Unknown

Dataset Information

0

Insulin resistance in brain alters dopamine turnover and causes behavioral disorders.


ABSTRACT: Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age-related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders.

SUBMITTER: Kleinridders A 

PROVIDER: S-EPMC4371978 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

Insulin resistance in brain alters dopamine turnover and causes behavioral disorders.

Kleinridders Andre A   Cai Weikang W   Cappellucci Laura L   Ghazarian Armen A   Collins William R WR   Vienberg Sara G SG   Pothos Emmanuel N EN   Kahn C Ronald CR  

Proceedings of the National Academy of Sciences of the United States of America 20150302 11


Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased l  ...[more]

Similar Datasets

| S-EPMC5148625 | biostudies-literature
| S-EPMC8879058 | biostudies-literature
2013-08-13 | E-GEOD-49797 | biostudies-arrayexpress
| S-EPMC4200504 | biostudies-other
| S-EPMC6168908 | biostudies-literature
| S-EPMC9661919 | biostudies-literature
2013-08-13 | GSE49797 | GEO
| S-EPMC5873875 | biostudies-literature
| S-EPMC3931397 | biostudies-literature
| S-EPMC4878419 | biostudies-literature