cerebellar circuit

Neural circuits for disinhibition in the cerebellum

ABSTRACT Our long-term goal is to understand how the cerebellum adapts and improves movements in response to motor errors. A critical component of this process is signaling from olivary climbing fibers that, by providing strong excitatory drive onto Purkinje cells, induces long-term synaptic plasticity to instantiate corrective adjustments in motor behavior. However, this signaling process is tightly regulated by molecular layer interneurons (MLIs). By strongly inhibiting Purkinje cells, MLIs oppose climbing fiber-driven excitation and gate the induction of corrective plasticity. Thus, for error-driven climbing fiber-induced plasticity and learning to occur effectively, Purkinje cells must undergo disinhibition through the suppression of MLI-mediated input. Notably, MLI ensembles are composed of several subtypes and have a highly structured interconnectivity and are responsive to convergent climbing fiber inputs, suggesting that climbing fiber synchrony- whose functional significance is poorly understood- can selectively engage MLI networks to alter the state of Purkinje cell inhibition. This engagement may balance inhibition and excitation of Purkinje cells during motor errors, creating a circuit mechanism conducive for the acquisition of adaptive learning. The objective of this proposal is to determine how distinct MLI circuits are organized to modulate Purkinje cell excitability through disinhibition in a context-dependent manner, enabling plasticity and learning in response to motor errors. We will employ functional recordings, circuit-targeted activity manipulations, and behavioral analysis to reveal how error-driven instructive signaling emerges from these circuits. In the first aim, we will use in vivo high-density electrophysiology to map functional interactions among MLIs, climbing fibers, and Purkinje cells in the flocculus during the vestibulo-ocular reflex. We will test whether, during motor errors, climbing fibers synchronize their firing to selectively engage disinhibition of Purkinje cells through MLI subtypes in adapting versus non-adapting contexts. In the second aim, we will combine acute slice recordings and molecular anatomy to define direct versus spillover climbing fiber synapses onto MLI subtypes. We will identify synaptic markers and measure climbing-fiber-evoked currents in MLI subtypes, revealing how structural connectivity supports rapid, subtype-specific circuit engagement. In the third aim, we will determine how long-range inputs to the inferior olive, specifically inhibitory projections from the vestibular nuclei, dynamically tune climbing fiber synchrony in vivo and thereby learning through differential engagement of disinhibitory MLI networks. Using functional recording and optogenetic manipulation during the vestibulo- ocular reflex performance, we will establish causal links between climbing fiber synchrony, MLI network state, and adaptive behavior. By fully understanding the logic of instructive signaling, emergent from cerebellar circuit organization and behavioral engagement, we will advance our knowledge of cerebellum-dependent learning processes and provide broader insights into the neural mechanisms of learning and adaptation more generally.

Understanding the complex behaviors of the ‘simple’ cerebellar circuit

Every movement we make requires us to precisely coordinate muscle activity across our body in space and time. In this talk I will describe our efforts to understand how the brain generates flexible, coordinated movement. We have taken a behavior-centric approach to this problem, starting with the development of quantitative frameworks for mouse locomotion (LocoMouse; Machado et al., eLife 2015, 2020) and locomotor learning, in which mice adapt their locomotor symmetry in response to environmental perturbations (Darmohray et al., Neuron 2019). Combined with genetic circuit dissection, these studies reveal specific, cerebellum-dependent features of these complex, whole-body behaviors. This provides a key entry point for understanding how neural computations within the highly stereotyped cerebellar circuit support the precise coordination of muscle activity in space and time. Finally, I will present recent unpublished data that provide surprising insights into how cerebellar circuits flexibly coordinate whole-body movements in dynamic environments.

Synchrony and Synaptic Signaling in Cerebellar Circuits

The cerebellum permits a wide range of behaviors that involve sensorimotor integration. We have been investigating how specific cellular and synaptic specializations of cerebellar neurons measured in vitro, give rise to circuit activity in vivo. We have investigated these issues by studying Purkinje neurons as well as the large neurons of the mouse cerebellar nuclei, which form the major excitatory premotor projection from the cerebellum. Large CbN cells have ion channels that favor spontaneous action potential firing and GABAA receptors that generate ultra-fast inhibitory synaptic currents, raising the possibility that these biophysical attributes may permit CbN cells to respond differently to the degree of temporal coherence of their Purkinje cell inputs. In vivo, self-initiated motor programs associated with whisking correlates with asynchronous changes in Purkinje cell simple spiking that are asynchronous across the population. The resulting inhibition converges with mossy fiber excitation to yield little change in CbN cell firing, such that cerebellar output is low or cancelled. In contrast, externally applied sensory stimuli elicits a transient, synchronous inhibition of Purkinje cell simple spiking. During the resulting strong disinhibition of CbN cells, sensory-induced excitation from mossy fibers effectively drives cerebellar outputs that increase the magnitude of reflexive whisking. Purkinje cell synchrony, therefore, may be a key variable contributing to the “positive effort” hypothesized by David Marr in 1969 to be necessary for cerebellar control of movement.

Sparse expansion in cerebellum favours learning speed and performance in the context of motor control

The cerebellum contains more than half of the brain’s neurons and it is essential for motor control. Its neural circuits have a distinctive architecture comprised of a large, sparse expansion from the input mossy fibres to the granule cell layer. For years, theories of how cerebellar architectural features relate to cerebellar function have been formulated. It has been shown that some of these features can facilitate pattern separation. However, these theories don’t consider the need for it to learn fast in order to control smooth and accurate movements. Here, we confront this gap. This talk will show that the expansion to the granule cell layer in the cerebellar cortex improves learning speed and performance in the context of motor control by considering a cerebellar-like network learning an internal model of a motor apparatus online. By expressing the general form of the learning rate for such a system, this talk will provide a calculation of how increasing the number of granule cells diminishes the effect of noise and increases the learning speed. The researchers propose that the particular architecture of cerebellar circuits modifies the geometry of the error function in a favourable way for learning faster. Their results illuminate a new link between cerebellar structure and function.

Recurrent problems in spinal-cord and cerebellar circuits

One of the best established recurrent inhibitory pathways is the recurrent inhibition of mammalian motoneurons through Renshaw cells. Golgi cells form an inhibitory feedback circuit in the granular layer of cerebellum. Feedback inhibitory pathways are long established “textbook” elements of neural circuitry, but in both cases their functional role has not been well established. Here I will present some new observations on the function of recurrent inhibition in the spinal-cord, supporting the idea that this connection frequency tunes transmission of inputs through motoneurons. Secondly, I will discuss evidence that the function of Golgi cells is much more complex than classical studies based on circuit connectivity suggest.

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Role of the transmembrane tyrosine kinase receptor c-KIT in the development of the olivocerebellar circuit

Exploring signal processing compartmentalization in the cerebellar circuit using a high-density multielectrode array

FENS Forum 2024

Interactions between sensory and motor systems: Corticocerebellar circuits and task engagement

FENS Forum 2024

Thalamic interaction of basal ganglia and cerebellar circuits during motor learning

FENS Forum 2024