Faculty and Staff
|Department:||Pharmacology, Physiology & Neuroscience
School of Medicine
Building 1, School of Medicine
Room D54 (office)
Room D53 (lab)
Post Doctoral Fellowship - University of Florida
The unifying goal of research in our laboratory is to understand how fundamental processes affiliated with neural aging interact with environmental, health and physiological factors to precipitate memory loss and increase susceptibility to related neurological disorders, such as Alzheimer’s disease (AD).
How does chronic stress influence risk for memory loss and disease in aging?
Stress is an ever-present, unpredictable and, often, unavoidable feature of daily life. The hypothalamic-pituitary-adrenal (HPA) axis coordinates behavioral and cellular responses to stressful experiences via secretion of glucocorticoids. In addition to their critical roles in working and declarative memory, the prefrontal cortex (PFC) and hippocampus collectively express high levels of glucocorticoid receptors that impart regulatory influences upon HPA axis activity. Consequently, the PFC and hippocampus are highly susceptible to dysregulated HPA axis activity and glucocorticoid secretion that accompanies normal aging or following chronic stress. We are investigating whether stress increases susceptibility to memory loss in aging through glucocorticoid-mediated epigenetic modifications and also examining the protective effects of attenuating glucocorticoid signaling during stressful experiences across the lifespan.
Can diet build neural resilience and cognitive reserve against aging and stress?
Aging is associated with metabolic changes such as obesity, insulin resistance and diabetes that are broadly related to dysregulation of glucose, the chief energy source fueling cellular respiration. Damaged and dysfunctional mitochondria accumulate in aging synaptic terminals and, as such, are well-positioned to contribute age-related synaptic deficits. Feeding aging rats a high fat/low carbohydrate “ketogenic” diet, which lowers blood glucose and increases circulating triglycerides, normalizes expression of synaptic proteins and improves cognition. We are now testing the hypothesis that a ketogenic diet improves cognition in aging by normalizing synaptic mitochondrial function. Additionally, we are exploring whether the ketogenic diet can modulate glucose signaling stimulated by glucocorticoid secretion and protect against the effects of stress on brain aging and metabolic health.
Can we optimize existing pharmacotherapies for treatment of age- and stress-related impairments?
NMDA receptor (NMDAR) antagonists such as NAMENDA and esketamine are prescribed for treatment of AD and stress-related mental health disorders. However, their therapeutic mechanisms are unclear, their benefits are often temporary, and their side effects can be considerable. NMDARs are tetrameric ion channels comprised of variable subunits that determine channel properties, subcellular localization and coupling with other signaling proteins. Our lab is developing new approaches to investigate the interactions among NMDAR subunits with the goal of defining the spectrum of normal functions accomplished by various receptor configurations and to develop precision ligands that will correct NMDAR dysfunction that emerges in aging, AD and neuropsychiatric disorders.
McQuail JA, Krause EG, Setlow B, Scheuer DA, Bizon JL (2018) Stress-induced corticosterone release covaries with working memory in aging. Neurobiology of Aging. 71:156-160.
Hernandez AR, Hernandez CM, Campos K, Truckenbrod L, Frederico Q, Moon B, McQuail JA, Maurer AP, Bizon JL, Burke SN (2018). A ketogenic diet improves cognition and has biochemical effects in prefrontal cortex that are dissociable from hippocampus. Frontiers in Aging Neuroscience. 10: 391.
Hernandez CM, McQuail JA, Schwabe MR, Burke SN, Setlow B, Bizon JL (2018) Age-related declines in prefrontal cortical expression of metabotropic glutamate receptors that support working memory. eNeuro. 5(3). pii: ENEURO.0164-18.2018.
Hernandez AR, Hernandez CM, Campos KT, Truckenbrod LM, Sakarya Y, McQuail JA, Carter CS, Bizon JL, Maurer AP, Burke SN (2018) The anti-epileptic ketogenic diet alters hippocampal transporter levels and reduces adiposity in aged rats. Journal of Gerontology: Medical Sciences. 73(4):450-458.
Beas, BS, McQuail JA, Bañuelos C, Setlow B, Bizon JL (2017) Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats. Neuroscience. 345:274-286.
McQuail JA, Beas BS, Simpson K, Kelly KB, Frazier CJ, Setlow B, Bizon JL (2016) NR2A-containing NMDARs in the prefrontal cortex are required for working memory and associated with age-related cognitive decline. Journal of Neuroscience. 36(50):12537-12548.
McQuail JA, Frazier CJ, Bizon JL (2015) Molecular aspects of age-related memory decline: Role of GABA signaling. Trends in Molecular Medicine. 21(7): 450-460.
McQuail JA, Nicolle MM (2015) Spatial reference memory in normal aging Fischer 344 × Brown Norway F1 hybrid rats. Neurobiology of Aging. 36(1): 323–333.
Bañuelos C, Beas BS, McQuail JA, Gilbert RJ, Frazier CJ, Setlow B, Bizon JL (2014) Prefrontal cortical GABAergic dysfunction contributes to age-related working memory impairment. Journal of Neuroscience, 34(10): 3457-3466.