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| Overview: My lab is interested in understanding how the brain works. Of course, the
answer to that broad question can take many forms and encompass many facets of
neuroscience, but the aspect of brain function which I find most compelling is neural
plasticity - the relatively slow and sustained changes which take place in the brain when
we learn, adapt to new levels of stimuli, express daily biological rhythms or shape
neural connections during our development. Neural plasticity can be described as a
constellation of related mechanisms in which cascades of intracellular signal
transduction pathways drive dynamic changes in gene expression which ultimately
impact upon the physiological state of neurons, synapses and networks. My laboratory
is currently pursuing research in two critical questions in neural plasticity, Imaging
Dynamic Gene Expression in the Brain’s Biological Clock and Neural Network
Adaptation in the Retina using a variety of cellular and molecular approaches. |
Imaging
Dynamic Gene Expression in the
Brain’s Biological Clock:
Genes are the blueprint for life
and their regulation determines
organismal development, physiology,
behavior and disease. The Human
Genome Project marks just the
beginning of genome-based investigations
because the function of the majority
of genes, and their links with
physiology, are not understood.
A critical challenge facing biological
science is to devise new approaches
for studying gene function so
that the promise of the Genome
Project can be fulfilled. Of all
the tissues of the body, the brain
by far exhibits the most intricate
and dynamic patterns of gene regulation,
yet traditional time-resolved
methods used in neuroscience research
have focused on recording the
electrochemical elements of brain
activity not the ongoing patterns
of gene activation in living neurons
and circuits. My laboratory has
developed methods which capture
the dynamics of brain activity
in the dimension of gene activity
and we are using them to study
the molecular physiology of the
brain’s biological clock . We
have produced transgenic mice
in which specific gene promoters
drive the expression of a short
half-life form of Green Fluorescent
Protein (Figure 1).
In these mice,
the biological clock neurons glow
bright green and the intensity
of the glow indicates the extent
of clock gene activation (Figure
2). 
Thus, we can precisely localize
biological clock neurons and also
read the molecular time on their
daily gene expression/physiological
clock. This is a generalizable
methodology for exploring gene
expression dynamics in the living
brain and we are currently using
these mice to target biological
clock neurons for electrophysiology
and RT-PCR by their promoter dynamics
(Figure 3), and to produce “molecular
circuitry maps” of neural function.
Click this link to watch our Quick-Time movie.
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Neural Network Adaptation in the Retina: A second research emphasis in my
laboratory explores the cellular and molecular mechanisms by which retinal neural
networks adapt to different levels of illumination. This project, which is in its twelfth year
of continuous funding by the NIH, focuses on how transmission at chemical synapses
(glutamatergic) and electrical synapses (gap junctions) is modified according to a
variety of adaptational signals in retinal circuits (Figure 4).
Whereas previous work has involved the neuromodulators dopamine and nitric oxide,
most recently we have been elucidating the actions of zinc, retinioc acid and the retinal
biological clock on glutamate receptors and gap junction channels and hemichannels.
We have established the basis for a novel action of retinoids in the nervous system by
showing that retinoic acid, a widely studied morphogen and metabolite of retinal light
adaptation, also acts as a synaptic neuromodulator at retinal electrical synpases (Figure
5). 
Strikingly, this action is mediated by a completely novel retinoid receptor
mechanism which is non-nuclear in nature and does not involve transcriptional
regulation. This new retinoid signaling path apparently increases the resolution of visual
signals when sufficient light is available by adjusting synaptic strength in retinal circuits.
In addition, we have demonstrated the action of endogenous retinal zinc in modulating
the responsiveness of retinal glutamate receptors, (Figure 6). 
Finally, we are just beginning to apply our Per1::GFP mouse model to the study of
retinal biological rhythms, using this preparation to identify populations of retinal
neurons that express clock gene rhythms and targeting these populations for
neurophysiological recording (Figure 7). 
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Future Plans: By continuing to study the underlying molecular bases of neural plasticity
we hope to contribute to a greater understanding of how specific brain genes and
processes mediate organismal perception and behavior. Specifically, my lab will
continue to exploit molecular genetic targeting with gene reporters (perhaps making
blue, yellow, red and multicolor mice to go with the green) to enable
electrophysiological, molecular and imaging experiments directed toward elucidating the
function of the visual and circadian systems of the brain.
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