Our laboratory is currently interested in a variety of research questions aimed at incorporating the neurobiology of learning and memory with the biological basis of several neurological/psychological disorders. Research projects in our laboratory focus on the cellular, molecular, and genetic mechanisms involved in various types of associative and spatial learning with particular emphasis on glutamate and GABA. Additional research projects focus on animal models of Alzheimer's disease and psychiatric disorders. Our interest in these disorders is in part that some of the neurological systems that may be responsible for the disorders play a prominent and sometimes necessary role in learning and memory. Further, several of the clinical characteristics of these disorders involve disruption of learning and memory performance. In several lines of research within the laboratory, we are pursuing possible changes in neuronal systems in these disorders to investigate the cause of the disorder, as well as how these changes relate to basic cellular activity that underlies learning. The investigation of these disorders incorporates identifying potential mechanisms responsible for the pathology as well as novel therapeutic targets. The laboratory utilizes psychopharmacological, behavioral genetic, and molecular biology techniques to address experimental questions.
We are currently investigating several risk factors that are associated with the onset of sporadic Alzheimer’s disease. Among these risk factors are disruptions to insulin signaling and brain inflammation. We investigate these risks factors separately, as well as together to better understand how they might interact to exacerbate the progression of Alzheimer’s disease. We are currently utilizing streptozotocin, a compound that impairs insulin signaling, by infusing directly into the brain (ICV) and peripheral administration, to understand how the different roles of insulin in the brain and in the systemic body can lead to common pathways that may underlie the onset of Alzheimer’s disease. We have found that STZ-ICV elevated levels of Ab peptides and phosphorylated tau, both pathological hallmarks of Alzheimer’s disease. Additionally, we activate the immune system, usually using lipopolysaccharide, in order to investigate the role of both acute and chronic inflammation to better understand the contribution of microglia and the immune response in exacerbating existing AD-like pathologies.
Probe trial performance in the Morris water maze in animals administered streptozotocin (STZ) and/or lipopolysaccharide (LPS). Figure 4 from our 2016 manuscript "Effect of acute lipopolysaccharide-induced inflammation in intracerebroventricular-streptozotocin injected rats" published in Neuropharmacology.
Hippocampal protein levels of kalirin and β-amyloid oligomers in animals administered streptozotocin (STZ) and/or lipopolysaccharide (LPS). Figure 7 from our 2016 manuscript "Effect of acute lipopolysaccharide-induced inflammation in intracerebroventricular-streptozotocin injected rats" published in Neuropharmacology.
GABAB RECEPTOR FUNCTION
GABA plays a major role in many aspects of neuronal functionality. We are particularly interested in the role of the metabotropic GABAB receptors. These receptors are responsible for slow and sustained inhibition. Post-mortem investigations of brains with Alzheimer's disease and schizophrenia indicate altered levels of this particular receptor and associated proteins, suggesting a possible role of the GABAB receptor in the progression of these diseases. We have demonstrated an effect of altered GABAB receptor signaling on learning and memory. The administration of baclofen, a GABAB agonist, produces a robust increase in freezing behavior after the acquisition of cued and contextual fear conditioning. Further, the administration of this ligand prevented the extinction of contextual fear association. These data may indicate a role for GABAB receptors in updating previously learned associations. Additionally, in some of our other GABAB-related studies, baclofen was administered during early life (on postnatal days 7, 9, and 12) and produced robust alterations to GABA signaling during adulthood. Future directions include elucidating the effect of GABAB receptor function within discrete hippocampal regions on learning and memory, as well as the role of GABAB receptor in inflammatory processes.
Developmental timeline comparing the brain development of humans and rodents. Arrows indicate administration of drugs during early-life, weaning, and when behavioral testing began. Figure 1 from our 2015 manuscript "Postnatal alterations in GABAB receptor tone produce sensorimotor gating deficits and protein level differences in adulthood" published in International Journal of Developmental Neuroscience.
Early-life administration of baclofen and phaclofen altered levels of GABAB1b and GABAB2 during adulthood in females (A,C,E) but not in males (B,D,F). Figure 3 from our 2015 manuscript, "Postnatal alterations in GABAB receptor tone produce sensorimotor gating deficits and protein level differences in adulthood" published in International Journal of Developmental Neuroscience.
NMDA RECEPTOR FUNCTION
Disrupted NMDA receptor function results in both behavioral deficits and expression in GABA related proteins. Studies in our laboratory have demonstrated altered number and location of parvalbumin expressing neurons in the hippocampus, which may have relevance to depression and other psychiatric disorders.
Administration of low-dose ketamine impairs learning and memory in the Morris water maze during hidden platform training (A) and probe trial performance (B). Figure 1 from our 2013 publication "Chronic ketamine produces altered distribution of parvalbumin-positive cells in the hippocampus of adult rats" published in Neuroscience Letters.
Administration of low-dose ketamine alters the number and positioning of parvalbumin-positive neurons in CA3 region of the hippocampus. Figure 2 from our 2013 publication "Chronic ketamine produces altered distribution of parvalbumin-positive cells in the hippocampus of adult rats" published in Neuroscience Letters.