Biology subjects

De Zeeuw, C. I.

Publications and source records attributed to De Zeeuw, C. I..

At least 19 recordsLinked to original sources

bioRxiv2026

Electrophysiological properties of mesodiencephalic junction neurons projecting to the inferior olive

Neocortex has the largest volume, while cerebellar cortex houses most neurons of the mammalian brain, underscoring paramount functions for interactions between them. Neocortex projects to the cerebellum via both the mossy fibre and climbing fibre system; whereas the mossy fibres find their origin in the pons, the climbing fibres are relayed via the subnuclei of the inferior olive (IO) that receive their cortical input from the mesodiencephalic junction (MDJ). Since climbing fibres regulate cerebellar plasticity in a timing-dependent manner, the MDJ-IO pathway probably contributes to both sensorimotor and cognitive learning. However, the physiological properties of IO-projecting MDJ neurons remain largely unknown. Here, we made targeted whole-cell recordings in acute brain slices of the murine MDJ, separating IO- from non-IO-projecting neurons following retrograde tracing. We show that IO-projecting neurons are spontaneously active and are capable of high frequency-bursts up to 350 Hz during current injections. Action potentials of IO-projecting MDJ neurons depolarize and re-polarize quickly, and hyperpolarizing inputs consistently trigger rebound action potentials upon stimulus offset. Instead, non-IO-projecting neurons in the same MDJ region are hardly spontaneously active with little rebound activation. Even so, IO-projecting MDJ neurons can also transform excitatory and inhibitory inputs into a proportional output, indicating that they can also employ rate coding. Moreover, neocortical inputs to IO-projecting MDJ neurons can directly be integrated with their inputs from the cerebellar nuclei. Our results highlight how neocortical inputs to the MDJ can be transformed into diverse IO firing patterns and thereby contribute to the required specifics of cerebellar learning. Key points summaryO_LIThe timing of complex spikes in cerebellar Purkinje cells is essential for cerebellar motor learning and proper timing is achieved through the modulation of activity in the inferior olive, the source of all climbing fibres. C_LIO_LIA major source of excitatory input to the inferior olive is the mesodiencephalic junction. C_LIO_LIWe find that that mesodiencephalic junction neurons projecting to the inferior olive represent a population of physiologically distinct neurons, capable of high firing frequencies and rebound activity following inhibition. C_LIO_LIWe reveal how mesodiencephalic junction neurons process excitatory inputs from the neocortex and cerebellar nuclei, as well as inhibitory inputs, enabling mesodiencephalic junction neurons to bidirectionally regulate their activity. C_LIO_LIThese findings shed light on how the inferior olive, critical for cerebellar motor learning, is controlled by the mesodiencephalic junction. C_LI

neuroscience↗

bioRxiv2026

Open- and Closed-Loop Microcomplexes in Neocerebellum

Neocerebellum facilitates motor and cognitive behavior via olivocerebellar modules, in which Purkinje cells (PCs), cerebellar nuclei (CN) neurons and olivary cells are supposed to form exclusively closed-loops. Here, we provide evidence that parts of the modules may be organized in an open-loop feedforward fashion where PCs do not contact the CN neurons that provide feedback to the olive. The PCs in the open-loop microcomplexes exclusively target projection CN neurons, through which cerebellum modulates downstream brainstem regions controlling behavior. This novel cerebellar architecture, containing open- and closed-loop microcomplexes within single modules, offers a mechanism by which mossy fiber information can be differentially used either as feedforward control of behavior and/or as feedback to the olivary subnuclei that regulates activity and plasticity within the module involved. This potential for both integrated and segregated regulation of behavior and feedback within single modules enriches the computational repertoire of the olivocerebellar system.

neuroscience↗

bioRxiv2025

Dopaminergic Control of Retinal Oscillations Driving Infantile Nystagmus

Infantile nystagmus is a debilitating involuntary eye movement disorder often associated with retinal diseases such as Congenital Stationary Night Blindness (CSNB). The oscillating eye movements of infantile nystagmus come with reduced visual acuity, strongly impairing quality of life. No cure exists for this condition. Previously, we demonstrated that nystagmus in the CSNB mouse model Nyxnob has a retinal cause. Specifically, we found that synchronized oscillations of retinal ganglion cells (RGCs) are transmitted to the accessory optic system, triggering compensatory eye movements. The RGC oscillations appear to originate from a specific retinal cell type, the AII amacrine cell (AII AC), making these cells the preferred target for treatment. Here we found that pharmacologically activating the dopaminergic input to AII ACs in Nyxnob mice completely suppresses the pathological oscillations of both AII ACs and RGCs and improves the signal fidelity of RGCs. Moreover, our retinal network simulations confirm that the experimentally observed changes to AII AC voltage-gated currents are sufficient to account for the dopamine-dependent abolishment of these oscillations. Our findings provide a novel mechanistic understanding of the retinal mechanism underlying infantile nystagmus as well as the associated low visual performance. Consequently, they offer the first pharmacological therapeutic strategy for this disorder. SignificanceOscillatory eye movements in infantile nystagmus arise from abnormal retinal activity, yet the cellular basis of this instability has remained unclear. Here we show that this abnormal activity stems from disrupted dopaminergic modulation. By defining how dopamine regulates the activity of a key retinal cell type, the AII amacrine cell, we demonstrate that restoring dopamine levels can return the retinal circuit to a stable state and improve the clarity of visual signals leaving the eye. This work links neuromodulation to retinal circuit instability and identifies dopaminergic control of AII amacrine cells as a pharmacologically targetable point of intervention. These findings suggest a retina-focused pharmacological treatment strategy for infantile nystagmus, a disorder that currently lacks effective therapeutic options.

neuroscience↗

bioRxiv2025

ATXN2 polyglutamine expansion impairs QKI-dependent alternative splicing and oligodendrocyte maintenance

BackgroundPolyglutamine (polyQ) tract expansion mutations in Ataxin-2 gene (ATXN2) are associated with neurodegenerative diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS), while the therapeutic reduction of ATXN2 confers strong health-/lifespan extension in models of both disorders. Although the involvement of ATXN2 in peripheral lipid metabolism has been elaborated in Atxn2 knock-out mice, its impact on nervous system lipid maintenance and a potential influence on oligodendrocytes remains unexplored. MethodsWe examine the nervous tissue of an authentic ATXN2 polyQ expansion mouse model in terms of (i) gross morphology of the brain and differential glial affection via immunohistochemical analyses, (ii) spinocerebellar proteome profile via label-free mass spectroscopy and (iii) alternative splicing patterns of oligodendroglial transcripts via quantitative RT-PCR. Finally, electrophysiological recording of sensory response in cerebellar Purkinje cells was performed as a phenotypic measure of demyelination. ResultsWe demonstrate a massive impairment in myelin maintenance due to ATXN2 polyQ expansion, affecting key oligodendroglial proteins accompanied by their splicing anomalies much earlier than disease manifestation. Oligodendroglial ATXN2 aggregates were documented for the first time in cerebellum, which sequestrated the RNA splicing factor Quaking (QKI). As an outcome of demyelination, our SCA2 model showed a significant delay in response to sensory stimuli. ConclusionsOverall, we provide pioneer evidence of oligodendroglial proteotoxicity leading to myelin maintenance defects in an authentic mouse model of SCA2. Our findings suggest that not only neuronal metabolism, but also that of oligodendroglia depends on ATXN2 and is affected during the disease course. This novel aspect of ATXN2 pathomechanism sheds light on potential outcomes of its therapeutic manipulation, and makes it relevant also for demyelination syndromes next to SCA2 and other polyQ disorders.

neuroscience↗

bioRxiv2025

Homeostatic bidirectional plasticity in Upbound and Downbound micromodules of the olivocerebellar system

Olivocerebellar learning is highly adaptable, unfolding over minutes to weeks depending on the task. However, the stabilizing mechanisms of the synaptic dynamics necessary for ongoing learning remain unclear. We constructed a model to examine plasticity dynamics under stochastic input and investigate the impact of inferior olive (IO) reverberations on Purkinje cell (PCs) activity and synaptic plasticity. We explored Upbound and Downbound cerebellar micromodules, which are organized loops of IO neurons, cerebellar nuclei neurons and microzones of PCs characterized by their unique molecular profiles and different levels of baseline firing. Our findings show synaptic weight convergence followed by stability of synaptic weights. In line with their relatively low and high intrinsic firing, we observed that Upbound and Downbound PCs have a propensity for potentiation and depression, respectively, with both PC types reaching stability at differential levels of overall strength of their parallel-fiber (PF) inputs. The oscillations and coupling of IO neurons participating in the Upbound and Downbound modules determine at which frequency band PFs can be stabilized optimally. Our results indicate that specific frequency components drive IO resonance and synchronicity, which, in turn, regulate temporal patterning across Upbound and Downbound zones, orchestrating their plasticity dynamics. Author SummaryThe olivocerebellar system is a part of the brain that facilitates learning and controlling movements. To coordinate movements it integrates sensorimotor information with motor command signals. The resulting behaviour needs to be continuously adjusted during motor learning. The leading hypothesis is that changes in strength of the synaptic connections between neurons underlie the learning process. The challenge is to elucidate the factors that determine the exact timing and precision of the learned movements. To answer this question we developed a computational model of the two main types of modules of the olivocerebellar system that can control different types of movements in a bidirectional fashion. We found that the rhythm and coupling of the olivary neurons play an important role in controlling and stabilizing plasticity in the cerebellar cortex of both types of modules, together shaping learning-dependent timing of motor behaviour.

neuroscience↗

bioRxiv2024

Mobile Human Brain Imaging using Functional Ultrasound

Imagine being able to study the human brain in real-world scenarios while the subject displays natural behaviors such as locomotion, social interaction, or spatial navigation. The advent of ultrafast ultrasound imaging brings us closer to this goal with functional Ultrasound imaging (fUSi), a new mobile neuroimaging technique. Here, we present real-time fUSi monitoring of brain activity during walking in a subject with a clinically approved sonolucent skull implant. Our approach utilizes personalized 3D-printed fUSi-helmets for stability, optical tracking for cross-modal validation with fMRI, advanced signal processing to estimate hemodynamic responses and facial tracking of a lick licking paradigm. These combined efforts allowed us to show consistent fUSi signals over 20 months, even during high-motion activities like walking. These results demonstrate the feasibility of fUSi for monitoring brain activity in real-world contexts, marking an important milestone for fUSi-based insights in clinical and neuroscientific research.

neuroscience↗

bioRxiv2024

Acute Aerobic Exercise Enhances Associative Learning in Active but not Sedentary Individuals

IntroductionPhysical exercise has repeatedly been reported to have advantageous effects on brain functions, including learning and memory formation. However, objective tools to measure such effects are often lacking. Eyeblink conditioning is a well-characterised method for studying the neural basis of associative learning. As such, this paradigm has potential as a tool to assess to what extent exercise affects one of the most basic forms of learning. Until recently, however, using this paradigm for testing human subjects in their daily life was technically challenging. As a consequence, no studies have investigated how exercise affects eyeblink conditioning in humans. Here we hypothesize that acute aerobic exercise is associated with improved performance in eyeblink conditioning. Furthermore, we explored whether the effects of exercise differed for people with an active versus a sedentary lifestyle. MethodsWe conducted a case-control study using a smartphone-based platform for conducting neurometric eyeblink conditioning in healthy adults aged between 18 - 40 years (n = 36). Groups were matched on age, sex, and education level. Our primary outcome measures included the amplitude and timing of conditioned eyelid responses over the course of eyeblink training. As a secondary measure, we studied the amplitude of the unconditioned responses. ResultsAcute exercise significantly enhanced the acquisition of conditioned eyelid responses; however, this effect was only true for individuals with an active lifestyle. No statistically significant effects were established for timing of the conditioned responses and amplitude of the unconditioned responses. DiscussionThis study highlights a facilitative role of acute aerobic exercise in associative learning and emphasises the importance of accounting for lifestyle when investigating the acute effects of exercise on brain functioning.

neuroscience↗

bioRxiv2024

Cerebellar control of targeted tongue movements

The cerebellum is critical for coordinating movements related to eating, drinking and swallowing. Cerebellar Purkinje cell activity has been shown to encode ongoing tongue movements, but it is unclear how this activity can alter the trajectory of the tongue. To elucidate the impact of Purkinje cells on goal-directed tongue movements, we recorded their activity in the vermis and hemispheres during spontaneous licking from a stationary or moving water spout. Some Purkinje cells encode rhythmic tongue movements with their complex spikes, others with their simple spikes or a combination of both. Complex spikes predominantly marked the start and end of a licking bout, and thus encoded behavioural state changes, while simple spike firing was more related to individual licks. In addition, complex spikes reported unexpected changes in the position of the water spout and subsequent modulation of simple spike firing caused bending of the tongue, reaching out for the new target position. Using machine learning, we demonstrated that it is possible to predict licking activity based on the spiking patterns of individual Purkinje cells. Using optogenetic stimulation of Purkinje cells, we could experimentally replicate the impact of modulated simple spike firing, suggesting that increased simple spike activity indeed causes ipsilateral bending of the tongue during goal-directed movements. Our data highlight that directional control of movements is paramount in cerebellar function and that complex spike and simple spike modulation complement each other during sensorimotor coordination. These results bring us closer to understanding clinical implications of cerebellar disorders during eating, drinking and swallowing. Key pointsO_LIWhen drinking, mice make rhythmic tongue movements directed towards the water source. C_LIO_LICerebellar Purkinje cells can fire rhythmically in tune with the tongue movements. C_LIO_LIPurkinje cells encode changes in the position of the water source with complex spikes. C_LIO_LIPurkinje cell simple spike firing affects the direction of tongue movements. C_LIO_LIPurkinje cells that report changes in the position of the target can also adjust movements in the right direction. C_LI

neuroscience↗

bioRxiv2024

Purkinje cells in Crus I and II encode the visual stimulus and the impending choice as monkeys learn a reinforcement based visuomotor association task

Visuomotor association involves linking an arbitrary visual cue to a well-learned movement. Transient inactivation of Crus I/II impairs primates ability to learn new associations and delays motor responses without affecting the kinematics of the movement. The simple spikes of Purkinje cells in the Crus regions signal cognitive errors as monkeys learn to associate specific fractal stimuli with movements of the left or right hand. Here we show that as learning progresses, the simple spike activity of individual neurons becomes more selective for stimulus-response associations, with selectivity developing closer to the appearance of visual stimuli. Initially, most neurons respond to both associations, irrespective of the identity of the stimulus and the associated movement, but as learning advances, more neurons distinguish between specific stimulus-hand associations. Using a linear decoder, it was found that in early learning stages, the visual stimulus can be decoded only when the choice can also be decoded. As learning improves, the visual stimulus is decoded earlier than the choice. A simple model can replicate the observed simple spike signals and the monkeys behavior in both the early and late learning stages.

neuroscience↗

bioRxiv2024

Encoding of cerebellar dentate neuronal activity during visual attention in rhesus macaques

The role of cerebellum in controlling eye movements is well established, but its contribution to more complex forms of visual behavior has remained elusive. To study cerebellar activity during visual attention we recorded extracellular activity of dentate nucleus (DN) neurons in two non-human primates (NHPs). NHPs were trained to read the direction indicated by a peripheral visual stimulus while maintaining fixation at the center, and report the direction of the cue by performing a saccadic eye movement into the same direction following a delay. We found that single unit DN neurons modulated spiking activity over the entire time-course of the task, and that their activity often bridged temporally separated intra-trial events, yet in a heterogeneous manner. To better understand the heterogeneous relationship between task structure, behavioral performance and neural dynamics, we constructed a behavioral, an encoding and a decoding model. Both NHPs showed different behavioral strategies, which influenced the performance. Activity of the DN neurons reflected the unique strategies, with the direction of the visual stimulus frequently being encoded long before an upcoming saccade. Moreover, the latency of the ramping activity of DN neurons following presentation of the visual stimulus was shorter in the better performing NHP. Labeling with the retrograde tracer CTB in the recording location in the DN indicated that these neurons predominantly receive inputs from Purkinje cells in the D1 and D2 zones of the lateral cerebellum as well as neurons of the principal olive and medial pons, all regions known to connect with neurons in the prefrontal cortex contributing to planning of saccades. Together, our results highlight that DN neurons can dynamically modulate their activity during a visual attention task, comprising not only sensorimotor but also cognitive attentional components.

neuroscience↗

bioRxiv2023

Neuronal dynamics of cerebellum and medial prefrontal cortex in adaptive motor timing

Precise temporal control of sensorimotor coordination and adaptation is a fundamental basis of animal behavior. How different brain regions are involved in regulating the flexible temporal adaptation remains elusive. Here we investigated the neuronal dynamics of cerebellar interposed nucleus (IpN) and medial prefrontal cortex (mPFC) neurons during temporal adaptation between delay eyeblink conditioning (DEC) and trace eyeblink conditioning (TEC). When mice trained for either DEC or TEC and subsequently subjected to a new paradigm, their conditioned responses (CRs) adapted virtually instantaneously. Changes in the activity of the IpN neurons to CR timing were prominent during DEC-to-TEC adaptation, but less so during TEC-to-DEC adaptation. In contrast, mPFC neurons could rapidly alter their modulation patterns during both adaptation paradigms. Accordingly, silencing of mPFC blocked the adaptation of CR timing. These results illuminate how cerebral and cerebellar mechanisms may play differential roles during adaptive control of associative motor timing.

neuroscience↗

bioRxiv2023

The sleep quality- and myopia-linked PDE11A-Y727C variant impacts neural physiology by reducing catalytic activity and altering subcellular compartmentalization of the enzyme

Recently, a Y727C variant in the dual-specific 3,5-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if 1) PDE11A protein is expressed in the retina or other eye segments in mouse, 2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and 3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT--but not KO mice--that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness, axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

neuroscience↗

bioRxiv2023

The modified elevated gap interaction test: A novel paradigm to assess social preference.

Social deficits play a role in numerous psychiatric, neurological and neurodevelopmental disorders. Relating complex behavior, such as social interaction, to brain activity remains one of the biggest goals and challenges in neuroscience. Availability of standardized behavioral tests that assess social preference is however, limited. Here, we present a novel behavioral set-up and paradigm that we developed to measure social behavior, the modified elevated gap interaction test (MEGIT). In this test, animals are placed on one of two elevated platforms separated by a gap, in which they can engage in whisker-interaction with either a conspecific or an object. This allows quantification of social preference in real interaction rather than just proximity and forms an ideal setup for social behavior-related neuronal recordings. We provide a detailed description of the paradigm and its highly reliable, deep-learning based analysis, and show test results obtained from wild-type animals as well as genetic mouse models for disorders characterized by either hyposocial (autism spectrum disorder; ASD) or hypersocial (Williams Beuren syndrome; WBS) behavior. Wild-type animals show a clear preference for whisker interaction with another mouse rather than an inanimate object. This preference proved to be significantly smaller in mice carrying a mutation that can cause ASD in humans, whereas it is larger in WBS murine models. Differences in social preference became even more pronounced when corrected for hyperactive or repetitive behavior. The results indicate that MEGIT is a sensitive and reliable test for detecting and investigating social phenotypes.

neuroscience↗

bioRxiv2023

Sleep-state dependent cerebellar processing in adult mice

The cerebellum is important for motor performance and adaptation as well as cognition. Sleep is essential for optimizing of all these functions, but it remains to be elucidated how sleep affects cerebellar processing. It has been suggested that sleep periods with muscle twitches entrain the cerebellum with a copy of motor commands and subsequent sensory feedback signals, to develop predictive coding of movements. If this hypothesis is correct, one expects phasic correlations between the muscle twitches and specific features of the electro-encephalography (EEG) recordings in the cerebellum during various sleep stages as well as the climbing fiber activity in the cerebellar cortex, the modulation of which is relayed from the cerebral cortex via mesodiencephalic junction and inferior olive. Here we provide evidence for coherent correlations between cerebellar and cerebral cortical sleep spindles, twitches as well as patterns of climbing fiber activity. Our data are compatible with the novel concept that muscle twitches evoke complex spike synchronicity during NREM, which in turn affects cerebellar spindle activity and cerebellar-cortical information flow, thereby entraining an internal forward model.

neuroscience↗

bioRxiv2023

Vascular abnormalities in heart and brain are associated with cardiovascular and neurological symptoms in a novel mouse model for Williams syndrome

Williams syndrome is a developmental disorder caused by a microdeletion entailing the loss of a single copy of 25-27 genes on chromosome 7q11.23. Patients suffer from cardiovascular and neuropsychological symptoms. Structural abnormalities of the cardiovascular system in Williams syndrome have been attributed to the hemizygous loss of the elastin (ELN) gene. In contrast, the neuropsychological consequences of Williams syndrome, including sensorimotor deficits, hypersociability and cognitive impairments, have been mainly attributed to altered expression of transcription factors like LIMK1, GTF2I and GTF2IRD1, while the potential impact of altered cerebrovascular function has been largely overlooked. To study the relationship between Williams syndrome mutations and vascularization of both the heart and brain, we generated a mouse model carrying a relatively long microdeletion (LD) that includes the Ncf1 gene, thereby minimizing the confounding impact of hypertension. LD mice had elongated and tortuous aortas but, unlike Eln haploinsufficient mice, showed no signs of structural cardiac hypertrophy. Remarkably, LD mice also displayed structural abnormalities in coronary and brain vessels, including disorganized extracellular matrices. Importantly, LD mice faithfully replicated both cardiovascular and neuropsychological symptoms observed in patients. The phenotype was even more comprehensive than former models, with structure-function correlations evident in aberrant auditory and motor behaviors resembling those in patients with Williams syndrome. Together, our findings suggest that not only cardiovascular but also neuropsychological symptoms in Williams syndrome may be driven in part by vascular abnormalities affecting both heart and brain. Significance StatementWilliams syndrome is caused by microdeletion of 25-27 genes on chromosome 7q11.23, resulting in cardiovascular and neuropsychological symptoms. It remains unclear how the affected genes interact and whether cardiovascular deficits influence brain function. We developed and characterized a mouse model with the longest Williams syndrome microdeletion to date. This model reveals interactions between genes that can be compensatory or additive: haploinsufficiency of Ncf1 may counteract the cardiac hypertrophy caused by Eln deletion, while vascular defects that are potentially due to Eln haploinsufficiency extend to the brain and may worsen neuropsychological symptoms. Our findings support the hypothesis that structural vascular deficits putatively contribute to both cardiac and cognitive phenotypes in Williams syndrome, opening new avenues for understanding and treating this syndrome.

systems biology↗

bioRxiv2023

A Common Cause for Nystagmus in Different Congenital Stationary Night Blindness Mouse Models

In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e., nystagmus. Given the distribution of mGluR6 and Cav1.4 in the retina as well as their clinical association with CSNB, we hypothesize that mGluR6-/- and Cav1.4-/- mutants show, like the Nyxnob mouse, oscillations that originate in the AII amacrine cells (AII ACs). Using eye movement and multi-electrode array (MEA) recordings of RGCs we show that the nystagmus as well as the underlying RGC oscillations are also present in mGluR6-/- and Cav1.4-/- mice. Yet, we find that the oscillations in the mGluR6-/- and Cav1.4-/- mutants slightly differ from each other and also from those of the Nyxnob mice. Moreover, each of the three mutations likely impacts the membrane potential of the AII ACs differently. Together our results indicate that nystagmus and oscillating RGCs are generalizable features associated with CSNB mutations localized at the photoreceptor-bipolar cell synapse.

neuroscience↗

bioRxiv2022

Membrane potential dynamics of cerebellar nuclei neurons during eyeblink conditioning

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not of climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.

neuroscience↗

bioRxiv2022

How inhibitory and excitatory inputs gate output of the inferior olive

The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that ride on their intrinsic oscillations. Using dual color optogenetic stimulation and whole cell recordings we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated approximately 50 ms after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated approximately 150 ms after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs.

neuroscience↗