Biology subjects

Jayant, K.

Publications and source records attributed to Jayant, K..

7 recordsLinked to original sources

bioRxiv2025

Synaptic phosphoproteome modifications and cortical circuit dysfunction are linked to the early-stage progression of alpha-synuclein aggregation

Cortical dysfunction is increasingly recognized as a major contributor to the non-motor symptoms associated with Parkinsons disease (PD) and other synucleinopathies. Although functional alterations in cortical circuits have been observed in preclinical PD models, the underlying molecular mechanisms are unclear. To bridge this knowledge gap, we investigated tissue-level changes in the cortex of rats and mice treated with alpha-synuclein (aSyn) seeds using a multi-omics approach. Our study revealed significant phosphoproteomic changes, but not global proteomic or lipid profiling changes, in the rat sensorimotor cortex 3 months after intra-striatal injection with aSyn preformed fibrils (PFFs). Gene ontology analysis of the phosphoproteomic data revealed that PFF administration impacted pathways related to synaptic transmission and cytoskeletal organization. Similar phosphoproteomic perturbations were observed in the sensorimotor cortex of mice injected intrastriatally or intracortically with aSyn PFFs. Functional analyses demonstrated increased neuronal firing rates and enhanced spike-spike coherence in the sensorimotor cortex of PFF-treated mice, suggesting that aSyn seeds induced cortical circuit dysfunction. Bioinformatics analysis of the altered phosphosites indicated the involvement of several kinases, including casein kinase-2 (CK2) and Protein Kinase A (PKA). Enrichment of kinase-activating pT/pY MAPK (ERK) phosphosites revealed apparent engagement of the ERK signaling cascade and led to the identification of pERK1/2-positive intraneuronal granulovacuolar body (GVB)-like structures specifically in aggregate-bearing neurons. Collectively, these findings highlight the importance of phosphorylation-mediated signaling pathways in the cortical response to aSyn pathology spread in PD and related synucleinopathies, setting the stage for developing new therapeutic strategies.

neuroscience↗

bioRxiv2024

Mild focal cooling selectively impacts computations in dendritic trees

Focal cooling is a powerful technique to temporally scale neural dynamics. However, the underlying cellular mechanisms causing this scaling remain unresolved. Here, using targeted focal cooling (with a spatial resolution of 100 micrometers), dual somato-dendritic patch clamp recordings, two-photon calcium imaging, transmitter uncaging, and modeling we reveal that a 5{degrees}C drop can enhance synaptic transmission, plasticity, and input-output transformations in the distal apical tuft, but not in the basal dendrites of intrinsically bursting L5 pyramidal neurons. This enhancement depends on N-methyl-D-aspartate (NMDA) and Kv4.2, suggesting electrical structure modulation. Paradoxically, and despite the increase in tuft excitability, we observe a reduced rate of recovery from inactivation for apical Na+ channels, thereby regulating back-propagating action potential invasion, coincidence detection, and overall burst probability, resulting in an "apparent" slowing of somatic spike output. Our findings reveal a differential temperature sensitivity along the basal-tuft axis of L5 neurons analog modulates cortical output.

neuroscience↗

bioRxiv2024

A TRANSLAMINAR SPACETIME CODE SUPPORTS TOUCH-EVOKED TRAVELING WAVES

Linking sensory-evoked traveling waves to underlying circuit patterns is critical to understanding the neural basis of sensory perception. To form this link, we performed simultaneous electrophysiology and two-photon calcium imaging through transparent NeuroGrids and mapped touch-evoked cortical traveling waves and their underlying microcircuit dynamics. In awake mice, both passive and active whisker touch elicited traveling waves within and across barrels, with a fast early component followed by a variable late wave that lasted hundreds of milliseconds post-stimulus. Strikingly, late-wave dynamics were modulated by stimulus value and correlated with task performance. Mechanistically, the late wave component was i) modulated by motor feedback, ii) complemented by a sparse ensemble pattern across layer 2/3, which a balanced-state network model reconciled via inhibitory stabilization, and iii) aligned to regenerative Layer-5 apical dendritic Ca2+ events. Our results reveal a translaminar spacetime pattern organized by cortical feedback in the sensory cortex that supports touch-evoked traveling waves. GRAPHICAL ABSTRACT AND HIGHLIGHTS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/593381v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@c98840org.highwire.dtl.DTLVardef@1105364org.highwire.dtl.DTLVardef@d2f2c9org.highwire.dtl.DTLVardef@1418744_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIWhisker touch evokes both early- and late-traveling waves in the barrel cortex over 100s of milliseconds C_LIO_LIReward reinforcement modulates wave dynamics C_LIO_LILate wave emergence coincides with network sparsity in L23 and time-locked L5 dendritic Ca2+ spikes C_LIO_LIExperimental and computational results link motor feedback to distinct translaminar spacetime patterns C_LI

neuroscience↗

bioRxiv2022

Probing Action Potential Generation and Timing under Multiplexed Basal Dendritic Computations Using Two-photon 3D Holographic Uncaging

Basal dendrites of layer 5 cortical pyramidal neurons exhibit Na+ and NMDAR spikes, and are uniquely poised to influence somatic output. Nevertheless, due to technical limitations, how multibranch basal dendritic integration shapes action-potential output remains poorly mapped. Here, we combine 3D two-photon holographic transmitter-uncaging, whole-cell dynamic-clamp, and biophysical modeling, to reveal how synchronously activated synapses (distributed and clustered) across multiple basal dendritic branches impacts action-potential generation - under quiescent and in vivo like conditions. While dendritic Na+ spikes promote milli-second precision, distributed inputs and NMDAR spikes modulate firing rates via axo-somatic persistent sodium channel amplification. Action-potential precision, noise-enhanced responsiveness, and improved temporal resolution, were observed under high conductance states, revealing multiplexed dendritic control of somatic output amidst noisy membrane-voltage fluctuations and backpropagating spikes. Our results unveil a critical multibranch integration framework in which a delicate interplay between distributed synapses, clustered synapses, and axo-somatic subthreshold conductances, dictates somatic spike precision and gain.

neuroscience↗

bioRxiv2022

Bi-Phasic Quasistatic Brain Communication for Fully Untethered Connected Brain Implants

Wireless communication using electro-magnetic (EM) fields acts as the backbone for information exchange among wearable devices around the human body. However, for Implanted devices, EM fields incur high amount of absorption in the tissue, while alternative modes of transmission including ultrasound, optical and magnetoelectric methods result in large amount of transduction losses due to conversion of one form of energy to another, thereby increasing the overall end-to-end energy loss. To solve the challenge of wireless powering and communication in a brain implant with low end-end channel loss, we present Bi-Phasic Quasistatic Brain Communication (BP-QBC), achieving < 60dB worst-case end-to-end channel loss at a channel length of ~55mm, by using Electro-quasistatic (EQS) Signaling that avoids transduction losses due to no field-modality conversion. BP-QBC utilizes dipole coupling based signal transmission within the brain tissue using differential excitation in the transmitter (TX) and differential signal pick-up at the receiver (RX), while offering ~41X lower power w.r.t. traditional Galvanic Human Body Communication (G-HBC) at a carrier frequency of 1MHz, by blocking any DC current paths through the brain tissue. Since the electrical signal transfer through the human tissue is electro-quasistatic up to several 10s of MHz range, BP-QBC allows a scalable (bps-10Mbps) duty-cycled uplink (UL) from the implant to an external wearable. The power consumption in the BP-QBC TX is only 0.52 W at 1Mbps (with 1% duty cycling), which is within the range of harvested power in the downlink (DL) from a wearable hub to an implant through the EQS brain channel, with externally applied electric currents < 1/5th of ICNIRP safety limits. Furthermore, BP-QBC eliminates the need for sub-cranial interrogators/repeaters, as it offers better signal strength due to no field transduction. Such low end-to-end channel loss with high data rates enabled by a completely new modality of brain communication and powering has deep societal and scientific impact in the fields of neurobiological research, brain-machine interfaces, electroceuticals and connected healthcare.

biophysics↗

bioRxiv2021

Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Scn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions. TEASERSevere NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels. HIGHLIGHTSO_LISevere NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice; C_LIO_LIIncreased neuronal excitability in MSNs is accompanied by elevated voltage threshold; C_LIO_LINaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous; C_LIO_LIThe expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability; C_LIO_LIThe enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures. C_LI

neuroscience↗

bioRxiv2018

Electrodiffusion model of synaptic potentials in dendritic spines

When modeling electric current flow in neurons and excitable cells, traditional cable theory ignores electrodiffusion (i.e. the interaction between electric fields and ionic diffusion) as it assumes that concentration changes associated with ionic currents are negligible. This assumption, while true for large neuronal compartments, fails when applied to femto-liter size compartments such as dendritic spines - small protrusions that form the main site of synaptic inputs in the brain. Here, we use the Poisson (P) and Nernst-Planck (NP) equations, which relate electric field to charge and couple Ficks law of diffusion to the electric field, to model ion concentration dynamics in dendritic spines. We use experimentally measured voltage transients from spines with nanoelectrodes to explore these dynamics with realistic parameters. We find that (i) passive diffusion and electrodiffusion jointly affect the kinetics of spine excitatory post-synaptic potentials (EPSPs); (ii) spine geometry plays a key role in shaping EPSPs; and, (iii) the spine-neck resistance dynamically decreases during EPSPs, leading to short-term synaptic facilitation. Our formulation can be easily adopted to model ionic biophysics in a variety of nanoscale bio-compartments.

biophysics↗