Benjamin Deneen, PhD, completed his undergraduate studies in Genetics at University of California Davis and focused his graduate studies at UCLA on Cancer Biology, studying pediatric sarcoma. Switching gears for his post-doctoral fellowship, Deneen studied Developmental Neuroscience at the California Institute of Technology.

In 2009, he started his laboratory at the Baylor College of Medicine in the Center for Cell and Gene Therapy and Department of Neuroscience. Over the past 17 years,  Deneen’s lab has made seminal contributions to our understanding of glial development, glial control of brain circuit function, and the neuroscience of brain tumors. 

In 2021, he founded the Center for Cancer Neuroscience, where he leads a multi-disciplinary program focused on understanding how brain tumors interact with neurons and the tumor ecosystem, while leveraging these insights to find new therapies. Basic discoveries from these efforts have launched several, cancer neuroscience-informed clinical trials.

Over the past twenty years our knowledge of astrocytes has undergone a renaissance highlighted by the identification of dynamic physiological activities, key roles in circuit function, and diverse molecular properties. Central to the physiological activities of every cell are transcription factors (TFs) and our molecular studies on astrocyte diversity highlighted the expression of developmental TFs in mature astrocytes, in the adult brain including Sox9 and NFIA. I will describe our recent studies that identified region-specific roles in mature astrocytes for Sox9 and NFIA, where olfactory bulb astrocytes require Sox9 for circuit function, while hippocampal astrocytes require NFIA to maintain circuit function and memory. I will further discuss new work in this area that expands these regional TF dependencies to experience dependent plasticity and pathological states, focusing on Alzheimer’s Disease and Psychiatric Disorders, including suicide.

Gord Fishell, PhD, is recognized for his work on the generation of cortical interneurons and for understanding their contribution to cortical development and function. Gord’s seminal discoveries concerning the interneuron properties both in normal brain development, as well as their involvement in neuropsychiatric diseases have allowed him to understand both their development and how they can be targeted and manipulated in less genetically amenable species, such as humans. His work has emphasized that cortical interneuron development combines early genetic programs imbued on interneurons at birth and modulated by the circuits they integrate into in the cortex. His work also emphasizes that development and circuit function are intimately connected in normal brain, as well as in dysfunction in disease.

Gord is a pioneer in the use of molecular genetic approaches to decipher the development, organization and function of cortical interneurons. His studies have provided fundamental understanding of the origins, genetic identities and physiological properties of cortical interneurons and how they are established in development. 

His laboratory has worked to understand the inhibitory cells that regulate excitatory signaling in the brain.  In its simplest sense, brain inhibition is the stop signal that prevents the brain from becoming over-excited.  In practice it is much more nuanced. 

Gord’s scientific contributions have been recognized in many ways, including giving the presidential lecture at the Society for Neuroscience (SFN) in 2014, a Harvey lecture in 2022, and election to the National Academy of Sciences in 2023.

Despite arising from a common structure, cortical interneurons are among the most diverse cell in the CNS. In this lecture, I will discuss work in my laboratory about our efforts to understand how this diversity is generated.  In the first portion of the lecture, I will discuss recent results in my laboratory that show how influences from the pyramidal neurons, as interneurons settle in the cortex, are essential for the specification of specific interneuron subtypes. In the second portion of the talk, I will discuss complementary work that arose from our efforts to characterize the genetic and epigenetic identity of interneurons as they mature. From this endeavor, we have recognized that we can identify CIS-acting DNA elements that direct the specific expression of subtype specific genes in particular interneuron subtypes. This effort has allowed us to identify enhancer-elements that allow associated adenoviruses in targeted interneuron subtypes. Although more an engineering achievement, this provides the means to target, manipulate and study specific subtypes of interneurons (and by proxy any neuronal subtype) without the need for specialized tools. This provides the tools to study interneurons and other subtypes in species such primates (including humans) to target and manipulate specific neurons in vivo. Together this work demonstrates how basic efforts to understand interneuron diversity provides the mean to understand both normal development and provides a route to create tools to understand and repair the CNS.

David D. Moore, PhD, is the Robert C. and Veronica Atkins Professor and Chair of the Department of Nutritional Sciences and Toxicology at the University of California, Berkeley. 

The focus of the Moore laboratory is the nuclear hormone receptor superfamily, particularly orphan and former orphan receptors with important regulatory functions in the areas of metabolism and cancer. He has authored more than 200 original research reports and has been awarded 11 patents on various technologies related to nuclear hormone receptors. He has received the Edwin B. Astwood Award from the Endocrine Society, the Transatlantic Medal from the UK Society for Endocrinology, the Adolf Windaus Prize from the Falk Foundation and is a fellow of the American Association for the Advancement of Science and a member of the National Academy of Sciences.  

Moore was the Robert R. P. Doherty Jr. - Welch Professor in the Department of Molecular and Cellular Biology and professor in the Departments of Medicine and Molecular and Human Genetics at the Baylor College of Medicine (BCM) until 2021. Before coming to BCM in 1997, he was an assistant and associate professor in the Department of Genetics at Harvard Medical School, as well as assistant and associate Molecular Biologist in the Department of Molecular Biology at Massachusetts General Hospital. 

The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also function coordinately to control other metabolic pathways relevant to liver energy balance, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. These receptors have opposite impacts on another pathway very relevant to energy balance, autophagy, which is induced by PPARα but suppressed by FXR. Autophagy repletes the intracellular pool of amino acids by recycling, but the process of secretion depletes the same pool. Because 40% of the mRNA in hepatocytes encodes secreted proteins and approximately 10% of the ATP used in the cell goes to their translation, secretion is very relevant to hepatic energy balance. Through both transcriptomic and proteomic profiling, we have found that the liver secretome is directly suppressed by PPARα but induced by FXR. This discovery is linked to human development by previous studies that demonstrated a striking deficiency in bile acid levels in malnourished mice and also in malnourished children. Further results confirm that the fasting responsive PPARα is activated in undernourished mouse models and we have found that multiple hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. This includes repression of liver secretome components in the complement and coagulation cascades, and undernourished mice show blood coagulation defects that are also observed in malnourished human subjects. Finally, we have found that chronic PPARα activation directly suppresses overall translation in the liver via a pathway linked, unexpectedly, to decreased hepatic iron and heme levels. Overall, we conclude that PPARα and FXR function coordinately to integrate liver energy balance.

Samuel L. Pfaff, PhD, is a professor at the Salk Institute for Biological Studies and the head of the Goldman Laboratory for Neural Circuit Dynamics in the Gene Expression Laboratory. He is the Benjamin H. Lewis Chair in Neuroscience at the Salk Institute and holds appointments with the Biology, Biomedical Sciences, Neuroscience and Bioengineering programs at the University of California, San Diego. He is the recipient of the Javits Neuroscience Investigator Award, McKnight Scholar Award, PEW Scholar Award, Alfred P. Sloan Research Fellow Award and Fellow of the American Association for the Advancement of Science. 

Pfaff is best known for characterizing one of the earliest examples of molecular diversification among neuronal subtypes through his analyses of the combinatorial activity of the LIM-homeodomain gene family in spinal neurons. The simple concept that genes can be used to mark specific neuronal subtypes is revolutionizing how functional studies of circuits are performed and has led to important tools for guiding the conversion of stem cells into neuron subtypes.

He received his bachelor's degree in biology from Carleton College and his doctorate in Molecular Biology from the University of California, Berkeley. His post doctoral training was completed at Vanderbilt University with William Taylor on gene regulation followed by Columbia University with Thomas Jessell on neural development. 

A major task of the central nervous system (CNS) is to control behavioral actions, which necessitates a precise regulation of muscle activity. The final components of the circuitry controlling muscles are the motorneurons, which settle into pools in the ventral horn of the spinal cord in positions that mirror the musculature organization within the body. This 'musculotopic' motor-map then becomes the internal CNS reference for the neuronal circuits that control motor commands. This talk will review recent progress in defining the neuroanatomical organization of the higher-order motor circuits in the cortex and spinal cord, and our current understanding of the integrative features that contribute to complex motor behaviors. We highlight emerging evidence that cortical and spinal motor command centers are loosely organized with respect to the musculotopic spatial-map, but these centers also incorporate organizational features that associate with the function of different muscle groups during commonly enacted behaviors.

Franck Polleux, PhD, is a professor of Neuroscience at Columbia University and a Principal Investigator at the Zuckerman Mind Brain Behavior Institute in New York. 

Polleux focuses on the identification of novel cellular and molecular mechanisms underlying the development and function of synapses, neurons and circuits in the mammalian neocortex. More recently, his lab started studying the genetic basis of human brain evolution by focusing on the role of human-specific gene duplications as genetic modifiers of synaptic connectivity, circuit function and their impact on cognition. His work demonstrates that human-specific genes such as SRGAP2B/C not only represent human-specific modifiers of brain development but also represent unique human-specific disease modifiers in the context of neurodevelopmental disorders such as autism spectrum disorders. In collaboration with the lab of Attila Losonczy, he recently started to study the synaptic and molecular basis of feature selectivity of place cell emergence using mouse CA1 hippocampal pyramidal neurons as a model. 

Polleux was awarded the Albert L. Lehninger Research Prize for postdoctoral research, the 2005 NARSAD Young Investigator Award, the 2015 Foundation Roger De Spoelberch Prize, a 2021 Nomis Foundation Award and the 2021 R35 Research Program Award, a career award from the NIH-National Institute of Neurological Disorders and Stroke (NINDS). 

He obtained his PhD at Université Claude Bernard in Lyon France under the supervision of Henry Kennedy and Colette Dehay. He completed his postdoctoral training with Anirvan Ghosh at Johns Hopkins University. He started his independent research career at UNC-Chapel Hill, then moved to Scripps Research Institute in La Jolla, CA.  

Two of the most striking features distinguishing human cortical pyramidal neurons (CPNs) from other mammals which are thought to play a role in the emergence of our unique cognitive abilities are: (1) human CPNs receive significantly more excitatory and inhibitory synapses than any other mammalian species including non-human primates and (2) synaptic development is strikingly neotenic in humans, taking years to reach maturation compared to weeks or months in other mammalian species. Our lab identified two human-specific gene duplications called SRGAP2B/C which, by inhibiting all known functions of the ancestral postsynaptic protein SRGAP2A, leads to slower (neotenic) rates of excitatory (E) and inhibitory (I) synaptic maturation and increased E and I synapse number (Charrier et al. Cell 2012; Fossatti et al Neuron 2016). We demonstrated that induction of expression of human-specific genes SRGAP2B/C in mouse CPNs increases specifically the number of cortico-cortical synaptic connections they receive leading to changes in the coding properties of these neurons in vivo as well as improved behavioral performance in a sensory discrimination task (Schmidt et al. Nature 2021). I will also present recent evidence demonstrating the function of human-specific SRGAP2B/C in human neurons as key mediators of synaptic neoteny, using a novel xenotransplantation model, in collaboration with Pierre Vanderhaeghen’s lab (Libé-Philippot et al. Neuron 2024). In this study, we also uncovered that SRGAP2A exerts its effects on synaptic maturation through cross-inhibition of the postsynaptic accumulation of SYNGAP1, a gene frequently mutated in Autism Spectrum Disroders (ASD). In fact, our results demonstrate that the phenotypic expression of Syngap1 mutations is essentially human-specific since it affect a human-specific traits: neotenic synaptic maturation. These results provide the first evidence that human-specific genes such as SRGAP2B/C are not only relevant to understand human brain evolution but also constitute human-specific disease modifiers. 

I will also present new unpublished results demonstrating that human-specific SRGAP2B/C genes also act as master regulators of the timing of structural and functional maturation of microglial cells using both humanized mouse models and SRGAP2B/C loss-of-function approaches using human iPSC-derived microglia xenotransplantation in mouse neonatal cortex. Our results demonstrate that SRGAP2B/C-dependent induction of neotenic maturation of microglial cells participates non-cell autonomously to the delayed timing of synaptic maturation in cortical pyramidal neurons. Our results reveal that, during human brain evolution, human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers in both neurons and microglia.

Robert G. Roeder, PhD, is the Arnold and Mabel Beckman Professor and Head of the Laboratory of Biochemistry and Molecular Biology at The Rockefeller University. For over 50 years he has pioneered biochemical studies of the mechanism and regulation of gene transcription in animal cells. He is best known for his discovery and mechanistic analyses of the nuclear enzymes (RNA polymerases I, II, III) that transcribe the three major classes of RNA ((Ribonucleic acid), cognate general initiation factors, the prototype gene-specific transcriptional activator and a variety of ubiquitous and tissue-specific transcriptional co-activators, such as the Mediator complex, that facilitate interactions between enhancers and promoters. Key features of these studies were the development of cell-free systems in which cloned genes (as DNA or recombinant chromatin templates) are accurately transcribed by purified factors as they are in the cell; and extensions to biological processes that include development, cell differentiation and cancer.

His numerous honors include the Eli Lilly Award in Biological Chemistry, the NAS-US Steel Award in Molecular Biology, the Alfred P. Sloan Prize, the Louisa Gross Horwitz Prize, the Gairdner Foundation International Award, the Albert Lasker Award in Basic Medical Research, the Salk Medal for Scientific Excellence, the Albany Medical Center Prize in Medicine and Biomedical Research, the Kyoto Prize in Basic Science and election to the National Academy of Sciences and the American Academy of Arts and Sciences. 

Roeder received a bachelor’s degree from Wabash College and a doctorate in biochemistry from the University of Washington. 

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor (NR) essential for adipocyte differentiation and function. MED1 is a Mediator coactivator complex subunit that interacts directly with various NRs in a ligand-dependent fashion and mediates strong ligand-dependent transcriptional activation of NR target genes. Although MED1 is dispensable for the general coactivator function of Mediator, it is essential for the ectopic PPARγ2-induced trans-differentiation of mouse embryonic fibroblasts into adipocytes, and also has been considered to be essential for  normal adipogenesis (formation and/or function of both white (WAT) and brown (BAT) adipose tissues). However, our previous studies revealed that the two MED1 LXXLL motifs responsible for the strong ligand-dependent MED1/Mediator-NR interactions are dispensable for adipogenesis in mice. This surprising finding motivated us to validate the MED1 requirement for normal adipocyte formation and function in vivo. Toward this objective, we employed Med1 conditional knockout (cKO) mice and three different Cre-drivers (Myf5Cre-, Ucp1Cre-, and AdipoqCre-) to conditionally delete Med1 in precursors of brown adipocytes, differentiated brown adipocytes and in all adipocytes, respectively. Results with these models led to the conclusion that MED1 is not required for BAT formation, whereas it is essential for the function/maintenance of both BAT and WAT. To further examine the domains necessary for MED1 function in vivo, we generated mouse lines in which the endogenous Med1 locus was engineered to modify MED1. Surprisingly, homozygous mice expressing a MED1 protein lacking most of the large C-terminal domain (including the intrinsically disordered region (IDR)) were viable, but with a decrease in body growth and intolerance to acute cold stress. Considering that the Med1-null mice die at mid-gestation (E10.5), our results indicate that the developmental processes in mice can be achieved with the MED1 structured domain alone. Conversely, our results also raise the possibility of a unique function(s) of the MED1-IDR both in postnatal growth and energy homeostasis.

John L. R. Rubenstein, MD, PhD, is a resident physician in child psychiatry at Stanford specializing in autism. Rubenstein devised a method to identify genes that are preferentially expressed in the embryonic forebrain, which led to the discovery of the Dlx2 and Tbr1 transcription factors. These genes served as entry points for his studies at UCSF where, since 1991, has performed genetic studies of mammalian forebrain development and human neuropsychiatric disorders. Rubenstein has investigated: organization of the embryonic forebrain; forebrain patterning centers and their regulation of cortical organization; transcription factors and enhancers that control regional and cell-type specification of brain subdivisions; differentiation, migration and function of GABAergic interneurons; translational studies of treatment for epilepsy; analyses of transcription factor mutations that may contribute to autism.

Rubenstein trained eight doctoral students and over 50 postdoctoral fellows. Rubenstein has extensive mentoring experience and several trainees are now professors, including: Stewart Anderson, Sonia Garel, Robert Hevner, Juhee Jeong, Eirene Markenscoff-Papadimitriou, Oscar Marin, Matt Porteus, Lori Sussel, Daniel Vogt.

Rubenstein earned a Phi Beta Kappa as a chemistry major at Stanford. In the Medical Scientist Training Program at Stanford Rubenstein, he earned a doctorate in Biophysics for his studies on the effect of cholesterol on the motions of phospholipids in membranes as well as the biogenesis of plasma membrane proteins with Harden McConnell and James Rothman. As a postdoctoral fellow at the Pasteur Institute with Francois Jacob and J.F. Nicolas, Rubenstein was one of the discoverers that antisense RNA can inhibit gene expression. 

The embryonic basal ganglia (ganglionic eminences) generate GABAergic projection neurons for nuclei such as the striatum and globus pallidus, as well as local circuit neurons that migrate to, and integrate within the cortex and hippocampus. We have been working on the early development of the medial ganglionic eminence (MGE) and have uncovered an unexpected feature of its morphogenesis. It has a rostrodorsal growth zone that generates new ventricular zone cells that are displaced caudoventrally. Over time the transcriptional profile of these progenitors change. We have identified a family of transcription factors that are induced as the ventricular zone matures – these proteins control the types of interneurons that are generated by the MGE.

Hongjun Song, PhD, is the Perelman Professor of Neuroscience at Perelman School of Medicine of University of Pennsylvania. The research in Song’s laboratory focuses on the development and plasticity in the mammalian nervous system, in particularly, adult neurogenesis and euroepigenetics/neuroepitranscriptomics. His laboratory also uses patient-derived stem cells and tumor cells in 2D cultures and 3D organoids to investigate human brain development and disorders.

Song has won a number of awards, including Young Investigator Award from the Society for Neuroscience (SFN), Jacob Javits Neuroscience Investigator Award and Landis Mentorship Award for Outstanding Mentorship from National Institutes of Health. He is a member of the National Academy of Medicine (NAM) and a fellow of the American Association for the Advancement of Science (AAAS).

Song received his bachelor's degree from Peking University, a master’s degree from Columbia University and a doctorate from University of California at San Diego.

The mammalian hypothalamus regulates endocrine, autonomic, and behavioral functions through its diverse nuclei and neuronal subtypes. However, the developmental mechanisms that establish its distinct nuclei and generate its neuronal diversity remain poorly understood compared to layered brain structures like the cortex. To define the molecular and cellular logic underlying the ontogeny of mouse hypothalamic nuclei, we identified combinatorial transcription factor codes—TBX3/OTP/DLX for the arcuate nucleus (Arc) and NKX2.1/SF1 or OTP/DLX for the ventromedial hypothalamus (VMH) and tuberal nucleus (TuN)—that delineate specific neuronal subpopulations. Developmental and clonal analyses revealed that Arc subpopulations arise mosaically from local progenitors, while VMH (glutamatergic) and TuN (GABAergic) neurons are sequentially generated from common embryonic progenitors. Clonal analysis further showed that multiphotent radial glia progenitors orchestrate this establishment through diverse lineages. At the molecular level, we show that the mRNA modification enzyme Mettl14, an m6A methyltransferase, is essential in the embryonic hypothalamus for generating feeding-related Arc neurons; its deletion leads to adult-onset obesity. Furthermore, we developed human iPSC-derived brain subregion specific arcuate nucleus organoids, demonstrating conserved epitranscriptomic regulation in Arc neurogenesis and modeling Prader-Willi syndrome using patient-derived iPSCs. Together, our study reveals integrated cellular and molecular mechanisms governing neuronal diversity and nucleus formation in the mammalian hypothalamus, providing models to study human development and disease.