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Hippocampal Contributions to the Temporal Dynamics of Behavior

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The capacity to track time in the seconds-to-minutes range, or interval timing, appears to be at least partially dependent on intact hippocampal (HPC) function. The current dissertation sought to dissociate timed responses, non-timed responses, and motivational aspects of behavior in order to propose a role of the HPC in specific…

The capacity to track time in the seconds-to-minutes range, or interval timing, appears to be at least partially dependent on intact hippocampal (HPC) function. The current dissertation sought to dissociate timed responses, non-timed responses, and motivational aspects of behavior in order to propose a role of the HPC in specific timing sub-processes. In Chapter 2, effects of dorsal HPC (dHPC) lesions on temporal responding in a switch-timing task revealed a critical role of dHPC in the acquisition of interval timing criteria. Following dHPC lesions, the start time of responding was systemically shortened, in a manner that was enhanced and sustained when encoding a novel long interval, consistent with a memory-based account of dHPC function in timed responding. Chapter 3 investigated effects of chronic stress, which has been shown to reliably induce HPC dendritic retraction, on interval timing, utilizing response-initiated schedules of reinforcement, which facilitate deconvolution of timing and motivation. This revealed task-dependent effects on interval timing and motivation, where stress induced transient effects on motivation in a prospective timing task, but transient effects on the variability of timed responding in a retrospective timing task, consistent with an effect on memory function in interval timing. Chapter 4 sought to bring timed responding, motivation, and non-timed behaviors under stronger procedural control, through the implementation of a response-initiated timing-with-opportunity-cost task, in which a cost is imposed on temporal food-seeking by the presence of a concurrent source of probabilistic reinforcement. This arrangement garnered strong schedule control of behavior, and revealed individual-subject differences in the effects of reward devaluation, such that it affected motivation in some rats, but temporal responding in others. Using this methodology, Chapter 5 investigated initial temporal entrainment of behavior under pharmacological deactivation of dHPC and revealed its critical involvement in updating memory to new temporal contingencies. Together, data from this dissertation contrast with prior conclusions that the HPC is not involved in learning temporal criteria, and instead suggest that its function is indeed critical to encoding temporal intervals in memory.
ContributorsGupta, Tanya A. (Author) / Sanabria, Federico (Thesis advisor) / Conrad, Cheryl (Committee member) / Olive, Foster (Committee member) / McClure, Samuel (Committee member) / Arizona State University (Publisher)
Created2022

Using Transgenic Mice (APP/PS1) to Model Alzheimer’s Disease to Understand Hippocampal-Dependent Memory

Description

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

Prenatal Maternal Stress Alters Alzheimer’s Disease Pathology in 12-Month Old 3xTg Alzheimer’s Disease Mouse Model

Description

Alzheimer’s Disease (AD) is the most prevalent form of dementia and is the sixth leading cause of death in the elderly. Evidence suggests that forms of stress, including prenatal maternal stress (PMS), could exacerbate AD development. To better understand the mechanism linking PMS and AD, we investigated behavior and specific…

Alzheimer’s Disease (AD) is the most prevalent form of dementia and is the sixth leading cause of death in the elderly. Evidence suggests that forms of stress, including prenatal maternal stress (PMS), could exacerbate AD development. To better understand the mechanism linking PMS and AD, we investigated behavior and specific epigenetic markers of the 3xTg-AD mouse model compared to aged-controls in offspring of stressed mothers and non-stressed mothers.
ContributorsBrookhouser, Leia (Author) / Coleman, Paul (Thesis director) / Velazquez, Ramon (Committee member) / Conrad, Cheryl (Committee member) / Judd, Jessica (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2022-12
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Deficits in Spatial Working Memory Depend on Age in a Novel Rat Model of Alzheimer's Disease

Description
There are currently no disease-modifying treatments to halt or attenuate the progression of Alzheimer’s disease (AD). Transgenic rodent models have provided researchers the ability to recapitulate particular pathological and symptomological events in disease progression. Complete reproduction of all features of AD in a rodent model has not been achieved, potentially…

There are currently no disease-modifying treatments to halt or attenuate the progression of Alzheimer’s disease (AD). Transgenic rodent models have provided researchers the ability to recapitulate particular pathological and symptomological events in disease progression. Complete reproduction of all features of AD in a rodent model has not been achieved, potentially lending to the inconclusive treatment results at the clinical level. Recently, the TgF344-AD transgenic rat model has started to be evaluated; however, it has not been well characterized in terms of its cognition, which is fundamental to understanding the trajectory of aging relative to pathology and learning and memory changes. Therefore, the aim of the current study was to identify cognitive outcomes at 6, 9, and 12 months of age in the TgF344-AD rat model. Sixty female transgenic (Tg) and wildtype (WT) rats were tested on the water radial arm maze, Morris water maze, and visible platform task to evaluate cognition. Results from the asymptotic phase of the water radial arm maze showed that the 6 mo-Tg animals had marginally impaired working memory compared to 6 mo-WT rats, and 12 mo-Tg rats had significantly impaired working memory compared to 12 mo-WT rats. The 9 mo-Tg animals did not demonstrate a significant difference in working memory errors compared to the 9 mo-WT animals. This pattern of impairment, wherein Tg animals made more working memory errors compared to WT animals at the 6 and 12 month time points, but not at the 9 month time point, may be indicative of an inflammatory response that proves helpful at incipient stages of disease progression but eventually leads to further cognitive impairment. These results provide insight into the potential earliest time point that prodromal cognitive symptoms of AD exist, and how they progress with aging. Brain tissue was collected at sacrifice for future analyses of pathology, which will be used to glean insight into the temporal progression of pathological and cognitive outcomes.
ContributorsBulen, Haidyn Leigh (Co-author) / Bulen, Haidyn (Co-author) / Bimonte-Nelson, Heather (Thesis director) / Presson, Clark (Committee member) / Conrad, Cheryl (Committee member) / Woner, Victoria (Committee member) / Peña, Veronica (Committee member) / School of International Letters and Cultures (Contributor) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05