(provided by candidate): Memory impairments accompany aging and can range in severity from very mild deficits to debilitating conditions such as Alzheimer's disease. The causes of these impairments are generally viewed in terms of anatomical, chemical, and physiological changes within the brain. However, alterations in peripheral neuroendocrine systems may also contribute to these deficits. Previous work in rodents and humans indicates that increases in blood glucose in response to endogenous epinephrine release are important for regulating memory formation and durability. Further, deficits in blood glucose availability to the brain during times of cognitive demand contribute to age-related memory impairments. Several findings suggest that fluctuations in glucose levels in the extracellular fluid of the brain may modulate memory processes by altering the release of the neurotransmitter acetylcholine. This in turn may affect downstream processes important for the formation of durable memories. This proposal addresses the hypothesis that age-related deficits in brain glucose availability produce memory impairments by limiting downstream signaling through a7 nicotinic acetylcholine receptors. Administration of agonists and antagonists to these receptors have effects on memory similar to those of glucose availability and depletion, respectively. In addition, glucose and a7 nicotinic acetylcholine receptors activate common downstream markers of synaptic plasticity. The proposed studies will test the hypothesis using behavioral pharmacological techniques in young adult and old rats. The experiments utilize inhibitory avoidance training, a widely accepted behavioral memory task that allows for post-training injections of drugs, thus isolating effects on memory. Further, the proposed experiments involve direct injections of drugs into the hippocampus, revealing mechanisms of memory occurring within a specific region of the brain. Age-related memory impairments characterize a number of clinical conditions, including Age-Associated Memory Impairment, Mild Cognitive Impairment, and Alzheimer's Disease. These conditions affect millions of older people in the United States and their prevalence is expected to increase dramatically over the next several decades. This proposal examines some of the important underlying mechanisms that lead to memory impairments and will potentially reveal strategies for early intervention or treatment of these deficits.
|Morris, Ken A; Gold, Paul E (2013) Epinephrine and glucose modulate training-related CREB phosphorylation in old rats: relationships to age-related memory impairments. Exp Gerontol 48:115-27|
|Morris, Ken A; Li, Sisi; Bui, Duat D et al. (2013) Glucose attenuates impairments in memory and CREB activation produced by an *4*2 but not an *7 nicotinic receptor antagonist. Neuropharmacology 67:233-42|
|Morris, Ken A; Gold, Paul E (2012) Age-related impairments in memory and in CREB and pCREB expression in hippocampus and amygdala following inhibitory avoidance training. Mech Ageing Dev 133:291-9|