Shaojie Ma

The cerebral cortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas forming distributed networks that support abstract cognition at the other^1-11. The developmental mechanisms shaping this axis remain unclear^9-24. Here we present converging multispecies evidence supporting the multinodal induction-exclusion in network development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion driven by two opposing transcriptomically defined programs. 'Pericentral' programs are induced around the frontotemporal poles, progress inwards toward the central regions of the undifferentiated neocortex and define higher-order association features. 'Central' programs are induced centrally through first-order sensorimotor thalamocortical inputs, establish primary areas and exclude pericentral programs. These conserved programs compete for space, resulting in compartmentalized expression of axon guidance, cell-cell adhesion, retinoic acid signalling, synaptogenesis, WNT signalling and autism-risk-associated genes. Notably, PLXNC1 and SEMA7A, a receptor-ligand pair representing pericentral and central programs, respectively, exhibit repulsive interactions between primary and higher-order association corticocortical axons. Induction and exclusion together establish an S-A organization in which primary areas emerge as focal islands within a broader ocean of distributed association networks. The MIND model provides a unifying framework for experimental, evolutionary and clinical phenomena, revealing induction and exclusion as antagonistic yet complementary principles shaping the S-A axis and processing hierarchies.

The principles organizing cellular diversity and connectivity in primate brains remain elusive. By integrating spatial transcriptomics, magnetic resonance imaging, and retrograde labeling in marmosets, we identified two opposing molecular gradients that undergo postnatal refinement, emanating from allocortices and primary sensory cortices, respectively. These gradients reconcile conflicting hypotheses on cortical expansion and characterize distinct cortical areas. Cortical gradients align with thalamic gene expression and thalamocortical projection patterns. At gradient intersections, the default mode network and frontal pole exhibited similar molecular features in humans and marmosets, despite species-specific differences in functional connectivity. Comparative analysis of gradient-related genes showed that marmoset and human auditory cortices are highly similar but differ from those of macaques, potentially reflecting complex vocalization. Together, these opposing gradients represent a fundamental organizing principle of the primate cortex.

The perinatal period witnesses dynamic structural reorganization and functional specialization essential for establishing later-life neural circuitry integrity. However, molecular mechanisms governing spatiotemporal developmental trajectories during this critical window remain poorly characterized due to limited accessibility of human perinatal specimens. Here, we analysed transcriptomes and proteomes from 336 samples across multiple time points and brain regions in perinatal Bama miniature pigs, showing their spatiotemporal organization and concordance between genes and proteins. We characterized pigs as an optimal large-animal model, demonstrating its closer analogy to humans, resemblance to monkeys, and superiority over mice and other species, while identifying its perinatal stage as a transitional hub bridging early prenatal to postnatal molecular trajectories in humans. We revealed a pan-regional developmental inflection point (E94-E104) during the perinatal period, manifesting as order-of-magnitude changes in the expression of genes and proteins associated with synaptogenesis and gliogenesis. While further analysing developmental velocities across pig brain regions, we discovered regional heterogeneity exhibits a remarkably synchronized rise-and-fall pattern during the perinatal period. Additionally, brain disorder risk genes exhibited a perinatal transition to an adult-like organization in pigs, establishing this multi-omics atlas as a translational framework for decoding neurodevelopmental disorder pathogenesis.

Here, to enable researchers to more fully harness the collective discovery potential of multiomic data in the public domain, we have assembled gene-level transcriptomic data from ~200 studies of neocortical development and in vitro models. Applying joint matrix decomposition to mouse, macaque and human data, we define transcriptome dynamics that are conserved across neocortical neurogenesis and identify a program that emerges in ventricular progenitors, is later expressed in neurogenic outer, or basal, radial glia of primates, but is limited to gliogenic precursors in the rodent. Decomposition of adult human neocortical data identified layer-specific signatures in excitatory neurons, enabling the charting of their developmental emergence and protracted maturation, which is in stark contrast to the early peaking expression of layer-defining transcription factors. Interrogation of data from cerebral organoids demonstrated that, although broad elements of in vivo development are recapitulated in vitro, many layer-specific transcriptomic programs in neuronal maturation are absent. We invite cell biologists without coding expertise to use NeMO Analytics in their research and to fuel it with their own emerging data at nemoanalytics.org/landing/neocortex.

Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified an enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells. Experimental data show that ZP2 expression in human granule cells is induced by pontine mossy fibers, reducing synaptic proteins at pontocerebellar glomerular synapses, and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explore the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identify risk genes expressed in brain organizers and sequential gene regulatory networks throughout corticogenesis, revealing disease-specific critical phases when NSCs may be more vulnerable to gene dysfunction and converging signaling across multiple diseases. Further, we simulate the impact of risk transcription factor (TF) depletions on neural cell trajectories traversing human corticogenesis and observe a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of autism-affected patient-derived NSCs in vitro reveals recurrent expression alteration of TFs orchestrating brain patterning and NSC lineage commitment. This work opens perspectives to explore human brain dysfunction at early phases of development.

Marmosets and macaques are common nonhuman primate models of cognition, yet marmosets appear more distractible and perform worse in cognitive tasks. The dorsolateral prefrontal cortex (dlPFC) is pivotal for sustained attention, and research in macaques suggests that dopaminergic modulation and inhibitory parvalbumin (PV) neurons could influence distractor resistance. Here we compare the two species using a visual fixation task with distractors, perform molecular and anatomical analyses in dlPFC, and link functional microcircuitry with cognitive performance using computational modeling. We show that marmosets are more distractible than macaques, and that marmoset dlPFC PV neurons contain higher levels of dopamine D1 receptor (D1R) transcripts and protein, similar to levels in mice. Our modeling indicates that higher D1R expression in marmoset dlPFC PV neurons may increase distractibility by making dlPFC microcircuits more vulnerable to disruptions of their task-related persistent activity, especially when dopamine is released in dlPFC in response to unexpected salient stimuli.

The neocortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas that form distributed networks supporting abstract cognition at the other. The developmental mechanisms shaping this axis remain elusive. Here, we present converging multispecies evidence supporting the Multinodal Induction-Exclusion in Network Development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion, driven by opposing transcriptional programs emerging from different nodes. Key molecular and connectional features of association cortices arise through pericentral programs, originating around fronto-temporal poles and partially regulated by retinoic acid. They progress inward toward central territories of the naive neocortex along fronto-temporally polarized trajectories. Central programs are induced through interactions between topographically separated first-order sensorimotor thalamocortical inputs and the neocortex, promoting the formation of primary areas while excluding pericentral programs. Influenced by SATB2 and ZBTB18, these evolutionarily conserved programs compete for the same territory and create spatial compartmentalization of axon guidance, cell-cell adhesion, retinoic acid signaling, synaptogenesis, Wnt signaling, and autism risk genes. Notably, PLXNC1 and SEMA7A exhibit anti-correlated expression and repulsive functions in shaping cortico-cortical connectivity along the S-A axis. These opposing processes of induction and exclusion establish an S-A equilibrium and topography in which primary sensorimotor areas emerge as focal islands within the broader ocean of distributed associative networks. The MIND model provides a unifying framework for understanding experimental, evolutionary, and clinical phenomena, revealing induction and exclusion as antagonistic complementary principles shaping the S-A axis and processing hierarchies.

Focal cortical dysplasia type II (FCDII) is a major cause of drug-resistant epilepsy, but genetic factors explain only some cases, suggesting other mechanisms. In this study, we conduct a molecular analysis of brain lesions and adjacent areas in FCDIIb patients. By analyzing over 217,506 single-nucleus transcriptional profiles from 15 individuals, we find significant changes in smooth muscle cells (SMCs) and astrocytes. We identify abnormal vascular malformations and a unique type of SMC that we call “Firework cells”, which migrate from blood vessels into the brain parenchyma and associate with VIM⁺ cells. These abnormalities create localized ischemic-hypoxic (I/H) microenvironments, as confirmed by clinical data, further impairing astrocyte function, activating the HIF-1α/mTOR/S6 pathway, and causing neuronal loss. Using zebrafish models, we demonstrate that vascular abnormalities resulting in I/H environments promote seizures. Our results highlight vascular malformations as a factor in FCDIIb pathogenesis, suggesting potential therapeutic avenues.

The ventrolateral pallial (VLp) excitatory neurons in the claustro-amygdalar complex and piriform cortex (PIR; which forms part of the palaeocortex) form reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that results in adaptive behaviours^1–5. Early-life disruptions in these circuits are linked to neuropsychiatric disorders^4–8, highlighting the importance of understanding their development. Here we reveal that the transcription factors SOX4, SOX11 and TFAP2D have a pivotal role in the development, identity and PFC connectivity of these excitatory neurons. The absence of SOX4 and SOX11 in post-mitotic excitatory neurons results in a marked reduction in the size of the basolateral amygdala complex (BLC), claustrum (CLA) and PIR. These transcription factors control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including in humans, identified conserved Tfap2d expression in developing excitatory neurons of BLC, CLA, PIR and the associated transitional areas of the frontal, insular and temporal cortex. Although the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat-response behaviours, differences emerge in the phenotypes at different Tfap2d dosages, particularly in terms of changes observed in BLC size and BLC–PFC connectivity. This underscores the importance of Tfap2d dosage in orchestrating developmental shifts in BLC–PFC connectivity and behavioural modifications that resemble symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial VLp excitatory neurons and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.