Matching Items (23)

158842-Thumbnail Image.png

Environmental Stimuli Activates Early Growth Response 3 (EGR3), an Immediate Early Gene Residing at the Center of a Biological Pathway Associated with Risk for Schizophrenia

Description

Schizophrenia, a debilitating neuropsychiatric disorder, affects 1% of the population. This multifaceted disorder is comprised of positive (hallucinations/psychosis), negative (social withdrawal/anhedonia) and cognitive symptoms. While treatments for schizophrenia have advanced

Schizophrenia, a debilitating neuropsychiatric disorder, affects 1% of the population. This multifaceted disorder is comprised of positive (hallucinations/psychosis), negative (social withdrawal/anhedonia) and cognitive symptoms. While treatments for schizophrenia have advanced over the past few years, high economic burdens are still conferred to society, totaling more than $34 billion in direct annual costs to the United States of America. Thus, a critical need exists to identify the factors that contribute towards the etiology of schizophrenia. This research aimed to determine the interactions between environmental factors and genetics in the etiology of schizophrenia. Specifically, this research shows that the immediate early gene, early growth response 3 (EGR3), which is upregulated in response to neuronal activity, resides at the center of a biological pathway to confer risk for schizophrenia. While schizophrenia-risk proteins including neuregulin 1 (NRG1) and N-methyl-D-aspartate receptors (NMDAR’s) have been identified upstream of EGR3, the downstream targets of EGR3 remain relatively unknown. This research demonstrates that early growth response 3 regulates the expression of the serotonin 2A-receptor (5HT2AR) in the frontal cortex following the physiologic stimulus, sleep deprivation. This effect is translated to the level of protein as 8 hours of sleep-deprivation results in the upregulation of 5HT2ARs, a target of antipsychotic medications. Additional downstream targets were identified following maximal upregulation of EGR3 through electroconvulsive stimulation (ECS). Both brain-derived neurotrophic factor (BDNF) and its epigenetic regulator, growth arrest DNA-damage-inducible 45 beta (GADD45B) are upregulated one-hour following ECS in the hippocampus and require the presence of EGR3. These proteins play important roles in both cellular proliferation and dendritic structural changes. Next, the effects of ECS on downstream neurobiological processes, hippocampal cellular proliferation and dendritic structural changes were examined. Following ECS, hippocampal cellular proliferationwas increased, and dendritic structural changes were observed in both wild-type and early growth response 3 knock-out (Egr3-/-) mice. Effects in the number of dendritic spines and dendritic complexity following ECS were not found to require EGR3. Collectively, these results demonstrate that neuronal activity leads to the regulation of schizophrenia risk proteins by EGR3 and point to a possible molecular mechanism contributing risk for schizophrenia.

Contributors

Agent

Created

Date Created
  • 2020

152103-Thumbnail Image.png

Optimization of menopausal hormone therapies for cognitive and brain aging using a rat model

Description

Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels

Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels of sex hormones, and a dysregulation of gonadotrophin feedback loops. Consequently, menopause is accompanied by hot flashes, urogenital atrophy, cognitive decline, and other symptoms that reduce quality of life. To ameliorate these negative consequences, estrogen-containing hormone therapy is prescribed. Findings from clinical and pre-clinical research studies suggest that menopausal hormone therapies can benefit memory and associated neural substrates. However, findings are variable, with some studies reporting null or even detrimental cognitive and neurobiological effects of these therapies. Thus, at present, treatment options for optimal cognitive and brain health outcomes in menopausal women are limited. As such, elucidating factors that influence the cognitive and neurobiological effects of menopausal hormone therapy represents an important need relevant to every aging woman. To this end, work in this dissertation has supported the hypothesis that multiple factors, including post-treatment circulating estrogen levels, experimental handling, type of estrogen treatment, and estrogen receptor activity, can impact the realization of cognitive benefits with Premarin hormone therapy. We found that the dose-dependent working memory benefits of subcutaneous Premarin administration were potentially regulated by the ratios of circulating estrogens present following treatment (Chapter 2). When we administered Premarin orally, it impaired memory (Chapter 3). Follow-up studies revealed that this impairment was likely due to the handling associated with treatment administration and the task difficulty of the memory measurement used (Chapters 3 and 4). Further, we demonstrated that the unique cognitive impacts of estrogens that become increased in circulation following Premarin treatments, such as estrone (Chapter 5), and their interactions with the estrogen receptors (Chapter 6), may influence the realization of hormone therapy-induced cognitive benefits. Future directions include assessing the mnemonic effects of: 1) individual biologically relevant estrogens and 2) clinically-used bioidentical hormone therapy combinations of estrogens. Taken together, information gathered from these studies can inform the development of novel hormone therapies in which these parameters are optimized.

Contributors

Agent

Created

Date Created
  • 2013

153819-Thumbnail Image.png

Examining multiple sleep behaviors and diurnal patterns of salivary cortisol and alpha-amylase: within- and between-person associations

Description

Sleep is essential for physical and psychological health. Sleep has also been linked to the daily patterns of key stress-responsive physiological systems, specifically the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous

Sleep is essential for physical and psychological health. Sleep has also been linked to the daily patterns of key stress-responsive physiological systems, specifically the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). Extant research examining sleep and diurnal patterns of cortisol, the primary end product of the HPA axis, is inconsistent. Moreover, it is not clear how specific aspects of sleep behavior (e.g., sleep duration, sleep quality, sleep variability) are related to specific components of diurnal cortisol rhythms. Salivary alpha-amylase (sAA) has been recognized as a surrogate marker of ANS activity, but limited research has explored relations between sleep and sAA diurnal rhythms. The current study utilized a modified ecological momentary assessment protocol to examine within- and between-person relations between multiple facets of sleep behavior using multiple methods (e.g., subjective report, actigraphy) and salivary cortisol and sAA. First year college students (N = 76) provided saliva samples and diary entries five times per day over the course of three days. Sleep was assessed via questionnaire, through daily diaries, and monitored objectively using actigraphy over a four day period. Between-person results revealed that shorter average sleep duration and greater sleep variability was related to lower levels of waking cortisol and flatter diurnal slopes across the day. Within-person results revealed that on nights when individuals slept for shorter durations than usual they also had lower levels of waking cortisol the next day. Sleep was not related to the cortisol awakening response (CAR) or diurnal patterns of sAA, in either between-person or within-person analyses. However, typical sleep behaviors measured via questionnaire were related to waking levels of sAA. Overall, this study provides a greater understanding of how multiple components of sleep, measured in naturalistic environments, is related to cortisol and sAA diurnal rhythms, and how day-to-day, within-person changes in sleep duration contribute to daily variations in cortisol.

Contributors

Agent

Created

Date Created
  • 2015

157225-Thumbnail Image.png

Chronic unpredictable intermittent restraint stress disrupts hippocampal-dependent spatial memory in male, but not female rats

Description

The present series of studies examined whether a novel implementation of an

intermittent restraint (IR) chronic stress paradigm could be used to investigate hippocampal-dependent spatial ability in both sexes. In experiments

The present series of studies examined whether a novel implementation of an

intermittent restraint (IR) chronic stress paradigm could be used to investigate hippocampal-dependent spatial ability in both sexes. In experiments 1 and 2, Sprague- Dawley male rats were used to identify the optimal IR parameters to assess spatial ability. For IR, rats were restrained for 2 or 6hrs/day (IR2, IR6, respectively) for five days and then given two days off, a process that was repeated for three weeks and compared to rats restrained for 6hrs/d for each day (DR6) and non-stressed controls (CON). Spatial memory was tested on the radial arm water maze (RAWM), object placement (OP), novel object recognition (NOR) and Y-maze. The results for the first two experiments revealed that IR6, but not IR2, was effective in impairing spatial memory in male rats and that task order impacted performance. In experiment 3, an extended IR paradigm for six weeks was implemented before spatial memory testing commenced in male and female rats (IR- M, IR-F). Unexpectedly, an extended IR paradigm failed to impair spatial memory in either males or females, suggesting that when extended, the IR paradigm may have become predictable. In experiment 4, an unpredictable IR (UIR) paradigm was implemented, in which restraint duration (30 or 60-min) combined with orbital shaking, time of day, and the days off from UIR were varied. UIR impaired spatial memory in males, but not females. Together with other reports, these findings support the interpretation that chronic stress negatively impairs hippocampal-dependent function in males, but not females, and that females appear to be resilient to spatial memory deficits in the face of chronic stress.

Contributors

Agent

Created

Date Created
  • 2019

158191-Thumbnail Image.png

From soul searching to community building: Understanding community identification through community "jen-tung" process

Description

This study provides insights into expanding the concepts of community arts in general and more specifically community-based art practices (CAP); highlights the participatory characteristics in the processes of CAP, and

This study provides insights into expanding the concepts of community arts in general and more specifically community-based art practices (CAP); highlights the participatory characteristics in the processes of CAP, and seeks to discern the mechanism that contributes to the formation of community collective identity. Revolving around Bhattacharyya’s (1995, 2004) conceptualization of community development, this study found it essential for exploring the fundamental concept of community in relation to community identity. To examine the concept of community identity, this research anchors the inquiry by studying how community-based art practice contributes to community identification and seeks to discover the connection between identity process and social change. The research also discusses the emergent concepts that serve as influential factors to the formation of community identity and proposes an alternative identification mechanism, ‘jen-tung’ process, which provides a needed new dimension to the existing theories of social identity formation and community efficacy development.

Contributors

Agent

Created

Date Created
  • 2020

151302-Thumbnail Image.png

Age related changes in cognition and brain: a focus on progestogens

Description

Cognitive function declines with normal age and disease states, such as Alzheimer's disease (AD). Loss of ovarian hormones at menopause has been shown to exacerbate age-related memory decline and may

Cognitive function declines with normal age and disease states, such as Alzheimer's disease (AD). Loss of ovarian hormones at menopause has been shown to exacerbate age-related memory decline and may be related to the increased risk of AD in women versus men. Some studies show that hormone therapy (HT) can have beneficial effects on cognition in normal aging and AD, but increasing evidence suggests that the most commonly used HT formulation is not ideal. Work in this dissertation used the surgically menopausal rat to evaluate the cognitive effects and mechanisms of progestogens proscribed to women. I also translated these questions to the clinic, evaluating whether history of HT use impacts hippocampal and entorhinal cortex volumes assessed via imaging, and cognition, in menopausal women. Further, this dissertation investigates how sex impacts responsiveness to dietary interventions in a mouse model of AD. Results indicate that the most commonly used progestogen component of HT, medroxyprogesterone acetate (MPA), impairs cognition in the middle-aged and aged surgically menopausal rat. Further, MPA is the sole hormone component of the contraceptive Depo Provera, and my research indicates that MPA administered to young-adult rats leads to long lasting cognitive impairments, evident at middle age. Natural progesterone has been gaining increasing popularity as an alternate option to MPA for HT; however, my findings suggest that progesterone also impairs cognition in the middle-aged and aged surgically menopausal rat, and that the mechanism may be through increased GABAergic activation. This dissertation identified two less commonly used progestogens, norethindrone acetate and levonorgestrel, as potential HTs that could improve cognition in the surgically menopausal rat. Parameters guiding divergent effects on cognition were discovered. In women, prior HT use was associated with larger hippocampal and entorhinal cortex volumes, as well as a modest verbal memory enhancement. Finally, in a model of AD, sex impacts responsiveness to a dietary cognitive intervention, with benefits seen in male, but not female, transgenic mice. These findings have clinical implications, especially since women are at higher risk for AD diagnosis. Together, it is my hope that this information adds to the overarching goal of optimizing cognitive aging in women.

Contributors

Agent

Created

Date Created
  • 2012

158360-Thumbnail Image.png

Chronic Stress Has Lasting Influences on Fear Extinction Cued Discrimination Early in Extinction That is Mediated by the Infralimbic Cortex

Description

Post-Traumatic Stress Disorder (PTSD) is characterized by intrusive memories from a traumatic event. Current therapies rarely lead to complete remission. PTSD can be modeled in rodents using chronic stress (creating

Post-Traumatic Stress Disorder (PTSD) is characterized by intrusive memories from a traumatic event. Current therapies rarely lead to complete remission. PTSD can be modeled in rodents using chronic stress (creating vulnerable phenotype) combined with fear conditioning (modeling a traumatic experience), resulting in attenuated extinction learning and impaired recall of extinction. Studies typically investigate cognition soon after chronic stress ends; however, as days and weeks pass (“rest” period) some cognitive functions may improve compared to soon after stress. Whether a rest period between chronic stress and fear conditioning/extinction would lead to improvements is unclear. In Chapter 2, male rats were chronically stressed by restraint (6hr/d/21d), a reliable method to produce cognitive changes, or assigned to a non-stressed control group (CON). After chronic stress ended, fear conditioning occurred within a day (STR-IMM), or after three (STR-R3) or six weeks (STR-R6). During the first three extinction trials, differences emerged in fear to the non-shock context: STR-R3/R6 showed significantly less fear to the context than did STR-IMM or CON. Differences were unlikely attributable to generalization or to second-order conditioning. Therefore, a rest period following chronic stress may lead to improved fear extinction and discrimination between the conditioned stimulus and environment. In Chapter 3, the infralimbic cortex (IL) was investigated due to the IL’s importance in fear extinction. Rats were infused with chemogenetics to target IL glutamatergic neurons and then assigned to CON, STR-IMM or STR-R3. During the rest period of STR-R3 and the restraint for STR-IMM, the IL was inhibited using CNO (1mg/kg BW, i.p., daily), which ended before behavioral testing. STR-R3 with IL inhibition failed to demonstrate a tone-shock association as spontaneous recovery was not observed. CON with IL inhibition behaved somewhat like STR-IMM; freezing to the extinction context was enhanced. Consequently, inhibiting IL function during the rest period following chronic stress was particularly disruptive for learning in STR-R3, impaired freezing to a safe context for CON, and had no effect in STR-IMM. These studies show that time since the end of chronic stress (recently ended or with a delay) can interact with IL functioning to modify fear learning and response.

Contributors

Agent

Created

Date Created
  • 2020

155287-Thumbnail Image.png

Effects of internet training in mindfulness meditation on variables related to cancer recovery

Description

Cancer survivors engaged in either six-week Internet-delivered mindfulness training or a usual-care control and were compared on the following outcome battery: The Hospital Anxiety and Depression Scale, the Profile of

Cancer survivors engaged in either six-week Internet-delivered mindfulness training or a usual-care control and were compared on the following outcome battery: The Hospital Anxiety and Depression Scale, the Profile of Mood States, the Pittsburgh Sleep Quality Index, and the Fatigue Symptom Inventory. Assessments were conducted before and after treatment and intervention compliance was monitored. Mindfulness treatments were delivered at a time and on a computer of the participants’ choosing. Multivariate analysis indicated that mindfulness training produced significant benefits on all measures (p < .05). Online mindfulness instruction represents a widely-accessible, cost-effective intervention for reducing psychological distress and its behavioral manifestations in cancer survivors, especially those who are unable to participate in in-person training.

Contributors

Agent

Created

Date Created
  • 2017

155803-Thumbnail Image.png

Future time perspective, socio-emotional regulation, and diurnal cortisol patterns in post-secondary engineering students

Description

Built upon Control Value Theory, this dissertation consists of two studies that examine university students’ future-oriented motivation, socio-emotional regulation, and diurnal cortisol patterns in understanding students’ well-being in the academic-context.

Built upon Control Value Theory, this dissertation consists of two studies that examine university students’ future-oriented motivation, socio-emotional regulation, and diurnal cortisol patterns in understanding students’ well-being in the academic-context. Study 1 examined the roles that Learning-related Hopelessness and Future Time Perspective Connectedness play in predicting students’ diurnal cortisol patterns, diurnal cortisol slope (DS) and cortisol awakening response (CAR). Self-reported surveys were collected (N = 60), and diurnal cortisol samples were provided over two waves, the week before a mid-term examination (n = 46), and the week during students’ mid-term (n = 40). Using multi-nomial logistic regression, results showed that Learning-related Hopelessness was not predictive of diurnal cortisol pattern change after adjusting for key covariates; and that Future Time Perspective Connectedness predicted higher likelihood for students to have low CAR across both waves of data collection. Study 2 examined students’ future-oriented motivation (Future Time Perspective Value) and socio-emotional regulation (Effortful Control and Social Support) in predicting diurnal cortisol patterns over the course of a semester. Self-reported surveys were collected (N = 67), and diurnal cortisol samples were provided over three waves of data collection, at the beginning of the semester (n = 63), during a stressful academic period (n = 47), and during a relaxation phase near the end of the semester (n = 43). Results from RM ANCOVA showed that Non-academic Social Support was negatively associated with CAR at the beginning of the semester. Multi-nomial logistics regression results indicated that Future Time Perspective Value and Academic Social Support jointly predicted CAR pattern change. Specifically, the interaction term marginally predicted a higher likelihood of students switching from having high CAR at the beginning or stressful times in the semester to having low CAR at the end the semester, compared to those who had low CAR over all three waves. The two studies have major limits in sample size, which restricted the full inclusion of all hypothesized covariates in statistical models, and compromised interpretability of the data. However, the methodology and theoretical implications are unique, providing contributions to educational research, specifically with regard to post-secondary students’ academic experience and well-being.

Contributors

Agent

Created

Date Created
  • 2017

156178-Thumbnail Image.png

Improved Discrimination Between Tone and Context During Fear Extinction in Chronically Stressed Rats Provided with a Post-Stress Rest Period

Description

The goal of the present study was to investigate whether a rest period following the end of chronic stress would impact fear extinction. Past research has indicated that chronic

The goal of the present study was to investigate whether a rest period following the end of chronic stress would impact fear extinction. Past research has indicated that chronic stress leads to impairments in the learning and recall of fear conditioning extinction. Moreover, the effects of chronic stress can return to levels similar to controls when a post-stress “rest” period (i.e., undisturbed except for normal husbandry) is given prior to testing. Male rats underwent chronic restraint stress for 6hr/day/21days (STR-IMM). Some rats, underwent a post-stress rest period for 6- or 3-weeks after the end of stress (STR-R6, STR-R3). Control (CON) rats were unrestrained for the duration of the experiment. In Experiment 1, following the stress or rest manipulation, all rats were acclimated to conditioning and extinction contexts, fear conditioned with 3 tone-foot shock pairings, and then had two days of extinction training. All groups froze similarly to the tone across all training sessions. However, STR-R6/R3 froze less in the non-shock context than did STR-IMM or CON. During extinction training, STR-IMM showed high levels of freezing to the non-shock context, leading to a concern they may be generalizing across contexts. Consequently, a follow-up experiment tested for context generalization. In Experiment 2, STR-IMM rats underwent a generalization test in an environment that was either different or the same as the conditioning environment, using STR-R6 as a comparison. STR-IMM and STR-R6 showed similar relative levels of freezing to tone and context, regardless of their conditioning environment to reveal that STR-IMM did not generalize and instead, maybe expressing hypervigilance. Thus, the present study demonstrated the novel finding that a rest period from chronic stress can lead to reduced fear responsiveness in a non-shock environment.

Contributors

Agent

Created

Date Created
  • 2018