Biology subjects

Cox, M. A.

Publications and source records attributed to Cox, M. A..

7 recordsLinked to original sources

bioRxiv2025

Human C. difficile-specific memory B cells encode protective IgG1 despite predominance of non-neutralizing antibodies.

Clostridioides difficile remains a common source of nosocomial infection resulting in a wide range of clinical outcomes and for which there is no vaccine and limited therapeutic options. C. difficile Toxin B (TcdB)-specific IgG is the best correlate of protection against severe and recurrent disease. However, there are very few therapeutic IgG fully human monoclonal antibodies (hmAbs) that have shown efficacy thus far. We therefore hypothesized that the memory B cell (Bmem) compartment of individuals who have recovered from infection may be dominated by non-protective IgG molecules but encode some antibodies that are protective. We therefore produced hmAbs from a library of Bmem-encoded IgG1 sequences. Most TcdB-specific hmAbs displayed low affinity binding and poor neutralization of TcdB in vitro while a few hmAbs had high affinity binding and good TcdB neutralization. The results correlated with in vivo studies in which high affinity, TcdB-neutralizing hmAbs provided moderate protection of C57Bl/6 mice against C. difficile disease. Similar protection was observed in Tg32 mice expressing the human FcRn transgene, indicating that gut delivery of hmAb did not account for limited efficacy. Although non-protective antibody sequences dominate the repertoire, human Bmem cells may be a good source of therapeutic hmAbs for C. difficile treatment.

immunology↗

bioRxiv2025

What one sees depends on how far the eye has moved

Humans explore visual scenes through frequent, rapid gaze shifts known as saccades. These movements redirect the high-acuity region of the retina toward objects of interest, thus selecting information based on location. Here, we show that saccade amplitude provides a separate and complementary form of selection, effectively filtering visual information by spatial frequency rather than location. Specifically, a reduction in saccade amplitude attenuates post-saccadic visual sensitivity in an amplitude-dependent range of low spatial frequencies. This effect is highly robust, so that even minute changes in saccade size considerably affect visibility. We show that this phenomenon arises from the way the magnitude-dependent kinematic characteristics of saccades transform the visual world into a spatiotemporal flow: post-saccadic visibility closely follows theoretical predictions based on the spatial information that saccade transients convey within the temporal bandwidth of retinal sensitivity. Thus, saccades not only guide selection based on location, but also filter visual information based on content, actively shaping perception.

neuroscience↗

bioRxiv2023

Near-field potentials index local neural computations more accurately than population spiking

Local field potentials (LFP) are low-frequency extracellular voltage fluctuations thought to primarily arise from synaptic activity. However, unlike highly localized neuronal spiking, LFP is spatially less specific. LFP measured at one location is not entirely generated there due to far-field contributions that are passively conducted across volumes of neural tissue. We sought to quantify how much information within the locally generated, near-field low-frequency activity (nfLFP) is masked by volume-conducted far-field signals. To do so, we measured laminar neural activity in primary visual cortex (V1) of monkeys viewing sequences of multifeatured stimuli. We compared information content of regular LFP and nfLFP that was mathematically stripped of volume-conducted far-field contributions. Information content was estimated by decoding stimulus properties from neural responses via spatiotemporal multivariate pattern analysis. Volume-conducted information differed from locally generated information in two important ways: (1) for stimulus features relevant to V1 processing (orientation and eye-of-origin), nfLFP contained more information. (2) in contrast, the volume-conducted signal was more informative regarding temporal context (relative stimulus position in a sequence), a signal likely to be coming from elsewhere. Moreover, LFP and nfLFP differed both spectrally as well as spatially, urging caution regarding the interpretations of individual frequency bands and/or laminar patterns of LFP. Most importantly, we found that population spiking of local neurons was less informative than either the LFP or nfLFP, with nfLFP containing most of the relevant information regarding local stimulus processing. These findings suggest that the optimal way to read out local computational processing from neural activity is to decode the local contributions to LFP, with significant information loss hampering both regular LFP and local spiking. Authors ContributionsConceptualization, D.A.T., J.A.W, and A.M.; Data Collection, J.A.W., M.A.C., K.D.; Formal Analysis, D.A.T. and J.A.W.; Data Visualization, D.A.T. and J.A.W.; Original Draft, D.A.T., J.A.W., and A.M.; Revisions and Final Draft, D.A.T., J.A.W., M.A.C., K.D., M.T.W., A.M.B., and A.M. Competing InterestsThe authors declare no conflicts of interest.

neuroscience↗

bioRxiv2019

Stimulus-specific information flow across the canonical cortical microcircuit

The vast majority of mammalian neocortex consists of a stereotypical microcircuit, the canonical cortical microcircuit (CCM), consisting of a granular input layer, positioned between superficial and deep layers. Due to this uniform layout, neuronal activation tends to follow a similar laminar sequence, with unique information extracted at each step. For example, the primate primary visual cortex (V1) combines the two eyes signals, extracts stimulus orientation and modulates its activity depending on stimulus history. Several theories have been proposed on when and where these processes happen within the CCMs laminar activation sequence, but it has been methodologically challenging to test these hypotheses. Here, we use time-resolved multivariate pattern analysis (MVPA) to decode information regarding the eye-of-origin, stimulus orientation and stimulus repetition from simultaneously measured spiking responses across V1s laminar microcircuit. We find that eye-of-origin information was decodable for the entire duration of stimulus presentation, but diminished in the deepest layers of V1, consistent with the notion that two eyes signals are combined within the upper layers. Conversely, orientation information was transient and equally pronounced across the microcircuit, in line with the idea that this information is relayed to other areas for further processing. Moreover, when stimuli were repeated, information regarding orientation was enhanced at the expense of eye-of origin information, suggesting that V1 modulates information flow to optimize specific stimulus dimensions. Taken together, these findings provide empirical evidence that adjudicates between long-standing hypotheses and reveals how information transfer within the CCM supports unique cortical functions.\n\nSignificance StatementDespite the brains daunting complexity, there are common organizing principles across brain areas. For example, neocortical activation follows a stereotypical pattern that spreads from input layers towards layers above and below. While this activation pattern is well known, it has been challenging to ascertain how unique types of information are extracted within this common sequence in different brain areas. Here we use machine learning to track the flow of stimulus-specific information across the layers of visual cortex. We found that information regarding several separate stimulus dimensions was routed uniquely within the common activation sequence in a manner that confirmed prior model predictions. This finding demonstrates how differences in information flow within the stereotypical neocortical activation sequence shape area-specific functions.

neuroscience↗

bioRxiv2018

Binocular modulation of monocular V1 neurons

In humans and other primates, sensory signals from each eye remain separated until they arrive in the primary visual cortex (V1), but their exact meeting point is unknown. In V1, some neurons are activated by stimulation of only one eye (monocular neurons) while most neurons are driven by stimulation of either eye (binocular neurons). Monocular neurons are most prevalent in the main input layers of V1 while binocular neurons dominate the layers above and below. This observation has given rise to the idea that the two eyes signals remain separate until they converge outside V1s input layers. Here, we show that despite responding to only one eye, monocular neurons in all layers, including the input layers, of V1 discriminate between stimulation of their driving eye alone and stimulation of both eyes. This finding suggests that binocular signals occur at an earlier processing stage than previously appreciated as even so-called monocular neurons across all V1 layers encode what is shown to both eyes.

neuroscience↗

bioRxiv2018

Adaptation of Intracortical Signaling Concurs with Enhanced Encoding Efficiency

Stimulus repetitions improve performance despite decreased brain responses, suggesting that the brain is more efficient when processing familiar stimuli. Previous work demonstrated that stimulus repetition enhances encoding efficiency in primary visual cortex (V1) by increasing synchrony and sharpening the orientation tuning of neurons. Here we show that these adaptive changes are supported by an altered flow of sensory activation across the V1 laminar microcircuit. Using a repeating stimulus sequence, we recorded laminar responses in V1 of two fixating monkeys. We found repetition-related response reductions that were most pronounced outside V1 layers that receive the main retinogeniculate input. This repetition-induced suppression was robust to alternating stimuli between the eyes, in line with the notion that repetition suppression is predominantly of cortical origin. Congruent with earlier reports, we found that V1 adaptation to repeating stimuli is accompanied by sharpened neural tuning as well as increased neural synchrony. Current source density (CSD) analysis, which provides an estimate of net synaptic activation, revealed that the responses to repeated stimuli were most profoundly affected within layers that harbor the bulk of cortico-cortical connections. Together, these results suggest that stimulus repetition induces an altered state of intracortical processing resulting in enhanced encoding efficiency of sensory stimuli.

neuroscience↗

bioRxiv2018

Binocular Integration Manifests as a Transient Spiking Increase Followed by Selective Suppression in Primary Visual Cortex

Research throughout the past decades revealed that neurons in primate primary visual cortex (V1) rapidly integrate the two eyes separate signals into a combined binocular response. The exact mechanisms giving underlying this binocular integration remain elusive. One open question is whether binocular integration occurs at a single stage of sensory processing or in a sequence of computational steps. To address this question, we examined the temporal dynamics of binocular integration across V1s laminar microcircuit of awake behaving monkeys. We find that V1 processes binocular stimuli in a dynamic sequence that comprises at least two distinct phases: A transient phase, lasting 50-150ms from stimulus onset, in which neuronal population responses are significantly enhanced for binocular stimulation compared to monocular stimulation, followed by a sustained phase characterized by widespread suppression in which feature-specific computations emerge. In the sustained phase, incongruent binocular stimulation resulted in response reduction relative to monocular stimulation across the V1 population. By contrast, sustained responses for binocular congruent stimulation were either reduced or enhanced relative to monocular responses depending on the neurons selectivity for one or both eyes (i.e., ocularity). These results suggest that binocular integration in V1 occurs in at least two sequential steps, with an initial additive combination of the two eyes signals followed by the establishment of interocular concordance and discordance.\n\nSignificance StatementOur two eyes provide two separate streams of visual information that are merged in the primary visual cortex (V1). Previous work showed that stimulating both eyes rather than one eye may either increase or decrease activity in V1, depending on the nature of the stimuli. Here we show that V1 binocular responses change over time, with an early phase of general excitation and followed by stimulus-dependent response suppression. These results provide important new insights into the neural machinery that supports the combination of the two eyes perspectives into a single coherent view.

neuroscience↗