Biology subjects

Cohen, M. R.

Publications and source records attributed to Cohen, M. R..

At least 19 recordsLinked to original sources

bioRxiv2026

How a highly acidic SH3 domain binds to its intrinsically disordered partner through the formation of an encounter complex intermediate

Electrostatic interactions often play a role in determining the thermodynamic and kinetic properties of protein-protein interactions. However, the role of long-range electrostatic interactions in intrinsically disordered protein (IDP) binding is less clear, as they often bind in multiple steps including initial formation of a disordered encounter complex, followed by rearrangement into the bound state. We varied the salt concentration to probe the role of long-range electrostatic interactions in the binding of the highly charged AbpSH3 domain and the oppositely charged IDP ArkA. Using isothermal titration calorimetry, we observe that salt enthalpically destabilizes the bound complex. Molecular dynamics and NMR experiments reveal that salt has little effect on the bound state structure. However, simulations show that salt destabilizes the encounter complex intermediate, which primarily affects the association rate as measured by NMR. Consistent with these results, salt has the largest stabilizing effect on the apo SH3 domain, as cations substitute for the transient and long-range electrostatic interactions that can form with ArkA in the complex. We reveal a detailed picture of how a highly charged domain uses long-range, fuzzy, electrostatic interactions to help reach the bound state, a mechanism that is likely common among other highly charged domains that bind IDPs. TOC Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/741257v1_ufig1.gif" ALT="Figure 1000"> View larger version (21K): org.highwire.dtl.DTLVardef@dfc7acorg.highwire.dtl.DTLVardef@1ae0438org.highwire.dtl.DTLVardef@19704adorg.highwire.dtl.DTLVardef@1b40b15_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

Progressive loss of independence in neuronal representations predicts cognitive decline

Intelligent behavior depends on the brains ability to represent multiple features of the environment simultaneously while keeping those representations independent1,2. Patients with Alzheimers disease often mix up objects, people, and events3-7, raising the possibility that disease mixes up the way that information is represented in the brain. Here we show that the independence of visual representations progressively breaks down during early stages of disease progression in a rhesus macaque model of Alzheimers disease and related dementias8-10. In visual area V4, representations of different visual features become progressively less independent, such that the representation of one feature is increasingly influenced by the value of another. We term this loss of independence neuronal feature confusion. This neuronal change predicts a specific behavioral consequence: because feature representations become less independent, preferences associated with one visual feature increasingly influence visually guided choices associated with other, independent features. Using an analogous image-selection task, we found the same behavioral signature in people with mild cognitive impairment, distinguishing them from age-matched controls. These results identify a specific and measurable alteration in neuronal population representations that predicts a behavioral change observed across species. More broadly, these findings demonstrate that neuronal population representations can guide the development of sensitive, non-invasive behavioral methods for early detection of functional changes associated with Alzheimers disease.

neuroscience↗

bioRxiv2026

Sequential experience reshapes population representations in visual cortex

Visual experience is organized in time. When riding the same bus route each day, the visual scene unfolds in a predictable order without requiring active choice. During goal-directed behavior, individuals organize actions into routines, such as repeatedly walking the same route to work even when alternatives are equally efficient. Because experience unfolds across sequences of events, identifying how it reshapes population activity requires examining representations over time. Many studies have shown that repeated experience reduces mean firing rates in visual cortex1-14. While firing rates effectively signal novelty or repetition, they are not well positioned to describe how populations of neurons represent temporal relationships. A growing body of work suggests that the geometry of population activity provides additional insight into how visual information is structured and read out15-26. We examined how experience with temporal structure reshapes the geometry of population activity in visual area V4. We recorded neuronal populations across three contexts that varied in temporal structure and behavioral relevance: repeated presentation of individual images, passive exposure to structured image sequences, and repeated execution of self-chosen visually guided action sequences for reward. Across contexts, experience constrained population responses toward a typical activity pattern. In sequence contexts, experience made temporal position more linearly accessible and, during active practice, increased the separability of task-relevant variables. These findings show that experience reorganizes the geometry of visual population activity to reflect temporal structure, constraining responses and altering how sequence-related information is represented.

neuroscience↗

bioRxiv2026

Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease

Alzheimers disease (AD) and related dementias (ADRD) are defined by molecular and cellular pathology and cognitive decline, but linking these levels requires understanding how pathology alters large-scale neuronal activity. We longitudinally tracked behavior, multi-area neuronal population activity, and fluid and histological biomarkers in a macaque model of early-stage ADRD. As pathology progressed, visually guided behavior became increasingly disorganized, reflected in less structured exploration despite preserved task performance. Guided by systems neuroscience principles linking neuronal population activity with organized goal-directed behavior, we found progressive reductions in coordinated neuronal population activity within and between visual and parietal cortices, even as single-neuron tuning and basic feature encoding remained stable. These changes emerged when tau pathology was largely confined to regions providing feedback to visual cortex. This disorganized state appears modifiable: proof-of-concept methylphenidate administration was associated with transient improvement in behavioral organization. Together, these findings identify disruption of neuronal population organization as a defining feature of early-stage ADRD and frame early dysfunction as a disorder of coordinated population activity.

neuroscience↗

bioRxiv2025

Behavioural and neuronal insights into multisensory combination of unpracticed cues.

Effective decision-making requires integrating multiple information sources, weighted by their reliability and context. While classic studies show near-optimal cue combination in extensively controlled laboratory settings and lengthy inperson experiments, everyday choices often occur in less controlled environments. We examined cue combination under these conditions using an online perceptual estimation task in large and diverse participant cohorts. Participants combined cues, including visual motion direction, spatial visual information, and sound. We investigated cue combination with and without cue conflict. Performance varied with age and self-reported ADHD or Autism. Visual cues were combined more optimally than audio-visual combinations. We observed qualitative similarities in an analagous task with non-human primates. We used electrical microstimulation in non-human primates, targeting unimodal or cross-modal association areas. Stimulation of visual cortex was integrated with sensory motion cues, while stimulation of prefrontal cortex promoted winner-take-all choices. These findings suggest distinctions between within- and across-modality integration, with deviations potentially informative of age or neurodiversity.

neuroscience↗

bioRxiv2025

Neuronal signatures of successful one-shot memory in mid-level visual cortex

High-capacity, one-shot visual recognition memory challenges theories of learning and neural coding because it requires rapid, robust, and durable representations. Most studies have focused on the hippocampus and other higher areas. However, behavioral evidence demonstrating links between image properties and memorability and revealing image specificity of visual memory suggests an important role for mid-level visual cortex. We tested the hypothesis that area V4 contains signals that could support recognition memory. Our task increased difficulty, allowing comparisons of neuronal population responses on correct and error trials. We observed signatures of several proposed memory mechanisms including magnitude coding, repetition suppression, sparse coding, and population response consistency, but only sparse coding and population response consistency predicted behavior. Familiar images also evoked faster dynamics, consistent with pattern completion. These findings demonstrate that the building blocks of fast, high-capacity memory are present in mid-level sensory cortex, highlighting its role in distributed memory networks.

neuroscience↗

bioRxiv2025

RNA polymerase II CTD Ser5 phosphorylation induces competing effects of expansion and compaction

The carboxy-terminal domain (CTD) of RNA Polymerase II, composed of tandem heptad repeats with the consensus sequence YSPTSPS, orchestrates the transcription cycle through a dynamic series of post-translational modifications. Among these, the phosphorylation of Ser5 is critical for initiator/promoter clearance and the recruitment of capping enzymes. However, the exact conformational consequences of these modifications are still not fully understood. This study investigates how Ser5 phosphorylation affects the local and global conformation of the CTD, its influence on proline isomerization, and how variations in the repeat sequence modulate these effects. We employed Gaussian accelerated Molecular Dynamics (GaMD) simulations on 3-heptad models of both the consensus CTD sequence and an Asn7 variant. We found that Ser5 phosphorylation promotes expansion of the peptide due to the repulsion between the negatively-charged phosphate groups, but also increases the population of cis-Pro6, which leads to compaction. We used a clustering algorithm to identify commonly populated conformations, with a focus on those conformations that change in population with Ser5 phosphorylation. Our simulations reveal that the expansion of the CTD due to Ser5 phosphorylation is accompanied by a change in local, intra-heptad interactions in both variants. Notably, phosphorylation significantly increases the population of cis-Pro6 due to steric repulsion between the Asn7 side chain and the large side chain of the phosSer5, but has a smaller increase in the consensus variant. These results clarify the underlying mechanisms by which phosphorylation can modulate the CTDs structural landscape to regulate the transcription cycle. SignificanceThe RNA Polymerase II CTD is a critical part of the machinery that regulates transcription, and therefore, understanding how it functions in this process is essential. However, the conformational effects of known modifications to the CTD, such phosphorylation and proline isomerization, are not fully understood. This paper uses all-atom molecular dynamics simulations to identify the specific conformational changes to the disordered CTD with phosphorylation, and with changing heptad sequence. We also identify the interactions that are responsible for these changes. Our results emphasize that two chemical properties of phosphate groups, their negative charge and their large size, can affect protein conformation. For the CTD, these properties have competing effects on the overall compaction of the disordered sequence.

biophysics↗

bioRxiv2025

Guided by Noise: Correlated Variability Channels Task-Relevant Information in Sensory Neurons

Shared trial-to-trial variability across sensory neurons is reliably reduced when perceptual performance improves, yet this variability is low-dimensional, so it could be ignored by an optimal readout mechanism. Why then is it so consistently related to behavior? We propose that shared variability both reflects circuit structure and reveals the information communicated to downstream areas. In this framework, the same connectivity that shapes signal propagation also shapes shared variability. Using a circuit model, we show that when sensory signals align with shared variability, behaviorally relevant information is amplified without compromising coding fidelity. Analyses of neural population recordings from multiple brain areas and tasks reveal that the dominant axis of shared variability consistently aligns with task-relevant stimulus features and action plans. Finally, the behavioral impact of microstimulation can be explained by the extent to which it changes projections onto the shared variability axis. These findings suggest that shared variability may illuminate, rather than obscure, the neural dimensions that guide behavior. Significance StatementThe brains ability to use different features of sensory information flexibly across many tasks is essential for complex decision-making. Our study reveals that the correlated variability in neural responses in mid-level visual areas indicates the visual feature that is relevant for behavior. Our biologically plausible network model predicted that it is beneficial for the representation of behaviorally relevant visual information to be aligned with the correlated variability in neurons. We tested and confirmed this in five independent neural data sets. Our results suggest that trial-by-trial variability does not affect the information encoded in sensory neurons but instead is a valuable signal for us to understand which combination of the encoded features is being used by the brain to guide choices.

neuroscience↗

bioRxiv2025

Linking neural population formatting to function

Animals capable of complex behaviors tend to have more distinct brain areas than simpler organisms, and artificial networks that perform many tasks tend to self-organize into modules (1-3). This suggests that different brain areas serve distinct functions supporting complex behavior. However, a common observation is that essentially anything that an animal senses, knows, or does can be decoded from neural activity in any brain area (4-6). If everything is everywhere, why have distinct areas? Here we show that the function of a brain area is more related to how different types of information are combined (formatted) in neural representations than merely whether that information is present. We compared two brain areas: the middle temporal area (MT), which is important for visual motion perception (7, 8), and the dorsolateral prefrontal cortex (dlPFC), which is linked to decision-making and reward expectation (9, 10)). When monkeys based decisions on a combination of motion and reward information, both types of information were present in both areas. However, they were formatted differently: in MT, they were encoded separably, while in dlPFC, they were represented jointly in ways that reflected the monkeys decision-making. A recurrent neural network (RNN) model that mirrored the information formatting in MT and dlPFC predicted that manipulating activity in these areas would differently affect decision-making. Consistent with model predictions, electrically stimulating MT biased choices midway between the visual motion stimulus and the preferred direction of the stimulated units (11), while stimulating dlPFC produced winner-take-all decisions that sometimes reflected the visual motion stimulus and sometimes reflected the preference of the stimulated units, but never in between. These results are consistent with the tantalizing possibility that a modular structure enables complex behavior by flexibly reformatting information to accomplish behavioral goals.

neuroscience↗

bioRxiv2024

Coordinated Response Modulations Enable Flexible Use of Visual Information

We use sensory information in remarkably flexible ways. We can generalize by ignoring task-irrelevant features, report different features of a stimulus, and use different actions to report a perceptual judgment. These forms of flexible behavior are associated with small modulations of the responses of sensory neurons. While the existence of these response modulations is indisputable, efforts to understand their function have been largely relegated to theory, where they have been posited to change information coding or enable downstream neurons to read out different visual and cognitive information using flexible weights. Here, we tested these ideas using a rich, flexible behavioral paradigm, multi-neuron, multi-area recordings in primary visual cortex (V1) and mid-level visual area V4. We discovered that those response modulations in V4 (but not V1) contain the ingredients necessary to enable flexible behavior, but not via those previously hypothesized mechanisms. Instead, we demonstrated that these response modulations are precisely coordinated across the population such that downstream neurons have ready access to the correct information to flexibly guide behavior without making changes to information coding or synapses. Our results suggest a novel computational role for task-dependent response modulations: they enable flexible behavior by changing the information that gets out of a sensory area, not by changing information coding within it. SignificanceNatural perceptual judgments are continuous, generalized, and flexible. We estimate the ripeness of a piece of fruit on a continuous scale, we generalize by judging the ripeness of either a mango or an avocado even though they look very different, we flexibly judge either the size or the ripeness of the same piece of fruit, and we can flexibly indicate the same perceptual judgment using a variety of behaviors such as by speaking or writing any of many languages. Here, we show that the response modulations in visual cortex long associated with cognitive processes, surround modulation, or motor planning are sufficient to guide all these aspects of natural perceptual decision-making. We find that across the population, these response modulations reorient and reformat visual representations so that the relevant information is used to guide behavior via communication with downstream neurons. Our results are an example of a general computational principle for flexible behavior that emerges from the coordinated activity of large populations of neurons.

neuroscience↗

bioRxiv2024

Task interference as a neuronal basis for the cost of cognitive flexibility

Humans and animals have an impressive ability to juggle multiple tasks in a constantly changing environment. This flexibility, however, worsens performance under uncertain task conditions. Here, we combined monkey electrophysiology, human psychophysics, and artificial neural network modeling to investigate the neuronal mechanisms underlying this performance cost. We developed a behavioural paradigm to measure and influence participants decision-making and perception in two distinct perceptual tasks. Our data reveal that both humans and monkeys, unlike an artificial neural network trained for the same tasks, make less accurate perceptual decisions when the task is uncertain. We generated a mechanistic hypothesis by comparing this neural network trained to produce correct choices with another network trained to replicate the participants choices. We hypothesized, and confirmed with further behavioural, physiological, and causal experiments, that the cost of task uncertainty and flexibility comes from what we term feature interference. Under uncertain conditions, interference between different tasks causes errors because it results in stronger representations of irrelevant features and entangled neuronal representations of different features. Our results suggest a tantalizing, general hypothesis: that cognitive capacity limitations, both in health and disease, stem from interference between neural representations of different stimuli, tasks, or memories.

neuroscience↗

bioRxiv2024

Orthogonal neural representations support perceptual judgements of natural stimuli

In natural behavior, observers must separate relevant information from a barrage of irrelevant information. Many studies have investigated the neural underpinnings of this ability using artificial stimuli presented on simple backgrounds. Natural viewing, however, carries a set of challenges that are inaccessible using artificial stimuli, including neural responses to background objects that are task-irrelevant. An emerging body of evidence suggests that the visual abilities of humans and animals can be modeled through the linear decoding of task-relevant information from visual cortex. This idea suggests the hypothesis that irrelevant features of a natural scene should impair performance on a visual task only if their neural representations intrude on the linear readout of the task relevant feature, as would occur if the representations of task-relevant and irrelevant features are not orthogonal in the underlying neural population. We tested this hypothesis using human psychophysics and monkey neurophysiology, in response to parametrically variable naturalistic stimuli. We demonstrate that 1) the neural representation of one feature (the position of a central object) in visual area V4 is orthogonal to those of several background features, 2) the ability of human observers to precisely judge object position was largely unaffected by task-irrelevant variation in those background features, and 3) many features of the object and the background are orthogonally represented by V4 neural responses. Our observations are consistent with the hypothesis that orthogonal neural representations can support stable perception of objects and features despite the tremendous richness of natural visual scenes. Significance StatementWe studied how the structure of the mid-level neural representation of multiple visual features supports robust perceptual decisions. We combined array recording with parametrically controlled naturalistic images to demonstrate that the representation of a central objects position in monkey visual area V4 is orthogonal to that of several background features. In addition, we used human psychophysics with the same stimulus set to show that observers ability to judge a central objects position is largely unaffected by variation in the same background features. This result supports the hypothesis that orthogonal neural representations can enable stable and robust perception in naturalistic visual environments and advances our understanding of how visual processing operates in the real world.

neuroscience↗

bioRxiv2023

Multiple objects evoke fluctuating responses in several regions of the visual pathway

How neural representations preserve information about multiple stimuli is mysterious. Because tuning of individual neurons is coarse (for example, visual receptive field diameters can exceed perceptual resolution), the populations of neurons potentially responsive to each individual stimulus can overlap, raising the question of how information about each item might be segregated and preserved in the population. We recently reported evidence for a potential solution to this problem: when two stimuli were present, some neurons in the macaque visual cortical areas V1 and V4 exhibited fluctuating firing patterns, as if they responded to only one individual stimulus at a time (Jun et al., 2022). However, whether such an information encoding strategy is ubiquitous in the visual pathway and thus could constitute a general phenomenon remains unknown. Here we provide new evidence that such fluctuating activity is also evoked by multiple stimuli in visual areas responsible for processing visual motion (middle temporal visual area, MT), and faces (middle fundus and anterolateral face patches in inferotemporal cortex - areas MF and AL), thus extending the scope of circumstances in which fluctuating activity is observed. Furthermore, consistent with our previous results in the early visual area V1, MT exhibits fluctuations between the representations of two stimuli when these form distinguishable objects but not when they fuse into one perceived object, suggesting that fluctuating activity patterns may underlie visual object formation. Taken together, these findings point toward an updated model of how the brain preserves sensory information about multiple stimuli for subsequent processing and behavioral action. Impact StatementNeural fluctuations in multiple areas along the visual cortical hierarchy could allow the brain to represent distinct co-occurring visual stimuli.

neuroscience↗

bioRxiv2023

Contributions of early and mid-level visual cortex to high-level object categorization

The complexity of visual features for which neurons are tuned increases from early to late stages of the ventral visual stream. Thus, the standard hypothesis is that high-level functions like object categorization are primarily mediated by higher visual areas because they require more complex image formats that are not evident in early visual processing stages. However, human observers can categorize images as objects or animals or as big or small even when the images preserve only some low- and mid-level features but are rendered unidentifiable ( texforms, Long et al., 2018). This observation suggests that even the early visual cortex, in which neurons respond to simple stimulus features, may already encode signals about these more abstract high-level categorical distinctions. We tested this hypothesis by recording from populations of neurons in early and mid-level visual cortical areas while rhesus monkeys viewed texforms and their unaltered source stimuli (simultaneous recordings from areas V1 and V4 in one animal and separate recordings from V1 and V4 in two others). Using recordings from a few dozen neurons, we could decode the real-world size and animacy of both unaltered images and texforms. Furthermore, this neural decoding accuracy across stimuli was related to the ability of human observers to categorize texforms by real-world size and animacy. Our results demonstrate that neuronal populations early in the visual hierarchy contain signals useful for higher-level object perception and suggest that the responses of early visual areas to simple stimulus features display preliminary untangling of higher-level distinctions.

neuroscience↗

bioRxiv2021

Methylphenidate as a causal test of translational and basic neural coding hypotheses

Most systems neuroscience studies fall into one of two categories: basic science work aimed at understanding the relationship between neurons and behavior, or translational work aimed at developing treatments for neuropsychiatric disorders. Here we use these two approaches to inform and enhance each other. Our study both tests hypotheses about basic science neural coding principles and elucidates the neuronal mechanisms underlying new, clinically relevant behavioral effects of systemically administered methylphenidate (Ritalin). We discovered that orally administered methylphenidate, used clinically to treat Attention Deficit Hyperactivity Disorder (ADHD) and generally to enhance cognition (Lakhan & Kirchgessner, 2012; Maher, 2008), increases spatially selective visual attention, enhancing visual performance at only the attended location. And as predicted by our previous work (Ni et al., 2018), we found that this causal manipulation enhances vision in rhesus macaques specifically when it decreases the mean correlated variability of neurons in visual area V4. Our findings demonstrate that the visual system is a platform for understanding the neural underpinnings of both complex cognitive processes (basic science) and neuropsychiatric disorders (translation). Addressing basic science hypotheses, our results are consistent with a scenario in which methylphenidate has cognitively specific effects by working through naturally selective cognitive mechanisms. Clinically, our findings suggest that the often staggeringly specific symptoms of neuropsychiatric disorders may be caused and treated by leveraging general mechanisms.

neuroscience↗

bioRxiv2021

Dynamic task-belief is an integral part of decision-making

Natural decisions involve two seemingly separable processes: inferring the relevant task (task-belief) and performing the believed-relevant task. The assumed separability has led to the traditional practice of studying task-switching and perceptual decision-making individually. Here, we used a novel paradigm to manipulate and measure macaque monkeys task-belief, and demonstrated inextricable neuronal links between flexible task-belief and perceptual decision-making. We showed that in animals, but not artificial networks that performed as well or better than the animals, stronger task-belief is associated with better perception. Correspondingly, recordings from neuronal populations in cortical areas 7a and V1 revealed that stronger task-belief is associated with better discriminability of the believed-relevant but not the believed-irrelevant feature. Perception also impacts belief updating: noise fluctuations in V1 help explain how task-belief is updated. Our results demonstrate that complex tasks and multi-area recordings can reveal fundamentally new principles of how biology affects behavior in health and disease.

neuroscience↗

bioRxiv2021

Attention improves information flow between neuronal populations without changing the communication subspace

Visual attention allows observers to flexibly use or ignore visual information, suggesting that information can be flexibly routed between visual cortex and neurons involved in decision-making. We investigated the neural substrate of flexible information routing by analyzing the activity of populations of visual neurons in the medial temporal area (MT) and oculomotor neurons in the superior colliculus (SC) while rhesus monkeys switched spatial attention. We demonstrated that attention increases the efficacy of visuomotor communication: trial-to-trial variability of the population of SC neurons was better predicted by the activity of MT neurons (and vice versa) when attention was directed toward their joint receptive fields. Surprisingly, this improvement in prediction was not explained or accompanied by changes in the dimensionality of the shared subspace or in local or shared pairwise noise correlations. These results suggest a mechanism by which visual attention can affect perceptual decision-making without altering local neuronal representations.

neuroscience↗

bioRxiv2021

Targeted comodulation supports flexible and accurate decoding in V1

Sensory-guided behavior requires reliable encoding of stimulus information in neural populations, and task-specific readout through a selective combination of these responses. The former has been the topic of extensive study, but the means by which the brain achieves the latter remain poorly understood, especially when adapting to changing task demands. Here we introduce a novel theory for adaptive sensory processing based on functionally-targeted stochastic modulation. We find that responses of neurons in area V1 of monkeys performing a visual orientation discrimination task exhibit low-dimensional, rapidly fluctuating gain modulation, which is stronger in neurons that are most informative for the current behavioral task. We propose that this modulation serves as a label that supports adaptive downstream readout. Our theoretical and experimental results show that V1 modulation can be used to decode from neural activity after only a small number of training trials, consistent with observed behavior. In a hierarchical visual neural network model, the modulator-induced labels are learned quickly and accompany task information across several processing stages to finally guide decisions. Consistent with this model, we find that the V1 modulatory signal is also present in the activity of simultaneously recorded MT units, and that its label of task information is preserved. Our findings provide evidence for a novel mechanism for task-adaptive information routing in the brain, through targeted co-modulation.

neuroscience↗