Browsing by Subject "Behavior, Animal"
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Item Effects of Regional Deletion of Rab3A-interacting Molecule and PTEN on Brain Function(2013-04-16) Haws, Michael; Eisch, Amelia J; Powell, Craig M; Huber, Kimberly; Goldberg, MatthewThis dissertation describes experiments designed to delete/knockdown molecules from targeted neuronal populations to study brain region-specific behavioral functions. To this end, I utilized two different conditional knockdown techniques to study the role of the presynaptic active zone molecule Rab3A-interacting Molecule (RIM1) and the phosphatase and tensin homologue on chromosome 10 (PTEN). The cre-lox system was used to eliminate RIM1 from the hippocampal dentate gyrus and area CA3, while adeno-associated virus expressing PTEN-directed interference RNA was injected into the basolateral amygdala to knockdown PTEN in local pyramidal neurons. In the case of RIM1, I hypothesized that deletion of RIM1 from the dentate gyrus or from area CA3 would replicate a subset of the learning and memory deficits found in RIM1à-/- mice. Though the conditional RIM1 knockout mice were not completely selective for the dentate gyrus or for area CA3, both conditional knockouts induced a different behavioral abnormality present in RIM1à-/- mice. My results help narrow the potential brain regions involved in key RIM1à-/- mice behavioral aberrations. In the case of PTEN, I hypothesized that deletion of PTEN specifically in the basolateral amygdala (BLA) would cause increased anxiety and neuronal hypertrophy. Knockdown of PTEN in the BLA did not induce anxiogenesis though it did increase soma volume, dendritic caliber, spine size, mushroom:thin spine ratio, and the frequency of spontaneous miniature excitatory post-synaptic currents. These findings are in contrast to previous findings of increased spine density with PTEN knockdown. This difference likely represents the more sensitive techniques employed in the present studies to ascertain dendritic spine type and density. Though PTEN knockdown had synaptic effects I did not observe any behavioral effects. However, limitations in viral knockdown of PTEN transcripts or viral infection rate may be responsible for the lack of effect. Indeed, limitations exist for both the transgenic and viral approaches used which proved to be challenging obstacles to designing experiments, interpreting data and coming to more extensive concrete conclusions. Transgene expression is often not as selective as desired. Virus injections may not localize to target region or may not infect enough neurons. Understanding and characterizing these and other limitations is vital.Item The Role of CREB in Social Isolation and Natural Reward Behavior(2007-12-18) Wallace, Deanna Lynette; Nestler, Eric JThe role of CREB (cyclic AMP Response Element Binding protein) has been known to play a role in complex behaviors such as learning and memory, drug reward and depression. The work presented in this dissertation examines the role of CREB in an inactive stress paradigm, social isolation. Social isolation is a model which decreases CREB-mediated transcription in the nucleus accumbens and results in depressive- and anxiety- like phenotypes, all reversed by chronic but not acute administration of imipramine. In addition, aspects of social isolation can be mimicked in non-isolated animals by inhibition of CREB in the nucleus accumbens and certain deficits in isolated animals can be reversed by wildtype overexpression of CREB. However, other behavioral deficits observed in the isolated phenotype, while reversed by imipramine administration, are unaffected by CREB manipulation in the nucleus accumbens. Potential gene targets are explored by microarray analysis comparing control doublehoused animals and isolated animals, and these groups treated with wildtype CREB or chronic imipramine administration. The array analysis led to the discovery that social isolation alone increases expression of several types of potassium channels in the nucleus accumbens. Investigating the electrophysiological properties of these neurons, social isolation results in a greater hyperpolarization of the resting membrane potential, and decreased potassium channel-mediated membrane resistance. Lastly, it is shown that inhibiting CREB leads to increases of potassium channel expression, and the anxiety-like effects observed in isolated animals can be mimicked in non-isolated animals by overexpression of the inward rectifying potassium channel kir2.1. These studies further the field of depression and anxiety research with a model sensitive to chronic but not acute antidepressant treatment and reveal potential novel mechanisms for the reversal of anxiety-like behaviors.