Matching Items (7)
Filtering by
- All Subjects: Chronic Stress
- Creators: Sanabria, Federico
- Creators: Newbern, Jason M.
- Creators: Boyll, Piper Savannah
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
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
Monoamine neurotransmitters (e.g., serotonin, norepinephrine, and dopamine) are powerful modulators of mood and cognitive function in health and disease. We have been investigating the modulation of monoamine clearance in select brain regions via organic cation transporters (OCTs), a family of nonselective monoamine transporters. OCTs are thought to complement the actions of selective monoamine transporters in the brain by helping to clear monoamines from the extracellular space; thus, assisting to terminate the monoamine signal. Of particular interest, stress hormones (corticosterone; CORT) inhibit OCT3-mediated transport of monoamine, to putatively lead to prolonged monoamine signaling. It has been demonstrated that stress levels of CORT block OCT3 transport in the rat hypothalamus, an effect that likely underlies the rapid, stress-induced increase in local monoamines. We examined the effect of chronic variable stress (CVS) on the development of mood disorders and OCT3 expression in limbic and hypothalamic regions of the rat brain. Animals subjected to CVS (14-days with random stressor exposure two times/day) showed reduced body weight gain, indicating that CVS was perceived as stressful. However, behavioral tests of anxiety and depressive-like behaviors in rats showed no group differences. Although there were no behavioral effects of stress, molecular analysis revealed that there were stress-related changes in OCT3 protein expression. In situ hybridization data confirmed that OCT3 mRNA is expressed in the hippocampus, amygdala, and hypothalamus. Analysis of Western blot data by two-way ANOVA revealed a significant treatment effect on OCT3 protein levels, with a significant decrease in OCT3 protein in the amygdala and hippocampus in CVS rats, compared to controls. These data suggest an important role for CORT sensitive OCT3 in the reduction of monoamine clearance during stress.
ContributorsBoyll, Piper Savannah (Author) / Orchinik, Miles (Thesis director) / Conrad, Cheryl (Committee member) / Talboom, Joshua (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.
ContributorsRoose, Cassandra Ann (Author) / Newbern, Jason M. (Thesis director) / Olive, Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
ContributorsHilbert, Alexander Robert (Author) / Newbern, Jason (Thesis director) / Olive, M. Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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