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 catech... read moreolaminergic 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
