SELECT-AND-ACT

"The role of striatum in selection of behaviour and motor learning - neuronal code, microcircuits and modelling"

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 Obiettivo del progetto (Objective)

'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 microcircuitry of 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 three or more identified subtypes of 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 neuronal recording in relation to defined motor behaviours 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, 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, 5-HT and histaminergic inputs will also be characterized.'

Introduzione (Teaser)

Many motor, psychiatric and neurological conditions involve dysfunction of the basal ganglia. Understanding the normal function of the striatum is therefore a prerequisite for determining the underlying pathology in a diseased state.

Descrizione progetto (Article)

The debilitating motor symptoms underlying Parkinson's disease (PD) are due to a deficiency of dopamine and other neuromodulators causing dysfunction of striatal microcircuits. It is therefore of critical importance to understand how these circuits function in order to develop new therapeutic interventions.

The striatum is an internal structure of the brain responsible for regulating motor behaviour and cognitive function. It receives input from many brain areas but sends output only to other components of the basal ganglia, essentially serving as a filter for cortical and thalamic signals. As a result, it takes part in determining which actions should be performed at a given instant.

The overall objective of the EU-funded Select-AND-ACT project was to delineate the intrinsic function of the basal ganglia located in the striatum. This would unveil the neural mechanisms involved in action determination.

To achieve this, partners analysed multicellular microcircuits of striatal sub-populations combining modeling and functional monitoring of neuronal activity during actual behaviour. Using fish, rats and primates as experimental models, they investigated input from the cortex and the thalamus, and modulatory inputs from dopaminergic, histaminergic and cholinergic (5-HT) neurons.

Patch electrodes were used to record the activity of neurons, and also monitor the synaptic response to different input systems. Results suggested that histamine release entrained striatal function, and cholinergic modulation had an inhibitory effect on GABAergic synapses.

Moreover, it was seen that the separate compartments within the striatum (referred to as striosomes and matriosomes) received input from separate types of cortex, but they affected the dopamine system and pallidal neurons separately. Detailed computer modelling was also developed to study neuronal function and synaptic interaction at the microcircuit level.

From a scientific perspective, the Select-AND-ACT consortium showed that the striatum is an evolutionary conserved region of the brain with the basal ganglia maintaining a specific organisation pattern throughout evolution. The project findings provided important knowledge on striatal function at the microcircuit level, linked to behaviour, and are expected to contribute to an understanding of basal ganglia disease symptoms and reasons for dysfunction.