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Andrews group research is centered on understanding the role of serotonin in normal and pathological anxiety. Human and nonhuman primate cell lines expressing native serotonin transporter gene variants, genetically engineered mice, drugs, neurotoxins and environmental agents (stress, aging) are used to probe the molecular bases of the neurochemistry of anxiety, and the mechanisms of drugs used to treat anxiety disorders. Bioanalytical techniques, including microelectrode voltammetry and microdialysis are used to investigate serotonin neurotransmission. Neuronal architectures, neurogenesis and the expression of key proteins, such as brain-derived neurotrophic factor, that are regulated by serotonin are studied using quantitative autoradiography, immunocytochemistry, RT qPCR and ELISA. Neurotransmitter-functionalized self-assembled materials have recently been designed for the development of novel in vivo nanobiosensors and functionally-directed proteomics.
Oxidative damage is implicated in the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, and in normal aging. Here, we model oxidative stress in neurons using photogenerated radicals in a simplified membrane-encapsulated microtubule system. Using fluorescence and differential interference contrast microscopies, we monitor photochemically induced microtubule breakdown on the supported region of membrane in encapsulating synthetic liposomes as a function of lipid composition and environment.
The serotonin transporter is the primary molecular target for the serotonin-selective reuptake inhibitors -- the most widely prescribed class of antidepressant. Preclinical studies have demonstrated that long-term antidepressant treatment increases the generation of new neurons in the hippocampus. Furthermore, increases in adult hippocampal neurogenesis have been shown to play a critical role in antidepressant-mediated reductions in anxiety and stress responsiveness. A commonly occurring functional polymorphism in the promoter region of the primate serotonin transporter gene has also received considerable attention due to its association with increased anxiety-related traits and susceptibility to depression. We are studying neurogenesis in the rhesus dentate gyrus of hippocampus because rhesus monkeys express a native serotonin transporter gene-linked promoter polymorphism (rh5HTTLPR) that is orthologus to the human SERT gene variant.
This is a chemical patterning technique that utilizes a modified form of microcontact printing to pattern isolated molecules within a preexisting self-assembled monolayer. By modifying the initial monolayer quality, the stamping duration, and/or the concentration of the inserted molecule, the extent of molecular exchange and precise control of the molecular composition of patterned self-assembled monolayers can be achieved.
2'-NH2-MPTP causes long-term depletions in cortical and hippocampal serotonin (5-HT) and norepinephrine (NE) that are accompanied by acute elevations in glial fibrillary acidic protein (GFAP) and argyrophilia. In this study, 2'-NH2-MPTP was administered to mice and innervation densities were determined immunocytochemically. Three days after 2'-NH2-MPTP, 5-HT axons exhibited a beaded, tortuous appearance indicative of ongoing degeneration. At 21 days, numbers of serotonin axons were significantly decreased, with the greatest axonal losses occurring in cortex and hippocampus. Serotonin axons in the amygdala were contrastingly spared longer-term damage, as were 5-HT and NE cell bodies in the brain stem. These results, in conjunction with previous findings, demonstrate that 2'-NH2-MPTP causes degeneration of serotonergic axons innervating the cortex and hippocampus on par with depletions in neurotransmitter levels.
One of our central long-range objectives is to develop and to utilize methods to study interneuronal serotonin signaling in the brain. Our goals are to understand how the serotonin transporter modulates serotonergic neurotransmission and thereby influences its postsynaptic targets. Ultimately, we aim to elucidate the mechanisms by which SERT impacts anxiety-related behavior. Using chronoamperometry, we have demonstrated that serotonin uptake is reduced in a gene dose-dependent manner in SERT deficient mice. Furthermore, using microdialysis, we have shown that basal and stimulated extracellular serotonin levels are elevated, even in SERT +/- mice. We are currently using carbon fiber and boron-doped diamond microelectrodes to investigate whether changes in serotonin neurotransmission occurring in response to constitutive decreases in SERT are substantively different from changes resulting from antidepressant inhibition of SERT.
We are exploiting recent developments in nanoscale chemical patterning for the development of new bioanalytical tools for the study of brain chemistry from fundamentally novel perspectives. Neurons that utilize different signaling molecules exhibit spatially distinct patterns of innervation, and this translates into highly heterogeneous chemistries in brain microenvironments. The information content of interneuronal signaling is encoded temporally and spatially on the nanoscale; therefore, one of the great challenges and potentials of the current nanotechnology revolution lies in the development of similarly scaled devices to measure rapid changes in neurotransmitter levels in specific brain regions, subregions and, ultimately, in individual synapses. It is also essential for advancing our understanding of the roles of altered neurotransmission in disease mechanisms and for designing more effective therapeutic strategies to combat and to prevent brain disorders.
Posters and other presentations by our group for the Society for Neuroscience Meeting and other conferences.
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Recent Publications
How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. D. L. Murphy, M. A. Fox, K. R. Timpano, P. Moya, R. Ren-Patterson, A. M. Andrews, A. Holmes, S. W. Watts. J. R. Wendland and K. -P. Lesch, Neuropharmacology 55:932-960 (2008) invited review
Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperseotonergic phenotype. B. P. Guiard, D. L. David, T. Deltheil, F. Chenu, E.L. Maitre, T. Renoir, I. Lerous-Nicollet, P. Sokoloff, L. Landumey, M. Hamon, A. M. Andrews, R. Hen and A. M. Gardier, International Journal of Neuropsychophamracology, Jun 11:1-14 (2008).
Biospecific recognition of tethered small molecules diluted in self-assembled monolayers. M. J. Shuster, A. Vaish, M. E. Szapacs, M. E. Anderson, P. S. Weiss and A. M. Andrews, Advanced Materials, 20:164-167 (2008).
Hybrid approaches to nanometer-scale patterning: Exploiting tailored intermolecular interactions. T. J. Mullen, C. Srinivasan, M. J. Shuster, M. W. Horn, A. M. Andrews, and P. S. Weiss, Journal of Nanoparticle Research, 10:1231-1240 (2008).
Microcontact insertion printing. T. J. Mullen, C. Srinivasan, J. N. Hohman, S. D. Gillmor, M. J. Shuster, M. W. Horn, A. M. Andrews and P. S. Weiss, Applied Physics Letters, 90:063114-063117 (2007).
Reduced BDNF is associated with a loss of serotonergic innervation in the hippocampus of aging mice. B. A. Luellen, L. E. Bianco, L. M. Schneider and A. M. Andrews, Genes, Brain and Behavior, 6:482-490 (2007).
Scanning electron microscopy of nanoscale chemical patterns. C. Srinivasan, T. J. Mullen, J. N. Hohman, M. E. Anderson, A. A. Dameron, A. M. Andrews, E. C. Dickey, M. W. Horn, P. S. Weiss, ACS Nano, 1:191-201 (2007).
