Biology subjects

Merchant, H.

Publications and source records attributed to Merchant, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Glycogen-Dependent Metabolic Reprogramming Regulates Microglial Activation and Dysfunction in Neurodegenerative Disease

Microglia are central regulators of neuroinflammation in Alzheimers disease (AD), yet how metabolic states modulate function remains unclear. Here we show that microglia from the APPNL-G-F mouse model revealed upregulation of glycolytic enzymes coinciding with onset of microglial activation. Surprisingly, this glycolytic shift occurred alongside reduced expression of glucose transporters, suggesting that extracellular glucose may not be the primary fuel source, implicating glycogenolysis as the potential metabolic driver. Consistent with this, significant microglial glycogen accumulation was noted in late disease, when cells exhibited features of metabolic exhaustion and functional impairment. Pharmacological inhibition of glycogenolysis blunted microglia responses to Abeta aggregates and markedly reduced Abeta uptake, confirming a functional role for glycogen metabolism in shaping microglial states. Together, these findings identify glycogen as a central regulator of microglial metabolic health and function, highlighting glycogen homeostasis as a potential therapeutic target for promoting Abeta clearance and preserving protective microglial functions in AD.

neuroscience↗

bioRxiv2025

Categorical rhythmic priors in macaques

Rhythmic ability is a universal aspect of human cultures and sets the basis for musical rhythm perception and synchronization. While humans can synchronize movements to complex rhythms, it is unclear whether this capability extends to our primate ancestors. In this study, we explore whether primates can synchronize to complex rhythms and acquire rhythmic representations with generalizability akin to humans. Using controlled behavioral experiments, we provide evidence that monkeys not only can synchronize to short-long or long-short rhythms but also learn representations that generalize across a wide range of rhythm ratios and total durations. These results indicate ability to flexibly represent ratios within a relative timing framework is not exclusive to humans, but it is also present in monkeys. In addition, the produced intervals show a bias towards rhythmic categories. Notably, in an iterative tapping task, macaques and humans showed large priors for isochrony and integer ratios (2:1, 3:1). These results demonstrate a common biological foundation for rhythm synchronization in primates, extending our understanding of the shared cognitive mechanisms between primates and humans, and highlight the enormous potential of using monkeys to study the neurophysiological basis of complex rhythm perception.

neuroscience↗

bioRxiv2025

Manifold properties in the macaque medial premotor cortex during switching from attending to tapping to a metronome

Animals synchronize their movements with external rhythms to coordinate perception and action, but the neural population mechanisms that allow them to attend and then initiate and sustain these rhythms remain unclear. Using high-density recordings from the medial premotor cortex (MPC) of two macaque monkeys, we investigated neural dynamics during an attend-then-synchronize tapping task with visual metronomes. We found low-dimensional neural manifolds that capture neural population trajectories. During the attention phase, trajectories exhibited increasing amplitude and oscillatory modulation along successive stimuli, consistent with a resonant-like mechanism. Transition to tapping was marked by a reliable shift into a distinct manifold subspace, enabling accurate decoding of the switch in behavior. In addition, large amplitude and oscillatory indices were higher in successful tapping synchronization trials than in incorrect ones. These findings demonstrate that macaque MPC activity evolves along smooth, low-dimensional trajectories whose geometry governs different perceptual and motor aspects of tapping synchronization.

animal behavior and cognition↗

bioRxiv2025

Flexible tapping synchronization in macaques: dynamic switching of timing strategies within rhythmic sequences

The ability to synchronize bodily movements with regular auditory rhythm across a broad range of tempos underlies humans capacity for playing music and dancing. This capability is prevalent across human cultures but relatively uncommon among non-human species. Recent research indicates that monkeys can predictively synchronize to regular, isochronous metronomes, exhibiting a preference for visual rather than auditory sequences. In this study, we trained macaques to perform a visual synchronization tapping task, testing their synchronization abilities over a wide tempo range and characterizing their precision and accuracy in timing intervals throughout rhythmic sequences. Additionally, we investigated whether the macaques employed priors or error correction strategies to maintain synchrony with the metronome. Our findings demonstrate that, following sufficient training, macaques exhibit a remarkable capability to synchronize across diverse tempos. Through an inference model analysis, we identified two distinct timing control strategies used by the macaques: an initial strong regression-to-the-mean effect transitioning dynamically into a more precise error correction approach at their preferred tempo. These results provide compelling evidence that primates possess sophisticated rhythmic timing mechanisms, effectively leveraging internal and external cues to regulate their tapping behavior according to task demands. NEW & NOTEWORTHYWe trained macaques in a visual synchronization tapping task and using an inference model we found that they are highly precise and accurate in their rhythmic performance. The model also captured a dynamic switch in behavior. At the beginning of the task, the monkeys used their prior knowledge about the interval statistics and then switched to an error correction mechanism to generate intervals depending on the previously produced duration.

neuroscience↗

bioRxiv2024

Representation of grasping type and force in the primate motor cortex

The primary motor cortex (M1) is strongly engaged by movement planning and movement execution. However, the role of M1 activity in voluntary grasping is still not completely understood. Here we analyze recordings of M1 neurons during the execution of a delayed reach-to-grasp task, where monkeys had to actively grasp an object with either a side or a precision grip, and then pull it with a low or high amount of force. Single cell and neural populations analyses showed that grip type was robustly and specifically encoded by a large population of neurons, while force level was weakly encoded within mixed-selective neurons that also provided grip type information. Notably, the grip type was stably decoded from motor cortical populations during the preparation and execution epochs of the task. Our results are consistent with the idea that planning and performing specific grasping movements are high-level skills that strongly engage M1 neurons, while the execution of grasping-pulling force might be prominently encoded at lower stages of the motor system. Significance statementGrasping behavior requires precise motor coordination exerted by multiple brain areas, including the primary motor cortex (M1), but the exact role of M1 in grasping preparation and execution remains elusive. Here, we analyzed the neural activity of M1 while two monkeys performed a delayed reach-to-grasp task. We found that two parameters of grasping: grip type and force level, were represented in the activity of single neurons and the neural population, although with important differences. While grip representation was stronger and more temporally stable, force encoding was weaker and short lived. Our results suggest that grip planning and execution is a high-level neural process that takes place independently of force control in M1.

neuroscience↗

bioRxiv2024

Common neural mechanisms supporting time judgements in humans and monkeys

There has been an increasing interest in identifying the biological underpinnings of human time perception, for which purpose research in non-human primates (NHP) is common. Although previous work, based on behaviour, suggests that similar mechanisms support time perception across species, the neural correlates of time estimation in humans and NHP have not been directly compared. In this study, we assess whether brain evoked responses during a time categorization task are similar across species. Specifically, we assess putative differences in post-interval evoked potentials as a function of perceived duration in human EEG (N = 24) and local field potential (LFP) and spike recordings in pre-supplementary motor area (pre-SMA) of one monkey. Event-related potentials (ERPs) differed significantly after the presentation of the temporal interval between "short" and "long" perceived durations in both species, even when the objective duration of the stimuli was the same. Interestingly, the polarity of the reported ERPs was reversed for incorrect trials (i.e., the ERP of a "long" stimulus looked like the ERP of a "short" stimulus when a time categorization error was made). Hence, our results show that post-interval potentials reflect the perceived (rather than the objective) duration of the presented time interval in both NHP and humans. In addition, firing rates in monkeys pre-SMA also differed significantly between short and long perceived durations and were reversed in incorrect trials. Together, our results show that common neural mechanisms support time categorization in NHP and humans, thereby suggesting that NHP are a good model for investigating human time perception.

neuroscience↗

bioRxiv2024

Sequential and dynamic coding of water-sucrose categorization in rat gustatory cortices

The gustatory system enables our conscious perception of sweetness, allowing us to distinguish sweet solutions from water. However, the neural mechanisms underlying this categorization process in rats remain poorly understood. We addressed this question by designing a novel sucrose categorization task in which rats classified varying sucrose concentrations against water. We found that in the anterior insular cortex (aIC) and orbitofrontal cortex (OFC), neural activity primarily encoded the categorical distinction between sucrose and water, rather than specific sucrose concentrations. Notably, aIC neurons encoded this distinction faster than OFC neurons. Conversely, the OFC slightly preceded the aIC in encoding choice information, although both cortices maintained parallel encoding of the rats choices. The encoding of sensory and categorical decisions was dynamic and sequential, forming a sequence of encoding neurons throughout the trial. These findings reveal that sucrose categorization relies on dynamic coding sequences in the neuronal activity of the aIC and OFC rather than static, long-lasting (sustained) neural representations. This dynamic coding, supported by single-cell population decoding and principal component analyses, suggests that the brain continuously updates its representation of sucrose categorization as new information emerges. Additionally, both the aIC and OFC rapidly encoded reward outcomes. Our data supports the notion that gustatory cortices employ sequential and dynamic coding to compute sensorimotor transformations, from taste detection to categorical taste decisions and reward processing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/590344v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@20b8f0org.highwire.dtl.DTLVardef@4da81eorg.highwire.dtl.DTLVardef@586151org.highwire.dtl.DTLVardef@5d4469_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Monkeys have rhythnm

Synchronizing movements to music is one of the hallmarks of human culture whose evolutionary and neurobiological origins remain unknown. The ability to synchronize movements requires 1) detecting a steady rhythmic pulse, or beat, out of a stream of complex sounds, 2) projecting this rhythmic pattern forward in time to predict future input, and 3) timing motor commands in anticipation of predicted future beats. Here, we demonstrate that the macaque is capable of synchronizing taps to a subjective beat in real music, and even spontaneously chooses to do so over alternative strategies. This contradicts the influential "vocal learning hypothesis" that musical beat synchronization is only possible in species with complex vocalizations such as humans and some songbirds. We propose an alternative view of musical beat perception and synchronization ability as a continuum onto which a wider range of species can be mapped depending on their ability to perform and coordinate the general abilities listed above through association with reward.

neuroscience↗

bioRxiv2023

Preconfigured cortico-thalamic neural dynamics constrain movement-associated thalamic activity

Neural preconfigured activity patterns (nPAPs) have been proposed as building blocks for cognitive and sensory processing. However, their existence and function in motor networks have not been explicitly studied. Here, we explore the possibility that nPAPs are present in the motor thalamus (VL/VM) and their potential contribution to motor-related activity. To this end, we developed a preparation where VL/VM multiunitary activity could be robustly recorded in mouse behavior evoked by primary motor cortex (M1) optogenetic stimulation and forelimb movements. VL/VM-evoked activity was organized as rigid stereotypical activity patterns at the single and population levels. These activity patterns were unable to dynamically adapt to different temporal architectures of M1 stimulation. Moreover, they were experience-independent and present in virtually all animals, confirming their preconfigured nature. Finally, subpopulations expressing specific M1-evoked patterns also displayed specific movement-related patterns. Our data demonstrate that the behaviorally related identity of specific neural subpopulations is tightly linked to nPAPs.

neuroscience↗

bioRxiv2023

Rhythmic tapping to a moving beat: motion kinematics overrules motion naturalness.

Beat induction is the cognitive ability that allow humans to listen to a regular pulse in music and move in synchrony with it. Although auditory rhythmic cues are known to induce more consistent synchronization than flashing visual metronomes, this asymmetry can be canceled out by visual moving metronomes. Here, we investigated whether the naturalness of the visual motion or its kinematics could provide a synchronization advantage over flashing metronomes. Subjects tap in sync with visual isochronous metronomes defined by vertically or horizontally accelerating and decelerating motion, either congruent or not with natural gravity, and then continue tapping with no metronome. We found that motion kinematics was the predominant factor determining rhythm synchronization, as accelerating moving metronomes in either cardinal direction produced more precise and predictive tapping than decelerating or flashing conditions. Notably, a Bayesian observer model revealed that error correction during tapping synchronization and regression towards the mean in accuracy during tapping continuation in the absence of external cues are optimal control strategies independently of the moving properties of the visual metronomes. Our results support the notion that accelerating visual metronomes convey a strong sense of beat as seen in the cueing movements of an orchestra director.

neuroscience↗

bioRxiv2023

Different time encoding strategies within the medial premotor areas of the primate

The measurement of time in the subsecond scale is critical for many sophisticated behaviors, yet its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the neural activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing. During interval categorization, we found that preSMA encodes a subjective category limit by reaching a peak of activity at a time that divides the set of test intervals into short and long. We also observed neural signals associated with the category selected by the subjects and the reward outcomes of the perceptual decision. On the other hand, we have studied the behavioral and neurophysiological basis of rhythmic timing. First, we have shown in different tapping tasks that macaques are able to produce predictively and accurately intervals that are cued by auditory or visual metronomes or when intervals are produced internally without sensory guidance. In addition, we found that the rhythmic timing mechanism in MPC is governed by different layers of neural clocks. Next, the instantaneous activity of single cells shows ramping activity that encode the elapsed or remaining time for a tapping movement. In addition, we found MPC neurons that build neural sequences, forming dynamic patterns of activation that flexibly cover all the produced interval depending on the tapping tempo. This rhythmic neural clock resets on every interval providing an internal representation of pulse. Furthermore, the MPC cells show mixed selectivity, encoding not only elapsed time, but also the tempo of the tapping and the serial order element in the rhythmic sequence. Hence, MPC can map different task parameters, including the passage of time, using different cell populations. Finally, the projection of the time varying activity of MPC hundreds of cells into a low dimensional state space showed circular neural trajectories whose geometry represent the internal pulse and the tapping tempo. Overall, these findings support the notion that MPC is part of the core timing mechanism for both single interval and rhythmic timing, using neural clocks with different encoding principles, probably to flexibly encode and mix the timing representation with other task parameters.

neuroscience↗

bioRxiv2022

Distinct beta frequencies reflect categorical decisions

Beta oscillations are involved in a variety of cognitive functions beyond their traditional sensorimotor role. Based on prior findings of content-specific beta synchronization during working memory and decision making, we hypothesized that beta activity supports the activation and reactivation of cortical representations by mediating neural ensemble formation within and between brain regions. We here found that beta activity in monkey dorsolateral prefrontal cortex (dlPFC) and in pre-supplementary motor area (preSMA) reflects the content of a stimulus in relation to the task context, regardless of its objective properties. In multiple versions of a categorization task, we changed the boundary between categories from one block of trials to the next, such that a stimulus which belonged to one of two categories during one block could belong to the other category during the next one. During a delay in which monkeys had to hold their categorical decision in mind, we found that two distinct beta-band frequencies were consistently associated with the same two relative categories, and that activity in these respective bands predicted the animals responses. We characterized beta at these frequencies as transient bursts with distinct temporal profiles. We further showed that dlPFC and preSMA are connected via these distinct frequency channels, with dlPFC driving the frequency separation, a result supported by Granger causality and spike-field coherence analyses. In sum, these results provide support for the role of beta in forming neural ensembles, and further show that such ensembles synchronize at different beta frequencies.

neuroscience↗

bioRxiv2022

White matter structural bases for predictive tapping synchronization

We determined the intersubject association between rhythmic entrainment abilities of human subjects during a synchronization continuation tapping task (SCT) and the macro and microstructural properties of their superficial (SWM) and deep (dWM) white matter. Diffusion-weighted images were obtained from 32 subjects who also performed the SCT with auditory or visual metronomes and five tempos ranging from 550 to 950 ms. We developed a method to determine the fiber density of U-fibers running tangentially to the cortex. Notably, the right audiomotor system showed individual differences in the density of U-fibers that were correlated with the degree of predictive entrainment across subjects. These correlations were selective for the synchronization epoch with auditory metronomes and were specific for tempos around 1.5 Hz. In addition, there was a significant association between predictive rhythmic entrainment and the density and bundle diameter of the corpus callosum (CC), forming a chronotopic map where behavioural correlations of short and long intervals were found with the anterior and posterior portions of the CC. Finally, the fiber bundle cross-section of the arcuate fasciculus, the CC, and the Superior Longitudinal Fasciculus showed a significant correlation with the mean asynchronies of the auditory SCT. These findings suggest that the structural properties of the SWM and dWM in the audiomotor system support the predictive abilities of subjects during rhythmic tapping, where the density of cortical U-fibers are linked to the preferred tapping tempo, and the bundle properties of CC define an interval selective topography that has an anterior posterior gradient.

neuroscience↗

bioRxiv2022

Premotor population dynamics as neural substrate for auditory and visual rhythmic entrainment

The neural substrate for beat extraction and response entrainment to auditory and visual rhythms is still unknown. Here we analyzed the population activity of hundreds of medial premotor neurons of monkeys performing an isochronous tapping guided by brief flashing stimuli or auditory tones. The animals showed a strong bias towards visual than auditory metronomes, with rhythmic tapping that was more precise and accurate on the former. The population dynamics shared the following properties across modalities: the circular dynamics of the neural trajectories formed a regenerating loop for every produced interval; the trajectories converged in similar state space at tapping times resetting the clock; the tempo of the synchronized tapping was encoded in the trajectories by a combination of amplitude modulation and temporal scaling. In addition, the modality induced a displacement in the neural trajectories in auditory and visual subspaces without greatly altering time keeping mechanism. These results suggest that the interaction between the MPC amodal internal representation of pulse and a modality specific external input generates a neural rhythmic clock whose dynamics governs rhythmic tapping execution across senses.

neuroscience↗

bioRxiv2022

DLK-dependent biphasic reactivation of herpes simplex virus latency established in the absence of antivirals

Understanding the molecular mechanism of herpes simplex virus type 1 (HSV-1) latent infection and reactivation in neurons requires the use of model systems. However, establishing a quiescent infection in cultured neurons is problematic as infectious virus released from any productively infected neuron can superinfect the cultures. Here, we describe a new reporter virus, HSV-1 Stayput-GFP, that is defective for cell-to-cell spread and can be used to model latency and reactivation at the single neuron level. Importantly, quiescent infection of neurons with Stayput-GFP can be established without the use of a viral DNA replication inhibitor. The establishment of a quiescent state requires a longer time frame than previous models of HSV latency using DNA replication inhibitors. This results in a decreased ability of the virus to reactivate, and the use of multiple reactivation triggers is required. Using this system, we demonstrate that an initial Phase I wave of lytic gene expression occurs independently of histone demethylase activity and viral DNA replication but is dependent on the neuronal cell stress protein, DLK. Progression into the later, Phase II wave of reactivation, characterized by detectable late viral protein synthesis and a requirement for histone demethylase activity, is also observed with the Stayput-GFP model system. These data demonstrate that the two waves of viral gene expression following HSV-1 reactivation are independent of secondary infection and occur when latent infections are established in the absence of a viral DNA replication inhibitor. ImportanceHerpes simplex virus-1 (HSV-1) enters a latent infection in neurons and periodically reactivates. Reactivation manifests as a variety of clinical symptoms. Studying latency and reactivation in vitro is invaluable, allowing the molecular mechanisms behind both processes to be targeted by therapeutics that reduce the clinical consequences. Here, we describe a novel in vitro model system using a cell-to-cell spread defective HSV-1, known as Stayput-GFP, which allows for the study of latency and reactivation at the single neuron level. We anticipate this new model system will be an incredibly valuable tool for studying the establishment and reactivation of HSV-1 latent infection in vitro. Using this model, we find that initial reactivation events are dependent on cellular stress kinase DLK, but independent of histone demethylase activity and viral DNA replication. Our data therefore demonstrate the essential role of DLK in mediating a wave of lytic gene expression unique to reactivation.

microbiology↗

bioRxiv2022

Keeping time and rhythm by replaying a sensory-motor engram

Imagine practicing a piece of music, or a speech, solely within the mind, without any sensory input or motor output. Our ability to implement dynamic internal representations is key for successful behavior, yet how the brain achieves this is not fully understood1-4. Here we trained primates to perceive, and internally maintain, rhythms of different tempos and performed large-scale recordings of neuronal activity across multiple areas spanning the sensory-motor processing hierarchy. Results show that perceiving and maintaining rhythms engage multiple brain areas, including visual, parietal, premotor, prefrontal, and hippocampal regions. Each area displayed oscillatory activity that reflected the temporal and spatial characteristics of an internal metronome which flexibly encoded fast, medium, and slow tempos on a trial-by-trial basis. The presence of widespread metronome-related activity across the brain, in the absence of stimuli and overt actions, is consistent with the idea that time and rhythm are maintained by a mechanism that internally replays the stimuli and actions that define well-timed behavior.

neuroscience↗

bioRxiv2020

The timing network is engaged in the practice of internally driven tapping independently of the learning transfer from perceptual to motor timing

When we intensively train a timing skill, such as learning to play the piano, we do not only produce brain changes associated with task-specific learning, but also improve the performance on other temporal behaviors that depend on these tuned neural resources. Since the neural basis of time learning and generalization are still unknown, we measured the changes in neural activity associated with the transfer of learning from perceptual to motor timing. We found that intense training in an interval discrimination task increased the acuity of time perception in a group of subjects that also showed learning transfer, expressed as a reduction in tapping variability during an internally-driven periodic motor task. However, we also found subjects with no learning and generalization effects, and a third group with no signs of learning but with practice-based decreases in temporal variability in the motor task. Notably, these heterogeneous populations of subjects shared a common increase of activity in the medial premotor areas and the putamen in the post-with respect to the pre-training session of the tapping task. These findings support the idea that the core timing network is constantly refining its ability to time behaviors in different contexts and that practice is critical for keeping the neural clock attuned and properly functioning.

neuroscience↗

bioRxiv2020

A collaborative resource platform for non-human primate neuroimaging

Neuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field.

neuroscience↗