Biology subjects

Zagha, E.

Publications and source records attributed to Zagha, E..

10 recordsLinked to original sources

bioRxiv2026

Lateral Propagation from Sensory Cortex Provides Differential Gain for Sensory Selection

Selectively responding to target stimuli while ignoring distractors is a fundamental cognitive ability. In neocortex, such selection is associated with enhanced responses to target stimuli relative to distractor stimuli, yet the gain mechanisms underlying this differential responsivity are poorly understood. Most proposed gain mechanisms emphasize modulation within the center response field of a stimulus. In contrast, here we investigate modulation of lateral propagation from the center response field as a potential gain mechanism during a whisker-based selective detection task in mice. Both target (Go) and distractor (NoGo) stimuli evoked activity that propagated beyond their center response fields, with substantially greater lateral propagation for target stimuli. Target-evoked propagation increased with task learning and, in expert mice, exhibited the spatiotemporal characteristics of a traveling cortical wave preferentially involving infragranular layers. Furthermore, we demonstrate that frontal cortex actively suppresses distractor-evoked sensory responses, including both center region activity and lateral cortical recruitment. Computational modeling showed that modulation of lateral excitation could reproduce key features of these experimental findings. Together, our results support the regulation of lateral cortical propagation as a mechanism for differentially amplifying behaviorally relevant sensory representations during sensory selection.

neuroscience↗

bioRxiv2026

Bracket Coding: The Optimal Balance Between Temporal Integration and Segregation in Early Visual Processing

Despite over a century of research into the neural code, the fundamental principles by which the brain encodes sensory information remain debated. In this study we provide converging evidence for the presence of a dynamic, fast-switching integration of rate and temporal coding in the thalamus, primary visual cortex, and higher-order visual cortical areas of mice viewing an array of visual stimuli. This scheme is primarily characterized by the presence of distinct, temporally coordinated "bracket"s that tile the duration of each trial, are rate-coded within, and are separated by boundaries that are precisely-timed and synchronized across the population. Using large-scale Neuropixels recordings from the Allen Institute Visual Coding dataset, we provide evidence for the robustness and generality of bracket coding across several visual tasks and brain regions, as well as its optimality for information decoding, functional relevance for information representation, pronounced hierarchical organization, long-range bottom-up synchrony across visual regions, and coherence with low-frequency local field oscillations. These findings were all subsequently validated in a second, independent dataset provided by the International Brain Laboratory consortium. Finally, we provide a computational model that can serve as a potential mechanism for the generation of bracket-coded population spiking activity. Together, our results demonstrate the presence of a novel form of sensory information encoding in the brain, with broad implications for neuroscience and neuroengineering.

neuroscience↗

bioRxiv2026

Biodegradable Intra-arterial Devices for Focal Drug Delivery to Targeted Organs

This study presents the development of biodegradable intra-arterial drug delivery (IADD) devices for the focal treatment of targeted organs. The IADD devices are fabricated using magnesium (Mg) and poly(glycerol sebacate) (PGS), leveraging their biocompatibility and tunable biodegradability, and are loaded with two model drugs, dexamethasone (DEX) or cisplatin (CIS). The IADD devices with helical and linear designs were fabricated for focal drug delivery to targeted organs and characterized for their microstructure and composition using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). The results confirmed the successful incorporation and stability of the drugs within the device. The IADD devices demonstrated in vitro release of DEX and CIS over 30 days, with drug-dependent and fabrication-dependent release profiles. The IADD devices demonstrated cytocompatibility with endothelial cells and sustained pharmacological activity against glioma cells throughout the in vitro release period. DEX-loaded IADD devices were implanted into the artery upstream of a target organ in rat models. The devices implanted into the renal artery to target the kidney and the carotid artery to target the brain achieved 109-fold and 68-fold improvements, respectively, in organ vs systemic drug levels compared to oral drug administration. Arterial histology and explanted-device analysis provided preliminary evidence of local vascular tolerability and device integrity over the examined implantation period. Overall, these results support IADD devices as a proof-of-concept approach for focal intra-arterial drug delivery to targeted organs, demonstrating substantially elevated target-organ drug levels relative to systemic exposure. HighlightsO_LIIntroduction of a novel intra-arterial drug delivery (IADD) platform C_LIO_LIIADD devices were fabricated from bioresorbable Mg and drug-loaded PGS C_LIO_LIDEX- and CIS-loaded IADD devices were evaluated for in vitro release and bioactivity C_LIO_LIIADD delivery achieved marked DEX enrichment in the kidney and brain C_LIO_LIPost-implantation studies support preliminary vascular safety C_LI

bioengineering↗

bioRxiv2024

Cellular and circuit features distinguish dentate gyrus semilunar granule cells and granule cells activated during contextual memory formation

The dentate gyrus is critical for spatial memory formation and shows task related activation of cellular ensembles considered as memory engrams. Semilunar granule cells (SGCs), a sparse dentate projection neuron subtype distinct from granule cells (GCs), were recently reported to be enriched among behaviorally activated neurons. However, the mechanisms governing SGC recruitment during memory formation and their role in engram refinement remains unresolved. By examining neurons labeled during contextual memory formation in TRAP2 mice, we empirically tested competing hypotheses for GC and SGC recruitment into memory ensembles. In support of the proposal that more excitable neurons are preferentially recruited into memory ensembles, SGCs showed greater sustained firing than GCs. Additionally, SGCs labeled during memory formation showed less adapting firing than unlabeled SGCs. Our recordings did not reveal glutamatergic connections between behaviorally labeled SGCs and GCs, providing evidence against SGC driven local circuit feedforward excitation in ensemble recruitment. Contrary to a leading hypothesis, there was little evidence for individual SGCs or labeled neuronal ensembles supporting lateral inhibition of unlabeled neurons. Instead, labeled GCs and SGCs received more spontaneous excitatory synaptic inputs than their unlabeled counterparts. Moreover, pairs of GCs and SGCs within labeled neuronal cohorts received more temporally correlated spontaneous excitatory synaptic inputs than labeled-unlabeled neuronal pairs, validating a role for correlated afferent inputs in neuronal ensemble selection. These findings challenge the proposal that SGCs drive dentate GC ensemble refinement, while supporting a role for intrinsic active properties and correlated inputs in preferential SGC recruitment to contextual memory engrams. Impact StatementEvaluation of semilunar granule cell involvement in dentate gyrus contextual memory processing supports recruitment based on intrinsic and input characteristics while revealing limited contribution to ensemble refinement. Major subject area, keywords and organismsSemilunar granule cell, inhibition, memory, engram, circuit, hippocampus

neuroscience↗

bioRxiv2023

Multiple Temporal and Object-Based Strategies Across Learning for a Selective Detection Task in Mice

New tasks are often learned in stages with each stage reflecting a different learning challenge. Accordingly, each learning stage is likely mediated by distinct neuronal processes. And yet, most rodent studies of the neuronal correlates of goal-directed learning focus on individual outcome measures and individual brain regions. Here, we longitudinally studied mice from naive to expert performance in a head-fixed, operant conditioning whisker discrimination task. In addition to tracking the primary behavioral outcome of stimulus discrimination, we tracked and compared an array of object-based and temporal-based behavioral measures. These behavioral analyses identify multiple, partially overlapping learning stages in this task, consistent with initial response implementation, early stimulus-response generalization, and late response inhibition. To begin to understand the neuronal foundations of these learning processes, we performed widefield Ca2+ imaging of dorsal neocortex throughout learning and correlated behavioral measures with neuronal activity. We found distinct and widespread correlations between neocortical activation patterns and various behavioral measures. For example, improvements in sensory discrimination correlated with target stimulus evoked activations of licking-related cortices along with distractor stimulus evoked global cortical suppression. Our study reveals multidimensional learning for a simple goal-directed learning task and generates hypotheses for the neuronal modulations underlying these various learning processes.

animal behavior and cognition↗

bioRxiv2022

Frontal Cortex Gates Distractor Stimulus Encoding in Target Sensory Cortex

Frontal cortex suppresses behavioral responses to distractor stimuli. One possible mechanism by which this occurs is by modulating sensory responses in sensory cortex. However, it is currently unknown how frontal cortex modulations of sensory cortex contribute to distractor response suppression. We trained mice to respond to target stimuli in one whisker field and ignore distractor stimuli in the opposite whisker field. During expert task performance, optogenetic inhibition of frontal cortex increased behavioral responses to distractor stimuli. During expert task performance, within sensory cortex we observed expanded propagation of target stimulus responses and contracted propagation of distractor stimulus responses. In contrast to current models of frontal cortex function, frontal cortex did not substantially modulate the response amplitude of preferred stimuli. Rather, frontal cortex specifically suppressed the propagation of distractor stimulus responses, thereby preventing target-preferring neurons from being activated by distractor stimuli. Single unit analyses revealed that wMC decorrelates target and distractor stimulus encoding in target-preferring S1 neurons, which likely improves selective target stimulus detection by downstream readers. Moreover, we observed proactive top-down modulation from frontal to sensory cortex, through the preferential activation of GABAergic neurons. Overall, our study provides important mechanistic details about how frontal cortex gates sensory propagation in sensory cortex to prevent behavioral responses to distractor stimuli. HighlightsO_LIPairing of frontal cortex optogenetic inhibition with sensory cortex recordings during a target-distractor Go/NoGo task. C_LIO_LIDuring expert task performance, we observed target stimulus response expansion and distractor stimulus response contraction. C_LIO_LIOptogenetic inhibition of frontal cortex increased false alarm rates and selectively increased the propagation of distractor evoked responses into target-aligned sensory cortex. C_LIO_LIEven before stimulus onset, frontal cortex preferentially drives GABAergic neurons in distractor-aligned sensory cortex. C_LI

neuroscience↗

bioRxiv2022

Dorsolateral Striatal Selection and Frontal Cortex Inhibition for a Selective Detection Task in Mice

A learned sensory-motor behavior engages multiple brain regions, including the neocortex and the basal ganglia. How a target stimulus is selected by these regions remains poorly understood. Here, we performed electrophysiological recordings and pharmacological inactivations of motor cortex and dorsolateral striatum to determine the representations within and functions of each region during performance in a selective whisker detection task in male and female mice. From the recording experiments, peak pre-response activity and significant choice probability emerged in the motor cortex before the dorsolateral striatum, suggesting a sensory-to-motor transformation in which the striatum is downstream of motor cortex. We performed pharmacological inactivation studies to determine the necessity of these brain regions for this task. We found that suppressing the dorsolateral striatum, but not motor cortex, severely disrupts responding to task-relevant stimuli, without disrupting the ability to respond. Together these data support the dorsolateral striatum, and not motor cortex, as an essential node in the sensory-to- motor transformation of this whisker detection task. Significance StatementWe learn to do various sensory-motor behavior in our daily life, such as clicking on a journal article that looks interesting, among other articles. There are parts of our brain that are active when we do these learned behaviors, such as motor cortex and basal ganglia. But what is the order of activation of these regions? Which of them is necessary for responding to task-relevant sensory information? To answer these questions, we trained mice in a whisker-based target selection task and used recording of neural activity and inactivation of subregions within motor cortex and basal ganglia in expert mice. Our findings show dorsolateral striatum, a region within basal ganglia, is a bottleneck for performing task-related sensory-to-motor transformation.

neuroscience↗

bioRxiv2021

Global, Low Amplitude Cortical State Predicts Response Outcomes in a Selective Detection Task

Spontaneous neuronal activity strongly impacts stimulus encoding and behavioral responses. We sought to determine the effects of neocortical prestimulus activity on stimulus detection. We trained mice in a selective whisker detection task, in which they learned to respond (lick) to target stimuli in one whisker field and ignore distractor stimuli in the contralateral whisker field. During expert task performance, we used widefield Ca2+ imaging to assess prestimulus and post-stimulus neuronal activity broadly across frontal and parietal cortices. We found that lower prestimulus activity correlated with enhanced stimulus detection: lower prestimulus activity predicted response versus no response outcomes and faster reaction times. The activity predictive of trial outcome was distributed through dorsal neocortex, rather than being restricted to whisker or licking regions. Using principal component analysis, we demonstrate that response trials are associated with a distinct and less variable prestimulus neuronal subspace. For single units, prestimulus choice probability was weak yet distributed broadly, with lower than chance choice probability correlating with stronger sensory and motor encoding. These findings support a low amplitude, low variability, optimal prestimulus cortical state for stimulus detection that presents globally and predicts response outcomes for both target and distractor stimuli.

neuroscience↗

bioRxiv2020

Functional Localization of an Attenuating Filter within Cortex for a Selective Detection Task in Mice

An essential feature of goal-directed behavior is the ability to selectively respond to the diverse stimuli in ones environment. However, the neural mechanisms that enable us to respond to target stimuli while ignoring distractor stimuli are poorly understood. To study this sensory selection process, we trained male and female mice in a selective detection task in which mice learn to respond to rapid stimuli in the target whisker field and ignore identical stimuli in the opposite, distractor whisker field. In expert mice, we used widefield Ca2+ imaging to analyze target-related and distractor-related neural responses throughout dorsal cortex. For target stimuli, we observed strong signal activation in primary somatosensory cortex (S1) and frontal cortices, including both the whisker representation of primary motor cortex (wMC) and anterior lateral motor cortex (ALM). For distractor stimuli, we observe strong signal activation in S1, with minimal propagation to frontal cortex. Our data support only modest subcortical filtering, with robust, step-like attenuation in distractor processing between mono-synaptically coupled regions of S1 and wMC. This study establishes a highly robust model system for studying the neural mechanisms of sensory selection and places important constraints on its implementation. SummaryResponding to task-relevant stimuli while ignoring task-irrelevant stimuli is critical for goal-directed behavior. Yet, the neural mechanisms involved in this selection process are poorly understood. We trained mice in a detection task with both target and distractor stimuli. During expert performance, we measured neural activity throughout cortex using widefield imaging. We observed responses to target stimuli in multiple sensory and motor cortical regions. In contrast, responses to distractor stimuli were abruptly suppressed beyond sensory cortex. Our findings localize the sites of attenuation when successfully ignoring a distractor stimulus, and provide essential foundations for further revealing the neural mechanism of sensory selection and distractor suppression.

neuroscience↗

bioRxiv2019

Movement and performance predict widespread cortical activity in a visual detection task

Recent studies in mice reveal widespread cortical signals during task performance, however the various task-related and task-independent processes underlying this activity are incompletely understood. Here we recorded wide-field neural activity, as revealed by GCaMP6s, from dorsal cortex while simultaneously monitoring orofacial movements, walking, and arousal (pupil diameter) of head-fixed mice performing a Go/NoGo visual detection task and examined the ability of task performance and spontaneous or task-related movements to predict cortical activity. A linear model was able to explain a significant fraction (33-55% of variance) of widefield dorsal cortical activity, with the largest factors being movements (facial, walk, eye), response choice (hit, miss, false alarm), and arousal, and indicate that a significant fraction of trial-to-trial variability arises from both spontaneous and task-related changes in state (e.g. movements, arousal). Importantly, secondary motor cortex was highly correlated with lick rate, critical for optimal task performance (high d), and was the first region to significantly predict the lick response on target trials. These findings suggest that secondary motor cortex is critically involved in the decision and performance of learned movements and indicate that a significant fraction of trial-to-trial variation in cortical activity results from spontaneous and task-related movements and variations in behavioral/arousal state.

neuroscience↗