The Role of Central Insulin Resistance in Neuronal Synaptic Plasticity Associated with Neuropsychiatric Disorders.
Xue, Chang.
2016
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Abstract: Diabetes and insulin resistance have been linked to cognitive impairment, mood disorders, and increased risk of Alzheimer's Disease. The mechanisms by which type 2 diabetes influences depression and anxiety are not known, but insulin resistance is associated with increased inflammation and cytokine production in some brain regions. Furthermore, ablation of insulin receptor in catecholami... read morenergic neurons attenuates insulin-induced excitability in dopaminergic neurons, whereas insulin administration into the central nervous system (CNS) of rats has been shown to increase dopamine transporter protein expression. The latter is important because alterations in the activity of dopamine and/or serotonin systems have been linked to depression. It has been previously demonstrated that mice with a targeted deletion of insulin receptors (IR) in the whole brain (NIRKO mice, produced through crossing of IR-lox with Nestin-Cre mice, showed anxiety and depressive-like behaviors. They were also characterized by mitochondrial dysfunction specific to the brain with reduced mitochondrial oxidative activity, increased levels of lipid and protein oxidation, as well as altered dopamine turnover in the CNS. Using carbon fiber amperometry to measure electrically evoked dopamine release in real time in acute brain coronal slices, our results demonstrated a 40±9% decrease in the average width of the dopamine signal in the nucleus accumbens and a 44±10% decrease in t1/2 (width at half height), resulting in a 39±14% decrease in dopamine molecules released per stimulation in NIRKO mice (p<.05, n=6-7 mice per genotype). This is indicative of a reduction in dopamine exocytosis and an increase in dopamine uptake in NIRKO mice. We further demonstrated changes in dopamine exocytosis in mice with a glial specific knockout of the insulin receptor (GIRKOs) produced through crossing of IR-lox with GFAP-Cre mice. We found a 39.3% decrease in the average number of dopamine molecules evoked per stimulation in the dorsal striatum, 28.6% decrease in the nucleus accumbens and 44.9% decrease in the medial prefrontal cortex (n=13-15 per genotype, p<.05). In addition, catecholamine quantal size in the adrenal glands of GIRKO mice was compromised by 50% in comparison to wild-type mice (n=12 per genotype, p<.05). The alterations in central and peripheral catecholamine signaling in NIRKO and GIRKO mice appear equivalent to those observed in major neurodegenerative and neuropsychiatric disorders that involve monoamine neurotransmitters and seem to be linked specifically to insulin resistance in glial cells in the brain. Central insulin resistance and insulin resistance in astrocytes could be one of the important underlying mechanisms that provide the link between type 2 diabetes, Parkinson's disease and Alzheimer's disease, as well as neuropsychiatric disorders like depression and anxiety.
Thesis (M.S.)--Tufts University, 2016.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisors: Emmanuel Pothos, and Margery Beinfeld.
Keyword: Health sciences.read less - ID:
- pz50h7650
- Component ID:
- tufts:20633
- To Cite:
- DCA Citation Guide EndNote
