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Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

Description
To date, it has been difficult to elucidate the role of tau in learning and memory during adulthood due to developmental compensation of other microtubule associated proteins in Tau knockout (KO) mice. Here, we generated an adeno-associated virus (AAV) expressing a doxycycline (doxy)-inducible short-hairpin (sh) RNA targeted to tau, and…

To date, it has been difficult to elucidate the role of tau in learning and memory during adulthood due to developmental compensation of other microtubule associated proteins in Tau knockout (KO) mice. Here, we generated an adeno-associated virus (AAV) expressing a doxycycline (doxy)-inducible short-hairpin (sh) RNA targeted to tau, and stereotaxically and bilaterally injected 7-month-old C57BL/6 mice with either the AAV-shRNAtau or an AAV expressing a scramble shRNA sequence. Seven days after the injections, all animals were administered doxy for thirty-five days to induce expression of shRNAs, after which they were tested in the open field, rotarod and Morris water maze (MWM) to assess anxiety like behavior, motor coordination and spatial reference memory, respectively. Our results show that reducing tau in the adult hippocampus produces significant impairments in motor coordination, endurance and spatial memory. Tissue analyses shows that tau knockdown reduces hippocampal dendritic spine density and the levels of BDNF and synaptophysin, two proteins involved in memory formation and plasticity. Our approach circumvents the developmental compensation issues observed in Tau KO models and shows that reducing tau levels during adulthood impairs cognition.
ContributorsTran, An Le (Author) / Oddo, Salvatore (Thesis director) / Velazquez, Ramon (Committee member) / Roberson, Erik (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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The role of nucleus accumbens NMDA receptors on rapid, transient synaptic plasticity induced by cued nicotine reinstatement

Description
Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement paradigm. Here, we used a nicotine self-administration and contingent cue-induced…

Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement paradigm. Here, we used a nicotine self-administration and contingent cue-induced reinstatement model to examine rapid, transient synaptic plasticity (t-SP) induced by nicotine cue-triggered motivation. Although preliminary, treatment with the NMDA GluN2B subunit antagonist, ifenprodil, reduced reinstated nicotine seeking, and increased the percentage of spines with smaller head diameters. Thus, future studies are needed to fully parse out the role of NAcore GluN2B receptors in cued nicotine seeking and t-SP.
ContributorsMccallum, Joseph John (Author) / Gipson-Reichardt, Cassandra (Thesis director) / Neisewander, Janet (Committee member) / Olive, Michael Foster (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05