Diversity of striatal interneurons : connectivity and functions

Multisensory integration of cortical and thalamic inputs by the striatal network, and its modulation by local acetylcholine and midbrain dopamine, are crucial components of movement control and striatal function. A flexible decision-making process, quick and smooth movement initiation, as well as proper habit-formation would not be possible without properly functioning striatal circuits. The efficient computation of the striatal network strongly relies on the local neural circuitry, provided by inhibitory projecting neurons and local GABAergic and cholinergic interneurons. Despite a growing body of research tackling the diversity of striatal GABAergic interneurons, and cell-type focused functional interrogations, many aspects of the striatal microcircuits remain unknown.

A central goal of this thesis was to investigate this diversity of striatal interneurons and its functional implications in the striatal network. In particular, we wanted to unravel the patterns of connectivity between GABAergic and cholinergic interneurons, characterize the neuronal population linking those two systems, and how this interconnected network is modulated by dopamine.

In Paper I, we focus on cholinergic and GABAergic interplay and its local modulation by midbrain dopamine. The balance between those systems is crucial for reward-related behaviors, formation of habits, and salience coding. Synchronized pauses in the activity of cholinergic cells, which are accompanied by dopamine bursts in response to reward-related stimuli, are a complex phenomenon and their underlying mechanism is still unknown. This paper investigates the connectivity of cholinergic cells with other striatal interneurons and proposes a local circuit that could contribute to their observed synchronicity, along with a characterization of its dopaminergic modulation.

Paper II focuses on a population of striatal interneurons marked by the alpha-2 subunit of the nicotinic acetylcholine receptor (Chrna2). This novel marker, characterized previously for neurons in the cortex and hippocampus, could potentially link the cholinergic and GABAergic systems in the striatum. In this paper, we provide a classification system for this heterogeneous population. Using multineuron patch- clamp recordings combined with optogenetic stimulation and immunohistochemistry, we describe the diverse electrical, morphological and molecular properties of striatal Chrna2 interneurons as well as their synaptic connectivity.

In Paper III, the data obtained from electrophysiological recordings were used to build an in silico model of the striatal network at the cellular level. The project was a multidisciplinary collaborative effort between computational and experimental neuroscientists, providing an expandable platform capable of simulating not only the local connectivity of different striatal interneurons and projection cells, but also the cortical and thalamic inputs and their modulation by dopamine.

Altogether, the studies included in this thesis provide detailed, single-cell resolution data on novel aspects of the local striatal connectivity, focusing on characterization of striatal GABAergic interneurons and their modulation by the cholinergic and dopaminergic systems. The studies presented here will, hopefully, shed new light on the functional organization of the striatal neural circuitry.

List of scientific papers

I. Dorst, Matthijs C., Anna Tokarska, Ming Zhou, Kwang Lee, Stefanos Stagkourakis, Christian Broberger, Sotiris Masmanidis, and Gilad Silberberg. Polysynaptic Inhibition between Striatal Cholinergic Interneurons Shapes Their Network Activity Patterns in a Dopamine-Dependent Manner. Nature Communications. 11, no. 1 (9 October 2020).
https://doi.org/10.1038/s41467-020-18882-y

II. Anna Tokarska and Gilad Silberberg. GABAergic interneurons expressing the α2 nicotinic receptor subunit are functionally integrated in the striatal microcircuit. Cell Reports. 39, 110842 (May 24 2022).
https://doi.org/10.1016/j.celrep.2022.110842

III. Hjorth, J. J. Johannes, Alexander Kozlov, Ilaria Carannante, Johanna Frost Nylén, Robert Lindroos, Yvonne Johansson, Anna Tokarska, Matthijs Dorst, Shreyas M. Suryanarayana, Gilad Silberberg, Jeanette Hellgren Kotaleski and Sten Grillner. The Microcircuits of Striatum in Silico. Proceedings of the National Academy of Sciences. 117, no. 17 (28 April 2020).
https://doi.org/10.1073/pnas.2000671117