Biology subjects

Kislin, M.

Publications and source records attributed to Kislin, M..

8 recordsLinked to original sources

bioRxiv2023

Structural covariation between cerebellum and cerebral cortex is atypically modulated by thalamus in autism spectrum disorder

Despite its strong interconnectivity with the cerebral cortex, the influence of the human cerebellum on neocortical structure and its role in the development of neuropsychiatric disorders is unclear. Because cerebellar damage in early postnatal life creates a high risk for autism spectrum disorder (ASD), we investigated inter-relationships in cerebello-cerebral morphology. Leveraging a large structural brain MRI dataset in neurotypical children (n=375) and those diagnosed with ASD (n=373), we examined whether volumetric variation in cerebellar structure across individuals was correlated with neocortical variation during development, modeling the thalamus as a moderating coupling factor. We found negative covariation between cerebellar cortical regions and thalamic/sensorimotor neocortical regions, and positive covariation between thalamic and sensorimotor neocortical regions. This pattern aligned with the major disynaptic path of cerebellar inhibition to thalamocortical excitation. Examining the dependence of this structural covariation on ASD diagnosis, we found that neurotypical and ASD children displayed inverted hemispheric biases. In ASD, the thalamus moderated structural associations between the left cerebellum and right sensorimotor cortex. For neurotypical children, right cerebellum and left sensorimotor cortex were coupled. Notably, structural coupling between cerebellum, thalamus, and neocortex was strongest in younger childhood and waned by early adolescence, a time during which behavioral differences were smallest between typically developing and autistic children. In addition to the sensorimotor cortex, cerebellar dentate nuclei in ASD displayed greater coupling to broad neocortical regions, and these nuclei related to cognitive function differently such that greater dentate nuclear volume was associated with greater behavioral impairment in ASD but not in controls. Graph analyses demonstrated that the cerebello-thalamocortical network was more densely and less prolifically interconnected in ASD than in typical development. Taken as a whole, our study reveals a developmental interplay between the cerebellum, thalamus, and neocortex which differs in ASD from neurotypical children. This pattern is consistent with a model of ASD in which early developmental influences of cerebellar output on brain maturation are specifically moderated by cerebello-thalamocortical pathways.

neuroscience↗

bioRxiv2021

Enhanced learning and sensory salience in a cerebellar mouse autism model

Perturbation to the cerebellum can lead to deficits in motor function, cognition, and behavioral flexibility. Here we report that a cerebellum-specific transgenic mouse autism model with disrupted Purkinje cell function shows unexpectedly accelerated learning on a sensory evidence-accumulation task, as well as enhanced sensory reactivity to touch and auditory cues. Computational latent-state analysis of behavior revealed that accelerated learning was associated with enhanced focus on current over past trials. In on-task states, a subset of Purkinje cells in crus I produced more complex spikes to sensory stimuli. Learning was accelerated by providing cue-locked optogenetic stimulation of Purkinje cells, but unaffected by continuous optogenetic interference with Purkinje cell activity. Complex spikes fired in response to both correct and incorrect choices, but less so when mice were on-task. Both transgenic mice and mice receiving cue-locked optogenetic stimulation showed prolonged sensory responses in Purkinje-cell complex spikes and anterior cingulate cortex. We suggest that cerebellar activity may shape evidence-accumulation learning by enhancing task focus and neocortical processing of current experience. HighlightsO_LIFaster learning and enhanced sensory salience with cerebellar manipulations in mice C_LIO_LIAccelerated learning arises from prolonged occupancy in an on-task behavioral state C_LIO_LICerebellar manipulations can influence neocortex via altered complex spike activity C_LIO_LICerebellum findings consistent with a weak global coherence account of autism C_LI eTOC blurbIn a cerebellum-based mouse autism model, perturbed function leads to faster learning of a working-memory task, mediated by higher focus on current trials. The effects are emulated by optogenetic perturbation of Purkinje cells, and both perturbations drive enhanced neocortical activity. Results are consistent with a weak coherence model for autism.

neuroscience↗

bioRxiv2021

Cerebellar contributions to a brainwide network for flexible behavior

The cerebellum regulates nonmotor behavior, but the routes by which it exerts its influence are not well characterized. Here we report a necessary role for the posterior cerebellum in guiding a reversal learning task, acting through a network of diencephalic and neocortical structures. After chemogenetic inhibition of Purkinje cells in lobule VI or crus I, mice could learn a water Y-maze task but were impaired in their ability to reverse their initial choice. To map targets of perturbation, we imaged c-Fos activation in cleared whole brains using light-sheet microscopy. Reversal learning activated diencephalic regions and associative neocortical regions. Distinctive subsets of structures were altered by perturbation of lobule VI (including thalamus and habenula) and crus I (including hypothalamus and prelimbic/orbital cortex), and both perturbations influenced anterior cingulate and infralimbic cortex. To identify functional networks, we used correlated variation in c-Fos activation within each test group. Lobule VI inactivation weakened within-thalamus correlations, while crus I inactivation divided neocortical activity into well-separated sensorimotor and associative subnetworks. In both groups, high-throughput automated analysis of complex whole-body movement revealed deficiencies in across-day adaptation to an open field environment. Neither perturbation affected gait, within-day open-field adaptation, or location preference. Taken together, these experiments reveal brainwide systems for cerebellar influence that can affect multiple flexible responses. Significance statementThe cerebellum, a part of all vertebrate brains, provides feedback to the rest of the brain on a split-second basis in response to unexpected events. The consequent changes can range from minute adjustments in movement to broad changes in behavior. In mice, we investigated cerebellar regions that help guide flexible behavior. Inactivation of these regions prevented mice from responding flexibly to a changing Y-shaped maze. We used light-sheet microscopy of c-fos protein expression to map brainwide effects of different stages of learning and cerebellar inactivation. Inactivation caused changes in thalamocortical activity that were similar in pattern, but opposite in sign, from normal learning. Lobule VI inactivation weakened thalamic functional networks, while crus I inactivation divided sensorimotor from associative neocortical networks. The same inactivation also impaired multiday adaptation to an open arena, as tracked using machine vision. Our work shows how the cerebellums influence over flexible response can be mediated by a widespread brain network.

neuroscience↗

bioRxiv2021

Deep behavioral phenotyping of mouse autism models using open-field behavior

AO_SCPLOWBSTRACTC_SCPLOWAutism is noted for both its genotypic and phenotypic diversity. Repetitive action, resistance to environmental change, and motor disruptions vary from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we use advances in computer vision and deep learning to develop a framework for characterizing mouse behavior on multiple time scales using a single popular behavioral assay, the open field test. We observed male and female C57BL/6J mice to develop a dynamic baseline of adaptive behavior over multiple days. We then examined two rodent models of autism, a cerebellum-specific model, L7-Tsc1, and a whole-brain knockout model, Cntnap2. Both Cntnap2 knockout and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure-to-adapt took the form of maintained ambling, turning, and locomotion, and an overall decrease in grooming. Adaptation in Cntnap2 knockout mice more broadly resembled that of wild-type. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics.

neuroscience↗

bioRxiv2020

Parallel organization of cerebellar pathways to sensorimotor, associative, and modulatory forebrain

Cerebellar outputs take polysynaptic routes to reach the rest of the brain, impeding conventional tracing. Here we quantify pathways between cerebellum and forebrain using transsynaptic tracing viruses and a whole-brain quantitative analysis pipeline. Retrograde tracing found a majority of descending paths originating from somatomotor cortex. Anterograde tracing of ascending paths encompassed most thalamic nuclei, especially ventral posteromedial, lateral posterior, mediodorsal, and reticular nuclei; in neocortex, sensorimotor regions contained the most labeled neurons, but higher densities were found in associative areas, including orbital, anterior cingulate, prelimbic, and infralimbic cortex. Patterns of ascending expression correlated with c-Fos expression after optogenetic inhibition of Purkinje cells. Our results reveal homologous networks linking single areas of cerebellar cortex to diverse forebrain targets. We conclude that shared areas of cerebellum are positioned to provide sensory-motor information to regions implicated in both movement and nonmotor function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/979153v3_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1bead0corg.highwire.dtl.DTLVardef@1531de2org.highwire.dtl.DTLVardef@1cf02f6org.highwire.dtl.DTLVardef@1cb6774_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

Cerebellar disruption impairs working memory during evidence accumulation

To select actions based on sensory evidence, animals must create and manipulate representations of stimulus information in memory. We found that during accumulation of somatosensory evidence, optogenetic manipulation of cerebellar Purkinje cells reduced the accuracy of subsequent memory-guided decisions and caused mice to downweight prior information. Behavioral deficits were consistent with the addition of noise and leak to the evidence accumulation process, suggesting the cerebellum can influence the maintenance of working memory contents.

neuroscience↗

bioRxiv2018

Fast animal pose estimation using deep neural networks

Recent work quantifying postural dynamics has attempted to define the repertoire of behaviors performed by an animal. However, a major drawback to these techniques has been their reliance on dimensionality reduction of images which destroys information about which parts of the body are used in each behavior. To address this issue, we introduce a deep learning-based method for pose estimation, LEAP (LEAP Estimates Animal Pose). LEAP automatically predicts the positions of animal body parts using a deep convolutional neural network with as little as 10 frames of labeled data for training. This framework consists of a graphical interface for interactive labeling of body parts and software for training the network and fast prediction on new data (1 hr to train, 185 Hz predictions). We validate LEAP using videos of freely behaving fruit flies (Drosophila melanogaster) and track 32 distinct points on the body to fully describe the pose of the head, body, wings, and legs with an error rate of <3% of the animals body length. We recapitulate a number of reported findings on insect gait dynamics and show LEAPs applicability as the first step in unsupervised behavioral classification. Finally, we extend the method to more challenging imaging situations (pairs of flies moving on a mesh-like background) and movies from freely moving mice (Mus musculus) where we track the full conformation of the head, body, and limbs.

animal behavior and cognition↗

bioRxiv2016

TrkB signaling underlies the rapid antidepressant effects of isoflurane

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3{beta} (GSK3{beta}). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

neuroscience↗