Our lab uses mouse models to study the neurological underpinnings of genetically derived neurological diseases and disorders. Our studies range from assays of animal behavior to molecular analyses of neuromolecular signaling. To accomplish this, our lab employs a wide battery of technical approaches. Our behavioral work utilizes well-validated mouse behavioral paradigms modeling human behavior with automated video capture based behavioral assessments. We combine these assays with a battery of other approaches in which we can manipulate the brain using viral transfection, brain region specific genetic and pharmacological interventions and in vivo electrophysiological recording. We have expertise in several areas of cognition: memory formation, spatial learning, affective behaviors, extinction learning, circadian activity, and social behavior. Our lab also uses ex vivo brain slice electrophysiology to examine neuronal circuit function and signaling in the hippocampus and other brain regions. We also use primary neuronal culture to ask more detailed neurophysiological questions at the single neuron level. The biochemical studies conducted in the lab include western analyses, spectrophotometric enzymatic assays, and real-time quantitative PCR to study molecular signaling pathways involved in neuronal function. It is our hope that this multi-faceted approach allows us to more deeply explore the mechanistic nature of human neuropsychiatric disorders and neurodegenerative diseases and then translate our findings to improved diagnostics and therapies for human patients. The lab has two major areas of focus with several smaller sub-projects contained within them.
Neurobiology of Alzheimer’s Disease
Project 1: Examining the impact of the Down Syndrome (DS) related gene, Regulator of Calcineurin 1 (RCAN1), on neurodegeneration associated with DS, aging, stress responses, and Alzheimer’s disease (AD). Using genetic constructs to manipulate RCAN1 expression in the brain we examine the effects of RCAN1 on mitochondrial fission and function.
Related publications: (Wong et al., Acta Neuropathologica, 2015)
Project 2: Determining the effects of pathological tau expression cell survival in the brain. Using transgenic mice expressing an inherited form of tau linked to familial frontotemporal lobe dementia (FTD) we have found that GABAergic cell populations are particular susceptible to the effects of pathological tau expression. We are currently using in vivo electrophysiology and behavioral testing to assess immunotherapeutic approaches to protect vulnerable cell populations from pathological tau.
Related publications: (Levenga et al., Acta Neuropathologica Communications, 2013)
Translational and Transcriptional regulation in Neurological Disorders
Project 1: Determining the isoform specific roles of Akt kinase in the brain. Akt is critical for memory formation and synaptic plasticity. Akt has also been implicated in the expression of several neuropsychiatric disorders including schizophrenia, major depression, autism and drug addiction. Several pharmacological agents are available for the modulation of Akt activity in vivo, however identifying the isoform specific roles for each Akt will allow for the development of improved diagnostic and therapeutic targeting of Akt in human patients.
Related publications: (Hoeffer et al., Journal of Neuroscience, 2008, Hoeffer and Klann, Trends in Neuroscience, 2010)
Project 2: Examining the impact of RCAN1 on Calcineurin (CaN) phosphatase signaling in the brain. While originally identified as an inhibitor of CaN, there is increasing evidence that RCAN1 can act as both an inhibitor and facilitator of CaN activity. This project aims to learn more about understanding the conditions in which RCAN1 can perform either regulatory role. We explore RCAN1 regulation of CaN using anxiety assays and CREB responsive gene expression assays as well as CaN based-FRET reporters in cell culture.
Related publications: (Wong et al., Journal of Neuroscience, 2013)