Biology subjects

Zur, G.

Publications and source records attributed to Zur, G..

7 recordsLinked to original sources

bioRxiv2025

From optimality to reality: decision-making in basal ganglia output

Value-based decision-making requires translating abstract representations of alternative values into concrete decisions. Although this process is widespread, the neural mechanisms underlying this transformation remain unclear. Here, we address this question by examining neural dynamics in the substantia nigra pars reticulata (SNpr) of two monkeys performing a decision-making task. We found a dynamic shift in SNpr activity during the decision process. Before choice, SNpr activity encoded the optimal selection regardless of the eventual action taken, representing the action and value of the optimal choice even when the non-optimal target was ultimately selected. During choice, the SNpr shifted to code the actual selection made by the monkey. This pattern was reinforced by trials with suboptimal choices, revealing a clear transition in SNpr coding from representing the abstract value of the optimal selection to encoding the chosen action, thus suggesting a neural mechanism that transforms value representations into concrete decisions.

neuroscience↗

bioRxiv2023

Chaperone Complexes From The Endoplasmic Reticulum (ER) And The Cytosol Inhibit wt-p53 By Activation The ER To Cytosol Signaling.

The Endoplasmic Reticulum (ER) is an essential sensing organelle responsible for the folding and secretion of almost one-third of eukaryotic cells total proteins. The ER contains numerous enzymes and chaperones which assist in oxidative protein folding and other posttranslational modifications. However, environmental, chemical, and genetic insults often lead to protein misfolding in the ER, accumulating misfolded proteins, altering homeostasis, and causing ER stress. Recently, we reported a novel ER surveillance mechanism by which proteins from the secretory pathway are refluxed to the cytosol to relieve the ER of its content during stress. In cancer cells, the refluxed proteins gain new pro-survival functions, thereby increasing cancer cell fitness. We termed this phenomenon ER to CYtosol Signaling (or "ERCY"). In yeast, ERCYS is regulated by HLJ1 (an ER-resident tail-anchored HSP40 cochaperone). Here, we found that in mammalian cells, HLJ1 has five putative orthologs possessing J-domains facing the cytosol. Among those, DNAJB12 and DNAJB14 appear to be the most significant. Mechanistically, we found that DNAJB12 and DNAJB14 bind the cytosolic HSC70 and its cochaperone - SGTA - through their cytosolically localized J-domains to facilitate ER-protein reflux to the cytosol. Moreover, we found that DNAJB12 is necessary and sufficient to drive this phenomenon to increase AGR2 reflux and inhibit wt-p53 during ER stress. Thus, we concluded that targeting the DNAJB12/14-HSC70/SGTA axis is a promising strategy to inhibit ERCYS and impair cancer cell fitness.

cell biology↗

bioRxiv2023

High-Dimensional Encoding of Movement by Single Neurons in Basal Ganglia Output

The Substantia Nigra pars reticulata (SNpr), an output structure of the basal ganglia, has been hypothesized to gate the execution of movements. Previous studies focusing mostly on saccadic eye movements have reported that SNpr neurons are tonically active and either pause or increase their firing during movements, consistent with the gating role. We recorded activity in the SNpr of two monkeys during smooth pursuit and saccadic eye movements. SNpr neurons exhibited highly diverse reaction patterns during pursuit, including frequent increases and decreases in firing rate, uncorrelated responses in different movement directions and in reward conditions resulting in the high dimensional activity of single neurons. These diverse temporal patterns surpassed those in other oculomotor areas in the frontal cortex, basal ganglia, and cerebellum. These results suggest that temporal properties of the responses enrich the coding capacity of the basal ganglia output beyond gating or permitting movement.

neuroscience↗

bioRxiv2022

The basal ganglia achieve a higher signal-to-noise ratio than the cerebellum by sharpening reward and movement signals

The basal ganglia and the cerebellum are major subcortical structures in the motor system. The basal ganglia have been cast as the reward center of the motor system, whereas the cerebellum is thought to be involved in adjusting sensorimotor parameters. Recent findings of reward signals in the cerebellum have challenged this dichotomous view. To compare the basal ganglia and the cerebellum directly, we recorded from oculomotor regions in both structures from the same monkeys. We partitioned the trial-by-trial variability of the neurons into reward and eye-movement signals to compare the coding across structures. Reward expectation and movement signals were the most pronounced in the output structure of the basal ganglia, intermediate in the cerebellum, and the smallest in the input structure of the basal ganglia. These findings suggest that reward and movement information is sharpened through the basal ganglia, resulting in a higher signal-to-noise ratio than in the cerebellum.

neuroscience↗

bioRxiv2019

Structural integrity following focused ultrasound thalamotomy and its correlation with tremor relief

BackgroundMagnetic-resonance-guided focused ultrasound ablation of ventral intermediate nucleus of the thalamus is a new treatment for tremor disorders.\n\nObjectivesWe sought to evaluate the white matter integrity prior to and following focused ultrasound ablation and its correlation with clinical outcome.\n\nMethods22 patients with essential tremor and 17 patients with Parkinsons disease underwent tremor and quality-of-life assessments prior to and at one and six months following focused ultrasound ablation. All patients underwent MRI including T1, T2-FLAIR and diffusion weighted imaging before treatment and at one day, 7-10 days, 1-3 months, and 6 months or more following it. Diffusivity parameters were calculated and fiber tractography measures were extracted. Change in diffusivity parameters were assessed inside the ablated core, in the motor thalamus and throughout the dentato-rubro-thalamo-cortical tract.\n\nResultsWe found short-term changes in the motor thalamus and in the tract between the thalamus and regions within the dentato-rubro-thalamo-cortical tract. Long term damage was found in the ablated core and in the tract connecting the thalamus and red-nucleus. Inverse correlation was found between fractional anisotropy in the motor thalamus one day following ablation and tremor improvement in both patient groups, with lower values before treatment associated with better outcome (tremor relief) in essential tremor patients.\n\nConclusionsShort-and long-term changes in white matter integrity are present following focused ultrasound thalamotomy. Regions demonstrating long-term white matter changes may be responsible for the tremor relief seen in patients, implicating these regions in the disorders pathogenesis.

neuroscience↗

bioRxiv2019

Loss of function in the autism and learning disabilities associated gene Nf1 disrupts corticocortical and corticostriatal functional connectivity in human and mouse

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1+/-). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1+/- mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1+/- mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.

neuroscience↗

bioRxiv2019

Using extracellular low frequency signals to improve the spike sorting of cerebellar complex spikes

The challenge of spike sorting has been addressed by numerous electrophysiological studies. These methods tend to focus on the information conveyed by the high frequencies, but ignore the potentially informative signals at lower frequencies. Activation of Purkinje cells in the cerebellum by input from the climbing fibers results in a large amplitude dendritic spike concurrent with a high frequency burst known as a complex spike. Due to the variability in the high frequency component of complex spikes, previous methods have struggled to sort these complex spikes in an accurate and reliable way. However, complex spikes have a prominent extracellular low frequency signal generated by the input from the climbing fibers. We exploited this to improve complex spike sorting by applying Principal Component Analysis (PCA) on the low frequencies of the signal and show that the low frequency first PC achieves a better separation of the complex spikes from noise. The low frequency data are more effective in detecting events entering into the analysis, and therefore can be harnessed to analyze the data with a larger signal to noise ratio. These two advantages make our method more effective for complex spike sorting. Our characterization of the dendritic low frequency components of complex spikes can be applied in other studies to gain insights into processing in the cerebellum.

neuroscience↗