The cerebellum computes frequency dynamics for motions with numerical precision and cross-individual uniformity.

Cross-individual variability is considered the essence of biology, preventing precise mathematical descriptions of biological motion1-7 like the physics law of motion. Here we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in-vivo electrophysiology and optogenetics in mice, we confirmed that deep cerebellar neurons encoded frequencies via populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism was consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform, or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validated the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating-current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for brain-computer interface for motor control.

Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients.

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

Tracking motion kinematics and tremor with intrinsic oscillatory property of instrumental mechanics.

Tracking kinematic details of motor behaviors is a foundation to study the neuronal mechanism and biology of motor control. However, most of the physiological motor behaviors and movement disorders, such as gait, balance, tremor, dystonia, and myoclonus, are highly dependent on the overall momentum of the whole-body movements. Therefore, tracking the targeted movement and overall momentum simultaneously is critical for motor control research, but it remains an unmet need. Here, we introduce the intrinsic oscillatory property (IOP), a fundamental mechanical principle of physics, as a method for motion tracking in a force plate. The overall kinetic energy of animal motions can be transformed into the oscillatory amplitudes at the designed IOP frequency of the force plate, while the target movement has its own frequency features and can be tracked simultaneously. Using action tremor as an example, we reported that force plate-based IOP approach has superior performance and reliability in detecting both tremor severity and tremor frequency, showing a lower level of coefficient of variation (CV) compared with video- and accelerometer-based motion tracking methods and their combination. Under the locomotor suppression effect of medications, therapeutic effects on tremor severity can still be quantified by dynamically adjusting the overall locomotor activity detected by IOP. We further validated IOP method in optogenetic-induced movements and natural movements, confirming that IOP can represent the intensity of general rhythmic and nonrhythmic movements, thus it can be generalized as a common approach to study kinematics.

Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology.

Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

Therapeutic potential and underlying mechanism of sarcosine (N-methylglycine) in N-methyl-D-aspartate (NMDA) receptor hypofunction models of schizophrenia.

BACKGROUND: Compelling animal and clinical studies support the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia and suggest promising pharmacological agents to ameliorate negative and cognitive symptoms of schizophrenia, including sarcosine, a glycine transporter-1 inhibitor. AIMS AND METHODS: It is imperative to evaluate the therapeutic potential of sarcosine in animal models, which provide indispensable tools for testing drug effects in detail and elucidating the underlying mechanisms. In this study, a series of seven experiments was conducted to investigate the effect of sarcosine in ameliorating behavioral deficits and the underlying mechanism in pharmacological (i.e., MK-801-induced) and genetic (i.e., serine racemase-null mutant (SR-/-) mice) NMDAR hypofunction models. RESULTS: In Experiment 1, the acute administration of 500/1000 mg/kg sarcosine (i.p.) had no adverse effects on motor function and serum biochemical responses. In Experiments 2-4, sarcosine significantly alleviated MK-801-induced (0.2 mg/kg) brain abnormalities and behavioral deficits in MK-801-induced and SR-/- mouse models. In Experiment 5, the injection of sarcosine enhanced CSF levels of glycine and serine in rat brain. In Experiments 6-7, we show for the first time that sarcosine facilitated NMDAR-mediated hippocampal field excitatory postsynaptic potentials and influenced the movement of surface NMDARs at extrasynaptic sites. CONCLUSIONS: Sarcosine effectively regulated the surface trafficking of NMDARs, NMDAR-evoked electrophysiological activity, brain glycine levels and MK-801-induced abnormalities in the brain, which contributed to the amelioration of behavioral deficits in mouse models of NMDAR hypofunction.