About

The Chen Lab at Harvard University and Boston Children's Hospital is interested in exploring the relationship between experience, plasticity, and neurodevelopment.

Research topics

• Cognitive psychology
• Psychology
• Physics
• Neuroscience
• Biology
• Cognitive science
• Optics
• Communication

Selected publications

• Astrocyte glucocorticoid receptor signalling restricts neuronal plasticity

  Nature · 2026-05-20

  articleOpen access

  , the environmental cues that restrain developmental plasticity as animals mature are less clear. Here we examine the experience-dependent maturation of the mouse primary visual cortex across postnatal development using paired single-cell transcriptomic and chromatin accessibility sequencing. In addition to identifying the activity-dependent gene programs that emerge within each cortical cell type, we find that light exposure drives astrocyte maturation through cell-type-specific recruitment of the glucocorticoid receptor (encoded by Nr3c1) to chromatin. Astrocyte glucocorticoid receptor signalling activates an extensive gene regulatory program that is partially conserved in human brain development and promotes maturation processes that may regulate critical period closure. Collectively, these findings reveal that astrocyte glucocorticoid receptor signalling restricts neuronal plasticity. Glucocorticoid regulation of astrocyte maturation may also contribute to the effects of early-life stress across the brain, and the disruption of this process may increase susceptibility to neuropsychiatric disease.

  PublisherDOI

• Reciprocal interaction between cortical SST and PV interneurons in top-down regulation of retinothalamic refinement

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-19

  preprintOpen accessSenior authorCorresponding

  Abstract Refinement of thalamic circuits is crucial for the proper maturation of sensory circuits. In the visual system, this process is regulated by corticothalamic feedback during the experience-dependent phase of development. Yet the cortical circuits modulating this feedback remain elusive. Here, we demonstrate opposing roles for cortical somatostatin (SST) and parvalbumin (PV) interneurons in shaping retinogeniculate connectivity during the thalamic sensitive period (P20-30). Early in the refinement process, SST interneurons promote the strengthening and pruning of retinal inputs in the thalamus, as evidenced by disrupted synaptic refinement following their ablation. In contrast, PV interneurons, which mature later, act as a brake on this refinement, with their ablation leading to enhanced pruning of retinogeniculate connections. Notably, manipulating the relative balance between these inhibitory circuits can regulate sensory deprivation-induced retinogeniculate remodeling. Taken together, our findings show that cortical SST and PV interneuron circuits drive reciprocal antagonism that gate experience-dependent feedforward thalamic refinement.

  PublisherOA PDFDOI

• Limited transmission of mixed convergent signals at the mouse retinogeniculate synapse

  Neuron · 2025-07-21 · 3 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Reciprocal interaction between cortical SST and PV interneurons in top–down regulation of retinothalamic refinement

  Proceedings of the National Academy of Sciences · 2025-06-18 · 1 citations

  articleOpen accessSenior authorCorresponding

  Refinement of thalamic circuits is crucial for the proper maturation of sensory circuits. In the visual system, this process is regulated by corticothalamic feedback during the experience-dependent phase of development. Yet the cortical circuits modulating this feedback remain elusive. Here, we demonstrate opposing roles for cortical somatostatin (SST) and parvalbumin (PV) interneurons in shaping retinogeniculate connectivity during the thalamic sensitive period (P20-30). Early in the refinement process, SST interneurons promote the strengthening and pruning of retinal inputs in the thalamus, as evidenced by disrupted synaptic refinement following their ablation. In contrast, PV interneurons, which mature later, act as a brake on this refinement, with their ablation leading to enhanced pruning of retinogeniculate connections. Notably, manipulating the relative balance between these inhibitory circuits can regulate sensory deprivation-induced retinogeniculate remodeling. Taken together, our findings show that cortical SST and PV interneuron circuits drive experience-dependent reciprocal antagonism that gates cortical feedback regulation of feedforward thalamic refinement.

  PublisherDOI

• Visual Recovery Reflects Cortical <scp>MeCP2</scp> Sensitivity in Rett Syndrome

  Annals of Clinical and Translational Neurology · 2025-11-19

  articleOpen access

  ABSTRACT Objective Rett syndrome (RTT) is a devastating neurodevelopmental disorder with developmental regression affecting motor, sensory, and cognitive functions. Sensory disruptions contribute to the complex behavioral and cognitive difficulties and represent an important target for therapeutic interventions. Although genetic medicine‐based therapies targeting MeCP2 have successfully restored motor and respiratory functions in animal models, their ability to reverse sensory deficits across levels of the visual pathway remains largely unexplored. Methods Using genetically reversible mouse models of MeCP2 deficiency (Mecp2 stop/y and Mecp2 stop/x ), we applied advanced electrophysiological, anatomical, and behavioral techniques to evaluate visual function, a critical sensory domain impaired in both animal models and RTT patients. Results In Mecp2 stop/y mice, initiating MeCP2 expression after postnatal day 35 (P35) reversed progressive cortical dysfunction, prevented thalamic circuit disorganization, and restored visual function, despite some remaining cortical anatomical abnormalities. Even in fully regressed adult Mecp2 stop/x heterozygous female mice, MeCP2 reactivation was sufficient to reduce the symptoms. Interpretation These findings highlight the remarkable sensitivity of cortical circuits to MeCP2 expression in both developing and mature brain. Importantly, restoring just 60%–70% of MeCP2 protein levels was sufficient to rescue sensory functions, even after the onset of regression. This underscores the transformative potential of genetic medicine‐based therapies in RTT, suggesting that even partial restoration of MeCP2 can meaningfully improve sensory processing and quality of life for patients.

  PublisherOA PDFDOI

• Noradrenergic Modulation of an Amygdalo-thalamic Circuit

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-14

  preprintOpen accessSenior author

  ABSTRACT Emotional and cognitive processing rely on communication between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). The BLA regulates mPFC both directly and indirectly via the medial sub-division of the medial dorsal thalamus (MDm). Although the BLA projection to MDm has been established anatomically, less is known about the functional properties of this synapse. Here, using patch-clamp electrophysiology and optogenetics in ex vivo mouse brain slices, we found that BLA neurons make potent synaptic connections onto MDm neurons capable of evoking action potentials. The site of this BLA input overlaps with strong innervation from locus coeruleus norepinephrine (NE) axons. We found that NE acts via α₂-adrenergic receptors to strongly reduce excitatory postsynaptic currents from BLA to MDm. NE also decreases the release probability of BLA axon terminals through a presynaptic mechanism. Postsynaptically, NE depolarizes MDm neurons and increases their tonic firing rates. These findings show that NE, whose levels are elevated during arousal and stress, can suppress transmission of affective information from BLA into MDm, thereby blunting this potent indirect pathway from BLA to mPFC. SIGNIFICANCE STATEMENT Previous anatomical studies have suggested the importance of amygdala input to the limbic thalamus. Here, using ex vivo electrophysiology and optogenetics in adult mice, we characterize the excitatory input from basolateral amygdala to mediodorsal thalamus, revealing the potency and physiological characteristics of this input. Further, we show that the stress-related neuromodulator, norepinephrine, binds to the α₂-adrenergic receptor to significantly dampen transmission of affective information carried by this synapse. These findings improve our understanding of key circuits involved in emotional processing and provide insight on how stress-induced neuromodulation may change circuit function, which is relevant to stress-related neuropsychiatric disorders such as depression, anxiety, schizophrenia, and PTSD.

  PublisherOA PDFDOI

• Experience influences the refinement of feature selectivity in the mouse primary visual thalamus

  Neuron · 2025-03-19 · 6 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Experience instructs the refinement of feature-selectivity in the mouse primary visual thalamus

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-01 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Neurons exhibit selectivity for specific features: a property essential for extracting and encoding relevant information in the environment. This feature-selectivity is thought to be modifiable by experience at the level of the cortex. Here, we demonstrate that selective exposure to a feature during development can instruct the population representation for that feature in the primary visual thalamus. This thalamic plasticity is not simply inherited from the cortex because it is still observed when recordings were performed in the absence of cortical feedback. Moreover, plasticity is blocked in mutant mice that exhibit deficits in retinogeniculate refinement, indicating that alterations in feature-selectivity are a direct result of changes in feedforward connectivity. These experience-dependent changes persist into older ages—highlighting the importance of this developmental period in shaping population coding in the thalamus. Our results show that salient environmental features are hard-wired into thalamic circuits during a discrete developmental window.

  PublisherOA PDFDOI

• Spinal projecting neurons in rostral ventromedial medulla co-regulate motor and sympathetic tone

  Cell · 2024-05-10 · 35 citations

  articleOpen access
  PublisherOA PDFDOI

• The secondary somatosensory cortex gates mechanical and heat sensitivity

  Nature Communications · 2024-02-12 · 17 citations

  articleOpen access

  The cerebral cortex is vital for the processing and perception of sensory stimuli. In the somatosensory axis, information is received primarily by two distinct regions, the primary (S1) and secondary (S2) somatosensory cortices. Top-down circuits stemming from S1 can modulate mechanical and cooling but not heat stimuli such that circuit inhibition causes blunted perception. This suggests that responsiveness to particular somatosensory stimuli occurs in a modality specific fashion and we sought to determine additional cortical substrates. In this work, we identify in a mouse model that inhibition of S2 output increases mechanical and heat, but not cooling sensitivity, in contrast to S1. Combining 2-photon anatomical reconstruction with chemogenetic inhibition of specific S2 circuits, we discover that S2 projections to the secondary motor cortex (M2) govern mechanical and heat sensitivity without affecting motor performance or anxiety. Taken together, we show that S2 is an essential cortical structure that governs mechanical and heat sensitivity.

  PublisherOA PDFDOI

Recent grants

• Plasticity of the Retinogeniculate Synapse

  NIH · $9.6M · 2003–2030

• NIH Grant R21HD058196

  NIH · $466k · 2010

• Behavior-dependent neuromodulation of retinogeniculate axonal boutons

  NIH · $503k · 2019–2021

• NIH Grant K08NS002056

  NIH · $550k · 2003

• Mechanisms of Synapse Remodeling in TSC

  NIH · $10.2M · 2021

Frequent coauthors

• Elizabeth Y. Litvina

  National Institute of Neurological Disorders and Stroke

  30 shared

• Liang Liang

  Yale University

  28 shared

• Bryan M. Hooks

  University of Pittsburgh

  24 shared

• Alex Fratzl

  Institute of Molecular and Clinical Ophthalmology Basel

  20 shared

• Jasmine D.S. Reggiani

  Harvard University

  18 shared

• Qiufen Jiang

  Boston Children's Hospital

  17 shared

• Mark L. Andermann

  Beth Israel Deaconess Medical Center

  16 shared

• Zhigang He

  Boston Children's Hospital

  15 shared

Labs

• Chen LabPI