The functional organisation of basal ganglia inputs

The basal ganglia allow organisms to adjust their behaviour according to changes in their internal state or their environment. One essential prerequisite for the selection and execution of appropriate movements is the convergence of inputs from various sources, conveying sensory information, motor commands, reward value, and more. These diverse inputs are integrated in the striatum, the input structure of the basal ganglia. In the last decades, numerous striatal cell types have been identified, their molecular profiles have been extracted and their local connectivity has been revealed. However, relatively little is known about the functional organisation of striatal inputs innervating these different neuron populations. The aim of this thesis is to examine how striatal inputs are integrated by the main cell types of this microcircuit. In Paper I, we uncover the mechanisms underlying sensory deficits in a mouse model of Parkinson’s disease. We show that one type of striatal projection neurons encodes the laterality of somatosensory inputs better than the other output neuron in healthy mice and that this encoding is lost in the dopamine-depleted state. In Paper II, we map the excitatory synaptic pathways of five striatal input structures (ipsiand contralateral somatosensory and motor cortex, and the parafascicular nucleus) onto five different classes of striatal neurons. The study characterises the synaptic strength, receptor composition, and shortterm plasticity of each pathway with an unprecedented level of detail and comparability, thereby contributing to the understanding of the role of different striatal cell types. In Paper III, we create an in silico model of the striatum that integrates data from the subcellular to the microcircuit level. This model will be publicly available for testing new hypotheses and continuously updated with novel findings. In summary, the work presented in this thesis provides a further step in untangling the heterogeneous excitatory inputs that drive the activity of the primarily inhibitory microcircuit of the striatum and thus basal ganglia. We show that each striatal input targets a different set of striatal neurons and that the intricate organisation of these afferents is a function of both the presynaptic region and the postsynaptic cell type. Ultimately, knowledge of the functional connectivity of corticoand thalamostriatal pathways as well as their synaptic properties will be essential for understanding and modelling the corticoand thalamo-basal ganglia network in health and disease. LIST OF SCIENTIFIC PAPERS I. Pollak Dorocic I, Fürth D, Xuan Y, Johansson Y, Pozzi L, Silberberg G, Carlén M, Meletis K. A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei. Neuron, 2014, 83: 663 678. II. Lazaridis I, Tzortzi O, Weglage M, Märtin A, Xuan Y, Parent M, Johansson Y, Fuzik J, Fürth D, Fenno LE, Ramakrishnan C, Silberberg G, Deisseroth K, Carlén M, Meletis K. A Hypothalamus-Habenula Circuit Controls Aversion. Molecular Psychiatry, 2019, 24(9): 1351-1368. I. Ketzef M, Spigolon G, Johansson Y, Bonito-Oliva A, Fisone G, Silberberg G. Dopamine Depletion Impairs Bilateral Sensory Processing in the Striatum in a Pathway-Dependent Manner. Neuron, 2017, 94: 855 – 865. II. Johansson Y & Silberberg G. The Functional Organisation of Cortical and Thalamic Inputs onto Five Different Types of Striatal Neurons is Determined by Source and Target Cell Identities. Cell Reports, 2020 III. Hjorth J, Kozlov AK, Carannante I, Frost Nylén J, Lindroos R, Johansson Y, Tokarska A, Dorst MC, Suryanarayana SM, Silberberg G, Hellgren Kotaleski J, Grillner S. The microcircuits of striatum in silico. PNAS, 2020, manuscript Publications not included in this thesis: