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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
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
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