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  1. KEEP
  2. Theses and Dissertations
  3. Barrett, The Honors College Thesis/Creative Project Collection
  4. Motor Learning Loss Due to MEK1 Hyperactivation in Cortical Excitatory Neurons
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Motor Learning Loss Due to MEK1 Hyperactivation in Cortical Excitatory Neurons

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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.

Date Created
2016-12
Contributors
  • Roose, 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)
Topical Subject
  • Behavioral Neuroscience
  • Mouse Model Systems
  • Erk/MAPK
  • Camek
  • Cre-Lox Recombination
  • RASopathies
  • Developmental Neuroscience
Resource Type
Text
Extent
50 pages
Language
eng
Copyright Statement
In Copyright
Primary Member of
Barrett, The Honors College Thesis/Creative Project Collection
Series
Academic Year 2016-2017
Handle
https://hdl.handle.net/2286/R.I.42804
Level of coding
minimal
Cataloging Standards
asu1
System Created
  • 2017-10-30 02:50:58
System Modified
  • 2021-08-11 04:09:57
  •     
  • 1 year 7 months ago
Additional Formats
  • OAI Dublin Core
  • MODS XML

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