The influence of cyclin D2 gene knockout on the hippocampus-dependent behavior in mice
Creators: name: Jedynak, Paulina
Publisher: name: figshare
Year: 2014
Subjects: Neuroscience
Behavioral Neuroscience

description: Better understanding of mechanisms underlying hippocampal functioning is crucial for prevention and treatment of brain dysfunctions based on altered hippocampus structure, integrity or connectivity with other brain areas. Adult hippocampal neurogenesis is proposed to be one of such mechanisms and recently it has become a subject of intense research. Adult neurogenesis means generation, differentiation, maturation and integration of new neurons into existing neuronal networks of adult animals, including humans. The exact function of this process remains elusive, although it has been suggested to play a role in learning and memory as well as in etiology and treatment of anxiety and mood disorders.<br>In the present study, we employed cyclin D2 gene knockout mice (cD2 KO), showing almost complete reduction of adult brain neurogenesis in the dentate gyrus. This deficit was already shown not to alter hippocampal-dependent learning ability and memory formation. Since cD2 KO mice transferred to a novel genetic background (c57BL/6) were used, the model had to be first characterized. Therefore, the first part of the study describes behavioral phenotyping and validation of cyclin D2 KO model necessary to identify possible alterations which could interfere with further hippocampus- and adult neurogenesis-dependent tasks. Although cD2 KO mice did not show impairment in accelerating rotarod test, they were hyperactive in the open field and automated motility chamber and showed increased exploration tendency in IntelliCage. Mutant mice showed also alterations in rodent-specific tasks: they were building none or poorer nests and were digging less robustly than control mice. All features described so far were previously observed in animals with hippocampal lesions. Nevertheless, cyclin D2 gene knockout neither altered the hippocampal-dependent learning ability nor the memory formation.<br>In the second part of the study emotional phenotype of cD2 KO mice, i.e. their initial level of anxiety and depressive-like behavior were characterized. Naïve cD2 KOs showed reduced anxiety and elevated levels of exploratory behavior when compared to their control wild-type littermates (WT). They spent more time in open parts of the elevated zero maze, paid more visits and traveled longer distance in the compartment with novel juvenile mouse in the sociability test, and buried less marbles and showed decreased latency to feed in the novelty suppressed feeding test (NSF). On the other hand, none of the tests revealed increased level of initial depressive-like behavior in cD2 KO animals. Moreover, naïve cD2 KO showed even shorter immobility time in forced swimming (FST) and tail suspension (TST) tests when compared to control animals. Interestingly, the difference observed for mutant mice was elevated, when they were subjected to acute stressor prior to the behavioral testing.<br>In the last part of the study cD2 KO mice were subjected to unpredictable chronic mild stress to induce depressive-like behavior, and then chronically administered with fluoxetine - a selective serotonin reuptake inhibitor showing antidepressive effects. In WT mice chronic stress caused decrease in the adult brain neurogenesis reversible by fluoxetine treatment. In cD2 KO mice, neither stress nor antidepressant administration affected the neurogenesis. Except for this difference, mutant animals displayed similar response to chronic stress as WT mice, i.e, showed decreased body weight gain and increased latency to feed in NSF, performed less grooming, and stayed immobile for longer time in FST and TST. The effect observed in the two latter tests was reversed by chronic fluoxetine treatment, irrespectively from animals’ genotype.<br>The results presented herein suggest that cyclin D2 gene knockout, irrespectively of the genetic background, caused impairment of adult hippocampal neurogenesis without influencing learning abilities. Moreover, morphological abnormalities of hippocampal formation or impairment of the adult brain neurogenesis (or both) altered activity and some hippocampal-<br>9<br>dependent behaviors as well as decreased levels of anxiety in mutant mice. Additionally, although it seems that missing adult brain neurogenesis in cD2 KO mice did not contribute to depression onset, it is possible that new neurons may play role in regulation of behavioral response following acute stress. Finally, present study does not support the hypothesis that new neurons are necessary for antidepressant action of fluoxetine.