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.
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.
 View more publications, see
Pubmed listing. |
