The Optogenetic Revolution in Cerebellar Investigations

Abstract

The cerebellum is most renowned for its role in sensorimotor control and coordination, but a growing number of anatomical and physiological studies are demonstrating its deep involvement in cognitive and emotional functions. Recently, the development and refinement of optogenetic techniques boosted research in the cerebellar field and, impressively, revolutionized the methodological approach and endowed the investigations with entirely new capabilities. This translated into a significant improvement in the data acquired for sensorimotor tests, allowing one to correlate single-cell activity with motor behavior to the extent of determining the role of single neuronal types and single connection pathways in controlling precise aspects of movement kinematics. These levels of specificity in correlating neuronal activity to behavior could not be achieved in the past, when electrical and pharmacological stimulations were the only available experimental tools. The application of optogenetics to the investigation of the cerebellar role in higher-order and cognitive functions, which involves a high degree of connectivity with multiple brain areas, has been even more significant. It is possible that, in this field, optogenetics has changed the game, and the number of investigations using optogenetics to study the cerebellar role in non-sensorimotor functions in awake animals is growing. The main issues addressed by these studies are the cerebellar role in epilepsy (through connections to the hippocampus and the temporal lobe), schizophrenia and cognition, working memory for decision making, and social behavior. It is also worth noting that optogenetics opened a new perspective for cerebellar neurostimulation in patients (e.g., for epilepsy treatment and stroke rehabilitation), promising unprecedented specificity in the targeted pathways that could be either activated or inhibited.

Anodal cerebellar stimulation increases cortical activation: Evidence for cerebellar scaffolding of cortical processing

“…While the impacts of tDCS are not always consistent in the cortex (Imburgio & Orr, 2018), and purportedly have differing polarityspecific effects in the cerebellum (Grimaldi et al, 2016;Prestori et al, 2020), our results show differential effects on cortical activation, and we have replicated effects on sequence learning (Ballard et al, 2019;Ferrucci et al, 2013;Pope & Miall, 2012), supporting the impact and utility of cerebellar tDCS. Together, this work provides novel insights into the potential cerebellar scaffolding mechanism.…”

“…Optogenetic work in rodents demonstrates that exciting Purkinje cells (i.e., increased inhibitory signal to DCN) in the cerebellum results in decreased excitatory signal to the neocortex. Conversely, cerebellar stimulation inhibits the inhibitory circuit (i.e., decreased inhibitory signal to DCN), resulting in increased excitatory signal to the neocortex (Grimaldi et al, 2014 ; Prestori et al, 2020 ). These are analogous to anodal and cathodal stimulation, respectively.…”

Molecular Tools for Targeted Control of Nerve Cell Electrical Activity. Part I

“…Optogenetics is a group of techniques that use visible light to control the functional activity of cells by means of light-sensitive proteins whose genes are introduced into the biological system in advance (for a detailed review, see [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]). Light is not only the primary energy source for anabolic processes in the entire biota, but also the most important physical stimulus playing a key role in the physiology and biochemistry of the representatives of all living kingdoms.…”

“…Small rodents (mice and rats) are the main model objects in neurobiological research involving optogenetic tools. There are hundreds of studies on neuronal ensembles, networks, rhythmic brain activity, transmission, memorizing, and storage of information in the brain, learning, synaptic plasticity, neurogenesis, regulation of motor activity, hunger and thirst, sleep and wakefulness, sensory organs, biological rhythms, respiratory activities, and social behavior of these animals [ 1 , 3 , 6 , 148 , 164 , 166 , 167 ]. The optogenetic toolbox is also used to explore the neurobiology of fish [ 168 ], birds [ 169 ], and primates [ 170 , 171 ].…”

Developmental timetables and gradients of neurogenesis in cerebellar Purkinje cells and deep glutamatergic neurons: A comparative study between the mouse and the rat

“…This region is part of the hindbrain, located above the brainstem and characterized by two lateral hemispheres and a medial area called the vermis. The adult cerebellum consists of a three-layered cortex and a set of deep nuclei enclosed in the white matter (Prestoni, Montagna, D'Angelo, & Mapelli, 2020). The cerebellum is composed by a limited number of cell types specifically integrated in a corticonuclear network and characterized by distinctive morphological and molecular markers (Leto et al, 2016;Schilling, Oberdick, Rossi, & Baader, 2008;Wang & Liu, 2019).…”