Matching Items (3)
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- All Subjects: Behavioral Neuroscience
- All Subjects: RASopathies
- All Subjects: Cell Signaling
- Creators: Hilbert, Alexander Robert
Description
Hormone therapy (HT) containing 17beta-estradiol (E2) can greatly reduce physiological symptoms associated with declines in ovarian hormones that are seen with menopause. HT containing E2 has also been shown to play a beneficial role in cognitive function. There is discrepancy, however, surrounding which dose of E2 is the most optimal for cognition. A previous rodent behavioral study in our laboratory evaluated the effects of different doses of E2 on spatial memory performance, and results indicated that rats treated with a low E2 dose (0.3 g E2) made fewer working memory incorrect (WMI) errors, indicating enhanced spatial memory performance, compared to vehicle (0.1ml sesame oil)- and high E2 (3.0 g E2)- treated groups. This finding warranted the present investigation with the overarching aim to evaluate underlying neuromolecular mechanisms that may be modulating these cognitive effects. Both the insulin-like growth factor-1 receptor (IGF1-R) and extracellular regulated kinase (Erk) 2 have been observed to mediate E2-induced memory enhancements. We used the Western Blot to measure IGF1-R and activated Erk1/2 expression in brain regions involved in learning and memory, including the dorsal hippocampus, ventral CA1/CA2 hippocampus, entorhinal cortex, and perirhinal cortex. Results demonstrated a linear relationship between IGF1-R expression and administered E2 dose in the perirhinal cortex, whereby IGF1-R expression increased as the dose of E2 increased. Additionally, in the perirhinal cortex, IGF1-R expression tended to increase as activated Erk1 increased for all treatment groups. Further, number of WMI errors tended to decrease as IGF1-R expression and activated Erk1 expression in the perirhinal cortex tended to increase in the low E2 treatment group. Collectively, these findings suggest a downstream-dependent relationship between IGF1-R and activated Erk1 in the perirhinal cortex that may be contributing to the enhancements in spatial memory performance observed in animals in the low E2 treatment group. These findings are a crucial piece in the greater understanding of what underlying molecular mechanisms may be modulating a cognitively beneficial dose of E2, and further contribute to the search for a HT that would be beneficial for cognition in menopausal women.
ContributorsNeeley, Rachel Elizabeth (Author) / Bimonte-Nelson, Heather (Thesis director) / George, Andrew (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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