Biology subjects

Feldman, D. E.

Publications and source records attributed to Feldman, D. E..

9 recordsLinked to original sources

bioRxiv2025

Degraded sensory coding in a mouse model of Scn2a-related disorder and its rescue by CRISPRa gene activation

Heterozygous loss-of-function mutations in SCN2A, a sodium channel gene expressed in cortical pyramidal (PYR) cells, lead to a neurodevelopmental disorder characterized by autism, intellectual disability, and cortical sensory dysfunction. In Scn2a+/- mice, PYR dendritic excitability and synapses are impaired, but cortical information processing deficits are unknown. In the whisker somatosensory cortex, we found strongly degraded somatotopic tuning of PYR cells, profoundly blurred whisker maps, and impaired population coding, despite normal overall firing rates. This constitutes a robust biomarker for Scn2a-related cortical dysfunction. Parvalbumin (PV) interneurons were also unexpectedly hypofunctional. We tested for rescue of coding deficits in post-critical period, young adult mice by viral delivery of CRISPR activation (CRISPRa) reagents that upregulate Scn2a. CRISPRa treatment normalized cortical sensory representations at the single-unit and map levels. This suggests that therapy to increase Scn2a expression may be effective in normalizing cortical function in Scn2a loss-of-function disorder, even in older children or adults.

neuroscience↗

bioRxiv2025

Distinct laminar origins of high-gamma and low-frequency ECoG signals revealed by optogenetics

Electrocorticography (ECoG) provides a high-spatiotemporal-resolution measure of cortical activity (cortical surface electrical potentials, CSEPs) in humans and animals. The CSEP high-gamma band (H{gamma}, 65-170 Hz) correlates with neuronal firing rates at the columnar spatial scale and is widely used as a biomarker of local activity. Whether H{gamma} reports all stages of columnar processing, intermediate processing in L2/3 (close to the ECoG electrode), or the main columnar output in L5, is unknown. We disentangled the laminar origins of H{gamma} and other ECoG bands by optogenetically suppressing L2/3 or L5 pyramidal cells during micro-ECoG recording in mouse somatosensory cortex. Whisker deflections evoked transient, topographically localized CSEPs. L5 optogenetic suppression most strongly reduced 65-450 Hz (H{gamma}-uH{gamma}) bands in sensory-evoked ECoG signals, whereas L2/3 suppression most strongly reduced 4-30 Hz ({theta}-{beta}) bands. Thus, different CSEP frequency bands reflect layer-specific activity and are biomarkers of distinct stages of columnar processing. Significance StatementElectrocorticography (ECoG) is widely used as a mesoscale measure of cortical activity in human and animals, providing a unique methodological from basic neuroscience discovery to understanding the human brain in health and disease. However, the cell types and laminar sources that generate ECoG signals are unknown, which impedes interpretation of ECoG findings in both the clinic and basic research. We disentangled the laminar origins of ECoG frequency bands by optogenetically suppressing L2/3 or L5 pyramidal cells during ECoG recording in mouse somatosensory cortex. We found that L5 optogenetic suppression most strongly reduced high frequencies whereas L2/3 suppression most strongly reduced lower frequencies. Thus, different ECoG frequency bands reflect layer-specific activity and are biomarkers of distinct stages of columnar processing.

neuroscience↗

bioRxiv2024

Reward history guides attentional selection in whisker somatosensory (S1) cortex

Prior reward is a potent cue for attentional capture, but the underlying neurobiology is largely unknown. In a novel whisker touch detection task, we show that mice flexibly shift attention between specific whiskers on a trial-by-trial timescale, guided by the recent history of stimulus-reward association. Two-photon calcium imaging and spike recordings revealed a robust neurobiological correlate of attention in the somatosensory cortex (S1), boosting sensory responses to the attended whisker in L2/3 and L5, but not L4. Attentional boosting in L2/3 pyramidal cells was topographically precise and whisker-specific, and shifted receptive fields toward the attended whisker. L2/3 VIP interneurons were broadly activated by whisker stimuli, motion, and arousal but did not carry a whisker-specific attentional signal, and thus did not mediate spatially focused tactile attention. Together, these findings establish a new model of focal attention in the mouse whisker tactile system, showing that the history of stimuli and rewards in the recent past can dynamically engage local modulation in cortical sensory maps to guide flexible shifts in ongoing behavior.

neuroscience↗

bioRxiv2022

Bacteriophage anti-defense genes that neutralize TIR and STING immune responses

Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as a central immune defense strategy to prevent the spread of bacteriophage viruses and other invasive genetic elements across a population. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to rapidly mobilize cognate death effectors. Here, we identify a large family of bacteriophage nucleotidyltransferases (NTases) that synthesize competitor cyclic dinucleotide (CDN) ligands, inhibiting NAD-depleting TIR effectors activated by a linked STING CDN sensor domain. Virus NTase genes are positioned within genomic regions containing other anti-defense genes, and through a functional screen, we uncover candidate anti-TIR defense (Atd) genes that confer protection against TIR-STING cytotoxicity. We show that a virus MazG-like nucleotide pyrophosphatase identified in the screen, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a role for the alarmone-activated host toxin MazF as a key executioner of TIR-directed abortive infection. Phage NTases and counter-defenses like Atd1 preserve host viability to ensure virus propagation, and may be exploited as tools to modulate TIR and STING immune responses.

microbiology↗

bioRxiv2021

VIP interneurons in mouse whisker S1 exhibit sensory and action-related signals during goal-directed behavior

Vasoactive intestinal peptide-expressing (VIP) interneurons, which constitute 10-15% of the cortical inhibitory neuron population1,2, have emerged as an important cell type for regulating excitatory cell activity based on behavioral state. VIP cells in sensory cortex are potently engaged by neuromodulatory and motor inputs during active exploratory behaviors like locomotion and whisking, which in turn promote pyramidal cell firing via disinhibition3-5. Such state-dependent modulation of activity by VIP cells in sensory cortex has been studied widely in recent years. However, the function of VIP cells during goal-directed behavior is less well understood. It is not clear how task-related events like sensory stimuli, motor actions, or reward activate VIP cells in sensory cortex since there is often temporal overlap in the occurrence of these events. We developed a Go/NoGo whisker touch detection task which incorporates a post-stimulus delay period to separate sensory-driven activity from action- or reward-related activity during behavior. We used 2-photon calcium imaging to measure task-related signals of L2/3 VIP neurons in S1 of behaving mice. We report for the first time that VIP cells in mouse whisker S1 are activated by both whisker stimuli and goal-directed licking. Whisker- and lick-related signals were spatially organized in relation to anatomical columns in S1. Sensory responses of VIP cells were tuned to specific whiskers, whether or not they also displayed lick-related activity.

neuroscience↗

bioRxiv2019

Whisker map organization in somatosensory cortex of awake, behaving mice

The whisker map in rodent somatosensory cortex is well characterized under anesthesia, but its organization during awake sensation, when cortical coding can differ strongly, is unknown. Using a novel behavioral task, we measured whisker receptive fields and maps in awake mice with 2-photon calcium imaging in vivo. During a whisker-attentive task, layer 2/3 pyramidal neurons were sharply tuned, with cells tuned to different whiskers intermixed in each column. This salt-and-pepper organization consisted of small clusters of similarly-tuned neurons superimposed on a mean subcolumnar map. Parvalbumin interneurons had broader tuning, and were more homogeneously tuned to the columnar whisker. During a sound-attentive task, whisker tuning of pyramidal cells was less heterogeneous in each column, and firing correlations increased. Thus, behavioral demands modulate fine-scale map structure, and decorrelate the whisker map during whisker-attentive behavior.

neuroscience↗

bioRxiv2018

Tactile enrichment drives emergence of functional columns and improves sensory coding in L2/3 of mouse S1

Sensory maps in layer (L) 2/3 of rodent cortex lack precise functional column boundaries, and instead exhibit locally heterogeneous tuning superimposed on smooth global topography. Could this organization be a byproduct of impoverished experience in laboratory housing? We compared whisker map somatotopy in L2/3 and L4 excitatory cells of somatosensory (S1) cortex in normally housed vs. tactile-enriched mice, using GCaMP6s imaging. Normally housed mice had a dispersed, salt-and-pepper whisker map in L2/3, but L4 was more topographically precise. Enrichment (P21 to P46-71) sharpened whisker tuning and decreased, but did not abolish, local tuning heterogeneity. In L2/3, enrichment strengthened and sharpened whisker point representations, and created functional boundaries of tuning similarity and noise correlations at column edges. Thus, tactile experience drives emergence of functional columnar topography in S1, and reduces salt-and-pepper tuning heterogeneity. These changes predict improved single-trial population coding of whisker deflections within each column.

neuroscience↗

bioRxiv2018

A normalized template matching method for improving spike detection in extracellular voltage recordings

Spike sorting is the process of detecting and clustering action potential waveforms from extracellular voltage recordings to identify spikes of putative single neurons. Typically, spike detection is done using a fixed voltage threshold and shadow period, but this approach can lead to missed spikes during high firing rate epochs or noisy conditions. We developed a novel spike detection method utilizing a computationally simple form of template matching that efficiently detects spikes from candidate single units and is tolerant of high firing rates and electrical noise without a whitening filter. Template matching was based on a sliding cosine similarity between mean spike waveforms of candidate single units and the extracellular voltage signal. Performance was tested in whisker somatosensory cortex (S1) of anesthetized mice in vivo. The method consistently detected whisker-evoked spikes that were missed by a standard fixed voltage threshold. Detection was most improved for spikes evoked by strong stimuli (40-70% increase), less improved for weaker stimuli, and unchanged for spontaneous spiking. This reflected the failure of standard detection during spatiotemporally dense spiking. Template-based detection revealed higher signal-to-noise ratio for sensory responses and sharper sensory tuning. Thus, this template matching method (and other model-based spike detection methods) critically improve the quantification of single-unit spiking activity.

neuroscience↗

bioRxiv2018

Increased excitation-inhibition ratio stabilizes synapse and circuit excitability in four autism mouse models.

Distinct genetic forms of autism are hypothesized to share a common increase in excitation-inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide the first systematic test of this hypothesis across 4 mouse models (Fmr1-/y, Cntnap2-/-, 16p11.2del/+, Tsc2+/-), focusing on somatosensory cortex. All autism mutants showed reduced feedforward inhibition in layer 2/3 coupled with more modest, variable reductions in feedforward excitation, driving a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization and spontaneous spiking were essentially normal. Modeling revealed that E and I conductance changes in each mutant were quantitatively matched to yield stable, not increased, synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo, despite detectably reduced inhibition. Thus, elevated E-I ratio is a common circuit phenotype, but appears to reflect homeostatic stabilization of synaptic drive, rather than driving network hyperexcitability in autism.

neuroscience↗