Biology subjects

Uusisaari, M. Y.

Publications and source records attributed to Uusisaari, M. Y..

7 recordsLinked to original sources

bioRxiv2026

Somatic Cx36 gap junctions expand the anatomical substrate for electrical coupling in the adult mouse inferior olive

The inferior olive (IO) is unique among adult mammalian brain nuclei in that its neurons communicate solely via gap junctions. For more than half a century, models of cerebellar timing, synchrony, and learning have therefore centered on how electrical coupling between olivary neurons is regulated. In the prevailing anatomical model, IO gap junctions reside on dendritic spines within olivary glomeruli, where nearby inhibitory terminals can locally regulate coupling through shunting conductances. Here we show that this view is incomplete. In the adult mouse IO, closely apposed neuronal somata are common, direct soma-soma appositions are visible by volume electron microscopy, Cx36 puncta occur at somatic contacts, and freeze-fracture replica labeling identifies Cx36-associated gap junction plaques on large continuous membrane surfaces. These soma-proximal gap junctions extend olivary electrical coupling beyond dendritic-spine glomeruli, challenging a core anatomical assumption in models of cerebellar coordination.

neuroscience↗

bioRxiv2026

Motor experience leads to structural changes in the adult male mouse inferior olive

The activity of the inferior olive (IO), conveyed to the cerebellar cortex via climbing fibers and manifesting as the complex spikes (CSs) in Purkinje neurons, is at the core of major theories of cerebellar function and motor learning. While the computational meaning of the CSs remains under intense debate, it is well accepted that changes in their occurrence and timing play a critical role in guiding cerebellar plasticity. However, it has not been examined whether the plastic processes leading to these changes in cerebellar CS activity are expressed in the IO, or whether they are entirely caused by changes in brain structures upstream of the climbing fibers, including the cerebellar nuclei. Here, we examine whether prolonged, kinematically challenging motor experience can lead to detectable changes in the IO network structure that could underlie shifts in cerebellar CS activity. As the IO neurons communicate exclusively via electrical synapses (gap junctions) residing on dendritic structures, we hypothesized that if long-term increases in electrical coupling related to the insertion of new gap junctions occur in response to novel motor experiences, morphological changes in the dendrites would also be expected. To investigate this, we quantitatively characterized the geometry of the IO neuropil revealed by immunohistochemical staining in adult male mice. We found that the neuropil structure varies across olivary subnuclei in naive animals, possibly underlying known differences in cerebellar complex spike co-activation patterns. Geometrical measures related to structural complexity also revealed that exposing the animals to a challenging high-speed treadmill running task requiring full-body coordination led to localized changes suggestive of increased network connectivity. In addition, the density of immunofluorescence puncta labeling Cx36 increased in the same regions, supporting the notion that exposure to contexts where novel motor skills need to be acquired may lead to changes in the clustering strength among IO neurons and thereby restructuring of the olivo-cerebellar micromodules. To our knowledge, this is the first report of experience-related plasticity within the IO, calling for renewed attention to the role of the IO in olivocerebellar function.

neuroscience↗

bioRxiv2024

A vestibulospinal pathway for context-dependent motor control of the mouse tail

The tail movement is critical for maintaining balance during locomotion in many animal species, yet its underlying neuro-muscular control remains poorly understood. In this study we investigated what are the neuronal substrates responsible for tail control in mice. Using high-resolution microCT scans and retrograde labeling, we lay out the neuro-muscular organization of the tail and identified distinct pools of motoneurons in the spinal cord that innervate proximal and distal muscles. We further show that the spinal vestibular nucleus (SpVN) in the brainstem sends direct projections to the same spinal cord segments where tail motoneurons are located. The activation of these vestibulospinal neurons using optogenetics results in more accurate tail movements during challenging balance tasks. Our results reveal that the vestibular systems influence on tail control is context-dependent, enhancing balance performance under uncertain sensory conditions. These findings provide novel insights into the neural circuits responsible for maintaining balance, highlighting the role of the vestibulospinal pathway in context-dependent modulation of tail movement to maintain stability during complex locomotor tasks.

neuroscience↗

bioRxiv2024

Anatomical and functional examination of superior colliculus projections to the inferior olivary neurons in mice

The Inferior olive (IO) is an important region for motor learning and movement coordination. Its climbing fibers projection to the Purkinje neurons in the cerebellar cortex is a sole source of the complex spikes, characterized by a strong depolarization in the Purkinje neurons dendrites. To generate spikes, the IO relies on inputs from various regions of the brain, including the superior colliculus (SC), a midbrain structure known for its role in orienting behaviors. This study investigates SC projections to the IO using viral tracers, calcium imaging, and optogenetic stimulation. We reveal that, in addition to the known projections to the medial accessory olive (MAO), SC axons also project to the ventral principal olive (PO). Despite projecting to different parts of the IO, SC-MAO and SC-PO neurons are intermingled within the lateral part of the SC with similar gross morphology. We show that SC axons terminate on both dendritic shafts and spines of IO neurons, potentially influencing not only spiking probability, but also the network synchronization mediated by gap junctions coupling on the dendritic spines. As a proof of principle, we recorded the in-vivo activity of neurons in ventral PO using calcium indicators and show that optogenetic activation of SC inputs can evoke spiking and enhance synchronization in IO neurons.

neuroscience↗

bioRxiv2024

Deep Imputation for Skeleton Data (DISK) for Behavioral Science

AbstractPose estimation methods and motion capture systems have opened doors to quan- titative measurements of animal kinematics. However, these methods are not perfect and contain missing data. Our method, Deep Imputation for Skeleton data (DISK), leverages deep learning algorithms to learn dependencies between keypoints and their dynamics to impute missing tracking data. We developed an unsupervised training scheme, which does not rely on manual annotations, and tested several neural network architectures for the imputation task. We found that transformer outperforms other architectures including graph con- volutional networks that were developed specifically for skeleton-based action recognition. We demonstrate the usability and performance of our imputation method on seven different animal skeletons including two multi-animal set-ups. With an optional estimated imputation error, DISK enables behavior scien- tists to assess the reliability of the imputed data. The imputed recordings allow to detect more episodes of motion, such as steps, and to obtain more sta- tistically robust results when comparing these episodes between experimental conditions. While animal behavior experiments are expensive and complex, track- ing errors make sometimes large portions of the experimental data unusable. DISK allows for filling in the missing information and for taking full advantage of the rich behavioral data. This stand-alone imputation package, freely available at https://github.com/bozeklab/DISK.git, is applicable to results of any track- ing method (marker-based or markerless) and allows for any type of downstream analysis.

animal behavior and cognition↗

bioRxiv2024

Mice tails function in response to external and self-generated balance perturbation on the roll plane

The functionality of mouse tails has been unexplored in the scientific literature, to the extent that they might seem to be considered as a passive appendage. Previous research on mouse locomotion has largely omitted tail dynamics, but hints at its potential use in balancing can be seen in the natural habitats and behaviors of these rodents. Here, leveraging high-speed videography, a novel naturalistic locomotory task and a simple biomechanical model analysis, we investigated the behavioral utility of the mouse tail. We observed that mice engage their tails on narrow ridge environments that mimic tree branches with narrow footholds prone to roll-plane perturbations, using different control strategies under two defined conditions: during external perturbations of the ridge where they primarily work to maintain posture and avoid falling, and during non-perturbated locomotion on the ridge, where the challenge is to dynamically control the center of mass while progressing forward. These results not only advance the existing understanding of mouse tail functionality but also open avenues for more nuanced explorations in neurobiology and biomechanics. Furthermore, we call for inclusions of tail dynamics for a holistic understanding of mammalian locomotor strategies. Author summaryWe describe and quantify the rapid mouse tail movements in response to external balance perturbations, possibly constituting a novel balance-compensatory motor program. Furthermore, we bring to light the consistent, context-dependent movements of the tail during increasingly precarious locomotion. The observations highlight the tail as an integral component of the mouse locomotory system, contributing to balancing and putatively movement efficacy, and call for inclusion of the tail in future works examining motor (dys)function.

neuroscience↗

bioRxiv2023

Endocannabinoid system modulation alters fine motor behavior in mice: insights from 3D motion capture

The neuromodulatory endocannabinoid system is a promising target for therapeutic interventions. One of the well-known behavioral effects of cannabinoid CB1 receptor activation with exogenous ligands such as THC is the inhibition of locomotor activity. However, the behavioral effects of endogenous cannabinoids are not understood. Enhancing endocannabinoid signaling offers an advantageous therapeutic strategy with limited cannabimimetic side effects, but their effects on motor function remain unclear. To reveal even the finest changes in motor function during voluntary locomotor tasks in mice, we adapted a high-speed, high-resolution marker-based motion capture, which so far has not been available in freely moving mice. Here we show that inhibition of distinct endocannabinoid metabolic pathways produces opposite effects on locomotor behavior that differ from those induced by exogenous cannabinoid receptor ligands. Selective upregulation of endocannabinoids 2-arachidonoylglycerol (2-AG) or N-arachidonoylethanolamine (AEA, anandamide) with inhibitors of their degradation (MJN110 and PF3845, respectively), produced bidirectional effects: MJN110 enhanced and PF3845 suppressed locomotor activity. Consistent differences in whole-body movement and precise step kinematics were found under distinct treatments, while analysis of locomotory episodes revealed invariant temporal microstructure, pointing towards motivational rather than motor-related mechanisms of action. The results show that the effects of manipulations of endocannabinoid system on locomotion are more diverse than previously assumed and result in distinct kinematic phenotypes.

animal behavior and cognition↗