodes, but not constant access, decreases hippocampal neurogenesis in adult rats." (Manuscript)

III. Åberg E, Karlen A, Josephson A, Olson L, Brene S (2007). "Voluntary running is Nogo receptor-sensitive and associated with changes of plasticity genes and neurogenesis in hippocampus." (Manuscript)

IV. Aberg E, Pham TM, Zwart M, Baumans V, Brené S (2005). "Intermittent individual housing increases survival of newly proliferated cells." Neuroreport 16(13): 1419-22
https://pubmed.ncbi.nlm.nih.gov/16110262

V. Zhu SW, Pham TM, Aberg E, Brené S, Winblad B, Mohammed AH, Baumans V (2006). "Neurotrophin levels and behaviour in BALB/c mice: impact of intermittent exposure to individual housing and wheel running." Behav Brain Res 167(1): 1-8. Epub 2005 Dec 15
https://pubmed.ncbi.nlm.nih.gov/16343654

VI. Åberg E, Perlmann T, Olson L, Brene S (2007). "Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus." (Manuscript)