Optogenetic analysis of striatal connections to determine functional connectomes

Abstract

Neural circuit function is determined not only by anatomical connections but also by the strength and nature of the connections, that is functional connectivity. To elucidate functional connectivity, selective stimulation of presynaptic terminals of an identified neuronal population is crucial. However in the central nervous system (CNS), intermingled input fibers make selective electrical stimulation impossible. With optogenetics this becomes possible, and enables the comprehensive study of functional synaptic connections between an identified population of neurons and defined postsynaptic targets to determine the functional connectome. By stimulating convergent synaptic inputs impinging on individual postsynaptic neurons, low frequency and small amplitude synaptic connections can be detected. Further, the optogenetic approach enables measurement of cotransmission and its relative strength. In this chapter, optogenetic studies in the striatum (Str) are introduced to demonstrate the functional connectome approach. For spiny projection neurons, this has revealed cell-type specific intra-striatal connections as well as striatal output connections. Cholinergic interneurons in the ventral striatum have been shown to use glutamate as a cotransmitter. Examining striatal afferents from the ventral midbrain has identified fast, direct dopaminergic connection onto cholinergic interneurons and preferential connections of γ-aminobutyric acid (GABA) neurons to cholinergic interneurons in the nucleus accumbens. Further, it has revealed regionally heterogeneous glutamate and GABA cotransmission of dopamine neurons in the Str. These connections can be quite plastic, revealing a new vista of connectivity that is likely to be important in understanding the circuitry of neuropsychiatric disorders.