Neuroscience is about communities: Inside and outside the brain

Neurons of the mammalian central nervous system are generated through intricate genetic and environmental interactions. While transcriptomic comparisons of the developing and adult cerebral cortex reveal greater neuronal diversity in postnatal stages, this suggests that extrinsic cues play a crucial role in shaping neuronal identity, connectivity, and function. We are particularly interested in exploring this period of neuronal fate plasticity and the class-specific interactions that guide circuit assembly. Our overarching goal is to uncover the mechanisms that establish and maintain neuronal identity in the cerebral cortex, define the limits of cell fate transitions, and apply these insights to understand neurodevelopmental disorders and develop therapeutic strategies. Central to this work is the integration of fundamental neurobiology with bioengineering, mathematics, computation, and artificial intelligence (AI).

Investigating Fate Plasticity and Circuit Wiring in the Cortex

To uncover the molecular logic of cortical identity, we leverage in vivo neuronal reprogramming models and chimeric in vitro cortical organoids. These models enable us to identify periods of fate refinement and examine how postsynaptic neuronal identity influences afferent circuit wiring. Additionally, human pluripotent stem cell (PSC)-derived cortical organoids provide a scalable and longitudinal platform to study the cortical microenvironment. Our work has demonstrated that the 3D cortical environment instructs PVALB+ interneuron identity, raising the possibility that external cues could misregulate their differentiation and function in disease states such as autism and schizophrenia.

To enhance the utility of these models, we collaborate with engineers and computational scientists to develop AI-driven approaches for analyzing neuronal development. Our efforts include:

• Neuronal Classifiers: A deep-learning algorithm optimized to match in vitro-derived neurons to primary cell atlases, aiding in the identification of pathways that improve differentiation fidelity.

• Bioelectronic Capillaries: Devices that deliver ions, neurotransmitters, and small molecules with high spatiotemporal precision to study microenvironmental influences on neuronal identity.

• High-Density Multielectrode Arrays (MEAs): Platforms for recording and manipulating neuronal activity to explore how electrical stimulation shapes differentiation and maturation.

Expanding Neuronal Diversity and Understanding Microenvironmental Influences

Despite their potential, organoids lack neuronal subtypes such as granular Layer 4 neurons and Fork neurons, which are essential for higher-order functions. To address this, we employ:

• Organoid Fusion and Cell Transplantation: Fusing regionalized organoids to generate neuronal subtypes absent in isolated models.

• Electrical Stimulation via MEAs: Leveraging electrophysiological recordings to replicate developmental electrical patterns and direct progenitor differentiation.

• Targeted Delivery of Signaling Molecules: Using bioelectronic capillaries to precisely deliver neurotransmitters like dopamine and serotonin to instruct neuronal fate.

• In Situ Reprogramming: Modifying neuronal subtypes using transcription factors to generate specialized cortical neurons.

By integrating these strategies, we aim to develop organoid models with greater fidelity to the in vivo cortex, validated through single-cell genomics, electrophysiology, and morphometry.

Multimodal Assessment of Neuronal Identity in Disease and Evolution

Neuronal identity involves complex, multimodal properties, including gene expression, electrophysiology, connectivity, and neurotransmitter profiles. To advance scalable assessments, we are developing:

• Deep Learning Models for Multimodal Data: AI algorithms that integrate transcriptomics, activity imaging, and electrophysiology to classify neurons and predict developmental trajectories.

• Multi-Species Organoid Models: Establishing organoids from various species, including humans, nonhuman primates. mice and birds, to investigate evolutionary adaptations in brain development.

• Genetic and Environmental Perturbation Integration: Leveraging high-throughput genomics and neuroinformatics to explore how neuropsychiatric mutations impact neuronal identity and function.

Building a Global Scientific Community Through Technology and Diplomacy

Beyond our core research, we are committed to fostering diverse and inclusive scientific communities. We develop technologies to make experimental science education freely accessible worldwide, focusing on students traditionally underrepresented in the sciences. By leveraging the Internet of Things and Augmented Reality, we aim to democratize access to neuroscience education.

In an era where neurodevelopmental disorders and neurological diseases affect nearly 1 in 6 people globally, we propose that "neurodiplomacy" can be a crucial framework for international collaboration. By uniting neuroscience with bioengineering, AI, and global outreach, we seek to advance scientific discovery, improve education, and create meaningful cross-border partnerships that contribute to the Sustainable Development Goals.