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      Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice

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          Abstract

          Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxiety.

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          Most cited references37

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          Mechanisms and functional implications of adult neurogenesis.

          The generation of new neurons is sustained throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. In this review, we discuss the factors that regulate proliferation and fate determination of adult neural stem cells and describe recent studies concerning the integration of newborn neurons into the existing neural circuitry. We further address the potential significance of adult neurogenesis in memory, depression, and neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
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            Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator.

            A stereological method for obtaining estimates of the total number of neurons in five major subdivisions of the rat hippocampus is described. The new method, the optical fractionator, combines two recent developments in stereology: a three-dimensional probe for counting neuronal nuclei, the optical disector, and a systematic uniform sampling scheme, the fractionator. The optical disector results in unbiased estimates of neuron number, i.e., estimates that are free of assumptions about neuron size and shape, are unaffected by lost caps and overprojection, and approach the true number of neurons in an unlimited manner as the number of samples is increased. The fractionator involves sampling a known fraction of a structural component. In the case of neuron number, a zero dimensional quantity, it provides estimates that are unaffected by shrinkage before, during, and after processing of the tissue. Because the fractionator involves systematic sampling, it also results in highly efficient estimates. Typically only 100-200 neurons must be counted in an animal to obtain a precision that is compatible with experimental studies. The methodology is compared with those used in earlier works involving estimates of neuron number in the rat hippocampus and a number of new stereological methods that have particular relevance to the quantitative study of the structure of the nervous system are briefly described in an appendix.
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              Regional dissociations within the hippocampus--memory and anxiety.

              The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                16 September 2010
                : 5
                : 9
                : e12769
                Affiliations
                [1 ]Department of Psychiatry and Psychotherapy, Central Institute of Mental Health Mannheim (ZI), University of Heidelberg, Mannheim, Germany
                [2 ]Department of Radiooncology, University of Heidelberg, Heidelberg, Germany
                [3 ]Department of Psychiatry, University of Medicine of Berlin, Campus Charité Mitte, Berlin, Germany
                UMR CNRS 5226 - Université Bordeaux 2, France
                Author notes

                Conceived and designed the experiments: JF NMBBA PG. Performed the experiments: JF NMBBA. Analyzed the data: JF NMBBA RH. Contributed reagents/materials/analysis tools: FWH KJW RH. Wrote the paper: JF NMBBA PG. Prepared and performed the irradiation procedure: FWH KJW.

                Article
                10-PONE-RA-18063R1
                10.1371/journal.pone.0012769
                2940841
                20862278
                fb9b2cf7-6cf4-4427-b69b-5e3b20f81a7e
                Fuss et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 18 April 2010
                : 23 August 2010
                Page count
                Pages: 9
                Categories
                Research Article
                Neuroscience/Behavioral Neuroscience
                Neuroscience/Neuronal and Glial Cell Biology
                Neurological Disorders/Neuropsychiatric Disorders

                Uncategorized
                Uncategorized

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