Jennifer L. Raymond

All Publications

• NeuroRoots, a bio-inspired, seamless brain machine interface for long-term recording in delicate brain regions. AIP advances Ferro, M. D., Proctor, C. M., Gonzalez, A., Jayabal, S., Zhao, E., Gagnon, M., Slézia, A., Pas, J., Dijk, G., Donahue, M. J., Williamson, A., Raymond, J., Malliaras, G. G., Giocomo, L., Melosh, N. A. 2024; 14 (8): 085109

  Abstract

  Scalable electronic brain implants with long-term stability and low biological perturbation are crucial technologies for high-quality brain-machine interfaces that can seamlessly access delicate and hard-to-reach regions of the brain. Here, we created "NeuroRoots," a biomimetic multi-channel implant with similar dimensions (7 μm wide and 1.5 μm thick), mechanical compliance, and spatial distribution as axons in the brain. Unlike planar shank implants, these devices consist of a number of individual electrode "roots," each tendril independent from the other. A simple microscale delivery approach based on commercially available apparatus minimally perturbs existing neural architectures during surgery. NeuroRoots enables high density single unit recording from the cerebellum in vitro and in vivo. NeuroRoots also reliably recorded action potentials in various brain regions for at least 7 weeks during behavioral experiments in freely-moving rats, without adjustment of electrode position. This minimally invasive axon-like implant design is an important step toward improving the integration and stability of brain-machine interfacing.

  View details for DOI 10.1063/5.0216979

  View details for PubMedID 39130131

  View details for PubMedCentralID PMC11309783

• Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome ELIFE Shakhawat, A. D., Foltz, J. G., Nance, A. B., Bhateja, J., Raymond, J. L. 2024; 12

  View details for DOI 10.7554/eLife.92543.3.sa3

  View details for Web of Science ID 001261799100001

• Synaptic weight dynamics underlying systems consolidation of a memory. bioRxiv : the preprint server for biology Bhasin, B. J., Raymond, J. L., Goldman, M. S. 2024

  Abstract

  Systems consolidation is a common feature of learning and memory systems, in which a long-term memory initially stored in one brain region becomes persistently stored in another region. We studied the dynamics of systems consolidation in simple circuit architectures modeling core features of many memory systems: an early- and late-learning brain region and two sites of plasticity. We show that the synaptic dynamics of the circuit during consolidation of an analog memory can be understood as a temporal integration process, by which transient changes in activity driven by plasticity in the early-learning area are accumulated into persistent synaptic changes at the late-learning site. This simple principle leads to two constraints on the circuit operation for consolidation to be implemented successfully. First, the plasticity rule at the late-learning site must stably support a continuum of possible outputs for a given input. We show that this is readily achieved by heterosynaptic but not standard Hebbian rules, that it naturally leads to a speed-accuracy tradeoff in systems consolidation, and that it provides a concrete circuit instantiation for how systems consolidation solves the stability-plasticity dilemma. Second, to turn off the consolidation process and prevent erroneous changes at the late-learning site, neural activity in the early-learning area must be reset to its baseline activity. We propose two biologically plausible implementations for this reset that suggest novel roles for core elements of the cerebellar circuit.Significance Statement: How are memories transformed over time? We propose a simple organizing principle for how long term memories are moved from an initial to a final site of storage. We show that successful transfer occurs when the late site of memory storage is endowed with synaptic plasticity rules that stably accumulate changes in activity occurring at the early site of memory storage. We instantiate this principle in a simple computational model that is representative of brain circuits underlying a variety of behaviors. The model shows how neural circuits can store new memories while preserving core features of older ones, and suggests novel roles for core elements of the cerebellar circuit.

  View details for DOI 10.1101/2024.03.20.586036

  View details for PubMedID 38585936

• Interactions between circuit architecture and plasticity in a closed-loop cerebellar system. eLife Payne, H. L., Raymond, J. L., Goldman, M. S. 2024; 13

  Abstract

  Determining the sites and directions of plasticity underlying changes in neural activity and behavior is critical for understanding mechanisms of learning. Identifying such plasticity from neural recording data can be challenging due to feedback pathways that impede reasoning about cause and effect. We studied interactions between feedback, neural activity, and plasticity in the context of a closed-loop motor learning task for which there is disagreement about the loci and directions of plasticity: vestibulo-ocular reflex learning. We constructed a set of circuit models that differed in the strength of their recurrent feedback, from no feedback to very strong feedback. Despite these differences, each model successfully fit a large set of neural and behavioral data. However, the patterns of plasticity predicted by the models fundamentally differed, with the direction of plasticity at a key site changing from depression to potentiation as feedback strength increased. Guided by our analysis, we suggest how such models can be experimentally disambiguated. Our results address a long-standing debate regarding cerebellum-dependent motor learning, suggesting a reconciliation in which learning-related changes in the strength of synaptic inputs to Purkinje cells are compatible with seemingly oppositely directed changes in Purkinje cell spiking activity. More broadly, these results demonstrate how changes in neural activity over learning can appear to contradict the sign of the underlying plasticity when either internal feedback or feedback through the environment is present.

  View details for DOI 10.7554/eLife.84770

  View details for PubMedID 38451856

  View details for PubMedCentralID PMC10919899

• Population calcium responses of Purkinje cells in the oculomotor cerebellum driven by non-visual input. Journal of neurophysiology Fanning, A., Shakhawat, A., Raymond, J. L. 2021

  Abstract

  The climbing fiber input to the cerebellum conveys instructive signals that can induce synaptic plasticity and learning by triggering complex spikes accompanied by large calcium transients in Purkinje cells. In the cerebellar flocculus, which supports oculomotor learning, complex spikes are driven by image motion on the retina, which could indicate an oculomotor error. In the same neurons, complex spikes also can be driven by non-visual signals. It has been shown that the calcium transients accompanying each complex spike can vary in amplitude, even within a given cell, therefore, we compared the calcium responses associated with the visual and non-visual inputs to floccular Purkinje cells. The calcium indicator GCaMP6f was selectively expressed in Purkinje cells, and fiber photometry was used to record the calcium responses from a population of Purkinje cells in the flocculus of awake behaving mice. During visual (optokinetic) stimuli and pairing of vestibular and visual stimuli, the calcium level increased during contraversive retinal image motion. During performance of the vestibulo-ocular reflex in the dark, calcium increased during contraversive head rotation and the associated ipsiverse eye movements. The amplitude of this non-visual calcium response was comparable to that during conditions with retinal image motion present that induce oculomotor learning. Thus, population calcium responses of Purkinje cells in the cerebellar flocculus to visual and non-visual input are similar to what has been reported previously for complex spikes, suggesting that multimodal instructive signals control the synaptic plasticity supporting oculomotor learning.

  View details for DOI 10.1152/jn.00715.2020

  View details for PubMedID 34346783

• Publisher Correction: Diversity and dynamism in the cerebellum. Nature neuroscience De Zeeuw, C. I., Lisberger, S. G., Raymond, J. L. 2021

  View details for DOI 10.1038/s41593-020-00782-5

  View details for PubMedID 33398139

• Mouse entorhinal cortex encodes a diverse repertoire of self-motion signals. Nature communications Mallory, C. S., Hardcastle, K., Campbell, M. G., Attinger, A., Low, I. I., Raymond, J. L., Giocomo, L. M. 2021; 12 (1): 671

  Abstract

  Neural circuits generate representations of the external world from multiple information streams. The navigation system provides an exceptional lens through which we may gain insights about how such computations are implemented. Neural circuits in the medial temporal lobe construct a map-like representation of space that supports navigation. This computation integrates multiple sensory cues, and, in addition, is thought to require cues related to the individual's movement through the environment. Here, we identify multiple self-motion signals, related to the position and velocity of the head and eyes, encoded by neurons in a key node of the navigation circuitry of mice, the medial entorhinal cortex (MEC). The representation of these signals is highly integrated with other cues in individual neurons. Such information could be used to compute the allocentric location of landmarks from visual cues and to generate internal representations of space.

  View details for DOI 10.1038/s41467-021-20936-8

  View details for PubMedID 33510164

• Diversity and dynamism in the cerebellum. Nature neuroscience De Zeeuw, C. I., Lisberger, S. G., Raymond, J. L. 2020

  Abstract

  The past several years have brought revelations and paradigm shifts in research on the cerebellum. Historically viewed as a simple sensorimotor controller with homogeneous architecture, the cerebellum is increasingly implicated in cognitive functions. It possesses an impressive diversity of molecular, cellular and circuit mechanisms, embedded in a dynamic, recurrent circuit architecture. Recent insights about the diversity and dynamism of the cerebellum provide a roadmap for the next decade of cerebellar research, challenging some old concepts, reinvigorating others and defining major new research directions.

  View details for DOI 10.1038/s41593-020-00754-9

  View details for PubMedID 33288911

• Research on the cerebellum yields rewards NATURE Raymond, J. L. 2020; 579 (7798): 202–3

  View details for Web of Science ID 000519378900016

  View details for PubMedID 32152606

• Increasing gender diversity in the STEM research workforce SCIENCE Greider, C. W., Sheltzer, J. M., Cantalupo, N. C., Copeland, W. B., Dasgupta, N., Hopkins, N., Jansen, J. M., Joshua-Tor, L., McDowell, G. S., Metcalf, J. L., McLaughlin, B., Olivarius, A., O'Shea, E. K., Raymond, J. L., Ruebain, D., Steitz, J. A., Stillman, B., Tilghman, S. M., Valian, V., Villa-Komaroff, L., Wong, J. Y. 2019; 366 (6466): 692-+

  View details for DOI 10.1126/science.aaz0649

  View details for Web of Science ID 000496500400032

  View details for PubMedID 31699926

• Cerebellar pukinje cells control eye movements with rapid that is invariant to spike irregularity ELIFE Payne, H. L., French, R. L., Guo, C. C., Nguyen-Vu, T., Manninen, T., Raymond, J. L. 2019; 8

  View details for DOI 10.7554/elife.37102

  View details for Web of Science ID 000466879200001

• Cerebellar Purkinje cells control eye movements with a rapid rate code that is invariant to spike irregularity. eLife Payne, H. L., French, R. L., Guo, C. C., Nguyen-Vu, T. B., Manninen, T., Raymond, J. L. 2019; 8

  Abstract

  The rate and temporal pattern of neural spiking each have the potential to influence computation. In the cerebellum, it has been hypothesized that the irregularity of interspike intervals in Purkinje cells affects their ability to transmit information to downstream neurons. Accordingly, during oculomotor behavior in mice and rhesus monkeys, mean irregularity of Purkinje cell spiking varied with mean eye velocity. However, moment-to-moment variations revealed a tight correlation between eye velocity and spike rate, with no additional information conveyed by spike irregularity. Moreover, when spike rate and irregularity were independently controlled using optogenetic stimulation, the eye movements elicited were well-described by a linear population rate code with 3-5 ms temporal precision. Biophysical and random-walk models identified biologically realistic parameter ranges that determine whether spike irregularity influences responses downstream. The results demonstrate cerebellar control of movements through a remarkably rapid rate code, with no evidence for an additional contribution of spike irregularity.

  View details for PubMedID 31050648

• Funders should evaluate projects, not people. Lancet (London, England) Raymond, J. L., Goodman, M. B. 2019; 393 (10171): 494–95

  View details for PubMedID 30739667

• Funders should evaluate projects, not people LANCET Raymond, J. L., Goodman, M. B. 2019; 393 (10171): 494–95

  View details for Web of Science ID 000458184300013

• Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei. eLife Ren, J. n., Isakova, A. n., Friedmann, D. n., Zeng, J. n., Grutzner, S. M., Pun, A. n., Zhao, G. Q., Kolluru, S. S., Wang, R. n., Lin, R. n., Li, P. n., Li, A. n., Raymond, J. L., Luo, Q. n., Luo, M. n., Quake, S. R., Luo, L. n. 2019; 8

  Abstract

  Serotonin neurons of the dorsal and median raphe nuclei (DR, MR) collectively innervate the entire forebrain and midbrain, modulating diverse physiology and behavior. To gain a fundamental understanding of their molecular heterogeneity, we used plate-based single-cell RNA-sequencing to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters. Systematic in situ hybridization mapped specific clusters to the principal DR, caudal DR, or MR. These transcriptomic clusters differentially express a rich repertoire of neuropeptides, receptors, ion channels, and transcription factors. We generated novel intersectional viral-genetic tools to access specific subpopulations. Whole-brain axonal projection mapping revealed that DR serotonin neurons co-expressing vesicular glutamate transporter-3 preferentially innervate the cortex, whereas those co-expressing thyrotropin-releasing hormone innervate subcortical regions in particular the hypothalamus. Reconstruction of 50 individual DR serotonin neurons revealed diverse and segregated axonal projection patterns at the single-cell level. Together, these results provide a molecular foundation of the heterogenous serotonin neuronal phenotypes.

  View details for DOI 10.7554/eLife.49424

  View details for PubMedID 31647409

• Depressed by LearningHeterogeneity of the Plasticity Rules at Parallel Fiber Synapses onto Purkinje Cells CEREBELLUM Suvrathan, A., Raymond, J. L. 2018; 17 (6): 747–55

  Abstract

  Climbing fiber-driven long-term depression (LTD) of parallel fiber synapses onto cerebellar Purkinje cells has long been investigated as a putative mechanism of motor learning. We recently discovered that the rules governing the induction of LTD at these synapses vary across different regions of the cerebellum. Here, we discuss the design of LTD induction protocols in light of this heterogeneity in plasticity rules. The analytical advantages of the cerebellum provide an opportunity to develop a deeper understanding of how the specific plasticity rules at synapses support the implementation of learning.

  View details for PubMedID 30069835

• Computational Principles of Supervised Learning in the Cerebellum. Annual review of neuroscience Raymond, J. L., Medina, J. F. 2018; 41: 233–53

  Abstract

  Supervised learning plays a key role in the operation of many biological and artificial neural networks. Analysis of the computations underlying supervised learning is facilitated by the relatively simple and uniform architecture of the cerebellum, a brain area that supports numerous motor, sensory, and cognitive functions. We highlight recent discoveries indicating that the cerebellum implements supervised learning using the following organizational principles: ( a) extensive preprocessing of input representations (i.e., feature engineering), ( b) massively recurrent circuit architecture, ( c) linear input-output computations, ( d) sophisticated instructive signals that can be regulated and are predictive, ( e) adaptive mechanisms of plasticity with multiple timescales, and ( f) task-specific hardware specializations. The principles emerging from studies of the cerebellum have striking parallels with those in other brain areas and in artificial neural networks, as well as some notable differences, which can inform future research on supervised learning and inspire next-generation machine-based algorithms.

  View details for PubMedID 29986160

• An Integrated Career Coaching and Time-Banking System Promoting Flexibility, Wellness, and Success: A Pilot Program at Stanford University School of Medicine. Academic medicine : journal of the Association of American Medical Colleges Fassiotto, M., Simard, C., Sandborg, C., Valantine, H., Raymond, J. 2018; 93 (6): 881-887

  Abstract

  Faculty in academic medicine experience multiple demands on their time at work and home, which can become a source of stress and dissatisfaction, compromising success. A taskforce convened to diagnose the state of work-life flexibility at Stanford University School of Medicine uncovered two major sources of conflict: work-life conflict, caused by juggling demands of career and home; and work-work conflict, caused by competing priorities of the research, teaching, and clinical missions combined with service and administrative tasks. Using human-centered design research principles, the 2013-2014 Academic Biomedical Career Customization (ABCC) pilot program incorporated two elements to mitigate work-life and work-work conflict: integrated career-life planning, coaching to create a customized plan to meet both career and life goals; and a time-banking system, recognizing behaviors that promote team success with benefits that mitigate work-life and work-work conflicts. A matched-sample pre-post evaluation survey found the two-part program increased perceptions of a culture of flexibility (P = .020), wellness (P = .013), understanding of professional development opportunities (P = .036), and institutional satisfaction (P = .020) among participants. In addition, analysis of research productivity indicated that over the two-year program, ABCC participants received 1.3 more awards, on average, compared with a matched set of nonparticipants, a funding difference of approximately $1.1 million per person. These results suggest it is possible to mitigate the effects of extreme time pressure on academic medicine faculty, even within existing institutional structures.

  View details for DOI 10.1097/ACM.0000000000002121

  View details for PubMedID 29298183

  View details for PubMedCentralID PMC5976513

• Yet another reason to walk instead of drive NATURE NEUROSCIENCE Raymond, J. L. 2018; 21 (5): 648–49

  View details for PubMedID 29662212

• An Integrated Career Coaching and Time Banking System Promoting Flexibility, Wellness, and Success: A Pilot Program at Stanford University School of Medicine Academic Medicine Fassiotto, M., Simard, C., Sandborg, C., Valantine, H., Raymond, J. 2018

  View details for DOI 10.1097/ACM.0000000000002121

• Magnetic eye tracking in mice ELIFE Payne, H. L., Raymond, J. L. 2017; 6

  Abstract

  Eye movements provide insights about a wide range of brain functions, from sensorimotor integration to cognition; hence, the measurement of eye movements is an important tool in neuroscience research. We describe a method, based on magnetic sensing, for measuring eye movements in head-fixed and freely moving mice. A small magnet was surgically implanted on the eye, and changes in the magnet angle as the eye rotated were detected by a magnetic field sensor. Systematic testing demonstrated high resolution measurements of eye position of <0.1°. Magnetic eye tracking offers several advantages over the well-established eye coil and video-oculography methods. Most notably, it provides the first method for reliable, high-resolution measurement of eye movements in freely moving mice, revealing increased eye movements and altered binocular coordination compared to head-fixed mice. Overall, magnetic eye tracking provides a lightweight, inexpensive, easily implemented, and high-resolution method suitable for a wide range of applications.

  View details for PubMedID 28872455

• A saturation hypothesis to explain both enhanced and impaired learning with enhanced plasticity. eLife Nguyen-Vu, T. B., Zhao, G. Q., Lahiri, S., Kimpo, R. R., Lee, H., Ganguli, S., Shatz, C. J., Raymond, J. L. 2017; 6

  Abstract

  Across many studies, animals with enhanced synaptic plasticity exhibit either enhanced or impaired learning, raising a conceptual puzzle: how enhanced plasticity can yield opposite learning outcomes? Here we show that recent history of experience can determine whether mice with enhanced plasticity exhibit enhanced or impaired learning in response to the same training. Mice with enhanced cerebellar LTD, due to double knockout (DKO) of MHCI H2-K(b)/H2-D(b) (K(b)D(b-/-)), exhibited oculomotor learning deficits. However, the same mice exhibited enhanced learning after appropriate pre-training. Theoretical analysis revealed that synapses with history-dependent learning rules could recapitulate the data, and suggested that saturation may be a key factor limiting the ability of enhanced plasticity to enhance learning. Moreover, optogenetic stimulation designed to saturate LTD produced the same impairment in WT as observed in DKO mice. Overall, our results suggest that recent history of activity and the threshold for synaptic plasticity conspire to effect divergent learning outcomes.

  View details for DOI 10.7554/eLife.20147

  View details for PubMedID 28234229

• Timing Rules for Synaptic Plasticity Matched to Behavioral Function NEURON Suvrathan, A., Payne, H. L., Raymond, J. L. 2016; 92 (5): 959-967

  Abstract

  It is widely assumed that the complexity of neural circuits enables them to implement diverse learning tasks using just a few generic forms of synaptic plasticity. In contrast, we report that synaptic plasticity can itself be precisely tuned to the requirements of a learning task. We found that the rules for induction of long-term and single-trial plasticity at parallel fiber-to-Purkinje cell synapses vary across cerebellar regions. In the flocculus, associative plasticity in vitro and in vivo is narrowly tuned for an interval of ∼120 ms, which compensates for the specific processing delay for error signals to reach the flocculus during oculomotor learning. In the vermis, which supports a range of behavioral functions, plasticity is induced by a range of intervals, with individual cells tuned for different intervals. Thus, plasticity at a single, anatomically defined type of synapse can have properties that vary in a way that is precisely matched to function.

  View details for DOI 10.1016/j.neuron.2016.10.022

  View details for Web of Science ID 000391264200008

  View details for PubMedID 27839999

  View details for PubMedCentralID PMC5165237

• Purkinje cell responses during visually and vestibularly driven smooth eye movements in mice BRAIN AND BEHAVIOR Katoh, A., Shin, S., Kimpo, R. R., Rinaldi, J. M., Raymond, J. L. 2015; 5 (3)

  Abstract

  An essential complement to molecular-genetic approaches for analyzing the function of the oculomotor circuitry in mice is an understanding of sensory and motor signal processing in the circuit. Although there has been extensive analysis of the signals carried by neurons in the oculomotor circuits of species, such as monkeys, rabbits and goldfish, relatively little in vivo physiology has been done in the oculomotor circuitry of mice. We analyzed the contribution of vestibular and nonvestibular signals to the responses of individual Purkinje cells in the cerebellar flocculus of mice.We recorded Purkinje cells in the cerebellar flocculus of C57BL/6 mice during eye movement responses to vestibular and visual stimulation.As in other species, most individual Purkinje cells in mice carried both vestibular and nonvestibular signals, and the most common response across cells was an increase in firing in response to ipsiversive eye movement or ipsiversive head movement. When both the head and eyes were moving, the Purkinje cell responses were approximated as a linear summation of head and eye velocity inputs. Unlike other species, floccular Purkinje cells in mice were considerably more sensitive to eye velocity than head velocity.The signal content of Purkinje cells in the cerebellar flocculus of mice was qualitatively similar to that in other species. However, the eye velocity sensitivity was higher than in other species, which may reflect a tuning to the smaller range of eye velocities in mice.

  View details for DOI 10.1002/brb3.310

  View details for Web of Science ID 000351776400004

  View details for PubMedID 25642393

  View details for PubMedCentralID PMC4309896

• Signals and learning rules guiding oculomotor plasticity. journal of neuroscience Shin, S., Zhao, G. Q., Raymond, J. L. 2014; 34 (32): 10635-10644

  Abstract

  The learning of motor skills is thought to occur largely through trial and error; however, the error signals and rules controlling the induction of motor learning have not been fully elucidated. We evaluated the learning rules that translate the sensory and motor cues available during training into learned changes in the gain and phase of the vestibulo-ocular reflex (VOR) of mice. Contrary to previous theories, neither the phase of retinal image motion relative to head motion nor the phase of retinal image motion relative to eye movement could consistently predict the direction of the learned change in the gain of the VOR across all training conditions tested. Instead, the phase of the gaze movement relative to head motion during training was the best predictor of whether learning would increase or decrease the gain of the VOR. Learned changes in the phase of the VOR were best predicted by a different cue-the phase of the eye movement relative to head motion during training. These results provide new constraints on the neural mechanisms implementing the adaptive calibration of the VOR by cerebellum-dependent motor learning.

  View details for DOI 10.1523/JNEUROSCI.4510-12.2014

  View details for PubMedID 25100597

  View details for PubMedCentralID PMC4122799

• Cerebellar encoding of multiple candidate error cues in the service of motor learning. journal of neuroscience Guo, C. C., Ke, M. C., Raymond, J. L. 2014; 34 (30): 9880-9890

  Abstract

  For learning to occur through trial and error, the nervous system must effectively detect and encode performance errors. To examine this process, we designed a set of oculomotor learning tasks with more than one visual object providing potential error cues, as would occur in a natural visual scene. A task-relevant visual target and a task-irrelevant visual background both influenced vestibulo-ocular reflex learning in rhesus monkeys. Thus, motor learning does not identify a single error cue based on behavioral relevance, but can be simultaneously influenced by more than one cue. Moreover, the relative weighting of the different cues could vary. If the speed of the visual target's motion on the retina was low (≪1°/s), background motion dominated learning, but if target speed was high, the effects of the background were suppressed. The target and background motion had similar, nonlinear effects on the putative neural instructive signals carried by cerebellar climbing fibers, but with a stronger influence of the background on the climbing fibers than on learning. In contrast, putative neural instructive signals carried by the simple spikes of Purkinje cells were influenced solely by the motion of the visual target. Because they are influenced by different cues during training, joint control of learning by the climbing fibers and Purkinje cells may expand the learning capacity of the cerebellar circuit.

  View details for DOI 10.1523/JNEUROSCI.5114-13.2014

  View details for PubMedID 25057191

  View details for PubMedCentralID PMC4107405

• Gating of neural error signals during motor learning ELIFE Kimpo, R. R., Rinaldi, J. M., Kim, C. K., Payne, H. L., Raymond, J. L. 2014; 3

  Abstract

  Cerebellar climbing fiber activity encodes performance errors during many motor learning tasks, but the role of these error signals in learning has been controversial. We compared two motor learning paradigms that elicited equally robust putative error signals in the same climbing fibers: learned increases and decreases in the gain of the vestibulo-ocular reflex (VOR). During VOR-increase training, climbing fiber activity on one trial predicted changes in cerebellar output on the next trial, and optogenetic activation of climbing fibers to mimic their encoding of performance errors was sufficient to implant a motor memory. In contrast, during VOR-decrease training, there was no trial-by-trial correlation between climbing fiber activity and changes in cerebellar output, and climbing fiber activation did not induce VOR-decrease learning. Our data suggest that the ability of climbing fibers to induce plasticity can be dynamically gated in vivo, even under conditions where climbing fibers are robustly activated by performance errors. DOI: http://dx.doi.org/10.7554/eLife.02076.001.

  View details for DOI 10.7554/eLife.02076

  View details for Web of Science ID 000334922600005

  View details for PubMedID 24755290

  View details for PubMedCentralID PMC3989583

• Obscuring Gender Bias with "Choice" SCIENCE Conner, A. L., Cook, K. S., Correll, S. J., Markus, H. R., Moss-Racusin, C. A., Muller, C. B., Raymond, J. L., Simard, C. 2014; 343 (6176): 1200-1200

  View details for PubMedID 24626914

• Gating of neural error signals during motor learning. eLife Kimpo, R. R., Rinaldi, J. M., Kim, C. K., Payne, H. L., Raymond, J. L. 2014; 3

  Abstract

  Cerebellar climbing fiber activity encodes performance errors during many motor learning tasks, but the role of these error signals in learning has been controversial. We compared two motor learning paradigms that elicited equally robust putative error signals in the same climbing fibers: learned increases and decreases in the gain of the vestibulo-ocular reflex (VOR). During VOR-increase training, climbing fiber activity on one trial predicted changes in cerebellar output on the next trial, and optogenetic activation of climbing fibers to mimic their encoding of performance errors was sufficient to implant a motor memory. In contrast, during VOR-decrease training, there was no trial-by-trial correlation between climbing fiber activity and changes in cerebellar output, and climbing fiber activation did not induce VOR-decrease learning. Our data suggest that the ability of climbing fibers to induce plasticity can be dynamically gated in vivo, even under conditions where climbing fibers are robustly activated by performance errors. DOI: http://dx.doi.org/10.7554/eLife.02076.001.

  View details for DOI 10.7554/eLife.02076

  View details for PubMedID 24755290

• Cerebellar Purkinje cell activity drives motor learning. Nature neuroscience Nguyen-Vu, T. D., Kimpo, R. R., Rinaldi, J. M., Kohli, A., Zeng, H., Deisseroth, K., Raymond, J. L. 2013; 16 (12): 1734-1736

  Abstract

  The climbing fiber input to the cerebellar cortex is thought to provide instructive signals that drive the induction of motor skill learning. We found that optogenetic activation of Purkinje cells, the sole output neurons of the cerebellar cortex, can also drive motor learning in mice. This dual control over the induction of learning by climbing fibers and Purkinje cells can expand the learning capacity of motor circuits.

  View details for DOI 10.1038/nn.3576

  View details for PubMedID 24162651

• Sexist attitudes: Most of us are biased. Nature Raymond, J. 2013; 495 (7439): 33-34

  View details for DOI 10.1038/495033a

  View details for PubMedID 23467152

• Motor Learning Reduces Eye Movement Variability through Reweighting of Sensory Inputs JOURNAL OF NEUROSCIENCE Guo, C. C., Raymond, J. L. 2010; 30 (48): 16241-16248

  Abstract

  Motor learning can improve both the accuracy and precision of motor performance. We analyzed changes in the average trajectory and the variability of smooth eye movements during motor learning in rhesus monkeys. Training with a compound visual-vestibular stimulus could reduce the variability of the eye movement responses without altering the average responses. This improvement of eye movement precision was achieved by shifting the reliance of the movements from a more variable, visual signaling pathway to a less variable, vestibular signaling pathway. Thus, cerebellum-dependent motor learning can improve the precision of movements by reweighting sensory inputs with different variability.

  View details for DOI 10.1523/JNEUROSCI.3569-10.2010

  View details for Web of Science ID 000284999900018

  View details for PubMedID 21123570

  View details for PubMedCentralID PMC3064501

• Elimination of climbing fiber instructive signals during motor learning NATURE NEUROSCIENCE Ke, M. C., Guo, C. C., Raymond, J. L. 2009; 12 (9): 1171-U23

  Abstract

  The climbing fiber input to the cerebellum from the inferior olive is thought to act as a teacher whose activity controls the induction of motor learning. We designed training conditions that did not elicit instructive signals in the climbing fibers, but nevertheless induced robust and consistent motor learning in the vestibulo-ocular reflex of rhesus monkeys. Our results indicate that instructive signals in the climbing fibers are not necessary for cerebellum-dependent learning. Instead, instructive signals carried by either the climbing fibers or Purkinje cell simple spikes may be sufficient to induce motor learning, with additive effects occurring when both instructive signals are present during training.

  View details for DOI 10.1038/nn.2366

  View details for Web of Science ID 000269317300020

  View details for PubMedID 19684593

• Disruption of Learned Timing in P/Q Calcium Channel Mutants PLOS ONE Katoh, A., Chapman, P. J., Raymond, J. L. 2008; 3 (11)

  Abstract

  To optimize motor performance, both the amplitude and temporal properties of movements should be modifiable by motor learning. Here we report that the modification of movement timing is highly dependent on signaling through P/Q-type voltage-dependent calcium channels. Two lines of mutant mice heterozygous for P/Q-type voltage-dependent calcium channels exhibited impaired plasticity of eye movement timing, but relatively intact plasticity of movement amplitude during motor learning in the vestibulo-ocular reflex. The results thus demonstrate a distinction between the molecular signaling pathways regulating the timing versus amplitude of movements.

  View details for DOI 10.1371/journal.pone.0003635

  View details for Web of Science ID 000265134300005

  View details for PubMedID 18982062

  View details for PubMedCentralID PMC2572847

• Impaired motor learning in the vestibulo-ocular reflex in mice with multiple climbing fiber input to cerebellar Purkinje cells JOURNAL OF NEUROSCIENCE Kimpo, R. R., Raymond, J. L. 2007; 27 (21): 5672-5682

  Abstract

  A unique feature of the cerebellar architecture is that Purkinje cells in the cerebellar cortex each receive input from a single climbing fiber. In mice deficient in the gamma isoform of protein kinase C (PKCgamma-/- mice), this normal architecture is disrupted so that individual Purkinje cells receive input from multiple climbing fibers. These mice have no other known abnormalities in the cerebellar circuit. Here, we show that PKCgamma-/- mice are profoundly impaired in vestibulo-ocular reflex (VOR) motor learning. The PKCgamma-/- mice exhibited no adaptive increases or decreases in VOR gain at training frequencies of 2 or 0.5 Hz. This impairment was present across a broad range of peak retinal slip speeds during training. We compare the results for VOR motor learning with previous studies of the performance of PKCgamma-/- mice on other cerebellum-dependent learning tasks. Together, the results suggest that single climbing fiber innervation of Purkinje cells is critical for some, but not all, forms of cerebellum-dependent learning, and this may depend on the region of the cerebellum involved, the organization of the relevant neural circuits downstream of the cerebellar cortex, as well as the timing requirements of the learning task.

  View details for DOI 10.1523/JNEUROSCI.0801-07.2007

  View details for Web of Science ID 000246720700015

  View details for PubMedID 17522312

• Motor deficits in homozygous and heterozygous P/Q-type calcium channel mutants JOURNAL OF NEUROPHYSIOLOGY Katoh, A., Jindal, J. A., Raymond, J. L. 2007; 97 (2): 1280-1287

  Abstract

  P/Q-type voltage-dependent Ca(2+) channels (VDCCs) are highly expressed in the cerebellum, and mutations of these channels are associated with disrupted motor function. Several allelic variants of the alpha1A pore-forming subunit of P/Q-type VDCCs have been described, and mice homozygous for these mutations exhibit gait ataxia, as do alpha1A knockout mice. Here we report that heterozygous alpha1A mutants also have a motor phenotype. Mice heterozygous for the leaner and alpha1A knockout mutations exhibit impaired motor learning in the vestibulo-ocular reflex (VOR), suggesting that subtle disruption of P/Q Ca(2+) currents is sufficient to disrupt motor function. Basal VOR and optokinetic reflex performance were normal in the heterozygotes but severely impaired in the leaner and alpha1A knockout homozygotes.

  View details for DOI 10.1152/jn.00322.2006

  View details for Web of Science ID 000244090500031

  View details for PubMedID 17005620

• Selective engagement of plasticity mechanisms for motor memory storage NEURON Boyden, E. S., Katoh, A., Pyle, J. L., Chatila, T. A., Tsien, R. W., Raymond, J. L. 2006; 51 (6): 823-834

  Abstract

  The number and diversity of plasticity mechanisms in the brain raises a central question: does a neural circuit store all memories by stereotyped application of the available plasticity mechanisms, or can subsets of these mechanisms be selectively engaged for specific memories? The uniform architecture of the cerebellum has inspired the idea that plasticity mechanisms like cerebellar long-term depression (LTD) contribute universally to memory storage. To test this idea, we investigated a set of closely related, cerebellum-dependent motor memories. In mutant mice lacking Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV), the maintenance of cerebellar LTD is abolished. Although memory for an increase in the gain of the vestibulo-ocular reflex (VOR) induced with high-frequency stimuli was impaired in these mice, memories for decreases in VOR gain and increases in gain induced with low-frequency stimuli were intact. Thus, a particular plasticity mechanism need not support all cerebellum-dependent memories, but can be engaged selectively according to the parameters of training.

  View details for DOI 10.1016/j.neuron.2006.08.026

  View details for Web of Science ID 000240997900019

  View details for PubMedID 16982426

• Distinct patterns of stimulus generalization of increases and decreases in VOR gain JOURNAL OF NEUROPHYSIOLOGY Kimpo, R. R., Boyden, E. S., Katoh, A., Ke, M. C., Raymond, J. L. 2005; 94 (5): 3092-3100

  Abstract

  Motor learning must be capable of increasing or decreasing the amplitude of movements to meet the demands of the environment. One way to implement such opposite learned changes would be to store them with bidirectional plasticity mechanisms (i.e., long-term potentiation and depression at the same synapses). At the behavioral level, this scheme should result in similar patterns of stimulus generalization of increases and decreases in movement amplitude because the same synapses would be modified but in opposite directions. To test this idea, we quantitatively compared the stimulus generalization of learned increases and decreases in the gain (amplitude) of the vestibuloocular reflex (VOR) in mice and in monkeys. When examined across different sinusoidal frequencies of head rotation, decreases in VOR gain generalized more than increases in gain. This difference was apparent not only in the gain, but also the phase (timing) of the VOR. Furthermore, this difference held when animals were trained with high-frequency rotational stimuli, a manipulation that enhances frequency generalization. Our results suggest that increases and decreases in VOR gain are not exact inverses at the circuit level. At one or more sites, the plasticity mechanisms supporting decreases in VOR gain must be less synapse-specific, or affect neurons more broadly tuned for head rotation frequency, than the mechanisms supporting increases in gain.

  View details for DOI 10.1152/jn.00048.2005

  View details for Web of Science ID 000232528900011

  View details for PubMedID 16033945

• Reversal of motor learning in the vestibulo-ocular reflex in the absence of visual input LEARNING & MEMORY Cohen, M. R., Meissner, G. W., Schafer, R. J., Raymond, J. L. 2004; 11 (5): 559-565

  Abstract

  Motor learning in the vestibulo-ocular reflex (VOR) and eyeblink conditioning use similar neural circuitry, and they may use similar cellular plasticity mechanisms. Classically conditioned eyeblink responses undergo extinction after prolonged exposure to the conditioned stimulus in the absence of the unconditioned stimulus. We investigated the possibility that a process similar to extinction may reverse learned changes in the VOR. We induced a learned alteration of the VOR response in rhesus monkeys using magnifying or miniaturizing goggles, which caused head movements to be accompanied by visual image motion. After learning, head movements in the absence of visual stimulation caused a loss of the learned eye movement response. When the learned gain was low, this reversal of learning occurred only when head movements were delivered, and not when the head was held stationary in the absence of visual input, suggesting that this reversal is mediated by an active, extinction-like process.

  View details for DOI 10.1101/lm.82304

  View details for Web of Science ID 000224178400012

  View details for PubMedID 15466309

  View details for PubMedCentralID PMC3225865

• Cerebellum-dependent learning: The role of multiple plasticity mechanisms ANNUAL REVIEW OF NEUROSCIENCE Boyden, E. S., Katoh, A., Raymond, J. L. 2004; 27: 581-609

  Abstract

  The cerebellum is an evolutionarily conserved structure critical for motor learning in vertebrates. The model that has influenced much of the work in the field for the past 30 years suggests that motor learning is mediated by a single plasticity mechanism in the cerebellum: long-term depression (LTD) of parallel fiber synapses onto Purkinje cells. However, recent studies of simple behaviors such as the vestibulo-ocular reflex (VOR) indicate that multiple plasticity mechanisms contribute to cerebellum-dependent learning. Multiple plasticity mechanisms may provide the flexibility required to store memories over different timescales, regulate the dynamics of movement, and allow bidirectional changes in movement amplitude. These plasticity mechanisms must act in combination with appropriate information-coding strategies to equip motor-learning systems with the ability to express learning in correct contexts. Studies of the patterns of generalization of motor learning in the VOR provide insight about the coding of information in neurons at sites of plasticity. These principles emerging from studies of the VOR are consistent with results concerning more complex behaviors and thus may reflect general principles of cerebellar function.

  View details for DOI 10.1146/annurev.neuro.27.070203.144238

  View details for Web of Science ID 000223246300021

  View details for PubMedID 15217344

• Active reversal of motor memories reveals rules governing memory encoding NEURON Boyden, E. S., Raymond, J. L. 2003; 39 (6): 1031-1042

  Abstract

  Learning systems must be able to store memories reliably, yet be able to modify them when new learning is required. At the mechanistic level, new learning may either reverse the cellular events mediating the storage of old memories or mask the old memories with additional cellular changes that preserve the old cellular events in a latent form. Behavioral evidence about whether reversal or masking occurs in a particular circuit can constrain the cellular mechanisms used to store memories. Here we examine these constraints for a simple cerebellum-dependent learning task, motor learning in the vestibulo-ocular reflex (VOR). Learning can change the amplitude of the VOR in two opposite directions. Contrary to previous models about memory encoding by the cerebellum, our results indicate that these behavioral changes are implemented by different plasticity mechanisms, which reverse each other with unequal efficacy.

  View details for Web of Science ID 000185296100015

  View details for PubMedID 12971901

• Contribution of background and target motion to the induction of motor learning in the interneurons VOR Conference on Recent Developments in Cerebellar Research Ke, M. C., Raymond, J. L. NEW YORK ACAD SCIENCES. 2002: 525–525

  View details for Web of Science ID 000180980000054

• Hypotheses about the neural trigger for plasticity in the circuit for the vestibulo-ocular reflex 2nd Symposium on Cerebellar Modules Raymond, J. L., Lisberger, S. G. ELSEVIER SCIENCE BV. 2000: 235–246

  View details for Web of Science ID 000180918700017

  View details for PubMedID 10943129

• Learning in the oculomotor system: from molecules to behavior CURRENT OPINION IN NEUROBIOLOGY Raymond, J. L. 1998; 8 (6): 770-776

  Abstract

  A combination of system-level and cellular-molecular approaches is moving studies of oculomotor learning rapidly toward the goal of linking synaptic plasticity at specific sites in oculomotor circuits with changes in the signal-processing functions of those circuits, and, ultimately, with changes in eye movement behavior. Recent studies of saccadic adaptation illustrate how careful behavioral analysis can provide constraints on the neural loci of plasticity. Studies of vestibulo-ocular adaptation are beginning to examine the molecular pathways contributing to this form of cerebellum-dependent learning.

  View details for Web of Science ID 000077737200013

  View details for PubMedID 9914237

• Neural learning rules for the vestibulo-ocular reflex JOURNAL OF NEUROSCIENCE Raymond, J. L., Lisberger, S. G. 1998; 18 (21): 9112-9129

  Abstract

  Mechanisms for the induction of motor learning in the vestibulo-ocular reflex (VOR) were evaluated by recording the patterns of neural activity elicited in the cerebellum by a range of stimuli that induce learning. Patterns of climbing-fiber, vestibular, and Purkinje cell simple-spike signals were examined during sinusoidal head movement paired with visual image movement at stimulus frequencies from 0.5 to 10 Hz. A comparison of simple-spike and vestibular signals contained the information required to guide learning only at low stimulus frequencies, and a comparison of climbing-fiber and simple-spike signals contained the information required to guide learning only at high stimulus frequencies. Learning could be guided by comparison of climbing-fiber and vestibular signals at all stimulus frequencies tested, but only if climbing fiber responses were compared with the vestibular signals present 100 msec earlier. Computational analysis demonstrated that this conclusion is valid even if there is a broad range of vestibular signals at the site of plasticity. Simulations also indicated that the comparison of vestibular and climbing-fiber signals across the 100 msec delay must be implemented by a subcellular "eligibility" trace rather than by neural circuits that delay the vestibular inputs to the site of plasticity. The results suggest two alternative accounts of learning in the VOR. Either there are multiple mechanisms of learning that use different combinations of neural signals to drive plasticity, or there is a single mechanism tuned to climbing-fiber activity that follows activity in vestibular pathways by approximately 100 msec.

  View details for Web of Science ID 000076616600052

  View details for PubMedID 9787014

• Multiple subclasses of Purkinje cells in the primate floccular complex provide similar signals to guide learning in the vestibulo-ocular reflex LEARNING & MEMORY Raymond, J. L., Lisberger, S. G. 1997; 3 (6): 503-518

  Abstract

  The neural "learning rules" governing the induction of plasticity in the cerebellum were analyzed by recording the patterns of neural activity in awake, behaving animals during stimuli that induce a form of cerebellum-dependent learning. We recorded the simple- and complex-spike responses of a broad sample of Purkinje cells in the floccular complex during a number of stimulus conditions that induce motor learning in the vestibulo-ocular reflex (VOR). Each subclass of Purkinje cells carried essentially the same information about required changes in the gain of the VOR. The correlation of simple-spike activity in Purkinje cells with activity in vestibular pathways could guide learning during low-frequency but not high-frequency stimuli. Climbing fiber activity could guide learning during all stimuli tested but only if compared with the activity present approximately 100 msec earlier in either vestibular pathways or Purkinje cells.

  View details for Web of Science ID A1997XF15800005

  View details for PubMedID 11536919

• Behavioral analysis of signals that guide learned changes in the amplitude and dynamics of the vestibulo-ocular reflex JOURNAL OF NEUROSCIENCE Raymond, J. L., Lisberger, S. G. 1996; 16 (23): 7791-7802

  Abstract

  We characterized the dependence of motor learning in the monkey vestibulo-ocular reflex (VOR) on the duration, frequency, and relative timing of the visual and vestibular stimuli used to induce learning. The amplitude of the VOR was decreased or increased through training with paired head and visual stimulus motion in the same or opposite directions, respectively. For training stimuli that consisted of simultaneous pulses of head and target velocity 80-1000 msec in duration, brief stimuli caused small changes in the amplitude of the VOR, whereas long stimuli caused larger changes in amplitude as well as changes in the dynamics of the reflex. When the relative timing of the visual and vestibular stimuli was varied, brief image motion paired with the beginning of a longer vestibular stimulus caused changes in the amplitude of the reflex alone, but the same image motion paired with a later time in the vestibular stimulus caused changes in the dynamics as well as the amplitude of the VOR. For training stimuli that consisted of sinusoidal head and visual stimulus motion, low-frequency training stimuli induced frequency-selective changes in the VOR, as reported previously, whereas high-frequency training stimuli induced changes in the amplitude of the VOR that were more similar across test frequency. The results suggest that there are at least two distinguishable components of motor learning in the VOR. One component is induced by short-duration or high-frequency stimuli and involves changes in only the amplitude of the reflex. A second component is induced by long-duration or low-frequency stimuli and involves changes in the amplitude and dynamics of the VOR.

  View details for Web of Science ID A1996VY43300040

  View details for PubMedID 8922435

• The cerebellum: A neuronal learning machine? SCIENCE Raymond, J. L., Lisberger, S. G., Mauk, M. D. 1996; 272 (5265): 1126-1131

  Abstract

  Comparison of two seemingly quite different behaviors yields a surprisingly consistent picture of the role of the cerebellum in motor learning. Behavioral and physiological data about classical conditioning of the eyelid response and motor learning in the vestibulo-ocular reflex suggests that (i) plasticity is distributed between the cerebellar cortex and the deep cerebellar nuclei; (ii) the cerebellar cortex plays a special role in learning the timing of movement; and (iii) the cerebellar cortex guides learning in the deep nuclei, which may allow learning to be transferred from the cortex to the deep nuclei. Because many of the similarities in the data from the two systems typify general features of cerebellar organization, the cerebellar mechanisms of learning in these two systems may represent principles that apply to many motor systems.

  View details for Web of Science ID A1996UM88900038

  View details for PubMedID 8638157

• Error signals in horizontal gaze velocity Purkinje cells under stimulus conditions that cause learning in the VOR Conference on New Directions in Vestibular Research Raymond, J. L., Lisberger, S. G. NEW YORK ACAD SCIENCES. 1996: 686–689

  View details for Web of Science ID A1996BF92G00073

  View details for PubMedID 8694477

• Neural recordings and behavioral observations in the monkey vestibule-ocular reflex constrain the cellular mechanisms for cerebellum-dependent behavioral learning Jacques Monod Conference on Synaptic Plasticity and Cellular Mechanisms of Memory Lisberger, S. G., Raymond, J. L. EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 1996: 381–82

  Abstract

  Recordings from the cerebellum under behavioral conditions that cause learning in the vestibulo-ocular reflex (VOR) constrain the cellular mechanisms that could mediate learning. Analysis of the complex-spike responses of Purkinje cells demonstrates a mismatch between the properties of cerebellar long-term depression (LTD) in vitro and the signals available to guide learning in vivo. To resolve this mismatch, it may be necessary to assume that there are multiple cellular mechanisms of VOR learning, including both depression and potentiation.

  View details for Web of Science ID A1996WQ67500024

  View details for PubMedID 9089517