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Alzheimer’s disease (AD) is an irreversible brain disorder that plagues millions of people with no current cure. Current clinical research is slowly advancing to more definitive treatments in hopes of reducing the effects of progressive cognitive and behavioral decline, but none so far can slow AD’s onset. A brain area

Alzheimer’s disease (AD) is an irreversible brain disorder that plagues millions of people with no current cure. Current clinical research is slowly advancing to more definitive treatments in hopes of reducing the effects of progressive cognitive and behavioral decline, but none so far can slow AD’s onset. A brain area known as the nucleus incertus (NI) was recently discovered to potentially impact AD because of its connections to brain targets that degenerate; however, the NI’s role is unknown. This goal of this experiment was to use a transgenic mouse model (APP/PS1) that expresses AD pathology slowly as found in humans, and to test the mice in a variety of cognitive and anxiety assessments. Mice of both sexes and two different ages were used, with the first being young adult before AD pathology manifests (around 3-4 months old), and the second being around the cusp of when AD pathology manifests (late adult, 8-10 months old). The mice were tested in a variety of cognitive tasks that included the novel object recognition (NOR), Morris water maze (MWM), and the object placement (OP), with the latter being the focus of my thesis. Anxiety measures were taken from the open field (OF) and elevated plus maze (EPM) with the visible platform (VP) used to ensure mice could perform on the rigorous MWM task. In the OP, we found an age effect, where the older mice were less likely to explore the moved object during the OP compared to the younger mice; motor ability was unlikely to explain this effect. We did not find any significant age by genotype effects. These findings indicate that cognitive impairment only just started to affect the older cohort, since OP impairment was found on one measure and not another. Other measures currently being quantified will be helpful in understanding this data, and to see whether learning, memory, and anxiety are affected.

ContributorsDapon, Bianca (Author) / Conrad, Cheryl (Thesis director) / Bimonte-Nelson, Heather (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2023-05
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Description
Neurological disorders are difficult to treat with current drug delivery methods due to their inefficiency and the lack of knowledge of the mechanisms behind drug delivery across the blood brain barrier (BBB). Nanoparticles (NPs) are a promising drug delivery method due to their biocompatibility and ability to be modified by

Neurological disorders are difficult to treat with current drug delivery methods due to their inefficiency and the lack of knowledge of the mechanisms behind drug delivery across the blood brain barrier (BBB). Nanoparticles (NPs) are a promising drug delivery method due to their biocompatibility and ability to be modified by cell penetrating peptides, such as transactivating transciptor (TAT) peptide, which has been shown to increase efficiency of delivery. There are multiple proposed mechanisms of TAT-mediated delivery that also have size restrictions on the molecules that can undergo each BBB crossing mechanism. The effect of nanoparticle size on TAT-mediated delivery in vivo is an important aspect to research in order to better understand the delivery mechanisms and to create more efficient NPs. NPs called FluoSpheres are used because they come in defined diameters unlike polymeric NPs that have a broad distribution of diameters. Both modified and unmodified 100nm and 200nm NPs were able to bypass the BBB and were seen in the brain, spinal cord, liver, and spleen using confocal microscopy and a biodistribution study. Statistically significant differences in delivery rate of the different sized NPs or between TAT-modified and unmodified NPs were not found. Therefore in future work a larger range of diameter size will be evaluated. Also the unmodified NPs will be conjugated with scrambled peptide to ensure that both unmodified and TAT-modified NPs are prepared in identical fashion to better understand the role of size on TAT targeting. Although all the NPs were able to bypass the BBB, future work will hopefully provide a better representation of how NP size effects the rate of TAT-mediated delivery to the CNS.
ContributorsCeton, Ricki Ronea (Author) / Stabenfeldt, Sarah (Thesis director) / Sirianni, Rachael (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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Description
Vagal Nerve Stimulation (VNS) has been shown to be a promising therapeutic technique in treating many neurological diseases, including epilepsy, stroke, traumatic brain injury, and migraine headache. The mechanisms by which VNS acts, however, are not fully understood but may involve changes in cerebral blood flow. The vagus nerve plays

Vagal Nerve Stimulation (VNS) has been shown to be a promising therapeutic technique in treating many neurological diseases, including epilepsy, stroke, traumatic brain injury, and migraine headache. The mechanisms by which VNS acts, however, are not fully understood but may involve changes in cerebral blood flow. The vagus nerve plays a significant role in the regulation of heart rate and cerebral blood flow that are altered during VNS. Here, we examined the effects of acute vagal nerve stimulation on both heart rate and cerebral blood flow. Laser Speckle Contrast Analysis (LASCA) was used to analyze the cerebral blood flow of male Long\u2014Evans rats. Results showed two distinct patterns of responses whereby animals either experienced a mild or severe decrease in heart rate during VNS. Further, animals that displayed mild heart rate decreases showed an increase in cerebral blood flow that persisted beyond VNS. Animals that displayed severe decreases showed a transient decrease in cerebral blood flow followed by an increase that was greater than that observed in mild animals but progressively decreased after VNS. The results suggest two distinct patterns of changes in both heart rate and cerebral blood flow that may be related to the intensity of VNS.
ContributorsHillebrand, Peter Timothy (Author) / Kleim, Jeffrey (Thesis director) / Helms Tillery, Stephen (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Alzheimer’s disease (AD) is characterized by memory decline and dementia, and conclusively diagnosed postmortem from tangles and plaques. Plaques come from β-amyloid protein (Aβ), which damages the brain, especially the hippocampus, a structure vital for memory formation. However, whether plaques and tangles cause or result from AD is unclear. Our

Alzheimer’s disease (AD) is characterized by memory decline and dementia, and conclusively diagnosed postmortem from tangles and plaques. Plaques come from β-amyloid protein (Aβ), which damages the brain, especially the hippocampus, a structure vital for memory formation. However, whether plaques and tangles cause or result from AD is unclear. Our goal was to use a preclinical AD model to identify the early stages of cognitive dysfunction before AD becomes severe to enhance targeted interventions. We used a transgenic mouse (APP/PS1) that slowly develops plaques, with minimal expression around 5-6 months (young adult) with more expression by 12 months (middle-age). Our aim was to determine whether young adult mice would show cognitive symptomatology that could be used as a future metric for targeted treatment before AD advances further. We had three independent variables: Sex (Male, Female), Age (5-6, 8-10 months) and Genotype (APP/PS1, wildtype, WT). We used behavioral assays to assess spatial memory (hippocampal function), working memory (prefrontal cortex function), and anxiety (amygdala function). For my honor’s thesis, I focused on using the Morris Water Maze (MWM) to assess hippocampal function and the Open Field (OF) to assess anxiety and locomotion. In MWM, all groups were given four trials/day for four days with a probe trial to assess strategy immediately after the last trial on day 4. All groups swam shorter distances across days to show they were learning and revealed sex differences. The APP/PS1 males (young and old) learned the task more slowly than their WT male counterparts, but were using spatial strategies as demonstrated by the probe trial. For the females, all groups learned the task similarly, but the probe trial revealed that the APP/PS1 females (young and old) were using non-spatial strategies. Moreover, the males significantly swam shorter distances than the females, learning faster. The use of the visible platform task confirmed that the mice were capable of performing the swim task. For the OF, mice were placed in a square arena and given 10 minutes to explore and found sex differences in anxiety profile. All the female mice expressed similar anxiety profiles, whereas the APP/PS1 males had higher anxiety profiles than their WT males counterparts. These results revealed that there were sex-specific differences in cognition and anxiety profiles in the APP/PS1 mouse model. This indicates that individual characteristics are important to consider when using tailored interventions. In summary, these findings emphasize the potential for early detection and targeted treatment strategies to help mitigate AD progression.
ContributorsMontero, Martina Anne (Author) / Conrad, Cheryl (Thesis director) / Gewirtz, Jonathan (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2024-05