Biology subjects

Bosman, L. W. J.

Publications and source records attributed to Bosman, L. W. J..

7 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↗

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↗

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↗

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↗

bioRxiv2019

Functional convergence of autonomic and sensorimotor processing in the lateral cerebellum

The cerebellum is involved in control of voluntary and autonomic rhythmic behaviors, yet it is largely unclear to what extent it coordinates these in a concerted action. Here, we studied Purkinje cell activity during unperturbed and perturbed respiration in cerebellar lobules simplex, crus 1 and 2. During unperturbed (eupneic) respiration complex spike and simple spike activity encoded respiratory activity, the timing of which corresponded with ongoing sensorimotor feedback. Instead, upon whisker stimulation mice concomitantly accelerated their simple spike activity and inspiration in a phase-dependent manner. Moreover, the accelerating impact of whisker stimulation on respiration could be mimicked by optogenetic stimulation of Purkinje cells and prevented by cell-specific genetic modification of their AMPA receptors that hampered increases in simple spike firing. Thus, the impact of Purkinje cell activity on respiratory control is context- and phase-dependent, suggesting a coordinating role for the cerebellar hemispheres in aligning autonomic and sensorimotor behaviors.

neuroscience↗

bioRxiv2018

Adaptation of Whisker Movements Requires Cerebellar Potentiation

Cerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading the behavioral response. Neuronal and behavior changes did not occur in two cell-specific mouse models with impaired long-term potentiation at parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity.\n\nImpact statementRomano et al. show that expression of cerebellar whisker learning can be mediated by increases in simple spike activity, depending on LTP induction at parallel fiber to Purkinje cell synapses.

neuroscience↗

bioRxiv2018

Atxn2-CAG100-knock-in affects mouse lifespan and vestibulo-cerebellar function via neural disconnection

Unstable expansions in the Q22-polyglutamine domain of human ATXN2 mediate risks for motor neuron diseases such as ALS/FTLD or cause the autosomal dominant Spinocerebellar Ataxia type 2 (SCA2), but the pathogenesis is not understood and models are unavailable.\n\nWe generated a novel knock-in mouse line with CAG100 expansion in Atxn2, transmitted unstably. The mutant protein accumulated in neuronal cytosolic aggregates, with a characteristic pattern of multi-system-atrophy. Loss-of-function phenotypes included less mutant offspring, initial weight gain and motor hyperactivity. Progressive toxic aggregation effects started around 20 weeks in homozygous animals showing weight loss, reduced muscle strength and gait ataxia. Lifespan was decreased. In the cerebellum, neuronal soma and dendrites were remarkably spared. However, myelin proteins MBP, CNP, PLP1 and transcripts Mal, Mobp, Rtn4 decreased markedly, especially adhesion factors MAG and MOG. In neurons, strong reductions were found for mRNAs of perineuronal elements Haplnl, Hapln2, Hapln4, of axonal myelin interactors Prnp and Klk6. At protein level, the adhesion factor neuroplastin and neurofilaments were strongly reduced, while presynaptic alpha-synuclein increased two-fold.\n\nOverall, this authentic SCA2 mouse model elucidates how altered function and aggregation toxicity of ATXN2 conspire to trigger axon-myelin disconnection. This model will promote the development of neuroprotective therapies and disease biomarkers.

neuroscience↗