Matching Items (12)
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 restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the hippocampus with adeno- associated viral vectors containing the coding sequence for short interfering (si)RNA directed against BDNF or a scrambled sequence (Scr), with both containing the coding information for green fluorescent protein to aid in anatomical localization. Rats were then chronically restrained (wire mesh, 6h/d/21d) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str-Imm) or following a 21-day post-stress recovery period (Str-Rec). All groups learned the RAWM task similarly, but differed on the memory retention trial. Rats in the Str-Imm group, regardless of viral vector contents, committed more errors in the spatial reference memory domain than did non-stressed controls. Importantly, the typical improvement in spatial memory following recovery from chronic stress was blocked with the siRNA against BDNF, as Str-Rec-siRNA performed worse on the RAWM compared to the non-stressed controls or Str-Rec-Scr. These effects were specific for the reference memory domain as repeated entry errors that reflect spatial working memory were unaffected by stress condition or viral vector contents. These results demonstrate that hippocampal BDNF is necessary for the recovery from stress-induced hippocampal dependent spatial memory deficits in the reference memory domain.
ContributorsOrtiz, J. Bryce (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Taylor, Sara (Committee member) / Bimonte-Nelson, Heather A. (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
With a growing number of adults with autism spectrum disorder (ASD), more and more research has been conducted on majority male cohorts with ASD from young, adolescence, and some older age. Currently, males make up the majority of individuals diagnosed with ASD, however, recent research states that the gender gap is closing due to more advanced screening and a better understanding of how females with ASD present their symptoms. Little research has been published on the neurocognitive differences that exist between older adults with ASD compared to neurotypical (NT) counterparts, and nothing has specifically addressed older women with ASD. This study utilized neuroimaging and neuropsychological tests to examine differences between diagnosis and sex of four distinct groups: older men with ASD, older women with ASD, older NT men, and older NT women. In each group, hippocampal size (via FreeSurfer) was analyzed for differences as well as correlations with neuropsychological tests. Participants (ASD Female, n = 12; NT Female, n = 14; ASD Male, n = 30; NT Male = 22), were similar according to age, IQ, and education. The results of the study indicated that the ASD Group as a whole performed worse on executive functioning tasks (Wisconsin Card Sorting Test, Trails Making Test) and memory-related tasks (Rey Auditory Verbal Learning Test, Weschler Memory Scale: Visual Reproduction) compared to the NT Group. Interactions of sex by diagnosis approached significance only within the WCST non-perseverative errors, with the women with ASD performing worse than NT women, but no group differences between men. Effect sizes between the female groups (ASD female vs. NT female) showed more than double that of the male groups (ASD male vs. NT male) for all WCST and AVLT measures. Participants with ASD had significantly smaller right hippocampal volumes than NT participants. In addition, all older women showed larger hippocampal volumes when corrected for total intracranial volume (TIV) compared to all older men. Overall, NT Females had significant correlations across all neuropsychological tests and their hippocampal volumes whereas no other group had significant correlations. These results suggest a tighter coupling between hippocampal size and cognition in NT Females than NT Males and both sexes with ASD. This study promotes further understanding of the neuropsychological differences between older men and women, both with and without ASD. Further research is needed on a larger sample of older women with and without ASD.
ContributorsWebb, Christen Len (Author) / Braden, B. Blair (Thesis advisor) / Azuma, Tamiko (Committee member) / Dixon, Maria (Committee member) / Arizona State University (Publisher)
Created2019
Description
Schizophrenia is a debilitating psychiatric disorder with poorly understood genetic and environmental factors. An allelic variant of complement component 4 (C4), a protein first identified in innate immune response is strongly associated with schizophrenia. In the brain, activity of C4 leads to dendritic pruning, a process that may be causal in disease progression. Environmental factors, such as early life exposure to significant stressors also associate with increased risk of schizophrenia in later life. My hypothesis is that these factors do not act independently, but rather in tandem to influence disease etiology.
This hypothesis is supported by previous studies demonstrating that stress-induced elevation of glucocorticoids increases the transcription of C4. I propose that activated glucocorticoid receptors directly increase C4 protein expression as a transcription factor activator. Additionally, I propose that activated glucocorticoid receptors inhibit the expression of the transcription factor nuclear factor-light-chain-enhancer of activated B cells (NF-κB), thereby leading to decreased expression of the C4 inhibitor CUB and Sushi multiple domains 1 (CSMD1).
Glucocorticoid receptors and C4 are richly expressed in the hippocampus, a region critical in memory consolidation, spatial, and declarative memory. I propose that stress-induced upregulation of C4 activity in the hippocampus promotes excessive synaptic pruning, contributing to specific deficits and hippocampal shrinkage seen in schizophrenia. Stress exposure during fetal development and adolescence likely acts through the proposed mechanisms to increase hippocampal C4 activity and subsequent schizophrenia risk. These mechanisms may reveal novel interactions between environmental and genetic risk factors in the etiology of schizophrenia through complement activation.
This hypothesis is supported by previous studies demonstrating that stress-induced elevation of glucocorticoids increases the transcription of C4. I propose that activated glucocorticoid receptors directly increase C4 protein expression as a transcription factor activator. Additionally, I propose that activated glucocorticoid receptors inhibit the expression of the transcription factor nuclear factor-light-chain-enhancer of activated B cells (NF-κB), thereby leading to decreased expression of the C4 inhibitor CUB and Sushi multiple domains 1 (CSMD1).
Glucocorticoid receptors and C4 are richly expressed in the hippocampus, a region critical in memory consolidation, spatial, and declarative memory. I propose that stress-induced upregulation of C4 activity in the hippocampus promotes excessive synaptic pruning, contributing to specific deficits and hippocampal shrinkage seen in schizophrenia. Stress exposure during fetal development and adolescence likely acts through the proposed mechanisms to increase hippocampal C4 activity and subsequent schizophrenia risk. These mechanisms may reveal novel interactions between environmental and genetic risk factors in the etiology of schizophrenia through complement activation.
ContributorsHoegh, Emily Marie (Author) / Orchinik, Miles (Thesis director) / Newbern, Jason (Committee member) / Talboom, Joshua (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects 5.4 million Americans. AD leads to memory loss, changes in behavior, and death. The key hallmarks of the disease are amyloid plaques and tau tangles, consisting of amyloid-β oligomers and hyperphosphorylated tau, respectively.
Rho-associated, coiled-coil-containing protein kinase (ROCK) is an enzyme that plays important roles in neuronal cells including mediating actin organization and dendritic spine morphogenesis. The ROCK inhibitor Fasudil has been shown to increase learning and working memory in aged rats, but another ROCK inhibitor, Y27632, was shown to impair learning and memory. I am interested in exploring how these, and other ROCK inhibitors, may be acting mechanistically to result in very different outcomes in treated animals.
Preliminary research on thirteen different ROCK inhibitors provides evidence that while Fasudil and a novel ROCK inhibitor, T343, decrease tau phosphorylation in vitro, Y27632 increases tau phosphorylation at a low dose and decreases at a high dose. Meanwhile, novel ROCK inhibitor T299 increases tau phosphorylation at a high dosage.
Further, an in vivo study using triple transgenic AD mice provides evidence that Fasudil improves reference memory and fear memory in both transgenic and wild-type mice, while Y27632 impairs reference memory in transgenic mice. Fasudil also decreases tau phosphorylation and Aβ in vivo, while Y27632 significantly increases the p-tau to total tau ratio.
Rho-associated, coiled-coil-containing protein kinase (ROCK) is an enzyme that plays important roles in neuronal cells including mediating actin organization and dendritic spine morphogenesis. The ROCK inhibitor Fasudil has been shown to increase learning and working memory in aged rats, but another ROCK inhibitor, Y27632, was shown to impair learning and memory. I am interested in exploring how these, and other ROCK inhibitors, may be acting mechanistically to result in very different outcomes in treated animals.
Preliminary research on thirteen different ROCK inhibitors provides evidence that while Fasudil and a novel ROCK inhibitor, T343, decrease tau phosphorylation in vitro, Y27632 increases tau phosphorylation at a low dose and decreases at a high dose. Meanwhile, novel ROCK inhibitor T299 increases tau phosphorylation at a high dosage.
Further, an in vivo study using triple transgenic AD mice provides evidence that Fasudil improves reference memory and fear memory in both transgenic and wild-type mice, while Y27632 impairs reference memory in transgenic mice. Fasudil also decreases tau phosphorylation and Aβ in vivo, while Y27632 significantly increases the p-tau to total tau ratio.
ContributorsTurk, Mari (Author) / Huentelman, Matt (Thesis advisor) / Kusumi, Kenro (Thesis advisor) / Jensen, Kendall (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2017
Description
The aim of this study was to explore cross-sectional and longitudinal aging differences in immediate and delayed visual and verbal memory abilities in individuals with Autism Spectrum Disorder (ASD) compared with neurotypicals (NTs). We measured hippocampal size, fornix fractional anisotropy (FA), and hippocampal and fornix freewater to understand how aging impacts memory structures. Longitudinal findings highlight vulnerabilities in immediate verbal memory and hippocampal volume, while cross-sectional findings indicate fornix freewater may increase at a faster rate in adults with ASD. Future research will examine cognitive and structural sex differences and will study how cognitive measures correlate with structural measures.
ContributorsSullivan, Georgia Rose (Author) / Braden, B. Blair (Thesis director) / Ofori, Edward (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
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
Description
Background: The hippocampus is a critical brain structure for memory formation and other aspects of cognition. The hippocampus and the white matter tracts connecting it to other parts of the brain are known to lose volume and integrity with aging. For populations with prior compromised hippocampal integrity, such as those with autism spectrum disorder (ASD), it is less well known how the hippocampus and its connections will respond to aging. In children with ASD, there may be an initial period of enlarged hippocampi, after which there is a trajectory of faster decline in volume compared to neurotypicals (NT). We have previously identified reduced hippocampal volumes and fornix white matter integrity in middle-age and older adults with ASD compared to matched NT adults. However, freewater (FW) may be a more sensitive structural integrity measure of the hippocampal complex. FW is present in the brain as cerebrospinal fluid but also accumulates within the extracellular spaces indicative of reduced gray matter density and increased axon degeneration. FW shows promise as a more sensitive biomarker for Parkinson’s and Alzheimer’s disease. This study evaluated age-related hippocampal complex FW differences in adults with and without ASD across the adult lifespan. We hypothesized that adults with ASD would demonstrate a larger age association with increasing FW in the hippocampus and fornix, compared to NT adults, and that FW would be a more sensitive brain measure than traditional fractional anisotropy (FA).
Methods: The study consisted of 79 participants with ASD (59 male, 20 female; ages 18-70, mean=40.27 [±17] years) and 77 NT participants (46 male, 31 female; ages 18-71, mean=40.33 [±16] years). Hippocampal and fornix FW and FA values were generated from diffusion tensor images obtained along 32 directions using a b-value of 2500 s/mm2 in the axial direction with 3 mm slice resolution. These images were then processed for eddy current, distortion, b-vec and motion correction, skull stripped, and non-linear registered using Advanced Normalization Tools (ANTs) to the subject’s T1 image. FW and FA maps were calculated using custom written MatLab code and standard atlases containing the hippocampus and fornix were applied.
Results: The right hippocampus showed a significant diagnosis by age interaction (p=0.018), such that the increase in FW with age was greater for adults with ASD. The left hippocampus diagnosis by age interaction approached significance (p=0.055). Similarly, the right fornix showed a significant diagnosis by age interaction (p=0.044), with increases in FW with age as greater for adults with ASD, and the left fornix diagnosis by age interaction approached significance (p=0.053). FA values showed no significant diagnosis by age interactions.
Conclusion: In the hippocampus and fornix, the association between increasing FW and increasing age was more pronounced for adults with ASD than matched NT adults. This may mean that as adults with ASD age, these regions will degenerate faster than their NT peers, which could have implications for accelerated age-related memory decline. However, a notable limitation is the cross-sectional nature of the study. Our ongoing longitudinal study will inform a more definitive picture of brain aging with ASD.
Methods: The study consisted of 79 participants with ASD (59 male, 20 female; ages 18-70, mean=40.27 [±17] years) and 77 NT participants (46 male, 31 female; ages 18-71, mean=40.33 [±16] years). Hippocampal and fornix FW and FA values were generated from diffusion tensor images obtained along 32 directions using a b-value of 2500 s/mm2 in the axial direction with 3 mm slice resolution. These images were then processed for eddy current, distortion, b-vec and motion correction, skull stripped, and non-linear registered using Advanced Normalization Tools (ANTs) to the subject’s T1 image. FW and FA maps were calculated using custom written MatLab code and standard atlases containing the hippocampus and fornix were applied.
Results: The right hippocampus showed a significant diagnosis by age interaction (p=0.018), such that the increase in FW with age was greater for adults with ASD. The left hippocampus diagnosis by age interaction approached significance (p=0.055). Similarly, the right fornix showed a significant diagnosis by age interaction (p=0.044), with increases in FW with age as greater for adults with ASD, and the left fornix diagnosis by age interaction approached significance (p=0.053). FA values showed no significant diagnosis by age interactions.
Conclusion: In the hippocampus and fornix, the association between increasing FW and increasing age was more pronounced for adults with ASD than matched NT adults. This may mean that as adults with ASD age, these regions will degenerate faster than their NT peers, which could have implications for accelerated age-related memory decline. However, a notable limitation is the cross-sectional nature of the study. Our ongoing longitudinal study will inform a more definitive picture of brain aging with ASD.
ContributorsAlvar, Jocelyn R (Author) / Braden, Brittany Blair (Thesis director) / Ofori, Edward (Committee member) / School of Life Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Down Syndrome (DS), caused by the trisomy 21, is the most common intellectual developmental disorder. Children with DS display deficits in ample memory tasks attributed to alterations in memory-related brain structures, including the hippocampus. Although, many studies in DS focused on development of the brain during prenatal stages, little is known about the cellular evolution of the hippocampus in postnatal periods in DS. Therefore, here we examined the neurochemical spatiotemporal development of neuronal profiles in pediatric postnatal hippocampus in DS and neurotypical developing (NTD) controls. A quantitative and qualitative neuronal distribution was performed in hippocampal sections containing the proper hippocampus, dentate gyrus (DG) and subiculum obtained at autopsy from 1 day to 3 year-old infants in DS and NTD age-matched controls using antibodies against the non-phosphorylated high-molecular-weight neurofilament, a marker of differentiated neurons (SMI-32), the calcium binding protein calbindin D-28k (CAB), and the migration neuronal marker microtubule-associated protein doublecortin (DCX). In addition, Aβ and phosphorylated tau was also immunohistochemically examined in the hippocampus using 6E10, Aβ1-42 and the phosphorylated CP-13 and AT8 tau antibodies, respectively. We found APP/Aβ immunoreactivity, but not Aβ1-42, in diffuse-like plaques in the hippocampus from 1 day to 3 year old infants and young children in DS and NTD cases. By contrast, phosphorylated fetal tau was not immunodetected in the hippocampus at any age in both groups. SMI-32 immunolabeled neurons were observed in the hilus, CA2 field and subiculum in early postnatal cases in DS and NTD. The number of SMI-32 immunoreactive (ir) granule cells in the DG were significantly decreased in DS compared to NTD. While a strong DCX immunoreactivity was observed in the granule cells of the DG in the hippocampus in both groups at early postnatal stages, a more accelerated reduction was observed in DS. CAB-ir neuronal distribution in the postnatal hippocampus was comparable between the youngest and the oldest infants in NTD and DS. In addition, strong positive correlations were observed between DG-DCX-ir cells numbers and both DG-CAB-ir and DG-SMI-32-ir values as well as negative correlations between the brain weight and DG granule cell-ir numbers for all markers in DS. These findings suggest that neuronal maturation and migration in the hippocampus are compromised in early postnatal stages of the development in DS and may contribute to the intellectual disabilities observed in this group.
ContributorsMoreno, David (Co-author) / Perez, Sylvia E. (Co-author, Thesis director) / Velazquez, Ramon (Thesis director) / Schafernak, Kristian T. (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2020-05