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Insulin Resistance in Brain Alters Dopamine Turnover and Causes Behavioral Disorders

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Insulin Resistance in Brain Alters Dopamine Turnover and Causes Behavioral Disorders Insulin resistance in brain alters dopamine turnover and causes behavioral disorders Andre Kleinriddersa, Weikang Caia, Laura Cappelluccib, Armen Ghazarianb, William R. Collinsc, Sara G. Vienberga, Emmanuel N. Pothosb,c, and C. Ronald Kahna,1 aSection of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and bDepartment of Integrative Physiology and Pathobiology and cGraduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111 Contributed by C. Ronald Kahn, February 2, 2015 (sent for review December 16, 2014) Diabetes and insulin resistance are associated with altered brain food reward system, synaptic plasticity, signal transmission, imaging, depression, and increased rates of age-related cognitive and neuroprotective functions (18–22). On the other hand, impairment. Here we demonstrate that mice with a brain-specific knockout of IRS-2 has been shown to have protective effects on knockout of the insulin receptor (NIRKO mice) exhibit brain brain pathology in a mouse model of Huntington’s disease (23). mitochondrial dysfunction with reduced mitochondrial oxidative In addition to the association between diabetes and acceler- activity, increased levels of reactive oxygen species, and increased ated cognitive decline, there is growing support for a link be- levels of lipid and protein oxidation in the striatum and nucleus tween diabetes and mood disorders, especially depression (24–26). accumbens. NIRKO mice also exhibit increased levels of mono- The mechanisms by which T2D influences depression are amine oxidase A and B (MAO A and B) leading to increased not known, but insulin resistance states are associated with in- dopamine turnover in these areas. Studies in cultured neurons and creased inflammation and cytokine production in some brain glia cells indicate that these changes in MAO A and B are a direct regions (27, 28). Furthermore, ablation of insulin receptor in consequence of loss of insulin signaling. As a result, NIRKO mice catecholaminergic neurons attenuates insulin-induced excitabil- develop age-related anxiety and depressive-like behaviors that can be ity in dopaminergic neurons (29), whereas insulin administration reversed by treatment with MAO inhibitors, as well as the tricyclic into the central nervous system (CNS) of rats has been shown to antidepressant imipramine, which inhibits MAO activity and reduces increase dopamine transporter protein expression (30). The latter oxidative stress. Thus, insulin resistance in brain induces mitochon- may be important, because alterations in the activity of dopamine drial and dopaminergic dysfunction leading to anxiety and depres- and/or serotonin systems have been linked to depression (31–33). sive-like behaviors, demonstrating a potential molecular link between Mechanistically, one potential link between insulin action and central insulin resistance and behavioral disorders. changes in brain function might be alterations in mitochondrial function. Insulin resistance and type 2 diabetes are well docu- insulin receptor | diabetes | mitochondrial function | monoamine oxidase | mented to be associated with mitochondrial dysfunction in dopamine signaling classical metabolic tissues, such as muscle (34) and liver (35), and we have recently demonstrated that obesity-induced insulin re- s life expectancy in humans has increased, we are faced with sistance is also associated with altered mitochondrial function in Aa worldwide epidemic of age-related diseases such as type the hypothalamus (36). Patients with major depression have also 2 diabetes (T2D) and Alzheimer’s disease (1). These parallel been shown to exhibit mitochondrial dysfunction in the brain epidemics may not be coincidental. Indeed, studies have dem- (37). Although it is still unknown how mitochondrial dysfunction onstrated an association between diabetes and a variety of brain might be linked to depression, it is worth noting that the two enzymes degrading monoamine neurotransmitters, monoamine alterations including depression, age-related cognitive decline, Alzheimer’s disease, and Parkinson’s disease (2, 3). In addition, individuals with both type 1 and type 2 diabetes have been shown Significance MEDICAL SCIENCES to have a variety of abnormalities in brain imaging, including altered brain activity and connectivity by functional MRI (4, 5), Both types 1 and 2 diabetes are associated with increased risks altered microstructure by diffusion tensor imaging (6, 7), and al- of age-related decay in cognitive function and mood disorders, tered neuronal circuitry in the striatum (8). Conversely, patients especially depression. Insulin action has been shown to regu- with Alzheimer’s disease show signs of central insulin resistance late neuronal signaling and plasticity. Here we investigate with increased insulin receptor substrate (IRS) 1 serine phosphor- whether brain-specific knockout of insulin receptor (NIRKO) in ylation in the brain and decreased insulin concentrations in the mice causes behavioral changes and how these are mechanis- cerebrospinal fluid (9, 10). Furthermore, pilot clinical trials of in- tically linked. We find that NIRKO mice exhibit age-related tranasal insulin administered to individuals with Alzheimer’sdis- anxiety and depressive-like behavior. This is due to altered mitochondrial function, aberrant monoamine oxidase (MAO) ease suggest decreased rates of cognitive decline (11). These observations in humans have been mechanistically sup- expression, and increased dopamine turnover in the meso- limbic system, and can be reversed by treatment with Mao ported by studies in rodents and cultured cells, which have inhibitors. Thus, brain insulin resistance alters dopamine turn- shown that insulin receptor signaling in brain has an important over and induces anxiety and depressive-like behaviors. These role in central regulation of metabolism and may also be crucial findings demonstrate a potential molecular link between cen- for proper brain function (12–14). We have previously demon- tral insulin resistance and behavioral disorders. strated that mice with insulin resistance in brain due to targeted deletion of the insulin receptor (NIRKO mice) develop hyper- Author contributions: A.K., E.N.P., and C.R.K. designed research; A.K., W.C., L.C., A.G., phagia, mild obesity, reduced fertility, and decreased counter- W.R.C., S.G.V., and E.N.P. performed research; A.K., E.N.P., and C.R.K. analyzed data; and regulatory response to hypoglycemia (15, 16). NIRKO mice also A.K. and C.R.K. wrote the paper. display glycogen synthase kinase 3 beta (GSK3-beta) activation, The authors declare no conflict of interest. resulting in hyperphosphorylation of tau protein, a hallmark of 1To whom correspondence should be addressed. Email: [email protected]. ’ early Alzheimer s disease (17). Other animal studies have dem- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. onstrated that insulin has direct effects on the hypothalamic 1073/pnas.1500877112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1500877112 PNAS | March 17, 2015 | vol. 112 | no. 11 | 3463–3468 Downloaded by guest on September 30, 2021 oxidase (MAO) A and B, whose dysregulation has been linked to A B depressive behaviors, reside in the outer mitochondrial membrane Control * (38–40). These data suggest that the relationship between mood 250 NIRKO 250 * disorders and diabetes could be the result of altered insulin regu- 200 200 lation of mitochondrial function and monoamine homeostasis. 150 150 100 100 In the present study, we demonstrate that insulin receptor 50 50 deficiency in the brain results in brain mitochondrial dysfunction. 0 0 Im m obility tim e (s) Im m obility tim e (s) 10 month 17 month Control NIRKO Whereas initially this is not accompanied by behavioral changes, Tail Suspension Test Forced Swimming Test with aging, NIRKO mice exhibit signs of anxiety and depressive- like behaviors. These changes are secondary to decreased do- CDE * ** * pamine signaling in the striatum and nucleus accumbens, which 250 20 (s) 100 r 200 e 80 15 t in turn is a consequence of increased levels of MAO A and B, est n 150 60 leading to increased dopamine turnover. In vitro data indicate 10 100 40 that this is due to a loss of insulin effect on expression of MAO A oce 5 NSF T 50 et 20 Dark Box Light Dark Light Box and MAO B in neuronal and glial cells, and is further supported im 0 0 0 t Control NIRKO Control NIRKO Control NIRKO time spent in dark (s) by the finding that these depressive behaviors are reversed by number of transitions treatment with the MAO inhibitors. Thus, central insulin re- FG sistance causes altered dopamine turnover and age-related be- * 80 havioral changes, creating a direct link between mood disorders 15 * 60 and insulin-resistant states like type 2 diabetes. 10 40 5 Results 20 Open Field Test Open Field Test 0 0 number of entries Age-Dependent Anxiety and Depressive-Like Behavior in NIRKO Mice. Control NIRKO Latency to enter (s) Control NIRKO NIRKO mice were created by breeding IRlox/lox mice and Nestin- Cre transgenic mice as previously described (15). Quantitative Fig. 1. Age-dependent anxiety and depressive-like behavior in NIRKO mice. PCR (qPCR) analysis of 4-mo-old mice revealed a 95% re- (A and B) Assessment of depressive-like behavior. (A) Immobility time was duction of Ir mRNA throughout the brain, including in isolated assessed using the tail suspension test for 10- and 17-mo-old female control = = hypothalamus (HTM), hippocampus (HCA), prefrontal cortex (n 7) and NIRKO mice (n 9). (B) Immobility time during a forced swim- ming test in 17-mo-old female control (n = 6) and NIRKO mice (n = 6). Values (PFC), striatum, nucleus accumbens (NAC), and ventral teg- in this panel and all subsequent figures are mean ± SEM; *P ≤ 0.05; **P ≤ mental area (VTA), which was paralleled by decreases in insulin 0.01; ***P ≤ 0.001, Student’s t test, unless otherwise stated. (C and D)As- receptor protein (Fig. S1A). Although NIRKO mice show mild sessment of anxiety via light/dark box.
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