About

Dr. Mark Bear is a Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology and an investigator at the Picower Institute for Learning and Memory. His laboratory is interested in how the brain is modified by experience, deprivation, and disease. He uses electrophysiological, biochemical, molecular, behavioral, and anatomical methods to examine the synaptic modifications that form the neurobiological basis of learning and memory. His research focuses on understanding developmental plasticity in the visual cortex and other forms of experience-dependent synaptic modification in the visual cortex and hippocampus. Dr. Bear has described novel forms of procedural learning in the visual system and investigated synaptic function in models of fragile X syndrome and other autism spectrum disorders. His work has contributed to understanding how experience and deprivation modify synaptic connections, with implications for memory, brain development, recovery after damage, and neurological and psychiatric diseases.

Research topics

• Neuroscience
• Biology
• Biophysics
• Physics
• Computer Science
• Internal medicine
• Telecommunications
• Biological system
• Biochemistry
• Genetics
• Immunology
• Optics
• Cell biology
• Medicine
• Chemistry

Selected publications

• Using the visual cliff and pole descent assays to detect binocular disruption in mice

  Visual Neuroscience · 2026-01-01

  articleOpen accessSenior author

  Amblyopia, a neurodevelopmental binocular visual disorder, is commonly modeled in animals using monocular deprivation (MD) during the critical period of visual development. Despite extensive research at synaptic, cellular and circuit levels, reliable behavioral assays to study stereoscopic deficits in mice are limited. This study aimed to characterize the visual cliff assay (VCA) and the pole descent cliff task (PDCT), and to evaluate their utility in detecting binocular dysfunction in mice. By using manipulations of binocular vision, including monocular occlusion, pupillary dilation, and amblyopia (by prior MD), we show that optimal performance in both the VCA and PDCT requires matched binocular input. However, deficits after MD in the VCA exhibited relatively small effect sizes (7%–14%), requiring large sample sizes. By comparison, the PDCT demonstrated larger effect sizes (43%–61%), allowing for reliable detection of binocular dysfunction with fewer animals. Following validation through multiple monocular manipulations that are relevant to clinical paradigms, the PDCT emerged as the preferred assay for detecting deficits in stereoscopic depth perception in mice. These findings provide a robust framework for using the VCA and PDCT in mechanistic and therapeutic studies in mice that will offer insights into the neural mechanisms of binocular vision and potential interventions for amblyopia.

  PublisherOA PDFDOI

• Tuning metaplasticity in the adult visual cortex using flickering light

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-18

  articleOpen accessSenior authorCorresponding

  Synaptic connections in the brain are refined by sensory experience during an early postnatal critical period, but by adulthood synaptic connectivity is resistant to further changes. A consequence of lost plasticity is limited recovery from brain injury, disease, and adverse sensory experience. Thus, there is great interest in treatments that can promote synaptic modifications in the adult brain. In a wide variety of contexts, it has been established that the qualities of synaptic plasticity are not fixed but rather vary depending on the recent history of cellular or synaptic activity 1 . This plasticity of plasticity, or metaplasticity 2 explains why temporary manipulations of brain activity (e.g., by drugs 3 , transcranial stimulation 4 , or sensory deprivation 5 ) can set the stage for subsequent, potentially therapeutic, long-lasting synaptic modifications 6 . Here we tested the hypothesis that plasticity in the adult mouse visual cortex is influenced by prior exposure to temporally modulated light and discovered that different flicker frequencies have qualitatively different effects. Exposure to 60 Hz stimulation increased microglia density, depleted perineuronal nets (PNNs), and restored ocular dominance plasticity in response to brief monocular deprivation (MD). Exposure to 40 Hz flicker also enabled ocular dominance plasticity, but it did so in a distinct way and without PNN remodeling. A key distinction is that unlike 60 Hz flicker, which enabled depression of synaptic strength by MD, 40 Hz flicker promoted synaptic strengthening. Indeed, we found that 40 Hz flicker primed a rapid and robust recovery from the effects of long-term MD that failed to occur after 60 Hz flicker. Thus, metaplasticity can be non-invasively “tuned” by light flickering at different frequencies to encourage different forms of synaptic plasticity in the cerebral cortex, including modifications that enable recovery of function.

  PublisherOA PDFDOI

• A human electrophysiological signature of Fragile X pathophysiology is shared in V1 of Fmr1-/y mice

  Figshare · 2026-01-01

  datasetOpen accessSenior author

  Pre-processed resting state EEG and LFP data from all mice (Figures 2-8 and supplementary figures 4-12).

  PublisherDOI

• A human electrophysiological signature of Fragile X pathophysiology is shared in V1 of Fmr1-/y mice

  Nature Communications · 2026-02-09 · 1 citations

  articleOpen accessSenior author

  Abstract Predicting clinical therapeutic outcomes from animal studies using conserved electrophysiological phenotypes could facilitate developing treatments for neuropsychiatric disorders. Alpha oscillations in human resting-state electroencephalogram recordings are altered in many disorders, but whether these disruptions exist in mouse models is unknown. Here, we employed a uniform analytical method to show in males with fragile X syndrome (FXS) that alpha oscillations in humans and alpha-like oscillations in the visual cortex of Fmr1 -/y mice are slowed, with a stronger phenotype in adults than juveniles and a juvenile-specific power phenotype in both species. We find that alpha-like oscillations are disrupted by deletion of Fmr1 in cortical excitatory neurons and glia, reflect differential activity of two classes of GABAergic interneurons, and are more sensitive to activation of GABA B receptors by Arbaclofen in wild-type than Fmr1 -/y mice. Our framework reveals evolutionary conservation of alpha oscillation disruptions, enables a deeper understanding of FXS pathophysiology, and narrows the gap between treatment promise and practice.

  PublisherDOI

• A human electrophysiological signature of Fragile X pathophysiology is shared in V1 of Fmr1-/y mice

  Figshare · 2026-01-01 · 1 citations

  datasetOpen accessSenior author

  Pre-processed resting state EEG and LFP data from all mice (Figures 2-8 and supplementary figures 4-12).

  PublisherDOI

• A human electrophysiological biomarker of Fragile X Syndrome is shared in V1 of <i>Fmr1</i> KO mice and caused by loss of FMRP in cortical excitatory neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-19

  preprintOpen accessSenior authorCorresponding

  Abstract Predicting clinical therapeutic outcomes from preclinical animal studies remains an obstacle to developing treatments for neuropsychiatric disorders. Electrophysiological biomarkers analyzed consistently across species could bridge this divide. In humans, alpha oscillations in the resting state electroencephalogram (rsEEG) are altered in many disorders, but these disruptions have not yet been characterized in animal models. Here, we employ a uniform analytical method to show in males with fragile X syndrome (FXS) that the slowed alpha oscillations observed in adults are also present in children and in visual cortex of adult and juvenile Fmr1 -/y mice. We find that alpha-like oscillations in mice reflect the differential activity of two classes of inhibitory interneurons, but the phenotype is caused by deletion of Fmr1 specifically in cortical excitatory neurons. These results provide a framework for studying alpha oscillation disruptions across species, advance understanding of a critical rsEEG signature in the human brain and inform the cellular basis for a putative biomarker of FXS.

  PublisherOA PDFDOI

• Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes

  Cell Reports · 2025-02-20 · 8 citations

  articleOpen accessSenior author

  N-methyl-D-aspartate (NMDA)-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis. Using subtype-selective pharmacological and genetic tools, we find that structural plasticity is dependent on ligand binding to GluN2B-containing NMDA receptors (NMDARs) and signaling via the GluN2B carboxy-terminal domain (CTD). Disruption of non-ionotropic signaling by replacing the GluN2B CTD with the GluN2A CTD leads to an increase in spine density, dysregulated basal protein synthesis, exaggerated long-term depression mediated by G-protein-coupled metabotropic glutamate receptors (mGluR-LTD), and epileptiform activity reminiscent of phenotypes observed in the Fmr1 knockout (KO) model of fragile X syndrome. By crossing the Fmr1 KO mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism.

  PublisherDOI

• The visual evoked potential is a sensitive and powerful measure of experience-dependent visual cortical plasticity in mice

  Current Opinion in Neurobiology · 2025-04-12 · 7 citations

  reviewOpen accessSenior authorCorresponding

  Despite the explosion of high-tech methods to measure activity in the mouse visual cortex, the venerable visually evoked potential (VEP) continues to prove its worth as a sensitive measure of experience-dependent cortical plasticity. The VEP recorded in layer 4 is a good estimate of the strength of feedforward synaptic excitation, and changes in amplitude correspond closely to changes in the peak firing rate of principal cells. Chronic recording of VEPs in awake mice have enabled longitudinal study of modifications induced by selective visual experience or deprivation, and these have revealed several novel forms of plasticity. The VEP provides a good estimate of spatial acuity that compares well with values obtained by behavioral approaches. Furthermore, recordings of the local field potential through the same electrodes reveal changes in oscillatory activity that reflect differential recruitment of inhibitory networks. Thus, the VEP remains a powerful tool for the study of visual cortical plasticity. • The VEP has proven to be a very sensitive measure of experience-dependent cortical plasticity in mouse V1. • VEPs are sensitive to timing and subthreshold synaptic events compared to imaging and single-unit recording methods. • VEPs provide insight into how plasticity shifts ocular dominance and codes spatial and temporal familiarity in V1. • Changes in VEP waveforms and local field oscillations correlate with changes in single unit neuronal responses.

  PublisherDOI

• Responses to conflicting binocular stimuli in mouse primary visual cortex

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-01 · 1 citations

  preprintOpen access

  Binocular vision requires that the brain integrate input from both eyes to form a unified percept. Small interocular differences support depth perception (stereopsis), while larger disparities can cause diplopia or binocular rivalry. The neural mechanisms by which early visual circuits process concordant versus conflicting binocular signals remain incompletely understood, particularly in the case of large disparities. Here, we used visually evoked potential (VEP) recordings, unit recordings, and 2-photon calcium imaging in the binocular region of mouse primary visual cortex (bV1) to examine how distinct forms of binocular disparity engage local circuits. Using a dichoptic display, we found that interocular phase disparities reduced VEP magnitude through decreased neuronal firing early in the response (40-80 ms after stimulus onset). In contrast, orientation disparities also decreased VEP magnitude, but via increased firing later in the response (100-200 ms). This late activity was enhanced in both regular-spiking (putative excitatory) and fast-spiking (putative parvalbumin-positive inhibitory) units. In contrast, calcium imaging revealed that somatostatin-positive interneurons were suppressed during orientation conflict. These findings suggest that phase differences suppress bV1 responses via feedforward mechanisms, while orientation disparities prolong activity through disinhibition mediated by somatostatin-positive interneurons. Our results identify distinct circuit pathways recruited by different forms of binocular conflict, clarify how early visual cortex contributes to binocular integration, and provide a foundation for investigating perceptual suppression and rivalry.

  PublisherOA PDFDOI

• Cell-intrinsic mechanisms underlying spontaneous activity in the mouse visual cortical slice: implications for fragile X pathophysiology

  Journal of Neurophysiology · 2025-12-01

  articleOpen accessSenior authorCorresponding

  As extracellular divalent cation concentrations are reduced, neocortical slices become spontaneously active. Here, we show that these conditions enhance persistent sodium currents, driving intrinsically generated activity in a subclass of layer 5 neurons. This spontaneous activity is no different in Fmr1-knockout mice, however, pointing toward a crucial role for external input in eliciting a well-studied form of hyperactivity in Fmr1-knockout visual cortex.

  PublisherDOI

Recent grants

• Training Program in the Neurobiology of Learning and Memory

  NIH · $1.7M · 2007–2017

• Validating a novel target for correction of pathophysiology in fragile X and TSC

  NIH · $404k · 2014–2017

• Mechanisms and Functions of FMRP in Neuronal Development

  NIH · $2.9M · 2003–2016

• NIH Grant P01NS039321

  NIH · $7.8M · 2005

• Using the principles of synaptic plasticity to promote recovery from amblyopia

  NIH · $2.4M · 2018–2023

Frequent coauthors

• Michael A. Paradiso

  Brown University

  122 shared

• Barry W. Connors

  113 shared

• Emily K. Osterweil

  Boston Children's Hospital

  68 shared

• Arnold J. Heynen

  Massachusetts Institute of Technology

  63 shared

• Alfredo Kirkwood

  Johns Hopkins University

  44 shared

• Sam F. Cooke

  University of Lincoln

  43 shared

• Eric D. Gaier

  Massachusetts Eye and Ear Infirmary

  43 shared

• Gül Dölen

  Discovery Institute

  38 shared

Education

• Ph.D., Neuroscience

  Harvard University

  1985

• B.A., Psychology

  University of California, San Diego

  1980