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Faculty D. Kent Morest
Professor of Neuroscience
kentmorest@neuron.uchc.edu
Areas of Interest:
There are four major lines of research
currently supported by NIH grants.
Our laboratory studies the synaptic organization and development of
specific cell types, their synaptic structure and microcircuitry, as
they relate to the cellular mechanisms of signal processing in the
mammalian auditory system. A project of current interest is to map out
local inhibitory circuits in the cochlear nucleus. This is correlated
with physiological observations of the effects of local inhibitory
synapses on central processing. One of the key techniques uses
retrograde or anterograde labeling in vivo, followed by fixation and
visualization of the labeled neuronal cell bodies and dendrites in brain
slices. This allows one to select individual cells for more detailed
study, including electron microscopy with immunogold localization of key
molecules, such as receptors and transporters.
At the molecular level we are using in situ hybridization, PCR,
transgenic mice, and related molecular and immunocytochemical
techniques, which we can apply to the mature or developing neurons and
their synaptic structures. The current interest is in the regulation of
gene expression for the subunits of the receptors for the major
neurotransmitters, amino acid transporters, growth factors, and
potassium channels in the cochlear nucleus and ganglion.
We have discovered that acoustic overstimulation with noise causes a
neurodegenerative disease in which synaptic endings continue to
degenerate in the brain and the ear for years after a single
exposure.This condition may account for the chronic progressive nature
of noise-induced hearing loss and tinnitus in humans. Our working
hypothesis is that this involves a presynaptic excitotoxic mechanism
mediated by the failure of the glial amino acid transporters. Recently
we showed that a new growth of excitatory interneurons forms new
synapses in the cochlear nucleus. Our future work will try to identify
the factors responsible for these changes and to evaluate their
application to cerebral transplants into noise-damaged brains.
Chinchillas and mice, including transgenics, are the animals used. We
think that this preparation can be used as a model for analysis of some
of the basic mechanisms in the pathogenesis of neurodegenerative
disorders in general.
A related project is to elucidate the role of cellular interactions
in migration and differentiation, especially the expression of the
synaptic and membrane properties of specific types of neurons in the
cochlear nucleus and ganglion. Currently we are studying the role of
growth factors and their receptors in the assembly of the glutamate
receptors and voltage-gated ion channels in the cochlear nucleus. We are
using cell cultures and slices in chicken and mouse embryos. This ties
into our research on transplantation of neuroblasts into the postnatal
mouse brain.
We have developed a cell culture system in which we can identify the
living precursors and immature forms of cochlear nucleus neurons,
cochlear ganglion cells, and the sensory epithelium. We are able to
co-culture these cell populations, so that they form synaptic
connections, which appear to have normal structure and function. We
study the effects of factors, such as FGF, neurotrophins and ion channel
blockers, on their differentiation by cell and molecular methods,
including their perturbation in vitro with antibodies to diffusible and
membrane-bound molecules. Our research has already taught us enough
about the roles of these factors in normal development that we have been
able to produce successful neuronal transplants to postnatal brains.
This a goal of our research which we are now eager to expand.
Lab Rotation Projects:
Students who wish to formulate their own novel questions are more
than welcome. In addition the following projects are available:
1) Developmental studies on differentiation of neurons and
synapses in the auditory system using microscopy, cell culture, and
transplantation. For example, we are looking at the fate of auditory
precursor cells, which undergo transformation by growth factors in vitro
and then are transplanted into a postnatal mouse brain.
2) In vivo and in vitro experiments to identify factors
controlling differentiation of the spike generator in the axonal initial
segment.
3) The auditory system is used to provide a structural basis for
study of signal processing by specific types of neurons, as defined by
their patterns of synaptic organization, using all available light and
electron microscopic methods, including immunocytochemistry with
immunogold electron microscopy. For example, we study plastic changes in
of the mature and immature auditory pathways following acoustic
stimulation. The focus is on the recent development of a concept of the
synaptic nest as a type of synaptic organization with high potential for
plasticity and pathology.
Laboratory Home Page
Publications
Selected Publications:
Hossain WA, DSa C, Morest DK. (2006) Site-specific interactions of
neurotrophin-3 and fibroblast growth factor (FGF2) in the embryonic
development of the mouse cochlear nucleus. J Neurobiol 66:897-915.
Feng JJ, Morest DK. (2006) Development of synapses and expression of a
voltage-gated potassium channel in chick embryonic auditory nuclei.
Hearing Res 216-217:116-126.
Hossain WA, Antic SD, Yang Y, Rasband MN, Morest DK (2005) Where is
the spike generator of the cochlear nerve? Voltage-gated sodium channels
in the mouse cochlea. J Neurosci 25:6857– 6868.
Kim, J.J., Gross, J., Potashner, S.J., Morest, D.K. (2004) Fine
structure of degeneration in the cochlear nucleus of the chinchilla
after acoustic overstimulation. J Neurosci Res 77:798-816, 817-828,
829-842.
Morest DK, Cotanche DA (2004) Regeneration of the inner ear as a
model of neural plasticity. J Neurosci Res 78:455-460.
Josephson EM, Morest DK (2003) Synaptic nests lack glutamate
transporters in the cochlear nucleus of the mouse. Synapse 49:29-46.
Morest DK, Silver J (2003) The precursors of neurons, neuroglia, and
ependymal cells in the CNS: What are they? Where are they from? How do
they get where they are going? Glia 43: 6-18.
Hossain WA, Brumwell CL, Morest DK (2002) Sequential interactions of
FGF-2, BDNF, NT-3 and their receptors define critical periods in the
development of cochlear ganglion cells. Exp Neurol 175:138-151.
Smith L, Gross J, Morest DK (2002) Fibroblast growth factors (FGFs)
in the cochlear nucleus of the adult mouse following acoustic
overstimulation. Hearing Res 169:1-12.
Bilak MM, Hossain WA, Morest DK (2002) Intracellular fibroblast
growth factor (FGF-2) produces different effects than extracellular
application on development of cochleo-vestibular ganglion cells in
vitro. J Neuroscience Res 71:629-647.
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