Matching Items (7)
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- All Subjects: Chronic Stress
- All Subjects: Inhibition
- Creators: Sanabria, Federico
Description
The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and motivation, key functions of the limbic system. Three structures of the limbic system in particular, the hippocampus, medial prefrontal cortex (mPFC), and amygdala, are of special interest due to documented structural changes and their implication in post-traumatic stress disorder (PTSD). One of many notable chronic stress-induced changes include dendritic arbor restructuring, which reflect plasticity patterns in parallel with the direction of alterations observed in functional imaging studies in PTSD patients. For instance, chronic stress produces dendritic retraction in the hippocampus and mPFC, but dendritic hypertrophy in the amygdala, consistent with functional imaging in patients with PTSD. Some have hypothesized that these limbic region's modifications contribute to one's susceptibility to develop PTSD following a traumatic event. Consequently, we used a familiar chronic stress procedure in a rat model to create a vulnerable brain that might develop traits consistent with PTSD when presented with a challenge. In adult male rats, chronic stress by wire mesh restraint (6h/d/21d) was followed by a variety of behavioral tasks including radial arm water maze (RAWM), fear conditioning and extinction, and fear memory reconsolidation to determine chronic stress effects on behaviors mediated by these limbic structures. In chapter 2, we corroborated past findings that chronic stress caused hippocampal CA3 dendritic retraction. Importantly, we present new findings that CA3 dendritic retraction corresponded with poor spatial memory in the RAWM and that these outcomes reversed after a recovery period. In chapter 3, we also showed that chronic stress impaired mPFC-mediated extinction memory, findings that others have reported. Using carefully assessed behavior, we present new findings that chronic stress impacted nonassociative fear by enhancing contextual fear during extinction that generalized to a new context. Moreover, the generalization behavior corresponded with enhanced functional activation in the hippocampus and amygdala during fear extinction memory retrieval. In chapter 5, we showed for the first time that chronic stress enhanced amygdala functional activation during fear memory retrieval, i.e., reactivation. Moreover, these enhanced fear memories were resistant to protein synthesis interference to disrupt a previously formed memory, called reconsolidation in a novel attempt to weaken chronic stress enhanced traumatic memory. Collectively, these studies demonstrated the plastic and dynamic effects of chronic stress on limbic neurocircuitry implicated in PTSD. We showed that chronic stress created a structural and functional imbalance across the hippocampus, mPFC, and amygdala, which lead to a PTSD-like phenotype with persistent and exaggerated fear following fear conditioning. These behavioral disruptions in conjunction with morphological and functional imaging data reflect a chronic stress-induced imbalance between hippocampal and mPFC regulation in favor of amygdala function overdrive, and supports a novel approach for traumatic memory processing in PTSD.
ContributorsHoffman, Ann (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Hammer, Jr., Ronald P. (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2013
Description
Smoking remains the leading cause of preventable death in the United States, and early initiation is associated with greater difficulty quitting. Among adolescent smokers, those with attention-deficit hyperactivity disorder (ADHD), characterized by difficulties associated with impulsivity, hyperactivity, and inattention, smoke at nearly twice the rate of their peers. Although cigarette smoking is highly addictive, nicotine is a relatively weak primary reinforcer, spurring research on other potential targets that may maintain smoking, including the potential benefits of nicotine on attention, inhibition, and reinforcer efficacy. The present study employs the most prevalent rodent model of ADHD, the spontaneously hypertensive rat (SHR) and its control comparison Wistar Kyoto (WKY) to examine the effects of acute and chronic subcutaneous nicotine injections on performance in three operant response inhibition paradigms. Functional activation in select regions of the prefrontal cortex and striatum was also explored. Acute (0.1, 0.3, 0.6 mg/kg) and chronic (0.3 mg/kg) nicotine increased impulsive responding regardless of strain, dose, or operant schedule. Dose-dependent decreases in latency to initiate the task were also observed. SHR receiving daily nicotine injections showed less activation in the nucleus accumbens shell compared to saline controls. Despite close similarities, one of the three operant tasks did not detect response inhibition deficits in SHR relative to WKY. A closer examination of these tasks may highlight critical components involved in the amelioration of response inhibition deficits.
ContributorsMazur, Gabriel Joseph (Author) / Sanabria, Federico (Thesis advisor) / Killeen, Peter R (Committee member) / Neisewander, Janet L (Committee member) / Wynne, Clive DL (Committee member) / Arizona State University (Publisher)
Created2014
Description
The failure to withhold inappropriate behavior is a central component of most impulse control disorders, including Attention Deficit Hyperactivity Disorder (ADHD). The present study examined the effects of housing environment and methylphenidate (a drug often prescribed for ADHD) on the performance of rats in two response inhibition tasks: differential reinforcement of low rate (DRL) and fixed minimum interval (FMI). Both tasks required rats to wait a fixed amount of time (6 s) before emitting a reinforced response. The capacity to withhold the target response (volitional inhibition) and timing precision were estimated on the basis of performance in each of the tasks. Paradoxically, rats housed in a mildly enriched environment that included a conspecific displayed less volitional inhibition in both tasks compared to rats housed in an isolated environment. Enriched housing, however, increased timing precision. Acute administration of methylphenidate partially reversed the effects of enriched housing. Implications of these results in the assessment and treatment of ADHD-related impulsivity are discussed.
ContributorsHill, Jade C (Author) / Sanabria, Federico (Thesis advisor) / Killeen, Peter (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2011
Description
Chronic stress results in functional and structural changes to the hippocampus. Decades of research has led to insights into the mechanisms underlying the chronic stress-induced deficits in hippocampal-mediated cognition and reduction of dendritic complexity of hippocampal neurons. Recently, a considerable focus of chronic stress research has investigated the mechanisms behind the improvements in hippocampal mediated cognition when chronic stress ends and a post-stress rest period is given. Consequently, the goal of this dissertation is to uncover the mechanisms that allow for spatial ability to improve in the aftermath of chronic stress. In chapter 2, the protein brain derived neurotrophic factor (BDNF) was investigated as a mechanism that allows for spatial ability to show improvements following the end of chronic stress. It was found that decreasing the expression of BDNF in the hippocampus prevented spatial memory improvements following a post-stress rest period. Chapter 3 was performed to determine whether hippocampal CA3 apical dendritic complexity requires BDNF to show improvements following a post-stress rest period, and whether a receptor for BDNF, TrkB, mediates the improvements of spatial ability and dendritic complexity in a temporal manner, i.e. during the rest period only. These experiments showed that decreased hippocampal BDNF expression prevented improvements in dendritic complexity, and administration of a TrkB antagonist during the rest period also prevented the improvements in spatial ability and dendritic complexity. In chapter 4, the role of the GABAergic system on spatial ability following chronic stress and a post-stress rest period was investigated. Following chronic stress, it was found that male rats showed impairments on the acquisition phase of the RAWM and this correlated with limbic glutamic acid decarboxylase, a marker for GABA. In chapter 5, a transgenic mouse that expresses a permanent marker on all GABAergic interneurons was used to assess the effects of chronic stress and a post-stress rest period on hippocampal GABAergic neurons. While no changes were found on the total number of GABAergic interneurons, specific subtypes of GABAergic interneurons were affected by stressor manipulations. Collectively, these studies reveal some mechanisms behind the plasticity seen in the hippocampus in response to a post-stress rest period.
ContributorsOrtiz, J. Bryce (Author) / Conrad, Cheryl D. (Thesis advisor) / Newbern, Jason M. (Committee member) / Orchinik, Miles (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2018
Description
The purpose of this study, originally, was to contribute to the completion of a meta-analysis conducted by Mara Wierstra from the University of Virginia. Wierstra had requested individual participant data from two separate studies conducted in our lab: "Acute bouts of assisted cycling improves cognitive and upper extremity movement functions in adolescents with Down syndrome" and "Assisted Cycling Therapy (ACT) improves inhibition in adolescents with autism spectrum disorder." From the data requested, the participants were required to complete three separate tests (i.e., Tower of London, Trail Making Task and the Stroop Test). After compiling the data and sending it to her, we decided to conduct a small meta-analysis of our own, drawing connecting conclusions from the data from the two studies. We concluded that observationally our data suggest an advantage for ACT over voluntary cycling and no cycling across two separate populations (i.e., Autism Spectrum Disorder and Down syndrome), and across different measures of executive function (i.e., Stroop Test, Trail Making Test, and Tower of London). The data suggest that the ACT interventions may promote the upregulation of neurotropic factors leading to neurogenesis in the prefrontal cortex of the brain.
ContributorsParker, Cade Joseph (Author) / Ringenbach, Shannon (Thesis director) / Holzapfel, Simon (Committee member) / School of Nutrition and Health Promotion (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Chronic stress impairs spatial working memory, attention set-shifting, and response inhibition. The relationship between these functions and the potential underlying neurocircuitry, such as the medial prefrontal cortex (mPFC), needs further research to understand how chronic stress impacts these functions. This study focused on the infralimbic (IL) and prelimbic (PRL) regions of the mPFC, to examine its involvement in two behavioral tasks, fixed minimum interval (FMI) and radial arm water maze (RAWM), following chronic stress, and the relationship between the two paradigms. A previous study failed to find a significant correlation between spatial working memory and response, both functions mediated by the PFC, even though chronic stress disrupted both outcomes. Thus, the purpose of this study was to investigate the functional activation of the mPFC, following chronic stress in these two paradigms, in order to gain an understanding of the neurocircuitry involved within this region. The behavioral outcomes were performed prior to my involvement in the project, and the results corroborate previous findings that chronic stress impairs response inhibition on FMI and spatial working memory on RAWM. My honors thesis involved quantifying the immunohistochemistry-stained tissue to assess the functional activation of the mPFC. Over the course of six months, my work involved identifying the border between IL and PRL regions by overlaying captured images of tissues, starting at a lower magnification of 40x. Afterwards, images were recaptured at higher magnifications (100x) to quantify Fos-like counts of functional activation. No overt changes were found following chronic stress in Fos-like counts after performance on FMI or RAWM. However, response inhibition on the FMI task showed a relationship with the IL function; non-stressed rats displayed a positive correlation between response inhibition and Fos-like profiles. In contrast, chronically stressed rats revealed a negative correlation between response inhibition and Fos-like profiles. The IL cortex is revealed to facilitate extinction of a learned behavior. Thus, these results present a possible interpretation that there is an association, non-stressed rats suppressing a previously learned response, being formed.
ContributorsLe, Brittany Quynh (Author) / Conrad, Cheryl (Thesis director) / Sanabria, Federico (Committee member) / Judd, Jessica (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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 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.
ContributorsJudd, Jessica Michelle (Author) / Conrad, Cheryl D. (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2020