Biology subjects

Stein, H.

Publications and source records attributed to Stein, H..

9 recordsLinked to original sources

bioRxiv2023

Cerebellar interneuron activity is triggered by reach endpoint during learning of a complex locomotor task

Locomotion in complex environments depends on the precise timing and active control of single paw movements in order to adapt steps to surface structure and coordinate paws. Such motor control crucially depends on the cerebellum, which is thought to support moment-to-moment prediction and correction of paw trajectories. Although cerebellar activity has been linked to limb kinematics on flat surfaces, it remains unknown how cerebellar cortical neurons encode paw movements when gait becomes irregular and the requirements for precise motor control vary dynamically. To address this question, we developed LocoReach: a new task which combines continuous and discrete aspects of motor control by requiring mice to walk on a runged treadmill, where each step involves reaching for the next rung. Over several days of learning, mice became increasingly proficient at LocoReach, so that they made fewer, longer strides with faster swings and fewer missteps. Through real-time optogenetic disruption of cerebellar processing, we shortened the swing of the perturbed paw highlighting the online contribution of lobule simplex to precise limb control the task. We next investigated the role of the cerebellar lobule simplex during LocoReach learning using electrophysiological recordings, with particular focus on molecular layer interneurons (MLIs) that shape the timing and gain of Purkinje cell (PC) output. When analyzing behaviorally-evoked responses in MLIs and PCs, we found sharp changes in activity around paw-specific transitions from swing to stance and vice versa. Cells in lobule simplex showed clear behavioral specificity: most neurons were tuned to swing-stance transitions of the ipsilateral paw, a large proportion encoded transitions of other or even multiple paws. Specifically MLIs exhibited larger amplitude firing-rate changes during longer strides acquired through learning, indicating increased engagement during higher-demand steps. These results show that cerebellar activity is tightly aligned to defined events in the step cycle, providing a mechanism through which cerebellar cortical circuits can contribute to the precise control of paw placement during adaptive locomotion.

neuroscience↗

bioRxiv2023

Linking cognitive integrity to working memory dynamics in the aging human brain

Aging is accompanied by a decline of multiple cognitive capacities, including working memory: the ability to maintain information online for the flexible control of behavior. Working memory involves stimulus-selective neural activity, persisting after stimulus presentation in widely distributed cortical areas. Here, we unraveled the mechanisms of working memory in healthy older adults and patients with mild cognitive impairment (MCI), a condition associated with increased risk of developing dementia. We studied a sample of 19 older adults diagnosed with MCI and 20 older healthy controls using a combination of model-based behavioral psychophysics, neuropsychological assessment, and magnetoencephalographic (MEG) recordings of brain activity. Twenty-one younger healthy adults were studied with model-based behavioral psychophysics only. All subjects performed a visuo-spatial delayed-match-to-sample working memory task under systematic manipulation of the temporal delay and the spatial distance between successively presented sample and test stimuli. We developed a computational model of the latent dynamics underlying task behavior and fit this to individual behavior. In the model, working memory representations diffused over time, a threshold was applied to produce a match/non-match decision about sample and test locations, and occasional lapses produced random decisions. For the older participants, we related the individual model parameters to a summary measure of individual cognitive integrity obtained from a large neuropsychological test battery, as well as to cortical MEG activity during the delay interval of the working memory task. For all groups, task accuracy decreased with delay duration and sample-test distance. When sample/test distances were small, older adults exhibited larger false alarm rates than younger adults. The behavioral effects were well captured by the model, which explained the age-related differences in terms of a deterioration of the quality of working memory representations, rather than differences in task strategy (i.e., threshold parameter). Task accuracy as well as the parameters governing behavioral stochasticity (diffusion noise and lapse rate combined) were correlated with overall cognitive integrity in the MCI group, but not in the older healthy controls. Individual task accuracy and stochasticity parameters (diffusion noise and lapse rate) were also correlated with stimulus-selective cortical activity during the delay interval, as assessed by decoding of the MEG signals, corroborating their validity as markers of cortical working memory mechanisms. Our findings provide insight into the mechanistic basis of aging-related changes in working memory maintenance and reveal a link between individual working memory dynamics and cognitive integrity in MCI.

neuroscience↗

bioRxiv2023

Disentangling Mixed Classes of Covariability in Large-Scale Neural Data

Recent work has argued that large-scale neural recordings are often well described by low-dimensional latent dynamics identified using dimensionality reduction. However, the view that task-relevant variability is shared across neurons misses other types of structure underlying behavior, including stereotyped neural sequences or slowly evolving latent spaces. To address this, we introduce a new framework that simultaneously accounts for variability that is shared across neurons, trials, or time. To identify and demix these covariability classes, we develop a new unsupervised dimensionality reduction method for neural data tensors called sliceTCA. In three example datasets, including motor cortical dynamics during a classic reaching task and recent multi-region recordings from the International Brain Laboratory, we show that sliceTCA can capture more task-relevant structure in neural data using fewer components than traditional methods. Overall, our theoretical framework extends the classic view of low-dimensional population activity by incorporating additional classes of latent variables capturing higher-dimensional structure.

neuroscience↗

bioRxiv2022

CWLP and PRP940 form plasma-membrane nanodomain complexes with aquaporins, interact with PP2A and contribute to dehydration tolerance

The C-type hybrid-proline-rich protein (HyPRP) AtCWLP and its homolog AtPRP940 are referred as cell wall (CW)-plasma-membrane (PM) linker proteins, but little is known about their functions. Here we show that N-terminal proline-rich domains of CWLP and PRP940, containing glycosylated hydroxyproline residues, contact the CW, while their C-terminal 8CM domains function as PM-scaffolds. Both proteins are detected in PM nanodomains (PM-ND) and show co-localization and co-immunoprecipitation with aquaporins PIP2;1 and PIP2;7. Inhibition of actin polymerization by latrunculin B promotes CWLP-endosome appearance, while blocking the actomyosin-based transport by a truncated form of myosin XI-K relaxes lateral boundaries of CWLP-PIP2;1 PD-NDs. Mass spectrometry data indicate that CWLP co-purifies with dynamins implicated in fission of endocytic PD-ND invaginations. Lack of co-localization and co-immunoprecipitation with aquaporin-binding flotillin (FLOT2) indicates that CWLP and PRP940 mark a new distinct type of PM-ND. Yeast two-hybrid and co-immunoprecipitation assays demonstrate that CWLP and PRP940 interact with multiple aquaporins and several protein phosphatase PP2A-B regulatory subunits. By preventing irreversible separation of CW and PM, and likely assisting PP2A-mediated dephosphorylation of aquaporins and closure of their water channels, overexpression of CWLP confers tolerance to plasmolysis, dehydration and freezing in Arabidopsis and to water shortage in potato plants. Summary StatementArabidopsis Hybrid-Proline-Rich Proteins CWLP and PRP940 occur in association with dynamins, recruit PP2A protein phosphatases to aquaporin water channels in plasma-membrane (PM) nanodomains and elevate tolerance to cellular dehydration.

plant biology↗

bioRxiv2021

A mechanistically interpretable model of the retinal neural code for natural scenes with multiscale adaptive dynamics

The visual system processes stimuli over a wide range of spatiotemporal scales, with individual neurons receiving input from tens of thousands of neurons whose dynamics range from milliseconds to tens of seconds. This poses a challenge to create models that both accurately capture visual computations and are mechanistically interpretable. Here we present a model of salamander retinal ganglion cell spiking responses recorded with a multielectrode array that captures natural scene responses and slow adaptive dynamics. The model consists of a three-layer convolutional neural network (CNN) modified to include local recurrent synaptic dynamics taken from a linear-nonlinear-kinetic (LNK) model [1]. We presented alternating natural scenes and uniform field white noise stimuli designed to engage slow contrast adaptation. To overcome difficulties fitting slow and fast dynamics together, we first optimized all fast spatiotemporal parameters, then separately optimized recurrent slow synaptic parameters. The resulting full model reproduces a wide range of retinal computations and is mechanistically interpretable, having internal units that correspond to retinal interneurons with biophysically modeled synapses. This model allows us to study the contribution of model units to any retinal computation, and examine how long-term adaptation changes the retinal neural code for natural scenes through selective adaptation of retinal pathways.

neuroscience↗

bioRxiv2021

Shiitake mycelium fermentation improves digestibility, nutritional value, flavor and functionality of plant proteins

Plant proteins can serve as inexpensive and environmentally friendly meat-replacements. However, poor taste characteristics and relatively low nutritional value prevent their full acceptance as meat substitutes. Fermentation of food has been historically used to improve the quality of foods. In this work we describe the improvement in digestibility, nutritional value, physical properties, and organoleptic characteristics, of a pea and rice protein concentrate blend through fermentation with shiitake mushroom mycelium. Ileal digestibility pig studies show increases in the DIAAS for the shiitake fermented pea and rice protein blend turning the blend into an "excellent source" of protein for humans. The fermentation also increases the solubility of the protein blend and reduces the content of the antinutrient compounds phytates and protease inhibitor. Mass spectrometry and sensory analyses of fermented protein blend indicates that fermentation leads to a reduction in off-note compounds substantially improving its organoleptic performance.

bioengineering↗

bioRxiv2019

Megakaryocytes, erythropoietic and granulopoietic cells express CAL2 antibody in myeloproliferative neoplasms carrying CALR gene mutations

The discovery of mutated Calreticulin (CALR) in myeloproliferative neoplasms (MPN) has provided proof of clonality, diagnostic importance, and influence on prognosis of this pathology. The identification of this MPN-associated driver mutation -currently based on molecular assays- is represented as a major diagnostic criterion for essential thrombocythaemia (ET), pre-fibrotic myelofibrosis and primary myelofibrosis (PMF) in the updated World Health Organization (WHO) 2008 classification. In the present study, we validated by immunohistochemistry the diagnostic usefulness of the monoclonal CAL2 antibody. Cases of acute myeloid leukaemia (AML) and myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) have been also investigated to assess the specificity of CAL2 antibody. For this purpose, the result of the CAL2 immunostaining was compared with the result of molecular assays. Additionally, we investigated by double staining whether expression of mutated CALR can also be demonstrated on cells of the erythroid and myeloid lineage. We confirmed the usefulness of the CAL2 monoclonal antibody in successfully detecting mutant CALR in bone marrow biopsies. We showed that the immune-reactivity of CAL2 was absolutely restricted to the presence of CALR mutations, which were seen only in ET and MDS/MPN biopsies, but not in AML biopsies (14/14). There was 100% concordance in biopsy specimens with the concomitant molecular results. We applied double staining technique and confirmed that a subpopulation of granulopoietic and erythropoietic cells express mutated CALR as demonstrated with the CAL2 antibody in cases of MPNs. This supports the suggestion that the CALR mutations occur in a multipotent progenitor capable of generating both myeloid and erythroid progeny with preferential expansion of megakaryocytic cell lineage as a result of CALR mutation in an immature hematopoietic stem cell.

pathology↗

bioRxiv2019

Disrupted serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

We report markedly reduced working memory-related serial dependence with preserved memory accuracy in anti-NMDAR encephalitis and schizophrenia. We argue that NMDAR-related changes in cortical excitation, while quickly destabilizing persistent neural activity, cannot fully account for a reduction of memory-dependent biases. Rather, our modeling results support a disruption of a memory mechanism operating on a longer timescale, such as short-term potentiation.

neuroscience↗

bioRxiv2019

Interplay between persistent activity and activity-silent dynamics in prefrontal cortex during working memory

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative, \"activity-silent\" substrates for memory. Using monkey and human electrophysiology, we show here that attractor dynamics that control neural spiking during mnemonic periods interact with activity-silent mechanisms in PFC. This interaction allows memory reactivation, which enhance serial biases in spatial working memory. Stimulus information was not decodable between trials, but remained present in activity-silent traces inferred from spiking synchrony in PFC. Just prior to the new stimulus, this latent trace was reignited into activity that recapitulated the previous stimulus representation. Importantly, the reactivation strength correlated with the strength of serial biases in both monkeys and humans, as predicted by a computational model integrating activity-based and activity-silent mechanisms. Finally, single-pulse TMS applied to human prefrontal cortex prior to trial start enhanced serial biases, demonstrating the causal role of prefrontal reactivations in determining working memory behavior.

neuroscience↗