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Overview

Specific goals

The input layer of the basal ganglia, the striatum, plays a critical role in the control of motor behaviour and cognitive function. It serves as a filter for cortical and thalamic signals and takes part in determining which actions should be performed at a given instant. Our goal is to define the cellular and network organisation underlying decision-making by analysing the striatal microcircuitry of the basal ganglia. We will investigate subpopulations of neurons in striatum (interneurons and projection neurons) concerned with the control of different patterns of behaviour, and their input from cortex (pallium), thalamus and the modulatory inputs from dopaminergic, histaminergic and 5-HT neurons. The microcircuitry will be studied in slices of striatum with patch electrode recordings from up to four identified neurons at the same time, while synaptic and membrane properties are investigated and also the synaptic response to the different input systems. Specific synaptic connections of the recorded neurons will be identified by electron microscopy and quantitative aspects of the connections of the different classes of neurons will be defined. Striatal neuronal activity will also be studied in behaving animals with multiunit extracellular neuronal recording in relation to defined decision making and motor behaviours (Barnes et al 2005) utilizing several vertebrate model systems (lamprey, rodent and primate). The primary focus will be on striato-pallidal projections indirectly controlling motor programs at the brainstem/spinal cord level (locomotion, posture, turning, steering, saccadic eye movements), rather than via the thalamo-cortical forebrain projections since these projections cannot as easily be interpreted. Neuronal function and synaptic interaction at the microcircuit level will be subjected to a detailed computer modelling based directly on the outcome of the experimental analyses. Plasticity underlying motor learning/synaptic plasticity, particularly in relation to the dopaminergic, cholinergic 5-HT and histaminergic inputs will also be characterized and modelled. An ultimate goal will be to achieve a large scale model of striatum with its cortical and thalamic inputs and the downstream activation of pallidum and different motor centres.

Since the debilitating motor (and ultimately the emotional and cognitive) symptoms underlying Parkinsonīs disease (PD) are due to dysfunction of striatal microcircuits (as a consequence of deficiency of dopamine and other neuromodulators), it is clearly of critical importance to understand how these circuits function - to enable one to identify additional sites of therapeutic intervention in PD. In addition a variety of severe psychiatric and neurological conditions like ADHD (attention deficit hyperactivity disorder), schizophrenia, Huntingtonīs and pharmacologically induced hyperkinesias, all involve a dysfunction of the basal ganglia. Knowledge of the normal function of striatum is therefore a prerequisite for an understanding of the underlying pathology in the diseased state.

Concepts and objectives

  1. The striatal "base line" microcircuitry as defined in rodent and lamprey striatal slices combined with detailed biologically realistic microcircuit modelling and structural analyses

    Characterization of the synaptic interaction between different classes of striatal interneurons and projection neurons using multi-neuron patch-clamp recordings in striatal brain slices allowing up to four synaptically connected cells to be simultaneously recorded.

  2. The impact of modulation on the operation of the striatal microcircuit- experiments and modulator focused modelling

    The aim is to characterize the overall effects of the 'modulator innervation' on the operation of striatal microcircuits with respect to interactions between MSNs and interneurons and their responsiveness to excitatory glutamatergic input from the cortex and thalamus.

  3. Neuronal activity in striatum studied during specific patterns of motor behaviour

    The striatal neuronal activity will also be studied in behaving animals with multiunit neuronal recording in relation to distinct motor behaviours utilizing three vertebrate model systems, the lamprey, rodent and primate. The focus for rodent and lamprey will be on the striato-pallidal projections that ultimately control motor programmes at the brainstem/spinal cord level (forward locomotion, turning, steering, posture, saccadic eye movements, and in the monkey in a more complex classical conditioning / decision-making task.

  4. Systems level modelling of the operation of basal ganglia circuits

    The knowledge acquired of the different striatal microcircuits will be the basis for developing a systems level model of the basal ganglia circuits. This will serve as a complement to the single cell and microcircuit models and allow a more accurate representation of the large (in terms of cell numbers) and very complex system under study.

Neuroinformatics dimension

Neuroinformatics, as defined by the OECD-initated "International Neuroinformatics Coordinating Facility" (INCF; www.INCF.org), consists of three parts, computational neuroscience (modelling), tool development and data bases. The current project has a considerable modelling component, and a substantial tool development particularly for "large scale computing" in WP 4. The data from the models will be deposited in the modelling databases initiated by INCF, and the experimental results in the available neuronal data bases.