David Cool (Committee Member), Khalid Elased (Committee Member), Michael Hennessy (Committee Member), Heather Hostetler (Committee Member), James Lucot (Advisor)
Doctor of Philosophy (PhD)
There is a high comorbidity of type-2 diabetes and neuropsychiatric disorders. However, there is paucity of preclinical research to study this phenomenon. The validity of the db/db mouse as an animal model to study type-2 diabetes and related macrovascular and microvascular complications is well established. The first part of this dissertation was designed to investigate comprehensively the db/db mouse behavior as preclinical evidence of type-2 diabetes related major neurobehavioral complications. Juvenile (5-6 weeks) and adult (10-11 weeks) db/db mice were screened for behavioral depression in forced swim test (FST), psychosis-like symptoms using pre-pulse inhibition (PPI) test, anxiety behavior employing elevated plus maze (EPM) test, locomotor behavior and thigmotaxis using open field test, emotional learning using fear potentiation of startle (FPS) test and working memory deficits in Y-maze test. Both juvenile and adult group db/db mice displayed behavioral despair with increased immobility time in FST. There was an age-dependent progression of psychosis-like symptoms with disrupted PPI in adult db/db mice. In the EPM test, db/db mice were less anxious as observed by increased percent open arms time and entries. They were also hypolocomotive as evident by a decrease in their basic and fine movements. There was no impairment of working memory in the Y-maze test in db/db mice. In the FPS test, db/db mice showed impaired learning response indicative of abnormalities in DA neuronal activity in the amygdala. The second specific aim of this dissertation was to examine possible neurochemical basis for the observed behavioral deficits. Monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) are elemental to normal functioning of the brain. Current theories of the basis for major neurobehavioral disorders involve abnormalities in use of NE, 5-HT and DA in specific brain regions. Recent studies report that the DA agonist reverses diabetes-related metabolic abnormalities, thus suggesting that DA abnormalities may provide a link to underlying the psychiatric and endocrine disorders in type-2 diabetics. To evaluate type-2 diabetes related neurochemical alterations, concentrations of NE, 5-HT, DA and its catabolites homovanilic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were measured in the frontal cortex, amygdala, hippocampus, hypothalamus and brainstem of db/db mice by reverse-phase high performance liquid chromatography (HPLC). There was abnormal DA metabolism pattern in the frontal cortex and amygdala of db/db mice that correlated with their psychosis-like behavior and impaired FPS response. Moreover, type-2 diabetes related changes in the expression of DA biosynthesis rate determining step (RDS) enzyme tyrosine hydroxylase (TH) were studied using western blot technique. No changes in TH expression pattern were seen in the frontal cortex and amygdala of db/db mice compared to age-matched lean controls. Thus, abnormal DA metabolism pattern in these brain regions of db/db mice may be related to changes in the enzymatic activity of DA metabolizing enzymes and/or firing pattern of DAergic neurons. The third specific aim of this research project was to examine the effect of long-term management of insulin resistance and hyperglycemia on neurobehavioral deficits in db/db mice. Rosiglitazone mixed in chow was administered to 5 week old db/db and lean control mice (20 mg/kg/day) for duration of 5 weeks. Separate groups of age-matched db/db and lean control mice were fed with standard chow. Mice were weekly monitored for blood glucose concentration. Five weeks after treatment onset, the mice were subjected to the forced swim test (FST), pre-pulse inhibition (PPI), open field test (OFT) and fear potentiated startle (FPS) test to examine for behavioral depression, psychosis-like behavior, locomotor activity and emotional learning, respectively. R...
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