Biology subjects

Syed, S.

Publications and source records attributed to Syed, S..

25 records · Page 2Linked to original sources

bioRxiv2020

Uncovering biomarkers during therapeutic neuromodulation with PARRM: Period-based Artifact Reconstruction and Removal Method

Advances in device development have enabled concurrent stimulation and recording at adjacent locations in the central nervous system. However, stimulation artifacts obscure the sensed underlying neural activity. Here, we developed a novel method, termed Period-based Artifact Reconstruction and Removal Method (PARRM), to remove stimulation artifacts from neural recordings by leveraging the exact period of stimulation to construct and subtract a high-fidelity template of the artifact. Benchtop saline experiments, computational simulations, five unique in vivo paradigms across animal and human studies, and an obscured movement biomarker were used for validation. Performance was found to exceed that of state-of-the-art filters in recovering complex signals without introducing contamination. PARRM has several advantages: it is 1) superior in signal recovery; 2) easily adaptable to several neurostimulation paradigms; and 3) low-complexity for future on-device implementation. Real-time artifact removal via PARRM will enable unbiased exploration and detection of neural biomarkers to enhance efficacy of closed-loop therapies. SummaryOnline, real-time artifact removal via PARRM will enable unbiased exploration of neural biomarkers previously obscured by stimulation artifact.

neuroscience↗

bioRxiv2020

Release sites are positioned to activate NMDA receptors

Neurotransmitter is released synchronously and asynchronously following an action potential. The release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement of release ensures maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are organized to efficiently activate NMDA receptors.

neuroscience↗

bioRxiv2019

A model to study NMDA receptors in early nervous system development

NMDA receptors (NMDARs) are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Pharmacological antagonism is an invaluable tool to study NMDARs, but is experimentally limited. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca2+ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b. Both grin1a-/- and grin1b-/- zebrafish are viable as adults. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double mutant fish (grin1a-/-; grin1b-/-), which lack all NMDAR-mediated synaptic transmission, survive until about 10 days post fertilization, providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey capture deficits and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Taken together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system.

neuroscience↗

bioRxiv2019

The nuclear to cytoplasmic ratio directly regulates zygotic transcription in Drosophila

Early embryos must rapidly generate large numbers of cells to form an organism. Many species accomplish this through a series of rapid, reductive, and transcriptionally silent cleavage divisions. Previous work has demonstrated that the number of divisions before both cell cycle elongation and zygotic genome activation (ZGA) is regulated by the ratio of nuclear content to cytoplasm (N/C). To understand how the N/C ratio affects the timing of ZGA, we directly assayed the behavior of several previously identified N/C-ratio-dependent genes using the MS2-MCP reporter system in living Drosophila embryos with altered ploidy and cell cycle durations. For every gene that we examined, we found that nascent RNA output per cycle is delayed in haploid embryos. Moreover, we found that the N/C ratio influences transcription through three separate modes of action. For some genes (knirps and snail) the effect of ploidy can be entirely accounted for by changes in cell cycle duration. However, for other genes (giant, bottleneck and fruhstart) the N/C ratio directly affects ZGA. For giant and bottleneck, the N/C ratio regulates the kinetics of transcription activation, while for fruhstart it controls the probability of transcription initiation. Our data demonstrate that the regulatory elements of N/C-ratio-dependent genes respond directly to the N/C ratio, through multiple modes of regulation, independent of interphase length.

developmental biology↗

bioRxiv2019

Daytime Color Preference in Drosophila Depends on the Circadian Clock and TRP Channels

By guiding animals towards food and shelter and repelling them from potentially harmful situations, light discrimination according to colour can confer survival advantages1,2. Such colour-dependent behaviour may be experiential or innate. Data on innate colour preference remain controversial in mammals3 and limited in simpler organisms4-7. Here we show that when given a choice among blue, green and dim light, fruit flies exhibit an unexpectedly complex pattern of colour preference that changes with the time of day. Flies show a strong preference for green in the early morning and late afternoon, a reduced green preference at midday and a robust avoidance of blue throughout the day. Genetic manipulations reveal that the peaks in green preference require rhodopsin-based photoreceptors, and are controlled by the circadian clock. The midday reduction in green preference in favour of dim light depends on the Transient Receptor Potential (TRP) channels dTRPA1 and Pyrexia (Pyx), and is also timed by the clock. In contrast, blue avoidance is primarily mediated by class IV multidendritic neurons, requires the TRP channel Painless (Pain) and is independent of the clock. With unexpected roles for several TRP channels in Drosophila colour-specific phototransduction, our results reveal distinct pathways of innate colour preference that coordinate the flys behavioural dynamics in ambient light.

neuroscience↗

bioRxiv2018

Ezh2-dependent epigenetic reprogramming controls a developmental switch between modes of gastric neuromuscular regulation

Physiological interconversion between specialized cell types has only been described in a few mammalian tissues and the mechanisms remain obscure. Using genetic lineage tracing during postnatal development and in-vitro models we demonstrate conversion of gastric interstitial cells of Cajal (ICC), regulatory cells that electrically pace phasic contractions and mediate nitrergic and cholinergic neural control of smooth muscle cells, into phenotypically distinct \"fibroblast-like\" interstitial cells (FLC), which only mediate purinergic signaling. Mechanistically, we find this transition to be epigenetically governed by H3K27 trimethylation of cell identity-related promoters whose susceptibility to repression is predicted by H3K27 acetylation patterns in ICC. The phenotypic switch was reversible by inhibition, knockdown or in-vivo genomic inactivation of the polycomb H3K27 methyl-transferase Ezh2. These results demonstrate a role for Ezh2-mediated epigenetic repression in physiological mammalian transdifferentiation and identify FLC as a reserve from which ICC can potentially be restored in common gastrointestinal disorders where ICC are depleted.\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC=\"FIGDIR/small/486423v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (38K):\norg.highwire.dtl.DTLVardef@e12f42org.highwire.dtl.DTLVardef@1e5c7beorg.highwire.dtl.DTLVardef@9cbc21org.highwire.dtl.DTLVardef@34f28_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIGastric pacemaker cells (ICC) transdifferentiate into quiescent cells (FLC) in vivo\nC_LIO_LIICC-to-FLC shift switches neural control from nitrergic/cholinergic to purinergic\nC_LIO_LIEzh2-mediated H3K27me3 represses cell-identity genes during ICC-to-FLC transition\nC_LIO_LIEzh2 inhibition restores ICC numbers, phenotype and function\nC_LI\n\neTOC BLURBSyed et al. find aging to cause transdifferentiation of gastric pacemaker cells (interstitial cells of Cajal, ICC), which also communicate cholinergic and nitrergic neurotransmission to smooth muscle cells, into quiescent \"fibroblast-like cells\" (FLC), which only mediate purinergic signals. This switch is governed by Ezh2, whose inhibition can reverse ICC depletion.

molecular biology↗

bioRxiv2017

Automated analysis of internally programmed grooming behavior in Drosophila using a k-nearest neighbors classifier

Despite being pervasive, the control of programmed grooming is poorly understood. We have addressed this gap in knowledge by developing a high-throughput platform that allows long-term detection of grooming in the fruit fly Drosophila melanogaster. Automatic classification of daily behavior shows flies spend 30% of their active time grooming. We show that a large proportion of this behavior is driven by two major internal programs. One of these programs is the circadian clock that modulates rhythms in daily grooming. The second program depends on cycle and clock and regulates the amount of time flies spend grooming. This emerging dual control model of programmed grooming in which one regulator controls the timing and another controls the duration, resembles the well-established two-process regulatory model of fly sleep. Together, our quantitative approach in Drosophila has revealed that grooming is an important internally driven behavior under the control of two regulatory programs.

bioinformatics↗