By 2050, one in three Americans is expected to have diabetes and will be at increased risk for dementia. While diabetes is associated with reduced availability of central insulin, little is known about how this deficiency specifically alters neuronal function, particularly in the acute state. Insulin has been shown to affect neuronal signaling, akin to a classic neuromodulator, where it can act on inhibitory and/or excitatory neurotransmission. Yet fundamental questions remain about how the loss of insulin receptor signaling might affect intact neuronal networks in vivo, and thus the biophysical behavior of neuronal membranes and molecular signaling that is important for learning and memory. Murine primary sensory cortex provides a model that enables these questions to be addressed. It has clear and well-known physiological roles in both sensory coding and learning, and advanced tools are available to quantify the effects of experimental changes, such as insulin-mediated neuromodulation. Questions asked in this animal model can be further explored in both mutant and transgenic mouse lines that yield diabetic phenotypes. Here we propose to use molecular biology, patch-clamp recording, and multi-electrode arrays coupled to in vivo pharmacology to elucidate roles for insulin neuromodulation at central sensory neurons. Experiments will be carried out in wildtype, untreated, and insulin-treated mutant Akita mice (model of insulin deficient Type 1 diabetes). Scientifically, this proposal is organized to address three main aims. We will determine: 1) the functional organization of insulin-associated circuits, and demonstrate the extent to which these networks are engaged by auditory experience 2) how insulin, and its deficiency, affects synaptic transmission in A l , and 3) how insulin, or dysfunctional insulin signaling, modulates the physiology of Al neurons during auditory processing and discrimination in the awake brain. The work proposed in this application is an important first step to investigate a possible need for the lifelong regulation of central insulin in people with diabetes. Moreover, the data may also support the use of treatments such as intra-nasal insulin to combat diabetes related cognitive impairment and dementias.

Public Health Relevance

Diabetes doubles one's risk for Alzheimer's disease or other dementias. While dementia patients treated with centrally acting insulin experience improved cognitive function, potential benefits of central insulin treatment in diabetics are not known. In part, this is because the physiological impacts of central insulin and the effects of its loss in diabetes are poorly understood. To address this gap, this study examines neuromodulatory roles of central insulin in wildtype and mutant mice with type 1 diabetes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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University of Oklahoma Health Sciences Center
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