Show simple item record

dc.contributor.authorStewart, Tara Moniqueen_US
dc.date.accessioned2016-02-10T16:56:38Z
dc.date.available2016-02-10T16:56:38Z
dc.date.issued2014
dc.identifier.urihttps://hdl.handle.net/2144/14363
dc.description.abstractSpatial navigation in humans correlates with activity of cells in hippocampus that respond when we traverse specific locations in our environment. Hippocampal pyramidal cells in rodents called "place cells" may contribute to episodic memory by encoding location in physical space. Place cells display plasticity by "remapping" or altering their firing rates and patterns of activity in response to changes in spatial environment. Impaired remapping may underlie age-related deficits in spatial memory tasks. Using in vivo high-density electrophysiology to record place cell activity in awake, behaving rats, we tested the hypothesis that CA3 neuron hyperactivity in aged animals could be normalized by pharmacotherapy. Results show that acute, systemic administration of low dose levetiracetam and sodium valproate ameliorates deficits in the aged hippocampal network by reducing firing rates, decreasing place field area, and increasing the spatial selectivity of CA3 place cells. We then tested the hypothesis that place cell activity, field area, and spatial selectivity may be an indicator for therapeutic enhancement of spatial memory in young adult rats. The results demonstrate that α5IA enhances hippocampal-dependent spatial memory as measured by the location novelty recognition task in rats, consistent with the previously established action of α5IA as an enhancer of spatial memory in the water maze test. Electrophysiological recordings on the same animals carried out in parallel demonstrate that α5IA increases place cell firing rates, reduces field area, and increases spatial selectivity. Together, these results suggest that reducing place field area and enhancing spatial selectivity correlate with the age-independent therapeutic improvement of spatial memory. The increase in place cell firing rates by α5IA likely results from its known action as a negative allosteric modulator of α5-subunit-containing receptors (α), which are located extrasynaptically at the base of dendritic spines on CA1 and CA3 pyramidal cells. Thus, to potentially target extrasynaptic tonic inhibition in the hippocampus, we synthesized and validated two α specific miRNAs as a platform for future attempts to improve spatial memory in young adult and aging animals via molecular genetics.en_US
dc.language.isoen_US
dc.subjectPharmacologyen_US
dc.subjectGABAen_US
dc.subjectAlpha5en_US
dc.subjectCognitive enhanceren_US
dc.subjectElectrophysiologyen_US
dc.subjectHippocampusen_US
dc.subjectPlace cellen_US
dc.titleA systems pharmacology approach to modulating spatial memoryen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2016-01-22T18:56:28Z
etd.degree.nameMaster of Arts/Doctor of Philosophyen_US
etd.degree.levelmastersen_US
etd.degree.disciplinePharmacology & Experimental Therapeuticsen_US
etd.degree.grantorBoston Universityen_US


This item appears in the following Collection(s)

Show simple item record