Research in the Laboratory of Translational Neurobiology focuses on studies of interacting genetic and environmental influences on neurodevelopment and aging, and their relevance to the pathogenesis of neuropsychological disorders, particularly Alzheimer’s disease and schizophrenia. The goal of our research programs is to use animal models of neuropsychiatric disorders to discover therapeutic strategies to slow and prevent disease onset and progression. Major projects:
1) Stress, CRF and Alzheimer’s disease
We propose to investigate the cellular and molecular mechanisms by which corticotropin-releasing factor (CRF) and/or its receptor (CRF1) contribute to Alzheimer’s disease (AD)-like pathology and cognitive deficits in an animal model of AD. We have already created and will further characterize a novel triple transgenic mouse strain that overexpresses human amyloid precursor protein (hAPP) and conditionally overexpresses CRF in the forebrain (APP+/CRF+/tTA+ mouse). This new mouse model will allow us to directly manipulate endogenous CRF to determine the effects of excessive CRF on the neuropathology and cognitive function in a mouse genetically predisposed to AD. Then, we will assess whether the impact of CRF and CRF1 on AD neuropathology and cognitive function is modulated by the protein kinase A (PKA) or protein kinase C (PKC) signaling pathways. Finally, we will evaluate the potential therapeutic value of CRF1 antagonists on AD by chronically administering CRF1 antagonists to stressed AD mice and APP+/CRF+/tTA+ mice.
2) Aging and antipsychotics efficacy –epigenetic mechanisms
Aging induces remarkable changes in the CNS of humans and other mammals, from organ systems all the way down to the genomic level, and it is possible that these changes undermine the capacity of older individuals to respond to psychotropic drugs.
The pharmacokinetics and pharmacodynamics alterations in aged population have been profoundly investigated. However, the ability of epigenetic mechanisms to influence the efficacy of drug treatments, particularly antipsychotics, in an aged brain via genomic modifications is unknown. In this project, we hypothesize that aging causes a change in the capacity for antipsychotic–induced c-fos gene expression due to histone modification at the c-fos gene promoter regions. As a result, it is possible histone deacetylase inhibitors could improve efficacy of antipsychotics in the aged population.
3) Genetics of schizophrenia-related traits in mice
Through collaborations with Washington University in St. Louis and the University of Tennessee at Memphis, we will investigate the function, cytoarchitecture, as well as genetic basis of thalamocortical circuitry in recombinant inbred (RI) mouse strains. In previous studies utilizing RI mouse strains, we investigated whether schizophrenia-associated neuroanatomical phenotypes are impacted by independent and/or shared genetic influences. We found three independent and one shared quantitative traits loci (QTLs) related to thalamus and cortex gray matter volumes. In this project, we will select BXD strains predicted to have large or small thalamic and cortical volumes along with the appropriate genotype at marker D16Mit100 (a marker affecting both thalamus and cortex gray matter volumes). We propose to test working memory and executive function and their relationship to variations in thalamic-cortical neuroanatomy. We will then compare the cytoarchitectural features of thalamocortical circuitry in these two groups of BXD RI strains after behavioral tests. Finally, we will measure patterns of gene expression in the thalamus and cortex in these two groups of BXD RI strains and determine whether these genes are located within the QTL of interest, or may be influenced by genes within the QTL of interest. This project will provide us with a greatly improved understanding of the structural, functional, and genetic basis of thalamic-cortical circuitry in selected BXD mouse strains, which may serve as a model of the genetic vulnerability to develop schizophrenia.