Mechanisms of postsynaptic density function.
The recipient side of excitatory neuronal communication, synaptic spines, are
characterized by a postsynaptic density consisting of an assembly of
proteins. These take part in transmission of the signal evoked by
receptor activation and subsequent generation of biochemical and
electrical activity. Changes to the efficacy of this transmission is
generally assumed to be of central importance to learning and
memory. We study by using computational modeling the amplitude
(roughly the efficacy of this transmission) and in particular
duration of changes to this efficacy. We are interested in the
relationship between molecular events in the postsynaptic density to
changes and their duration. We are also studying more principal
functions of the molecular assembly as an information-processing device.
Mechanisms of chronic peripheral pain.
Acute pain is relatively well treated by today's pain killers or
compounds like lidocaine. However, for treatment of chronic pain,
there is a large unmet need for new drugs. Research is in part
unsuccessful due to the lack of an understanding of what changes in ion
channels underlie the changes in excitability of peripheral
nerves. One of the key problems is that the intracellular membrane
potential of these nerves is not experimentally accessible. The
present project uses computational neuroscience to construct a model
of a peripheral nerve, a C-fiber. We are thereby able to provide a
causal link between ion channel function and function of the axon, as
well as between changes in ion channels and pathological changes in disease.
Biomolecular target design using computational search strategies
In this project, we develop a computational search method to design
ion channels so that they can achieve optimal
physiological/terapeutical effect on cell or network function. The
project currently evaluates direct search strategies to find optimal
characteristics. In each cycle of the procedure, new channel
parameters are set, next biophysical simulations include the channel
in the cells of the network/system at study. From the simulations,
resulting physiological function is measured/evaluated. Based on this
evaluation, new parameters are computed using the search method.
Reducing epileptogenic activity using modulation of dendritic potassium channels.
Synchronous activity is an integral part of brain function. At the
single neuron level, there may under normal conditions be mechanisms
that maximizes processing while proving sufficient safety margins to
undesirable hypersynchronous states such as epilepsy. In this
project using quantitative modeling we are studying the possibility of
controlling a neurons bias to respond to synchronous synaptic input by
adding a novel potassium current. Experimentally, pharmacological
manipulation of endogenous ion channel types, or genetic knock-in of
new channels, might provide possible ways of implementing our results.
Intrinsic cellular mechanisms of memory
In learning and memory it has recently become clear that in addition
to synaptic plasticity there are cellular changes in excitability due
to changes in ion channels. The project focuses on cationic (TRP)
currents which are known from in vitro studies to produce long-lasting
depolarizing plateau potentials. Further, these currents are activated
by group I metabotropic glutamate receptors as well as muscarinic type
1 receptors, and blocking of these receptors have been shown to
produce behavioral deficits in long-term and working memory
experiments. In the project, we combine pharmacological,
electrophysiological and modeling techniques.
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