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Epigenetic regulation of stroke recovery : changes in DNA methylation and micro-RNA regulation following stroke and EGF/EPO neurogenesis therapyLowings, Michael D, University of Lethbridge. Faculty of Arts and Science January 2010 (has links)
Stroke is one of the most common, and damaging, neurological afflictions.
Stroke causes widespread and variable chronic effects, due to the limited regenerative
ability of the adult brain. Altered gene expression induces neuronal changes
necessary for plasticity-dependent recovery, effects which can be enhanced by growth
hormone-based pharmaceuticals. These processes are driven by alterations in the
informational capacity of the genome – changes driven by epigenetic regulators.
Following experimental strokes, and treatment with EGF and EPO, this study shows
that two epigenetic regulatory mechanisms, DNA methylation and microRNA
regulation, are significantly altered, both in treated and untreated animals.
Specifically, treatment induces a net global suppression of miRNA activity, which
appears to modify the physical behaviour of neurons in domains ranging from
plasticity and memory formation, growth and replication, and potentially even to
neurological disease signalling. The confirmation of epigenetic alterations following
a stroke indicates a future role for epigenetic neuro-pharmacology in stroke
management. / x, [99] leaves : ill. (some col.) ; 29 cm
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Adrenalectomy-induced neuronal degeneration : development of a novel animal model of cognitive dysfuntion and neurogenic treatment strategiesSpanswick, Simon, University of Lethbridge. Faculty of Arts and Science January 2010 (has links)
Long-term adrenalectomy (ADX) results in a specific loss of dentate gyrus granule cells in the hippocampus of adult rats, occurring over a period of weeks to months. This loss of granule cells results in cognitive deficits in a number of tasks that depend on intact hippocampal function. The gradual nature of ADX-induced cell death and the ensuing deficits in cognition are similar to those experienced by patient populations suffering from a variety of pathological conditions. Here we present an animal model by which we use ADX to produce a loss of granule cells within the hippocampus of rats. We also provide experimental evidence for a treatment strategy by which the lost granule cells may be replaced, with the goal of functional recovery in mind. / xii, 191 leaves : ill. (chiefly col.) ; 28 cm
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Experienced-induced immediate early gene expression in hippocampus after granule cell lossCardiff, James W January 2012 (has links)
Adrenalectomy
(ADX)
has
been
shown
to
cause
selective
degeneration
of
granule
cells
in
the
dentate
gyrus
(DG).
This
occurs
due
to
the
reduction
of
corticosterone
(CORT)
and
behavioural
deficits
are
associated
with
the
loss
of
these
neurons.
Dentate
lesions
and
cell
loss
associated
with
ADX
have
been
shown
to
effect
behaviour
in
a
number
of
spatial
tasks.
In
contras,
it
has
been
shown
granule
cell
loss
does
not
affect
the
specificity
of
place
cells
in
CA3
and
CA1.
We
used
the
ADX
model
to
examine
the
role
of
DG
granule
cells
plays
in
representing
space
using
immediate
early
gene
(IEG)
activation
in
the
principal
hippocampal
subfields
after
exploration
of
novel
environments.
Rats
were
allowed
to
free
explore
multiple
novel
environments
and
then
the
mRNA
for
the
IEG
Homer
1a
(H1a)
was
used
as
a
marker
of
neural
activity.
After
degeneration
of
approximately
half
of
the
DG
granule
cells
we
found
a
significant
increase
in
number
of
active
cells
in
the
DG,
CA3
and
CA1
in
ADX
animals.
The
results
indicate
a
reduction
in
granule
cells
causes
a
dramatic
increase
in
the
proportion
of
remaining
DG
granule
cells
in
response
to
exploration.
The
change
in
DG
activation
disrupts
the
representations
in
CA3
and
CA1
and
thereby
affects
behaviour. / vii, 60 leaves : ill. (some col.) ; 29 cm
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Experience dependent plasticity of stroke outcomeRakai, Brooke D., University of Lethbridge. Faculty of Arts and Science January 2008 (has links)
Stroke outcome is highly variable. Experiments in this thesis test the hypothesis that experience prior to a stroke is an important variable in the manifestation of stroke. Optokinetic tracking was used to evaluate the effects of visual cortex stroke and MCA occlusion in rats. Normal laboratory rats showed a small, but significant decrease in tracking thresholds following visual cortex stroke. Animals with developmental visuomotor experience or reach training experience in adulthood, however, had tracking thresholds which were substantially increased, and the effects of visual cortex strokes were greater. MCA occlusions did not affect tracking behaviour. These data indicate that specific experiences engage neural plasticity that can alter brain function. These changes can, in turn, affect the behavioural manifestation of a stroke. Understanding the effect that environmental experience has on stroke outcome promises to enable better characterization of strokes, and set appropriate behavioural baselines for the measurement of recovery of function. / vi, 135 p. : ill. ; 29 cm
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The effect of playful experiences on the plasticity and metaplasticity of the brainHimmler, Brett T, University of Lethbridge. Faculty of Arts and Science January 2011 (has links)
The influence of play behavior on the brain was investigated through plasticity and metaplasticity methodology. Regions in both cortical and sub-cortical areas were investigated. Animals in both studies either experienced play with juvenile partners or did not experience play by being paired with an adult. Play experience alone was shown to affect the plasticity in the prefrontal cortex, although it did not show structural changes to sub-cortical regions. If animals were given nicotine after play experiences, the affects of play in the prefrontal cortex were abolished. In addition, playful behaviors appear to prime some sub-cortical regions of the brain for expression of later plasticity. Thus, play appears to alter the structure of multiple brain areas, but do so in different ways. / ix, 67 leaves ; 29 cm
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Modulation of compensation and recovery in a rat model of motor cortex stroke : implications of transcranial direct current stimulationGidyk, Darryl C January 2011 (has links)
The present thesis examines the effects of transcranial direct current stimulation and
forelimb rehabilitation on motor recovery after stroke in rats. Post-stroke motor outcomes were
quantified using an innovative battery of behavioural tests and high resolution, in vivo
electrophysiology was employed to examine coherence of neural activity between hemispheres.
It was shown that rats that received brain stimulation concurrently with forelimb rehabilitation
displayed functional recovery, whereas rats that received rehabilitation alone partially regained
motor function, but the improvements were not due to restitution of original movement
patterns. Results from electrophysiological recordings showed that rats that received brain
stimulation and rehabilitation regained pre-stroke levels of interhemispheric coherence, but rats
that received rehabilitation alone did not. The present thesis suggests that transcranial direct
current stimulation may be a viable adjunct therapy to increase the efficacy of physical
rehabilitation with regard to post-stroke motor outcomes. Interhemishperic coherence between
homotopic neuronal populations may represent a biomarker of genuine motor recovery after
stroke. / ix, 75 leaves : col. ill. ; 29 cm
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Novel regulation of neuronal genes implicated in Alzheimer disease by microRNALong, Justin M. 11 December 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β peptide (Aβ) as neuritic plaques in the brain. The short Aβ peptide is derived from a large transmembrane precursor protein, APP. Two different proteolytic enzymes, BACE1 and the gamma-secretase complex, are responsible for cleaving Aβ peptide from APP through an intricate processing pathway. Dysregulation of APP and BACE1 levels leading to excess Aβ deposition has been implicated in various forms of AD. Thus, a major goal in this dissertation was to discover novel regulatory pathways that control APP and BACE1 expression as a means to identify novel drug targets central to the Aβ-generating process. MicroRNAs (miRNA) are short, non-coding RNAs that act as post-transcriptional regulators of gene expression through specific interactions with target mRNAs. Global analyses predict that over sixty percent of human transcripts contain evolutionarily conserved miRNA target sites. Therefore, the specific hypothesis tested was that miRNA are relevant regulators of APP and BACE1 expression.
In this work, several specific miRNA were identified that regulate APP protein expression (miR-101, miR-153 and miR-346) or BACE1 expression (miR-339-5p). These miRNAs mediated their post-transcriptional effects via interactions with specific target sites in the APP and BACE1 transcripts. Importantly, these miRNA also altered secretion of Aβ peptides in primary human fetal brain cultures. Surprisingly, miR-346 stimulated APP expression via target sites in the APP 5’-UTR. The mechanism of this effect appears to involve other RNA-binding proteins that bind to the APP 5’-UTR.
Expression analyses demonstrated that these miRNAs are expressed to varying degrees in the human brain. Notably, miR-101, miR-153 and miR-339-5p are dysregulated in the AD brain at various stages of the disease. The work in this dissertation supports the hypothesis that miRNAs are important regulators of APP and BACE1 expression and are capable of altering Aβ homeostasis. Therefore, these miRNA may possibly serve as novel therapeutic targets for AD.
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