Biology subjects

Horwitz, G. D.

Publications and source records attributed to Horwitz, G. D..

9 recordsLinked to original sources

bioRxiv2026

Enhancer-based AAV approach for selective AADC delivery reduces motor symptoms and dyskinesia in Parkinson's mouse models

Degeneration of midbrain dopamine (DA) neurons and the resulting loss of striatal dopamine signaling are hallmarks of Parkinsons disease (PD). Although the dopamine precursor levodopa (L-DOPA) provides symptomatic relief, prolonged treatment often leads to abnormal involuntary movements (dyskinesia). Previous adeno-associated virus (AAV) approaches delivering aromatic L-amino acid decarboxylase (AADC) to the striatum under a ubiquitous promoter enhanced local dopamine synthesis and improved PD motor deficits, but this broad targeting strategy limited insight into the cellular populations underlying the behavioral improvements. Here, we engineered enhancer-driven AAVs to direct AADC expression to defined striatal and midbrain cell populations and paired these regulatory elements with a blood-brain barrier-penetrant capsid to enable both systemic and direct delivery. Targeted expression restored motor performance at reduced L-DOPA doses and decreased dyskinesia-like behaviors, producing improvements comparable to or greater than those achieved with ubiquitous expression. Distinct neuronal and non-neuronal populations each supported motor rescue but improved different behavioral domains to different extents, indicating complementary cell type-specific roles within PD-relevant circuits. Together, these findings establish enhancer-driven, cell type-specific AADC delivery as a better-tolerated strategy that enables rescue of motor deficits at lower L-DOPA doses in PD models.

neuroscience↗

bioRxiv2025

OpenIrisDPI: An Open-Source Digital Dual Purkinje Image Eye Tracker for Visual Neuroscience

BackgroundVideo-based eye trackers are widely used in vision science, psychology, clinical assessment, and neurophysiology. Many such systems track the pupil center and corneal reflection (P-CR) and compare their positions to estimate the direction of gaze. However, P-CR eye trackers are often too imprecise for applications with stringent eye tracking quality requirements. New methodWe present OpenIrisDPI, an open-source plugin for the OpenIris frame-work that implements dual Purkinje image (DPI) tracking. OpenIrisDPI supports simultaneous pupillography, a technique widely used in perceptual psychology and neuroscience, and it enables direct comparison between P-CR and DPI signals. ResultsData collected from macaque monkeys using OpenIrisDPI show that the P-CR method overestimates the amount of fixational drift between saccades compared to DPI. The accuracy of the DPI signal was further validated using high-density extracellular recording of neurons in the lateral geniculate nucleus. Compensating for the effects of fixational eye movements using DPI signals produced sharper estimates of neuronal receptive fields than using simultaneously collected P-CR signals. Comparison with existing methodsOpenIrisDPI is provided as open-source software and operates on consumer-grade hardware, making it more accessible than previously described DPI eye trackers and less costly than many P-CR systems. To our knowledge, OpenIrisDPI is the first eye tracker to perform both pupillography and DPI eye tracking. ConclusionOpenIrisDPI makes high-precision eye tracking readily available to the research community. It is well suited for visual neuroscience applications, where accurate knowledge of the retinal image during experiments is critical. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/649589v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@596dd2org.highwire.dtl.DTLVardef@139027borg.highwire.dtl.DTLVardef@1d1e526org.highwire.dtl.DTLVardef@11b321c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIOpenIrisDPI is a new open-source eye tracking system. C_LIO_LIOpenIrisDPI tracks the pupil, corneal reflection, & fourth Purkinje image at 500 Hz. C_LIO_LIDual Purkinje image-based eye tracking is more precise than pupilbased tracking. C_LIO_LIDPI improves receptive field characterization of LGN neurons in fixating macaques. C_LI

neuroscience↗

bioRxiv2021

Deficits in decision-making induced by parietal cortex inactivation are compensated at two time scales

Perceptual decisions arise through the transformation of samples of evidence into a commitment to a proposition or plan of action. Such transformation is thought to involve cortical circuits capable of computation over time scales associated with working memory, attention, and planning. Neurons in the lateral intraparietal area (LIP) are thought to play a role in all of these functions, and much of what is known about the neurobiology of decision making has been influenced by studies of LIP and its network of cortical and subcortical connections. However a causal role of neurons in LIP remains controversial. We used pharmacological and chemogenetic methods to inactivate LIP in one hemisphere of four rhesus monkeys. Inactivation produced clear biases in decisions, but the effects dissipated despite the persistence of neural inactivation, implying compensation by other unaffected areas. Compensation occurs on a rapid times scale, within an experimental session, and more gradually, across sessions. The findings resolve disparate studies and inform interpretation of focal perturbations of brain function.

neuroscience↗

bioRxiv2021

Temporal filtering of luminance and chromaticity in macaque visual cortex

The visibility of a periodic light modulation depends on its temporal frequency and spectral properties. Contrast sensitivity is highest at 8-10 Hz for modulations of luminance but is substantially lower for modulations between equiluminant lights. This difference between luminance and chromatic contrast sensitivity is rooted in retinal filtering, but additional filtering occurs in the cerebral cortex. To measure the cortical contributions to luminance and chromatic temporal contrast sensitivity, signals in the lateral geniculate nucleus (LGN) were compared to the behavioral contrast sensitivity of macaque monkeys. Long wavelength-sensitive (L) and medium wavelength-sensitive (M) cones were modulated in phase, to produce a luminance modulation (L+M), or in counterphase, to produce a chromatic modulation (L-M). The sensitivity of LGN neurons was well matched to behavioral sensitivity at low temporal frequencies but was approximately 7 times greater at high temporal frequencies. Similar results were obtained for L+M and L-M modulations. These results show that differences in the shapes of the luminance and chromatic temporal contrast sensitivity functions are due almost entirely to pre-cortical mechanisms. Simulations of cone photoreceptor currents show that temporal information loss in the retina and at the retinogeniculate synapse exceeds cortical information loss under most of the conditions tested.

neuroscience↗

bioRxiv2021

Coding of chromatic spatial contrast by macaque V1 neurons

Color perception relies on spatial comparisons of chromatic signals, but how the brain performs these comparisons is poorly understood. Here, we show that many V1 neurons compare signals across their receptive fields (RF) using a common principle. We estimated the spatial-chromatic RFs of each neuron, and then measured neural selectivity to customized colored edges that were sampled using a novel closed-loop technique. We found that many double-opponent (DO) cells, which have spatially and chromatically opponent RFs, responded to chromatic contrast as a weighted sum, akin to how simple cells respond to luminance contrast. Other neurons integrated chromatic signals non-linearly, confirming that linear signal integration is not an obligate property of V1 neurons. The functional similarity of DO and simple cells suggests a common underlying neural circuitry, promotes the construction of image-computable models for full-color image representation, and sheds new light on V1 complex cells.

neuroscience↗

bioRxiv2020

Single-cell RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates and humans

Abundant anatomical and physiological evidence supports the presence of at least three distinct types of relay glutamatergic neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex. Relay neuron diversity has also been described in the mouse dLGN (also known as LGd). Different types of relay neurons in mice, humans and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to other cellular properties and differences in dLGN between human, macaque, and mice, we profiled gene expression in single nuclei and cells using RNA-sequencing. These efforts identified four distinct types of relay neurons in the primate dLGN, magnocellular neurons, parvocellular neurons, and two cell types expressing canonical marker genes for koniocellular neurons. Surprisingly, despite extensive documented morphological and physiological differences between magno- and parvocellular neurons, we identified few genes with significant differential expression between transcriptomic cell types corresponding to these two neuronal populations. We also detected strong donor-specific gene expression signatures in both macaque and human relay neurons. Likewise, the dominant feature of relay neurons of the adult mouse dLGN is high transcriptomic similarity, with an axis of heterogeneity that aligns with core vs. shell portions of mouse dLGN. Together, these data show that transcriptomic differences between principal cell types in the mature mammalian dLGN are subtle relative to striking differences in morphology and cortical projection targets. Finally, we align cellular expression profiles across species and find homologous types of relay neurons in macaque and human, and distinct relay neurons in mouse.

neuroscience↗

bioRxiv2020

Spatial receptive field structure of double-opponent and simple cells in macaque primary visual cortex

The spatial processing of color is important for visual perception. Double-opponent (DO) cells likely contribute to this processing by virtue of their spatially opponent and cone-opponent receptive fields (RFs). However, the representation of visual features by DO cells in the primary visual cortex of primates is unclear because the spatial structure of their RFs has not been fully characterized. To fill this gap, we mapped the RFs of DO cells in awake macaques with colorful, dynamic white noise patterns. The spatial RF of each neuron was fitted with a Gabor function and a Difference of Gaussians (DoG) function. The Gabor function provided the more accurate description for most DO cells, a result that is incompatible with the traditionally assumed center-surround RF organization. A slightly modified (non-concentric) DoG function, in which the RFs have a circular center and a crescent-shaped surround, performed nearly as well as the Gabor model. For comparison, we also measured the RFs of simple cells. We found that the superiority of the Gabor fits over DoG fits was slightly more decisive for simple cells than for DO cells. The implications of these results on biological image processing and visual perception are discussed.

neuroscience↗

bioRxiv2018

Focal optogenetic suppression in macaque area MT biases direction discrimination and choice confidence, but only transiently

Insights from causal manipulations of brain activity depend on targeting the spatial and temporal scale most relevant for behavior. Using a sensitive perceptual decision task in monkeys, we examined the effects of randomly-interleaved, rapid, reversible inactivation on a spatial scale previously achieved only with electrical microstimulation. Inactivating neurons in area MT with consistent direction tuning produced systematic effects on choice and confidence. Behavioral effects were attenuated over the course of each session, suggesting compensatory adjustments in the downstream readout of MT over tens of minutes. Compensation also occurred on a sub-second time scale: behavior was largely unaffected on trials with visual stimuli (and concurrent suppression) longer than [~]350ms. These trends were similar for choice and confidence, consistent with the idea of a common mechanism underlying both measures. The findings demonstrate the utility of hyperpolarizing opsins for linking neural population activity at fine spatial and temporal scales to cognitive functions in primates.

neuroscience↗

bioRxiv2017

Dethroning the Fano Factor: a flexible, model-based approach to partitioning neural variability

Neurons in many brain areas exhibit high trial-to-trial variability, with spike counts that are over-dispersed relative to a Poisson distribution. Recent work (Goris et al., 2014) has proposed to explain this variability in terms of a multiplicative interaction between a stochastic gain variable and a stimulus-dependent Poisson firing rate, which produces quadratic relationships between spike count mean and variance. Here we examine this quadratic assumption and propose a more flexible family of models that can account for a more diverse set of mean-variance relationships. Our model contains additive Gaussian noise that is transformed nonlinearly to produce a Poisson spike rate. Different choices of the nonlinear function can give rise to qualitatively different mean-variance relationships, ranging from sub-linear to linear to multiplicative. Intriguingly, a rectified squaring nonlinearity produces a linear mean-variance function, corresponding to responses with constant Fano factor. We describe a computationally efficient method for fitting this model to data, and demonstrate that a majority of neurons in a V1 population are better described by a model with non-quadratic relationship between mean and variance. Lastly, we develop an application to Bayesian adaptive stimulus selection in closed-loop neurophysiology experiments, which shows that accounting for overdispersion can lead to dramatic improvements in adaptive tuning curve estimation.

neuroscience↗