Biology subjects

Murthy, A.

Publications and source records attributed to Murthy, A..

32 records · Page 2Linked to original sources

bioRxiv2021

Antigen-derived peptides directly engage the unfolded-protein sensor IRE1α to curb cross-presentation by dendritic cells

Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER) and upload onto major histocompatibility type I (MHC-I) protein complexes for cell-surface transport and cross-presentation. Perplexingly, DCs often exhibit activation of the ER-stress sensor IRE1 in the absence of classical ER stress--leaving the underlying mechanism unexplained. Here we show that antigen-derived hydrophobic peptides directly engage ER-resident IRE1 by masquerading as unfolded proteins. Furthermore, IRE1 activation depletes MHC-I heavy-chain mRNAs through regulated IRE1-dependent decay (RIDD), thereby curtailing antigen cross-presentation. In tumor-bearing mice, IRE1 disruption increased MHC-I expression on tumor-infiltrating DCs, and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1 inhibition synergized with anti-PD-L1 antibody treatment to cause tumor regression. Our findings elucidate the mechanism and consequence of antigen-driven IRE1 activation in DCs, yielding a promising combination strategy for cancer immunotherapy.

cell biology↗

bioRxiv2021

Motor learning in reaching tasks leads to homogenization of task space error distribution

A human arm, up to the wrist, is often modelled as a redundant 7 degree-of-freedom serial robot. Despite its inherent nonlinearity, we can perform point-to-point reaching tasks reasonably fast and with reasonable accuracy in the presence of external disturbances and noise. In this work, we take a closer look at the task space error during point-to-point reaching tasks and learning during an external force-field perturbation. From experiments and quantitative data, we confirm a directional dependence of the peak task space error with certain directions showing larger errors than others at the start of a force-field perturbation, and the larger errors are reduced with repeated trials implying learning. The analysis of the experimental data further shows that a) the distribution of the peak error is made more uniform across directions with trials and the error magnitude and distribution approaches the value when no perturbation is applied, b) the redundancy present in the human arm is used more in the direction of the larger error, and c) homogenization of the error distribution is not seen when the reaching task is performed with the non-dominant hand. The results support the hypothesis that not only magnitude of task space error, but the directional dependence is reduced during motor learning and the workspace is homogenized possibly to increase the control efficiency and accuracy in point-to-point reaching tasks. The results also imply that redundancy in the arm is used to homogenize the workspace, and additionally since the bio-mechanically similar dominant and non-dominant arms show different behaviours, the homogenizing is actively done in the central nervous system. SignificanceThe human arm is capable of executing point-to-point reaching tasks reasonably accurately and quickly everywhere in its workspace. This is despite the inherent nonlinearities in the mechanics and the sensorimotor system. In this work, we show that motor learning enables homogenization of the task space error thus overcoming the nonlinearities and leading to simpler internal models and control of the arm movement. It is shown, across subjects, that the redundancy present in the arm is used to homogenize the task space. It is further shown, across subjects, that the homogenization is not an artifact of the biomechanics of the arm and is actively performed in the central nervous system since homogenization is not seen in the non-dominant hand.

neuroscience↗

bioRxiv2021

Neck motor unit activity displays neural signatures of temporal control during sequential saccade planning

Goal-directed behavior involves the transformation of neural movement plans into appropriate muscle activity patterns. Studies involving single saccades have shown that a rapid, direct pathway links saccade planning in frontal eye fields (FEF) to neck muscle activity. It is unknown if the rapid connection between FEF and neck muscle is maintained during sequential saccade planning. We show that sequence planning signals in the FEF are preserved in the neck EMG, although the activity is delayed specifically for the second saccade. Our results suggest that while the direct link between FEF and neck muscle facilitates downstream continuation of FEF response patterns, an indirect route exists through an inhibitory control center like the basal ganglia, limiting the information flow during processing of saccade sequences. Thus, the indirect and direct pathways from the FEF may function together to enable rapid synchronous, but controlled eye-head responses to sequential gaze shifts.

neuroscience↗

bioRxiv2021

Preparatory activity links frontal eye field activity with small amplitude motor unit recruitment of neck muscles during gaze planning

A hallmark of intelligent behavior is that we can separate intention from action. To understand the mechanism that gates the flow of information between motor planning and execution, we compared the activity of frontal eye field neurons with motor unit activity from neck muscles in the presence of an intervening delay period in which spatial information regarding the target was available to plan a response. Whereas we could infer spatially-specific delayed period activity from the activity of frontal eye field neurons, neck motor unit activity during the delay period could not be used to infer the direction of an upcoming movement, Nonetheless, motor unit activity was correlated with the time it took to initiate saccades. Interestingly, we observed a heterogeneity of responses amongst motor units, such that only units with smaller amplitudes showed a clear modulation during the delay period. These small amplitude motor units also had higher spontaneous activity compared to the units which showed modulation only during the movement epoch. Taken together, our results suggest that the temporal information is visible in the periphery amongst smaller motor units during eye movement planning and explains how the delay period primes muscle activity leading to faster reaction times. Significance statementThis study shows that the temporal aspects of a motor plan in the oculomotor circuitry can be accessed by peripheral neck muscles hundreds of milliseconds prior to the instruction to initiate a saccadic eye movement. The coupling between central and peripheral processes during the delay time is mediated by the recruitment pattern of motor units with smaller amplitude in the periphery. Besides giving insight into how information processed in cortical areas is read out by the muscles, these findings could be useful to decode intentional signals from the periphery to control brain machine interface devices.

neuroscience↗

bioRxiv2020

Capacity sharing between concurrent movement plans in the frontal eye field during the planning of sequential saccades

Sequences of saccadic eye movements are instrumental in navigating our visual environment. While neural activity has been shown to ramp up to a threshold before single saccades, the neural underpinnings of multiple saccades is unknown. To understand the neural control of rapid saccade sequences, we recorded from the frontal eye field (FEF) of macaque monkeys while they performed a sequential saccade task. We show that concurrent planning of two saccade plans brings forth processing bottlenecks, specifically by decreasing the growth rate and increasing the threshold of saccade-related ramping activity. The rate disruption affected both saccade plans, and a computational model wherein activity related to the two saccade plans bilaterally and asymmetrically inhibited each other, predicted the behavioral and neural results observed experimentally. Borrowing from models in psychology, our results demonstrate a capacity-sharing mechanism of processing bottlenecks, wherein multiple saccade plans in a sequence, compete for the processing capacity by perturbation of the saccade-related ramping activity. Finally, we show that in contrast to movement related neurons, visual activity in FEF neurons is not affected by the presence of multiple saccade targets, indicating that for perceptually simple tasks, inhibition amongst movement-related neurons mainly instantiates capacity sharing. Taken together, we show how psychology-inspired models of capacity sharing can be mapped onto neural responses to understand the control of rapid saccade sequences.

neuroscience↗

bioRxiv2020

A velocity plan with internal feedback control best explains modulation of saccade kinematics during eye-hand coordination.

Fast movements like saccadic eye movements that occur in the absence of sensory feedback are often thought to be under internal feedback control. In this framework, a desired input in the form of desired displacement signal is widely believed to be encoded in a spatial map of the superior colliculus (SC). This is then converted into a dynamic velocity signal that drives the oculomotor neurons. However, recent evidence has shown the presence of a dynamic signal within SC neurons, which correlates with saccade velocity. Hence, we used models based on optimal control theory to test whether saccadic execution could be achieved by a velocity based internal feedback controller. We compared the ability of a trajectory control model based on velocity to that of an endpoint control model based on final displacement to capture saccade behavior of modulation of peak saccade velocity by the hand movement, independent of the saccade amplitude. The trajectory control model tracking the desired velocity in optimal feedback control framework predicted this saccade velocity modulation better than an endpoint control model. These results suggest that the saccadic system has the flexibility to incorporate a velocity plan based internal feedback control that is imposed by task context. NEW & NOTEWORTHYWe show that the saccade generation system may use an explicit velocity tracking controller when demand arises. Modulation of peak saccade velocity due to modulation of the velocity of the accompanying hand movement was better captured using a velocity tracking stochastic optimal control model compared to an endpoint model of saccade control. This is the first evidence of trajectory planning and control for the saccadic system based on optimal control theory.

neuroscience↗

bioRxiv2020

Proteomics of autophagy deficient macrophages reveals enhanced antimicrobial immunity via the oxidative stress response

Defective autophagy is associated with chronic inflammation. Loss-of-function of the core autophagy gene Atg16l1 increases risk for Crohns disease by enhancing innate immunity in macrophages. However, autophagy also mediates clearance of intracellular pathogens. These divergent observations prompted a re-evaluation of ATG16L1 in antimicrobial immunity. In this study, we found that loss of Atg16l1 in macrophages enhanced the killing of virulent Shigella flexneri (S.flexneri), an enteric bacterium that resides within the cytosol by escaping all membrane-bound compartments. Quantitative multiplexed proteomics revealed that ATG16L1 deficiency significantly upregulated proteins involved in the glutathione-mediated antioxidant response to compensate for elevated oxidative stress, which also promoted S.flexneri killing. Consistently, myeloid cell-specific deletion of Atg16l1 accelerated bacterial clearance in vivo. Finally, pharmacological modulation of oxidative stress by suppression of cysteine import conferred enhanced microbicidal properties to wild type macrophages. These findings demonstrate that control of oxidative stress by ATG16L1 regulates antimicrobial immunity against intracellular pathogens. Impact statementMaculins et al utilize multiplexed mass spectrometry to show that loss of the autophagy gene Atg16l1 in macrophages enhances antimicrobial immunity against intracellular pathogens via the oxidative stress response.

cell biology↗

bioRxiv2020

Rapid genomic expansion and purging associated with habitat transitions in a clade of beach crustaceans (Haustoriidae: Amphipoda)

Genome sizes vary by orders of magnitude across the Tree of Life and lack any correlation with organismal complexity. Some crustacean orders, such as amphipods, have genome sizes that correlate with body size, temperature, and water depth, indicating that natural selection may constrain genome sizes due to physiological pressures. In this study, we examine the relationship between genome size, repetitive content, and environmental variables on a clade of sand-burrowing amphipods (Haustoriidae) that are distributed across the Gulf of Mexico and the North Atlantic. We uncover a 6-fold genome size variation within a clade that is less than 7 million years old. Unlike previous studies, we find no correlation between genome size and latitude, but do uncover a significant relationship between genome size and body length. Further, we find that the proportion of repetitive content predicts genome size, and that the largest genomes appear to be driven by expansions of LINE elements. Finally, we find evidence of genomic purging and body size reduction in two lineages that have independently colonized warm brackish waters, possibly indicating a strong physiological constraint of transitioning from surf-swept beaches to protected bays. Significance StatementThe evolution of genome size has been a long-standing puzzle in biology. In this work, we find that genome sizes may be driven by different selection regimes following shifts to a new habitat. Dramatic genome size changes can occur rapidly, in only a few million years. Data Availability StatementRaw data sheets have been deposited on Dryad: SUBMITTED. Raw sequence reads are available at from NCBI under Bioproject SUBMITTED.

evolutionary biology↗

bioRxiv2020

A displacement and velocity based dual model of saccadic eye movements best explains kinematic variability

Noise is a ubiquitous component of motor systems which leads to behavioral variability of all types of movements, including saccadic eye movements. Nonetheless, systems-based models of saccadic eye movements are deterministic and do not explain the observed saccade variability, only their central tendencies. Using stochastic models, we studied the variability in saccade behavior to test and distinguish between previously proposed deterministic saccade models. For this, the inter-trial variability in saccade displacement trajectories of human subjects was quantified while they performed repeated saccadic eye movements to a peripheral target. Based on fits to the data, we showed that existing models based on either displacement or velocity failed to capture the observed patterns in the variability of saccade trajectories. However, the observed behavior was captured by a dual control system, using a combination of displacement and velocity signal. The proposed model fits the mean displacement trajectory as well as the existing deterministic models. Taken together, our results suggest that the saccade system uses both desired displacement and velocity information. New and NoteworthyWe studied saccade behavior with a focus on the variability of the saccade trajectory. A stochastic model of the saccade system suggests that a dual control involving the control of displacement and velocity explains saccade behavior better than previously proposed models that utilize only displacement or velocity information. Our study resolves previous ambiguity regarding the use of displacement or velocity signals to guide saccades and provides a natural explanation for neural recordings that indicate multiplexing of displacement and velocity related information in the firing activity of neurons in the superior colliculus, a critical node in the oculomotor network that codes for saccadic eye movements.

neuroscience↗

bioRxiv2019

Neural correlates of goal-directed and non-goal-directed movements

What are the neural correlates that distinguish goal-directed (G) from non-goal-directed movements (nG)? We investigated this question in the monkey frontal eye field, which is implicated in voluntary control of saccades. We found that only for G-saccades, the variability in spike rate across trials decreased, the regularity of spike timings within trials increased, the neural activity increased earlier from baseline and had a concurrent reduction of LFP beta band power.

neuroscience↗

bioRxiv2019

Implicit perceptual memory can increase or decrease with ageing

A decline in declarative or explicit memory has been extensively characterized in cognitive ageing and is a hallmark of cognitive impairments. However, whether and how implicit perceptual memory varies with ageing or cognitive impairment is unclear. Here, we compared implicit perceptual memory and explicit memory measures in three groups of subjects: (1) 59 healthy young volunteers (20-30 years); (2) 238 healthy old volunteers (50-90 years) and (3) 21 patients with mild cognitive impairment MCI (50-90 years). To measure explicit memory, subjects were tested on standard recognition and recall tasks. To measure implicit perceptual memory, we used a classic perceptual priming paradigm. Subjects had to report the shape of a visual search pop-out target. Implicit priming was measured as the speedup in response time for targets with the same vs different color/position on consecutive trials.\n\nOur main findings are as follows: (1) Explicit memory was weaker in old compared to young subjects, and in MCI compared to age-matched controls; (2) Surprisingly, implicit perceptual memory did not always decline with age: color priming was smaller in older subjects but position priming was larger; (3) Position priming was less frequent in the MCI group compared to age-matched controls; (4) Implicit and explicit memory measures were uncorrelated in all three groups. Thus, implicit memory can increase or decrease with age or cognitive impairment, but this decline does not covary with explicit memory. We propose that incorporating explicit and implicit measures can yield a richer characterization of memory.

animal behavior and cognition↗

bioRxiv2019

Decrease in within-trial variability contributes to a decrease in across-trial variability of neural firing in the primate cortex during neural computations

The conventional approach to understanding neural responses underlying complex computations is to study across-trial averages of repeatedly performed computations from single neurons. When a brain region performs complex computations, such as processing stimulus related information or motor planning, it has been repeatedly shown through measures such as the Fano factor (FF) that neural variability across trials in the network decreases. However, in reality, multiple neurons contribute to a common computation on a single trial, rather than a single neuron contributing to a computation on multiple trials. Therefore, on individual trials the concept of FF loses significance. In this study, we extended previous work using measures of variability that are confined to a single trial and found that neurons perform a common computation, they briefly fire with increased regularity in spike timings, with similar inter-spike interval durations. We propose that this decrease in within-trial variability in neural spiking contributes to a decrease in across-trial variability in neural firing rates during network level computations. We confirmed our hypothesis by testing it on the activity of frontal eye field neurons recorded as two monkeys performed a memory-guided saccade task, and also on simulated spike trains. Furthermore, this phenomenon also has important behavioral correlates: the reaction time of the animal was faster when the within-trial variability was lower. We show that a decrease in within-trial variability is linked to a decrease in across-trial variability in neural response and indicates stationarity of neural network variability across time.\n\nNew & NoteworthyDuring computations, neural variability across trials decreases. In reality, multiple neurons contribute to a common computation on a single trial, rather than a single neuron contributing to a computation on multiple trials. We found that when a network of neurons performs a common computation, they briefly fire with increased regularity in spike timings. We propose that this decrease in within-trial variability in neural spiking contributes to a decrease in the observed across-trial variability.

neuroscience↗

bioRxiv2019

Basal ganglia contributions during the learning of a visuomotor rotation: effect of dopamine, deep brain stimulation and reinforcement

It is commonly thought that visuomotor adaptation is mediated by the cerebellum while reinforcement learning is mediated by the basal ganglia. In contrast to this strict dichotomy, we demonstrate a role for the basal ganglia in visuomotor adaptation (error-based motor learning) in patients with Parkinsons disease (PD) by comparing the degree of motor learning in the presence and absence of dopamine medication. We further show similar modulation of learning rates in the presence and absence of subthalamic deep brain stimulation. We also report that reinforcement is an essential component of visuomotor adaptation by demonstrating the lack of motor learning in patients with PD during the ON-dopamine state relative to the OFF-dopamine state in the absence of a reinforcement signal. Taken together, these results suggest that the basal ganglia modulate the gain of visuomotor adaptation based on the reinforcement received at the end of the trial.

neuroscience↗

bioRxiv2018

Concurrent neural representations of the current and forthcoming movement plans in the frontal eye field during a saccade sequence

We use sequences of saccadic eye movements to continually explore our visual environments. Previous studies have established that saccades in a sequence may be programmed in parallel by the oculomotor system. In this study, we tested the neural correlates of parallel programming of saccade sequences in the frontal eye field (FEF), using single-unit electrophysiological recordings from macaques performing a double-step saccade task. Neurons in the FEF range from visual neurons instantiating target selection, to movement neurons which prepare a saccadic response towards the selected target. The question of whether the FEF movement neurons undertake concurrent processing of multiple goals or saccade plans is yet unresolved. We show that when a peripheral target is foveated by a sequence of two saccades, FEF movement activity for the second saccade can be initiated whilst the first is still underway. Moreover, the onset of the movement activity varied parametrically with the behaviorally measured time available for parallel programming. Finally, the concurrent activity was specific for the final remapped motor vector connecting the first and the second targets and not the goal of the second saccade. In contrast, the upstream FEF visual-related neurons showed concurrent activity related to the goal of the second saccade, but not the remapped vector connecting the first and the second targets. Taken together, the results indicate that movement neurons, although located terminally in the FEF visual-motor spectrum, can accomplish concurrent processing of multiple saccade plans, leading to rapid execution of saccade sequences.

neuroscience↗