Lu Chen

Simultaneous recording of neural activity across multiple interacting brain regions is a central objective in systems neuroscience and neural engineering. Penetrating multi-electrode arrays (MEAs) are essential for this purpose, yet their performance is fundamentally constrained by the complex three-dimensional anatomy of the brain and by substantial variability across species and brain regions. As a result, fixed or generic MEA designs, with periodic electrode distribution, often provide limited spatial coverage and suboptimal recording efficiency. In this work, we present a systematic design framework for conformal planar penetrating MEAs that explicitly links neuroanatomical constraints to key engineering decisions, including probe geometry, shank arrangement, electrode distribution, and implantation strategy. The framework integrates anatomical analysis, surgical considerations, device prototyping, electrophysiological validation, and histological verification within an iterative workflow, enabling progressive refinement from initial concept to final design. We illustrate this approach through representative case studies with an initial emphasis on hippocampal arrays, where highly curved and layered cytoarchitecture presents stringent design challenges, and subsequent extensions to other brain regions and animal models. These examples demonstrate how anatomy-aware, conformal designs can improve access to targeted neural structures and enable multi-region recordings. Overall, this work provides a practical, generalizable methodology for designing conformal planar penetrating MEAs. The proposed framework complements existing high-density and/or flexible probes, offering a unifying perspective for developing anatomically tailored neural recording technologies for basic neuroscience research and future translational applications.

SATB2-associated syndrome (SAS) is a severe neurodevelopmental disorder caused by de novo heterozygous SATB2 mutations, yet how haploinsufficiency disrupts brain development remains poorly understood. While homozygous Satb2 loss causes profound embryonic cell-fate defects, we demonstrate using a heterozygous mouse model that SAS phenotypes emerge primarily during postnatal circuit maturation. Integrating chromatin profiling, transcriptomics, electrophysiology, and behavior, we show that SATB2 acts as a dose-sensitive chromatin regulator that binds conserved enhancer–promoter landscapes to orchestrate networks linked to human intelligence. Although excitatory neuron subtype specification is preserved, Satb2 heterozygotes adopt an intermediate epigenetic state that drives cell-type-specific dysregulation of genes enriched for intellectual disability risk variants. Consequently, mutant neurons exhibit simplified dendritic arborization, reduced intrinsic excitability, and weakened layer 2/3-to-layer 5 intracortical connectivity. These circuit deficits culminate in the disorganization of the somatosensory barrel cortex and severe impairments in whisker-dependent texture discrimination. Finally, by restricting Satb2 heterozygosity to the cortex, we decouple these cortical sensory deficits from subcortical vocalization phenotypes. Together, our work links SATB2 dosage to chromatin architecture and postnatal circuit maturation, revealing a critical, post-mitotic therapeutic window for intervention in SAS.

Thapliyal S, Arendt KL, Lau AG, Chen L. 2022. Retinoic acid-gated BDNF synthesis in neuronal dendrites drives presynaptic homeostatic plasticity. eLife 11:e79863. doi: 10.7554/eLife.79863.

Editorial: Synaptic plasticity and dysfunction, friend or foe?

The development of self-organizing 3D brain organoids derived from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) has attracted immense attention and enthusiasm in the field of neuroscience. These neural organoids provide an excellent in vitro platform to study early human brain development and present an exceptional, long-awaited model to understand early developmental defects in neurological diseases. However, one of the major limitations observed in the organoid field is the lack of intrinsic cues that guide proper neuronal differentiation, maturation, and final integration into appropriate neural circuits capable of driving behavioral functions. In this elegant study, Revah and colleagues reported successful maturation and integration of transplanted whole dorsal forebrain organoids into the somatosensory cortex of athymic newborn rats, driving a major advance in the applicability of brain organoid research. Once successfully transplanted into the developing brain, these cortical organoids differentiate into multiple neuronal and non-neuronal cell populations. Compared to their in vitro age-matched dorsal forebrain organoids, neurons originating from the transplanted human organoids display more complex morphology and mature functionality, as assessed by electrophysiological measurements. To further emphasize the relevance of this study, the authors applied this approach to investigate Timothy syndrome (TS), a major neurodevelopmental disorder caused by a gain-of-function mutation in the gene encoding calcium channel subunit Cav1.2, by transplanting organoids derived from TS patient iPSCs into newborn pups. They found that transplanted TS organoids more accurately recapitulate morphological deficits in dendrite length and density than their in vitro counterparts, thus validating organoid transplantation as a more effective disease-modeling approach. Using viral tracing experiments, they further showed that transplanted organoids can receive functional sensory inputs from multiple brain regions and show robust activity upon behavior-driven stimulation of those sensory connections. Further, optogenetic activation of transplanted organoids can successfully modulate and drive animal behavior, emphasizing the ability of these transplanted organoids to effectively integrate and mature to become an integral part of an intrinsic behavioral circuit. This valuable study bridges our understanding of brain organoids and human-animal hybrid brains. This new approach has the potential to provide better models applicable to understanding and developing therapeutic interventions for various human neurological and psychiatric disorders.

Homeostatic synaptic plasticity is a non-Hebbian synaptic mechanism that adjusts synaptic strength to maintain network stability while achieving optimal information processing. Among the molecular mediators shown to regulate this form of plasticity, synaptic signaling through retinoic acid (RA) and its receptor, RARα, has been shown to be critically involved in the homeostatic adjustment of synaptic transmission in both hippocampus and sensory cortices. In this study, we explore the molecular mechanism through which postsynaptic RA and RARα regulates presynaptic neurotransmitter release during prolonged synaptic inactivity at mouse glutamatertic synapses. We show that RARα binds to a subset of dendritically sorted brain-derived neurotrophic factor (Bdnf) mRNA splice isoforms and represses their translation. The RA-mediated translational de-repression of postsynaptic BDNF results in the retrograde activation of presynaptic tropomyosin receptor kinase B (TrkB) receptors, facilitating presynaptic homeostatic compensation through enhanced presynaptic release. Together, our study illustrates an RA-mediated retrograde synaptic signaling pathway through which postsynaptic protein synthesis during synaptic inactivity drives compensatory changes at the presynaptic site.