About

Andre M.M. Sousa is an Assistant Professor in the Department of Neuroscience at the University of Wisconsin–Madison. His research focuses on the molecular and cellular mechanisms of human brain development and evolution. His lab aims to identify and characterize the genetic and biological processes that govern human brain development, with particular interest in understanding how these processes differ from other species, including primates. This research is driven by the recognition that many developmental programs are human-specific and that uncovering these mechanisms has significant biomedical implications, especially in relation to neurodevelopmental and psychiatric disorders. To achieve these goals, Sousa employs a multifaceted approach that includes functional genomic studies to identify critical genes and decipher their regulatory logic, developmental neurobiology studies utilizing induced pluripotent stem cells, mouse genetic models, and postmortem human and non-human primate brains to study gene functions in brain development, and molecular and cellular biology studies to understand the biological processes disrupted by alterations in these genes. His work contributes to advancing the understanding of the molecular basis of human brain development and evolution, with potential applications in understanding human cognition, behavior, and neuropsychiatric conditions.

Research topics

• Neuroscience
• Biology
• Genetics
• Psychology
• Immunology
• Cell biology
• Medicine
• Computational biology

Selected publications

• Adaptive evolution of gene regulatory networks in mammalian neocortex

  Nature · 2026-03-18 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

• Human-specific features of the cerebellum and ZP2-regulated synapse development

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-09 · 1 citations

  preprintOpen access

  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.

  PublisherDOI

• A historical and technological perspective on the evolution of the human brain transcriptome

  Evolution of Nervous Systems · 2025-10-25 · 1 citations

  book-chapterSenior author
  PublisherDOI

• Common coordinate framework of developmental macaque brain from birth to early childhood based on ultra-high-resolution diffusion MRI

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: Macaque brain structures undergo significant changes from birth through adulthood. However, there are no age-specific macaque brain common coordinate frameworks (CCFs) serving as neuroanatomical references for mapping genetic, cellular, and molecular information. Goal(s): To establish ultra-high-resolution CCFs for macaque brain at birth and early childhood (10-months). Approach: We acquired ultra-high resolution diffusion MRI (dMRI) of neonate and early-childhood macaque brains and delineated whole-brain neuroanatomical structures. We also investigated macaque white matter tract maturation through dMRI-based tractography. Results: The established neonate and early childhood macaque brain CCFs feature 0.2mm isotropic ultra-high diffusion imaging resolution, comprehensive gray and white matter labels, and a coordinate framework. Impact: These first age-specific developmental macaque brain CCFs, featuring 0.2mm isotropic ultra-high-resolution diffusion imaging, serve as neuroanatomical references. They facilitate the mapping of genetic, cellular, and molecular data and offer image templates, establishing foundations for discoveries in brain development and evolution.

  PublisherDOI

• Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-04 · 6 citations

  preprintOpen accessSenior authorCorresponding

  Down syndrome is a genetic condition that causes intellectual disability and is characterized by early-onset delays in motor, cognitive, and language development. The molecular mechanisms underlying these neurodevelopmental impairments remain poorly understood. We used single-nucleus multiomic sequencing to simultaneously profile gene expression and chromatin accessibility in the Down syndrome prefrontal cortex during early postnatal development, a critical period for synaptogenesis, neural maturation, and developmental neuroimmune interactions. Our findings reveal widespread dysregulation of chromatin accessibility and gene expression, with deficits spanning metabolic and synaptic pathways, oligodendrocyte lineage progression, and a pronounced neuroinflammatory signature. We present a molecular atlas of Down syndrome neuropathology at a critical stage of brain development, highlighting convergent neurodevelopmental and neurodegenerative pathways and informing potential targeted therapies for Down syndrome-associated neuroinflammation.

  PublisherOA PDFDOI

• Single‐nucleus analysis reveals oxidative stress in Down syndrome basal forebrain neurons at birth

  Alzheimer s & Dementia · 2025-07-01 · 6 citations

  articleOpen access

  INTRODUCTION: Basal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, and are prone to degeneration in Down syndrome (DS), Alzheimer's disease, and other neurodegenerative diseases. However, the mechanisms that lead to the degeneration of these neurons are not known. METHODS: Single-nucleus gene expression and Assay for Transposase-Accessible Chromatin (ATAC) sequencing were performed on postmortem human basal forebrain from unaffected control and DS tissue samples at 0-2 years of age (n = 4 each). RESULTS: Sequencing analysis of postmortem human basal forebrain identifies gene expression differences in DS early in life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation and glycolysis, and genes encoding antioxidant enzymes are upregulated in DS BFCNs. DISCUSSION: Multiomic analyses reveal that energy metabolism may be disrupted in DS BFCNs by birth. Increased oxidative phosphorylation and the accumulation of reactive oxygen species byproducts may be early contributors to DS BFCN neurodegeneration. HIGHLIGHTS: First multiomic gene expression and ATAC analysis of human basal forebrain. Basal forebrain pathology in DS begins by birth. Cell type proportions are altered in early postnatal DS basal forebrain. Gene expression suggests dysregulated energy metabolism in DS BFCNs. Genes encoding oxidative phosphorylation subunits and glycolysis enzymes are dysregulated in DS BFCNs.

  PublisherOA PDFDOI

• Maturation of marmoset cortical cytoarchitecture from birth to adolescence with ultra-high-resolution diffusion MRI

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: Understanding cortical cytoarchitectural maturation in the developing non-human primate brain is crucial for insights into evolution and neurodevelopment. Goal(s): To uncover spatiotemporal changes of cortical cytoarchitectural maturation in marmoset brains from birth to adolescence with cutting-edge ultra-high-resolution multi-shell diffusion-MRI (dMRI) at 100μm isotropic resolution. Approach: Ultra-high resolution multi-shell dMRI at 9.4T was performed on marmoset brains at birth, 10-months, and 2 years. Diffusion tensor and kurtosis were fitted. Region-specific cortical microstructure maturation trendlines were delineated. Results: Our findings reveal the cortical cytoarchitectural maps with mean kurtosis and fractional anisotropy as well as distinct, region-specific temporal courses of these measures. Impact: We reveal heterogenous cortical cytoarchitecture maturation patterns in developing marmoset brains, highlighting increased mean kurtosis and decreased fractional anisotropy over time. Our study provides a foundation for understanding neurodevelopmental milestones and evolutionary aspects of cortical maturation in primate models.

  PublisherDOI

• Dynamic landscapes of gene regulatory networks in early mammalian neurogenesis: Insights into brain evolution and disorder risk

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-08

  preprintOpen access

  Neurogenesis-the process of generating neurons-is governed by dynamic transcriptional programs that vary across time, brain regions, and cell types, forming regionally specialized neuronal circuits. To understand these dynamics, we constructed a comprehensive gene regulatory network (GRN) resource encompassing 22 neurogenic lineages from human, macaque, and mouse, enabling cross-species and cross-regional comparisons. Leveraging state-of-the-art trajectory analysis and GRN inference, we characterized temporal regulatory dynamics and introduced a "dynamic score" to identify key subnetworks with lineage-specific dynamics, including hundreds of regulons and co-regulatory modules. Our analysis uncovered both known and novel candidate regulators driving neuronal differentiation and regional identity, spanning the entire human brain, as well as evolutionary divergence in neurogenic GRNs distinguishing human brains. Mapping risk genes to the resource helped understand associated early gene regulatory dynamics with 35 neurodevelopmental disorders and traits including autism, schizophrenia, severe intellectual disability, and microcephaly. This resource is publicly available as an interactive online platform.

  PublisherOA PDFDOI

• Common coordinate frameworks of developmental marmoset brain from birth to adolescence based on ultra-high-resolution diffusion MRI

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: A standardized anatomical common coordinate framework (CCF) is essential to integrate spatially resolved, molecularly defined cell atlases with neurophysiology and behavior for developmental marmoset brain. Ultra-high-resolution diffusion-MRI (dMRI) improves anatomical determinations and provides rich contrasts and microstructural information. Goal(s): To build the first dMRI-based anatomical CCFs for marmoset brains from birth to adolescence. Approach: Ultra-high resolution dMRI at 9.4T was performed on neonate, 10-month-old, and 2-year-old marmoset brains. Anatomical regions were delineated. Results: Ultra-high-resolution CCFs for developmental marmoset brains at isotropic 0.1mm diffusion MRI imaging resolution, characterized by comprehensive labels of fine neuroanatomical structures. Impact: The first developmental marmoset brain CCFs from birth to adolescence will allow integrating spatially resolved and molecularly defined cell atlas with studies of developing brain function, neurophysiology, and behavior. They will provide insights into evolution and human-specific features of brain development relevant to brain disorders.

  PublisherDOI

• Adaptive Evolution of Gene Regulatory Networks in Mammalian Neocortical Neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-21 · 1 citations

  preprintOpen access

  Abstract Mammals have evolved a plethora of adaptations that have enabled them to thrive in diverse environments. Among the most significant is the emergence of a more complex brain, exemplified by the dramatic transformation of the dorsal cortex from a single layer of excitatory projection neurons (ExNs) in ancestors to a multilayered cerebral neocortex enriched with diverse intratelencephalic (IT) and extratelencephalic (ET) ExN subtypes. These ExNs established specialized projection systems, such as the corticospinal tract and corpus callosum, enhancing brain connectivity and functionality. However, the evolutionary mechanisms underlying these mammalian-specific adaptations remain elusive. By comparing the landscape of gene expression and cis-regulatory elements (CREs) in mouse ExN subtypes and by cross-species examination of mammalian and non-mammalian CREs, we identified mammalian-specific CREs and expression patterns. The mammalian-specific CREs include a subset bound by ZBTB18 that are associated with genes defining IT and ET subtypes and connectivity. Both ZBTB18 and these target genes have previously been implicated in intellectual disability and autism. Deletion of Zbtb18 in mouse ExNs dysregulated target gene expression, reduced molecular diversity, diminished corticospinal and callosal projections, and increased intrahemispheric cortico-cortical association projections to the prefrontal cortex, resembling features of non-mammalian dorsal pallium. Interestingly, ZBTB18 binding motifs are highly enriched in callosally projecting IT-biased CREs, where they show higher conservation specifically in mammals. This study uncovers critical components and mammalian-specific evolutionary adaptations within a regulatory node essential for neocortical ExN identity and connectivity, with implications for neurodevelopmental and neuropsychiatric disorders.

  PublisherOA PDFDOI

Frequent coauthors

• Nenad Šestan

  47 shared

• Gabriel Santpere

  Barcelona Biomedical Research Park

  37 shared

• Daifeng Wang

  26 shared

• Mingfeng Li

  23 shared

• Patrick R. Hof

  Icahn School of Medicine at Mount Sinai

  18 shared

• Mihovil Pletikos

  Yale University

  17 shared

• Zhen Li

  Shanghai Sixth People's Hospital

  15 shared

• Daniel H. Geschwind

  Center for Autism and Related Disorders

  15 shared

Labs

• Sousa LabPI

  Not provided

Education

• Ph.D., Neuroscience

  University of Wisconsin–Madison

  2007

• M.S., Neuroscience

  University of Wisconsin–Madison

  2003

• B.S., Neuroscience

  University of Wisconsin–Madison

  2001