Biology subjects

Cullen, K. E.

Publications and source records attributed to Cullen, K. E..

13 recordsLinked to original sources

bioRxiv2026

A canonical input to the head direction compass carries predominantly eye movement signals

The mammalian head direction (HD) system is thought to update its internal compass using angular head velocity (AHV) signals relayed from the brainstem. We tested this canonical interpretation by recording from the nucleus prepositus hypoglossi (NPH), a proposed AHV relay known to be important for accurate HD tracking, while simultaneously measuring eye and head movements in mice. Neurons classified as AHV-tuned instead predominantly encoded eye movements: most showed saccade-related bursts or pauses, and apparent AHV tuning was largely explained by eye rather than head motion. Optotagging showed that even NPH neurons projecting directly to the HD circuit predominantly encoded eye movements. Empirically constrained population models reconstructed eye position and gaze direction, but head-direction readouts failed when eye and head motion were dissociated. These findings overturn the canonical view of NPH as a dedicated AHV relay, revealing eye movements as a major, previously unmeasured component of the signals entering the mammalian HD circuit and thereby changing the computational problem that the HD system must solve to maintain a stable representation of heading.

neuroscience↗

bioRxiv2026

Eye-head coordination during goal-directed orienting in mice

In afoveate species such as mice, it is accepted that gaze is typically redirected by head movements with a saccade-and-fixate strategy, while the eyes primarily stabilize vision within a limited oculomotor range. This view suggests that the accompanying eye movements are primarily reflexive, driven by mechanisms like the vestibulo-ocular reflex (VOR). However, emerging evidence challenges this assumption, suggesting that eye movements during active head motion may not be purely reflex-driven. Here, we directly test whether eye movements in mice are actively coordinated as part of voluntary gaze redirection rather than being reflexive. By systematically monitoring head and pupil positions during goal-directed orienting in a cohort of male mice, we find that mice generated active saccadic eye movements whose onsets are tightly linked to head movements. Furthermore, these saccadic eye movements occur at markedly shorter latencies than reflexive quick-phase eye movements evoked by comparable passive head rotations. Importantly, the interplay between coordinated eye and head movements during voluntary orienting resemble the predictable, stereotyped gaze patterns seen in foveate animals, such as primates. Our results suggest that mice possess an evolutionarily conserved mechanism for gaze redirection, integrating voluntary eye-head coordination similar to that of foveate vertebrates. These findings reframe the prevailing view by demonstrating an actively coordinated eye-head component to gaze redirection under goal-directed conditions in mice, complementing established reflexive mechanisms.

neuroscience↗

bioRxiv2026

Acceleration and Velocity Dissociate Temporal Phases of Postural Control in Rhesus Macaques

Maintaining balance requires the nervous system to transform sensory signals about unexpected postural perturbations into precisely timed motor commands. Although human studies have established that postural responses unfold in distinct temporal phases, how specific kinematic variables structure these phases during rotational perturbations remains unresolved, because angular acceleration and velocity are typically confounded. Here, we developed a rhesus macaque model of postural control that independently manipulates angular acceleration and peak velocity during transient pitch and roll tilts in monkeys of either sex. By simultaneously measuring head kinematics--directly relevant to vestibular signaling--and center-of-pressure dynamics, we quantified how sensory inputs and motor outputs evolve across successive phases of the postural response. We show that short-latency postural responses (<100 ms) are primarily governed by angular acceleration, whereas medium-latency responses (100-200 ms) scale with angular velocity. This dissociation was robust across perturbation axes and accompanied by axis-dependent control strategies: roll tilts elicited constrained head motion consistent with active stabilization in space, whereas pitch tilts produced more compliant, platform-following behavior. Together, these findings identify distinct kinematic variables governing successive phases of balance control and establish a primate framework for linking neural circuit activity to the temporal organization of postural responses. Significance StatementMaintaining balance requires transforming sensory signals about unexpected body motion into precisely timed motor commands. Progress in understanding this process has been limited because angular acceleration and velocity are inherently coupled during rotational perturbations. Here, using a rhesus macaque model, we dissociate these kinematic variables and show that they govern distinct temporal phases of postural control: angular acceleration determines short-latency (<100 ms) responses, whereas angular velocity shapes medium-latency (100-200 ms) adjustments. We further demonstrate axis-dependent postural strategies that parallel those observed in humans. Together, these findings resolve a longstanding confound in balance research and establish a primate framework that will enable future studies to link neural circuit activity to the biomechanics of postural control.

neuroscience↗

bioRxiv2026

Bat eye movements resolve a long-standing question in gaze control

Eye movements enable visual information gathering and stabilize gaze via optokinetic (OKR) and vestibulo-ocular reflex (VOR) pathways.1 Echolocating bats, despite their rapid and agile flight maneuvers to land upside down and navigate 3D space, have long been thought not to move their eyes, an assumption originating from Wallss influential assertion over 80 years ago2 but never tested with empirical measurements. Here we present quantitative analysis of eye movements driven by visual and vestibular signals in Sebas short-tailed bat (Carollia perspicillata). Bats generated robust visually driven OKR with an oculomotor range of [~]{+/-}10{degrees}, and displayed strong otolith-mediated responses during off-vertical axis rotation. In contrast, they showed minimal semicircular canal-driven angular VOR (aVOR) for passive head rotations that elicit large, sustained responses in mice. Micro-CT reconstructions revealed that bats and mice have similar semicircular canal geometry, indicating that the weak aVOR does not reflect peripheral anatomical constraints. These findings provide the first empirical demonstration that bats make robust eye movements and exhibit strong visual and otolith-driven components of gaze stabilization. We propose that semicircular canal signals may be more strongly engaged during active flight and modulated by behavioral state-dependent tuning of vestibular pathways to support ecologically specialized behaviors.

physiology↗

bioRxiv2025

CUSP: Complex Spike Sorting from Multi-electrode Array Recordings with U-net Sequence-to-Sequence Prediction

BackgroundComplex spikes (CSs) in cerebellar Purkinje cells convey unique signals complementary to Simple spike (SS) action potentials, but are infrequent and variable in waveform. Their variability and low spike counts, combined with recording artifacts such as electrode drift, make automated detection challenging. New MethodWe introduce CUSP (CS sorting via U-net Sequence Prediction), a fully automated deep learning framework for CS sorting in high-density multi-electrode array recordings. CUSP uses a U-Net architecture with hybrid self-attention inception blocks to integrate local field potential and action potential signals and outputs CS event probabilities in a sequence-to-sequence manner. Detected events are clustered and paired with concurrently detected SSs to reconstruct the complete Purkinje cell activity. ResultsTrained on cerebellar neuropixels recordings in rhesus macaques, CUSP achieves human-expert performance (F1 = 0.83 {+/-} 0.03) and even captures valid CS events overlooked during manual annotation. Comparison with Existing MethodsCUSP outperforms traditional and state-of-the-art CS and SS sorting algorithms on CS detection. It remains robust to waveform variability, spikelet composition, and electrode drift, enabling accurate CS tracking in long-term recordings. In contrast, existing methods often show false-positive biases or degrade under drift. ConclusionsCUSP provides a scalable, robust framework for analyzing burst-like or dynamically complex spike patterns. Its generalizability makes it valuable for large-scale cerebellar datasets and other neural systems, such as hippocampal pyramidal cells, where complex bursts are critical for computation. By combining expert-level accuracy with automation, CUSP offers a broadly applicable solution for studying information coding across circuits.

neuroscience↗

bioRxiv2025

Striatal and cerebellar interactions during reward-based motor performance

Goal-directed motor performance relies on the brains ability to distinguish between actions that lead to successful and unsuccessful outcomes. The basal ganglia (BG) and cerebellum (CBL) are integral to processing performance outcomes, yet their functional interactions remain underexplored. This study scanned participants brains with functional magnetic imaging (fMRI) while they performed a skilled motor task for monetary rewards, where outcomes depended on their motor performance and also probabilistic events that were not contingent on their performance. We found successful motor outcomes increased activity in the ventral striatum (VS), a functional sub-region of the BG, whereas unsuccessful motor outcomes engaged the CBL. In contrast, for probabilistic outcomes unrelated to motor performance, the BG and CBL exhibited no differences in activity between successful and unsuccessful outcomes. Dynamic causal modeling revealed that VS-to-CBL connectivity was inhibitory following successful motor outcomes, suggesting that the VS may suppress CBL error processing for correct actions. Conversely, CBL-to-VS connectivity was inhibitory after unsuccessful motor outcomes, potentially preventing reinforcement of erroneous actions. Additionally, interindividual differences in task preference, assessed by having participants choose between performing the motor task or flipping a coin for monetary rewards, were related to inhibitory VS-CBL connectivity. These findings highlight a performance-mediated functional network between the VS and CBL, modulated by motivation and subjective preferences, supporting goal-directed behavior.

neuroscience↗

bioRxiv2025

KV1.8 (Kcna10) potassium channels enhance fast, linear signaling in vestibular hair cells and facilitate vestibulomotor reflexes and balance

Vestibular hair cells (HCs) faithfully and rapidly detect head motions and gravity, driving motor reflexes that stabilize balance and gaze during locomotion. With the transition from water to land, the amniote vestibular inner ear added type I HCs, which differ from amniote type II HCs and anamniote HCs by their large calyx afferent synapse, non-quantal afferent transmission, and a large, low-voltage-activated K+ conductance (gK,L). We recently showed that both gK,L and the major type II K+ conductances (A-type and delayed rectifier) require KV1.8 (Kcna10) subunits. Here we compared KV1.8-null (Kcna10-/-) and control animals to see how KV1.8 affects function as measured by receptor potentials and nonquantal postsynaptic potentials evoked by direct hair bundle motions, and by vestibulomotor behaviors. Recordings were taken from extrastriolar zones of the utricle. In both HC types, KV1.8 affected receptor potentials by reducing response time and gain, increasing dampening, and expanding the frequency bandwidth toward high frequencies. Effects are most prominent in type I HCs: lowpass corner frequencies of receptor potentials in Kcna10-/- HCs of both types were [~]20 Hz, vs. [~]400 Hz in control type I and [~]70 Hz in control type II. We recorded nonquantal postsynaptic potentials from extrastriolar calyces, and found that the synaptic transfer function had lower gain and greater phase lag in Kcna10-/- mice. In behavioral tests, Kcna10-/- mice had vestibular-ocular reflexes with different response dynamics at low frequencies, impaired performance on a narrow balance beam, abnormal body posture and abnormal head motions in water and on land, and also rarely assumed bipedal stances. These vestibulomotor deficits in Kcna10-/- mice likely reflect the changes noted in HCs, where KV1.8 expression is concentrated; that is, slower signaling of high-frequency head motions by Kcna10-/- HCs fails to fully stabilize body and head position during locomotion. Thus, gK,L (KV1.8) contributes to fast signal transmission in the amniote vestibular inner ear and supports improved performance on challenging vestibulomotor tasks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/634388v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@126570borg.highwire.dtl.DTLVardef@1cab5borg.highwire.dtl.DTLVardef@36240corg.highwire.dtl.DTLVardef@789617_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function

Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically-evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered - swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.

neuroscience↗

bioRxiv2023

Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels

Calcium and integrin-binding protein 2 (CIB2) and CIB3 bind to transmembrane channel-like 1 (TMC1) and TMC2, the pore-forming subunits of the inner-ear mechano-electrical transduction (MET) apparatus. These interactions have been proposed to be functionally relevant across mechanosensory organs and vertebrate species. Here we show that both CIB2 and CIB3 can form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea and vestibular end organs as well as in zebrafish inner ear and lateral line. Our AlphaFold 2 models suggest that vertebrate CIB proteins can simultaneously interact with at least two cytoplasmic domains of TMC1 and TMC2 as validated using nuclear magnetic resonance spectroscopy of TMC1 fragments interacting with CIB2 and CIB3. Molecular dynamics simulations of TMC1/2 complexes with CIB2/3 predict that TMCs are structurally stabilized by CIB proteins to form cation channels. Overall, our work demonstrates that intact CIB2/3 and TMC1/2 complexes are integral to hair-cell MET function in vertebrate mechanosensory epithelia.

neuroscience↗

bioRxiv2023

An Open-Source Tool for Automated Human-Level Circling Behavior Detection

Quantifying behavior and relating it to underlying biological states is of paramount importance in many life science fields. Although barriers to recording postural data have been reduced by progress in deep-learning-based computer vision tools for keypoint tracking, extracting specific behaviors from this data remains challenging. Manual behavior coding, the present gold standard, is labor-intensive and subject to intra-and inter-observer variability. Automatic methods are stymied by the difficulty of explicitly defining complex behaviors, even ones which appear obvious to the human eye. Here, we demonstrate an effective technique for detecting one such behavior, a form of locomotion characterized by stereotyped spinning, termed circling. Though circling has an extensive history as a behavioral marker, at present there exists no standard automated detection method. Accordingly, we developed a technique to identify instances of the behavior by applying simple postprocessing to markerless keypoint data from videos of freely-exploring (Cib2-/-;Cib3-/-) mutant mice, a strain we previously found to exhibit circling. Our technique agrees with human consensus at the same level as do individual observers, and it achieves >90% accuracy in discriminating videos of wild type mice from videos of mutants. As using this technique requires no experience writing or modifying code, it also provides a convenient, noninvasive, quantitative tool for analyzing circling mouse models. Additionally, as our approach was agnostic to the underlying behavior, these results support the feasibility of algorithmically detecting specific, research-relevant behaviors using readily-interpretable parameters tuned on the basis of human consensus.

animal behavior and cognition↗

bioRxiv2022

Internal states as a source of subject-dependent movement variability and their representation by large-scale networks

A humans ability to adapt and learn relies on reflecting on past performance. Such reflections form latent factors called internal states that induce variability of movement and behavior to improve performance. Internal states are critical for survival, yet their temporal dynamics and neural substrates are less understood. Here, we link internal states with motor performance and neural activity using state-space models and local field potentials captured from depth electrodes in over 100 brain regions. Ten human subjects performed a goal-directed center-out reaching task with perturbations applied to random trials, causing subjects to fail goals and reflect on their performance. Using computational methods, we identified two internal states, indicating that subjects kept track of past errors and perturbations, that predicted variability in reaction times and speed errors. These states granted access to latent information indicative of how subjects strategize learning from trial history, impacting their overall performance. We further found that large-scale brain networks differentially encoded these internal states. The dorsal attention network encoded past errors in frequencies above 100 Hz, suggesting a role in modulating attention based on tracking recent performance in working memory. The default network encoded past perturbations in frequencies below 15 Hz, suggesting a role in achieving robust performance in an uncertain environment. Moreover, these networks more strongly encoded internal states and were more functionally connected in higher performing subjects, whose learning strategy was to respond by countering with behavior that opposed accumulating error. Taken together, our findings suggest large-scale brain networks as a neural basis of strategy. These networks regulate movement variability, through internal states, to improve motor performance. Key pointsO_LIMovement variability is a purposeful process conjured up by the brain to enable adaptation and learning, both of which are necessary for survival. C_LIO_LIThe culmination of recent experiences--collectively referred to as internal states--have been implicated in variability during motor and behavioral tasks. C_LIO_LITo investigate the utility and neural basis of internal states during motor control, we estimated two latent internal states using state-space representation that modeled motor behavior during a goal-directed center-out reaching task in humans with simultaneous whole-brain recordings from intracranial depth electrodes. C_LIO_LIWe show that including these states--based on error and environment uncertainty--improves the predictability of subject-specific variable motor behavior and reveals latent information related to task performance and learning strategies where top performers counter error scaled by trial history while bottom performers maintain error tendencies. C_LIO_LIWe further show that these states are encoded by the large-scale brain networks known as the dorsal attention network and default network in frequencies above 100 Hz and below 15 Hz but found neural differences between subjects where network activity closely modulates with states and exhibits stronger functional connectivity for top performers. C_LIO_LIOur findings suggest the involvement in large-scale brain networks as a neural basis of motor strategy that orchestrates movement variability to improve motor performance. C_LI

neuroscience↗

bioRxiv2021

Distinct Representations of Body and Head motion are Dynamically Encoded by Purkinje cell Populations in the Macaque Cerebellum

The ability to accurately control our posture and perceive spatial orientation during self-motion requires knowledge of the motion of both the head and body. However, whereas the vestibular sensors and nuclei directly encode head motion, no sensors directly encode body motion. Instead, the integration of vestibular and neck proprioceptive inputs is necessary to transform vestibular information into the body-centric reference frame required for postural control. The anterior vermis of the cerebellum is thought to play a key role in this transformation, yet how its Purkinje cells integrate these inputs or what information they dynamically encode during self-motion remains unknown. Here we recorded the activity of individual anterior vermis Purkinje cells in alert monkeys during passively applied whole-body, body-under-head, and head-on-body rotations. Most neurons dynamically encoded an intermediate representation of self-motion between head and body motion. Notably, these neurons responded to both vestibular and neck proprioceptive stimulation and showed considerable heterogeneity in their response dynamics. Furthermore, their vestibular responses demonstrated tuning in response to changes in head-on-body position. In contrast, a small remaining percentage of neurons sensitive only to vestibular stimulation unambiguously encoded head-in-space motion across conditions. Using a simple population model, we establish that combining responses from 40 Purkinje cells can explain the responses of their target neurons in deep cerebellar nuclei across all self-motion conditions. We propose that the observed heterogeneity in Purkinje cells underlies the cerebellums capacity to compute the dynamic representation of body motion required to ensure accurate postural control and perceptual stability in our daily lives.

neuroscience↗

bioRxiv2021

The Rules of Pulsatile Neurostimulation

Electrical stimulation is a key tool in neuroscience, both in brain mapping studies and in many therapeutic applications such as cochlear, vestibular, and retinal neural implants. Due to safety considerations, stimulation is restricted to short biphasic pulses. Despite decades of research and development, neural implants lead to varying restoration of function in patients. In this study, we use computational modeling to provide an explanation for how pulsatile stimulation affects axonal channels and therefore leads to variability in restoration of neural responses. The phenomenological explanation is transformed into equations that predict induced firing rate as a function of pulse rate, pulse amplitude, and spontaneous firing rate. We show that these equations predict simulated responses to pulsatile stimulation with a variety of parameters as well as several features of experimentally recorded vestibular afferent responses to pulsatile stimulation. We then discuss the implications of these effects for improving clinical stimulation paradigms and electrical stimulation-based experiments.

neuroscience↗