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. A s life expectancy in humans has increased, we are faced with a worldwide epidemic of age-related diseases such as type 2 diabetes (T2D) and Alzheimer's disease (1). These parallel epidemics may not be coincidental. Indeed, studies have demonstrated an association between diabetes and a variety of brain 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 to have a variety of abnormalities in brain imaging, including altered brain activity and connectivity by functional MRI (4, 5), altered microstructure by diffusion tensor imaging (6, 7), and altered neuronal circuitry in the striatum (8). Conversely, patients with Alzheimer's disease show signs of central insulin resistance with increased insulin receptor substrate (IRS) 1 serine phosphorylation in the brain and decreased insulin concentrations in the cerebrospinal fluid (9, 10). Furthermore, pilot clinical trials of intranasal insulin administered to individuals with Alzheimer's disease suggest decreased rates of cognitive decline (11).These observations in humans have been mechanistically supported by studies in rodents and cultured cells, which have shown that insulin receptor signaling in brain has an important role in central regulation of metabolism and may also be crucial for proper brain function (12)(13)(14). We have previously demonstrated that mice with insulin resistance in brain due to targeted deletion of the insulin receptor (NIRKO mice) develop hyperphagia, mild obesity, reduced fertility, and decreased counterregulatory response to hypoglycemia (15, 16). NIRKO mice also display glycogen synthase kinase 3 beta (GSK3-beta) activation, resulting in hyperphosphorylation of tau protein, a hallmark of e...

Adverse metabolic and mental health outcomes associated with shiftwork in a population-based study of 277,168 workers in UK biobank

“…Mood and metabolic disorders are frequent co-morbidities, [41,42] with overlapping pathophysiology (eg inflammation, insulin resistance, neurocognitive deficits), and animal studies link central insulin resistance to behavioural changes. [43] It should be considered if the effects of shiftwork on mental health might contribute to the increased metabolic disease already associated with these work schedules.…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…Moreover, changes in insulin signalling in different models of rodents led to memory impairments [55, 123] and other age-related cognitive alterations [124]. Noteworthy, paradoxically, deletion of IRS-2 in AD mouse model has previously been shown to reduce amyloid deposition and to rescue behavioral deficits [54].…”

A Key Role of Insulin Receptors in Memory

“…A recent study provided an important advance in this field by showing that specific deletion of brain insulin receptors in mice (NIRKO mice) led to augmented anxiety and depressive-like behavior (9). NIRKO mice further presented brain alterations in mitochondrial morphology and function, elevated oxidative stress, and decreased dopamine signaling (9).…”

“…NIRKO mice further presented brain alterations in mitochondrial morphology and function, elevated oxidative stress, and decreased dopamine signaling (9). While an early study found that NIRKO mice do not show major learning and memory impairment (10), the study by Kleinridders et al (9) demonstrated that deletion of insulin receptors led to important defects in brain function.…”