Cooper, Daniel D. (2019) What underlies the benefits of environmental enrichment on the brain? : investigation of a neurotrophin-stimulaed kinase reveals its role in regulating sociability and experience-dependent changes in hippocampal gene expression. PhD thesis, University of Warwick.

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Abstract

Cognitive impairment, as a result of developmental issues, age and diseases such as dementia have the potential to affect anyone, and are a significant source of socioeconomic burden to both the healthcare system and the families of those affected. Environmental enrichment has emerged as a non-pharmacological intervention that can improve cognitive function and ameliorate the effects of cognitive impairment. Understanding the mechanisms underpinning these enrichment-mediated benefits are of great interest for designing effective interventions to boost cognitive function. MSK1 is thought to act as a transducer of MAPK signalling to gene expression within neurons, in response to extracellular signals upregulated by environmental enrichment, by phosphorylating the nuclear transcription factor CREB, and modifying chromatin structure through histone H3 phosphorylation. As such, MSK1 is positioned to play an important role in mediating neuronal changes within the hippocampus in response to environmental enrichment by regulating activity-dependent transcriptional changes.

Here, mice homozygous for a kinase-inactivate form of MSK1 fail to phosphorylate CREB in response to BDNF-TrkB stimulation, and the kinase activity of MSK1 is demonstrated to regulate over half of the transcriptional changes induced following 3 months of environmental enrichment. Genes regulated by MSK1 included the IEGs Egr1 and Arc/Arg3.1, and appeared to be involved in restructuring the hippocampal extracellular environment, regulating primary cilium structure and MAPK signalling. Interestingly expression of MSK1 itself and MAPK pathway signalling appeared to be regulated in a homeostatic manner by environmental enrichment.

Further experiments with a shorter 1 week period of enrichment indicated a potential role for the kinase activity of MSK1 in a transient environmental enrichment-induced decrease in AMPAR-mediated glutamatergic transmission and a potential effect in remodelling CA3/CA1 synaptic signalling, however both 1 week and 5 week periods of EE failed to show an MSK1 kinase activity-dependent effect on several aspects of CA1 neuron morphology, synaptic transmission, short-term presynaptic plasticity and synaptic transmission. Exposure to 1 week and 5 week periods of EE was also associated with xiv decreased postsynaptic expression of calcium-permeable AMPARs which could act as a potential form of EE-regulated metaplasticity at SC/CA1 synapses. Behavioural assays also revealed a novel role for MSK1 in regulating novelty-motivated behaviour, with kinase inactivation associated with reduced object investigation and impaired social memory, regardless of enrichment. This work implicates MSK1 as an important regulator of experience-dependent structural and synaptic changes within the hippocampus, further adding to the body of work characterising the kinase function of MSK1 already established by the Frenguelli lab.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QH Natural history > QH426 Genetics Q Science > QP Physiology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Library of Congress Subject Headings (LCSH):	Cognition disorders -- Treatment, Developmental disabilities -- Treatment, Protein kinases, Gene expression, Hippocampus (Brain), Neuroplasticity
Official Date:	September 2019
Dates:	Date Event September 2019 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	School of Life Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Frenguelli, Bruno ; Hebenstreit, Dr. Daniel ; Wall, Dr. Mark ; Ludvig, Dr. Elliot
Sponsors:	Biotechnology and Biological Sciences Research Council (Great Britain)
Format of File:	pdf
Extent:	xx, 231 leaves : illustrations (chiefly color), color charts.
Language:	eng

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