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- All Subjects: Anxiety
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Description
The current study investigated whether intermittent restraint stress (IRS) would impair fear extinction learning and lead to increased anxiety and depressive- like behaviors and then be attenuated when IRS ends and a post- stress rest period ensues for 6 weeks. Young adult, male Sprague Dawley rats underwent restraint stress using wire mesh (6hr/daily) for five days with two days off before restraint resumed for three weeks for a total of 23 restraint days. The groups consisted of control (CON) with no restraint other than food and water restriction yoked to the restrained groups, stress immediate (STR-IMM), which were restrained then fear conditioned soon after the end of the IRS paradigm, and stress given a rest for 6 weeks before fear conditioning commenced (STR-R6). Rats were fear conditioned by pairing a 20 second tone with a footshock, then given extinction training for two days (15 tone only on each day). On the first day of extinction, all groups discriminated well on the first trial, but then as trials progressed, STR-R6 discriminated between tone and context less than did CON. On the second day of extinction, STR- IMM froze more to context in the earlier trials than compared to STR-R6 and CON. As trials progressed STR-IMM and STR-R6 froze more to context than compared to CON. Together, CON discriminated between tone and context better than did STR-IMM and STR-R6. Sucrose preference, novelty suppressed feeding, and elevated plus maze was performed after fear extinction was completed. No statistical differences were observed among groups for sucrose preference or novelty suppressed feeding. For the elevated plus maze, STR-IMM entered the open arms and the sum of both open and closed arms fewer than did STR- R6 and CON. We interpret the findings to suggest that the stress groups displayed increased hypervigilance and anxiety with STR-R6 exhibiting a unique phenotype than that of STR-IMM and CON.
ContributorsShah, Vrishti Bimal (Author) / Conrad, Cheryl (Thesis director) / Newbern, Jason (Committee member) / Judd, Jessica (Committee member) / School of Life Sciences (Contributor) / Sanford School of Social and Family Dynamics (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Neuroinflammation is an important secondary injury response occurring after traumatic brain injury (TBI). Anxiety-like disorders are commonly exacerbated after TBI and are mediated through the amygdala; however, the amygdala remains understudied despite its important contribution in processing emotional and stressful stimuli. Therefore, we wanted to study neuroinflammation after experimental TBI using midline fluid percussion in rodent models. We assessed microglia morphology over time post-injury in two circuit related nuclei of the amygdala, the basolateral amygdala (BLA) and central amygdala of the nucleus (CeA), using skeletal analysis. We also looked at silver staining and glial fibrillary acidic protein (GFAP) to evaluate the role of neuropathology and astrocytosis to evaluate for neuroinflammation in the amygdala. We hypothesized that experimental diffuse TBI leads to microglial activation in the BLA-CeA circuitry over time post-injury due to changes in microglial morphology and increased astrocytosis in the absence of neuropathology. Microglial cell count was found to decrease in the BLA at 1 DPI before returning to sham levels by 28 DPI. No change was found in the CeA. Microglial ramification (process length/cell and endpoints/cell) was found to decrease at 1DPI compared to sham in the CeA, but not in the BLA. Silver staining and GFAP immunoreactivity did not find any evidence of neurodegeneration or activated astrocytes in the respectively. Together, these data indicate that diffuse TBI does not necessarily lead to the same microglial response in the amygdala nuclei, although an alternative mechanism for a neuroinflammatory response in the CeA likely contributes to the widespread neuronal and circuit dysfunction that occurs after TBI.
ContributorsHur, Yerin (Author) / Newbern, Jason (Thesis director) / Thomas, Theresa Currier (Committee member) / Beitchman, Joshua (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Adults with autism spectrum disorder (ASD) face heightened risk of co-occurring psychiatric conditions, especially depression and anxiety disorders, which contribute to seven-fold higher suicide rates than the general population. Mindfulness-based stress reduction (MBSR) is an 8-week meditation intervention centered around training continuous redirection of attention toward present moment experience, and has been shown to improve mental health in autistic adults. However, the underlying therapeutic neural mechanisms and whether behavioral and brain changes are mindfulness-specific have yet to be elucidated. In this randomized clinical trial, I utilized functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to characterize fMRI functional activity (Study 1) and connectivity (Study 2) and EEG neurophysiological (Study 3) changes between MBSR and a social support/relaxation education (SE) active control group. Study 1 revealed an MBSR-specific increase in the midcingulate cortex fMRI blood oxygen level dependent signal which was associated with reduced depression. Study 2 identified nonspecific intervention improvements in depression, anxiety, and autistic, and MBSR-specific improvements in the mindfulness trait ‘nonjudgment toward experience’ and in the executive functioning domain of working memory. MBSR-specific decreases in insula-thalamus and frontal pole-posterior cingulate functional connectivity was associated with improvements in anxiety, mindfulness traits, and working memory abilities. Both MBSR and SE groups showed decreased amygdala-sensorimotor and frontal pole-insula connectivity which correlated with reduced depression. Study 3 consisted of an EEG spectral power analysis at high-frequency brainwaves associated with default mode network (DMN) activity. Results showed MBSR-specific and nonspecific decreases in beta- and gamma-band power, with effects being generally more robust in the MBSR group; additionally, MBSR-specific decreases in posterior gamma correlated with anxiolytic effects. Collectively, these studies suggest: 1) social support is sufficient for improvements in depression, anxiety, and autistic traits; 2) MBSR provides additional benefits related to mindfulness traits and working memory; and 3) distinct and shared neural mechanisms of mindfulness training in adults with ASD, implicating the salience and default mode networks and high-frequency neurophysiology. Findings bear relevance to the development of personalized medicine approaches for psychiatric co-morbidity in ASD, provide putative targets for neurostimulation research, and warrant replication and extension using advanced multimodal imaging approaches.
ContributorsPagni, Broc (Author) / Braden, B. Blair (Thesis advisor) / Newbern, Jason (Thesis advisor) / Davis, Mary (Committee member) / Brewer, Gene (Committee member) / Arizona State University (Publisher)
Created2022
Description
MicroRNAs are small, non-coding transcripts that post-transcriptionally regulate expression of multiple genes. Recently microRNAs have been linked to the etiology of neuropsychiatric disorders, including drug addiction. Following genome-wide sequence analyses, microRNA-495 (miR-495) was found to target several genes within the Knowledgebase of Addiction-Related Genes (KARG) database and to be highly expressed in the nucleus accumbens (NAc), a pivotal brain region involved in reward and motivation. The central hypothesis of this dissertation is that NAc miR-495 regulates drug abuse-related behavior by targeting several addiction-related genes (ARGs). I tested this hypothesis in two ways: 1) by examining the effects of viral-mediated miR-495 overexpression or inhibition in the NAc of rats on cocaine abuse-related behaviors and gene expression, and 2) by examining changes in NAc miR-495 and ARG expression as a result of brief (i.e., 1 day) or prolonged (i.e., 22 days) cocaine self-administration. I found that behavioral measures known to be sensitive to motivation for cocaine were attenuated by NAc miR-495 overexpression, including resistance to extinction of cocaine conditioned place preference (CPP), cocaine self-administration on a high effort progressive ratio schedule of reinforcement, and cocaine-seeking behavior during both extinction and cocaine-primed reinstatement. These effects appeared specific to cocaine, as there was no effect of NAc miR-495 overexpression on a progressive ratio schedule of food reinforcement. In contrast, behavioral measures known to be sensitive to cocaine reward were not altered, including expression of cocaine CPP and cocaine self-administration under a low effort FR5 schedule of reinforcement. Importantly, the effects were accompanied by decreases in NAc ARG expression, consistent with my hypothesis. In further support, I found that NAc miR-495 levels were reduced and ARG levels were increased in rats following prolonged, but not brief, cocaine self-administration experience. Surprisingly, inhibition of NAc miR-495 expression also decreased both cocaine-seeking behavior during extinction and NAc ARG expression, which may reflect compensatory changes or unexplained complexities in miR-495 regulatory effects. Collectively, the findings suggest that NAc miR-495 regulates ARG expression involved in motivation for cocaine. Therefore, using microRNAs as tools to target several ARGs simultaneously may be useful for future development of addiction therapeutics.
ContributorsBastle, Ryan (Author) / Neisewander, Janet (Thesis advisor) / Newbern, Jason (Committee member) / Nikulina, Ella (Committee member) / Perrone-Bizzozero, Nora (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2016