About

Ronald P. Hart, Ph.D., is a Professor in the Department of Cell Biology and Neuroscience at Rutgers University. His research focuses on using stem cells to study neurogenesis and neural diseases. He aims to create normal and disease-specific induced pluripotent stem cells (iPSC) to understand mechanisms of neurogenesis and model diseases of the human nervous system. As part of the NIMH Stem Cell Center in collaboration with RUCDR Infinite Biologics®, he has developed iPSC from conditions such as Ataxia-telangiectasia, Schizophrenia, nicotine addiction disorders, Alzheimer's Disease, and autism. His laboratory uses iPSC to program stem cells into specific neuronal subtypes for disease modeling and therapeutic transplantation. Additionally, he studies the role of microRNAs in neurogenesis, identifying new microRNAs involved in early stem cell development and exploring their potential to program stem cells for therapeutic purposes. His work includes collaboration with the Broad Institute on studying small RNAs as regulators of epigenetic chromatin marking.

Research topics

• Genetics
• Medicine
• Biology
• Pathology
• Neuroscience
• Immunology
• Developmental psychology
• Psychology
• Psychiatry
• Cell biology
• Clinical psychology

Selected publications

• Uncovering NMDA receptor-mediated high firing activity in excitatory human neurons

  iScience · 2026-02-17

  articleOpen access

  -free ACSF across multiple donor lines, uncovering donor-specific firing phenotypes. This protocol facilitates functional analyses of iGlut neurons while preserving single-cell resolution, enabling detailed characterization of iGlut neurons in diverse applications such as CNS disease modeling and drug screening. This protocol establishes a versatile framework for large-scale studies of neuronal network dynamics and individual excitability in iPSC-derived iGlut neurons.

  PublisherDOI

• Multiplex Portuguese Families as a Lens into rare mutations and the Shared Genetic Architecture of Schizophrenia, Mood Disorders, and Autism Spectrum Disorders

  medRxiv · 2026-04-07

  articleOpen access

  Abstract In an analysis of 173 multiplex families from the Portuguese Island Collection (PIC) this study characterizes the shared genetic architecture of serious mental illnesses (SMI) including schizophrenia (SZ) , bipolar disorder (BP) , major depression (MDD) , and autism (ASD) . Within this cohort, co-segregation of psychotic and mood disorders occurred in 28% of families, while 7% demonstrated co-segregation of intellectual disability or ASD with SZ and mood disorder phenotypes. Whole-genome sequencing (WGS) was performed on a three-generation PIC family to identify rare, large-effect variants. This led to the identification of an extremely rare predicted loss of function (LoF) mutation in the Chromodomain Helicase DNA Binding Protein 2 (CHD2) gene. These results demonstrate that high-density multiplex families in founder populations are a powerful resource for mapping rare, large-effect variants that cross clinical diagnostic boundaries, as the identified CHD2 mutation suggests that the disruption of a single neurodevelopmental gene may lead to diverse SMI phenotypes. By combining population and family-based methodologies, this approach leverages shared genetic backgrounds and environments to provide a unique opportunity for cellular studies to explore the biological mechanisms underlying SMI, offering significant potential to inform future functional research and identify novel therapeutic targets.

  PublisherOA PDFDOI

• Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia

  Nature Communications · 2025-10-21 · 1 citations

  articleOpen access

  The maintenance of metabolic homeostasis relies on the ability to flexibly transit between catabolic and anabolic states in response to insulin signaling. Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α. In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance. Consequently, cells exhibit a compensatory dependence on glutamine as an alternative metabolite for energy metabolism. Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin. Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration. These findings suggest that peripheral metabolic deficiencies may contribute to sustained neurodegenerative changes in A-T, underscoring the importance of screening, monitoring and addressing these metabolic disruptions in patients.

  PublisherOA PDFDOI

• Creatine mitigates neurogenesis impairment caused by defective DcpS decapping

  Scientific Reports · 2025-05-23 · 1 citations

  articleOpen access

  Biallelic mutations in the DCPS gene disrupting the decapping activity of the scavenger decapping protein DcpS, leads to neurodevelopmental deficiencies and intellectual disability. However, the molecular basis for the neurogenesis defects in these individuals remains unknown. Here we show that cells derived from individuals with a DCPS mutation harbor a creatine deficiency and a corresponding elevation of the creatine precursor, guanidinoacetate (GAA). The altered metabolite levels are a consequence of a reduction in both the mRNA and protein levels for the enzyme that converts GAA into creatine, guanidinoacetate methyltransferase. Importantly, the compromised neurogenesis and neurite outgrowth phenotypes observed during the differentiation of DcpS mutant patient derived induced pluripotent stem cells into neurons was reversed upon supplementation of creatine monohydrate. These findings suggest creatine deficiency as an underlying factor for the neurogenetic defect detected in DcpS mutant cells and a potential driver of the neurological deficiencies in affected individuals.

  PublisherOA PDFDOI

• Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-06

  preprintOpen accessSenior authorCorresponding

  Abstract Alcohol use disorders (AUDs) affect substantial populations worldwide and increase the risk of developing cognitive impairments and alcohol-associated dementia. While chronic inflammatory signaling likely plays an important role in alcohol-associated neurological sequalae, the precise mechanisms underlying alcohol-associated neuropathology remain enigmatic. We hypothesize that alcohol leads to neuroimmune dysregulation among neurons, astrocytes, and microglia; and is perpetuated by innate immune signaling pathways involving cell-cell signaling. To investigate how alcohol dysregulates neuroimmune interactions in a human context, we constructed a triculture model comprising neurons, astrocytes, and microglia derived from human induced pluripotent stem cells. After exposure to ethanol, we observed significant differential gene expression relating to innate immune pathways, inflammation, and microglial activation. Microglial activation was confirmed with morphological analysis and expression of CD68, a lysosomal-associated membrane protein and marker for phagocytic microglial activation. A striking finding in our study was the elevation of TREM2 expression and, specifically, TREM2 alternative splice variants that are predicted to give rise to soluble TREM2. TREM2 has been reported to be a risk factor for Alzheimer’s disease. These results suggest that ethanol exposure in the brain may lead to increased microglial activation and production of soluble isoform named TREM2 219 through alternate splicing. Deciphering the molecular and cellular mechanisms underpinning ethanol-related neuroimmune dysregulation within a human context promises to shed light on the etiology of AUD-related disorders, potentially contributing to the development of effective therapeutic strategies. Highlights We prepared a “triculture” of human iPSC-derived neurons, astrocytes and microglia Ethanol treatment produces substantial changes in gene expression with prominent effects on neuroimmune signaling Several microglia-specific genes are induced by ethanol in tricultures but not in cultures of microglia alone TREM2 expression is increased following ethanol treatment and results indicate a differential splicing of isoforms, encoding a soluble form of TREM2

  PublisherOA PDFDOI

• Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer’s risk via ERRα dysregulation and energy dyshomeostasis

  Nature Communications · 2025-11-22 · 1 citations

  articleOpen access

  Sex-biased differences in Alzheimer's disease (AD) are well documented, but the mechanisms underlying increased vulnerability in postmenopausal women remain unclear. This study aimed to model the effects of perimenopausal hormonal fluctuations on AD pathophysiology. Using a VCD-induced accelerated ovarian failure model in young female C57BL/6 J and 3xTg mice, we simulated a perimenopausal state with hormonal changes characterised by elevated oestradiol levels and reduced progesterone levels. Supporting human brain transcriptomic and metabolomic data from the ROSMAP study revealed that impaired oestrogen-related receptor alpha (ERRα) function was a key driver of female sex-biased vulnerability. In female mice, progesterone-guided oestrogen receptor signalling maintained ERRα activity by regulating neuronal cholesterol homoeostasis and the TCA cycle. Hormonal imbalances disrupted this mechanism, triggering an aspartate-driven "minicycle," which increased glutamate release, neuronal excitability, ATP depletion, and energy crisis susceptibility. This study demonstrates how perimenopausal hormonal imbalances exacerbate AD risk via ERRα dysfunction, linking neuronal cholesterol and energy homeostasis to disease vulnerability.

  PublisherDOI

• Protocol for Creating iPSCs from Erythroblasts v1

  2025-10-24

  articleOpen accessSenior author

  Genetics repositories usually store cryopreserved lymphocytes (CPL) from individual subjects. After GWAS or other types of genotyping, it is desirable to reprogram selected CPL with known diagnoses, genotypes, or other useful parameters into induced pluripotent stem cells (iPSC) for initiating functional assays on specific cell types. De-identified repository specimens are specifically excluded from human subjects regulations. We have optimized the production of iPSC by first expanding erythroblasts, which are then infected with commercial Sendai vectors expressing reprogramming factors. The expanded erythroblasts can be frozen as backup in case reprogramming fails to produce iPSC colonies. This protocol covers each step in the process.

  PublisherOA PDFDOI

• Integrated single-cell multiomic profiling of caudate nucleus suggests key mechanisms in alcohol use disorder

  Nature Communications · 2025-10-13 · 5 citations

  articleOpen access

  Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. A significant portion of the alcohol-related differences in gene expression were accompanied by a corresponding difference in chromatin accessibility within the gene. We observed transcriptional differences in medium spiny neurons that impact RNA metabolism and immune response pathways. A small cluster of D1/D2 hybrid neurons showed AUD-induced differences distinct from the D1 and D2 types, suggesting a unique role in AUD. Those with AUD had a higher proportion of microglia in an inflammatory state; astrocytes entered a reactive state partially regulated by JUND. Oligodendrocyte dysregulation was driven in part by OLIG2 activity and increased TGF-β1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1β pathway. These findings provide valuable insights into the genetic and cellular mechanisms in the caudate related to AUD. They also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.

  PublisherOA PDFDOI

• Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model

  Alcohol · 2025-11-07

  articleOpen accessSenior author
  PublisherOA PDFDOI

• High-throughput measurements of neuronal activity in single human iPSC-derived glutamate neurons

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

  preprintOpen access

  Abstract Induced pluripotent stem cell (iPSC)-derived neurons provide a promising platform for studying neuronal function and modeling central nervous system (CNS) diseases. However, functional analysis of large populations of iPSC-derived neurons has been challenging. Here, we developed a high throughput strategy targeting N-methyl-D-aspartate receptors (NMDA-R) to enhance neuronal activity and reveal functional phenotypes in human iPSC-induced glutamatergic neurons (iGlut). Using a genetically encoded calcium indicator (GCaMP8f), we first demonstrate that using artificial cerebrospinal fluid (ACSF) lacking Mg 2 + (Mg 2 +-free) significantly increases neuronal firing, and that firing is enhanced by a potentiator (glycine) but inhibited by the NMDA-R antagonist AP-V. Similarly, multi-electrode array (MEA) recordings also show robust firing in Mg 2 +-free ACSF. Lastly, single-cell patch-clamp electrophysiology confirms the high firing rates in Mg 2 +-free ACSF across multiple iPSC donor lines and also reveals iPSC donor-specific tonic and bursting firing phenotypes. This new methodology provides a scalable, high-throughput method to study neuronal activity in iGlut neurons while preserving single-cell resolution. The strategy also reveals different functional phenotypes, enabling detailed characterization of iGlut neurons in diverse applications such as CNS disease modeling and drug screening. These findings establish a versatile framework for future studies of neuronal network dynamics and individual excitability in iPSC-derived neuronal cultures.

  PublisherOA PDFDOI

Recent grants

• NIH Grant K02MH000855

  NIH · $396k · 1995

• NIH Grant R01MH051564

  NIH · $386k · 1998

• NIH Grant RC1CA147187

  NIH · $996k · 2012

• NIH Grant R21DA035594

  NIH · $409k · 2016

• NIH Grant R21DA032984

  NIH · $425k · 2014

Frequent coauthors

• Zhiping P. Pang

  Rutgers Sexual and Reproductive Health and Rights

  64 shared

• Nancy York

  Bellarmine University

  50 shared

• Heather Johnson

  University of Pittsburgh

  50 shared

• Harvey Brooks

  50 shared

• Howard J. Edenberg

  Indiana University – Purdue University Indianapolis

  39 shared

• Jay A. Tischfield

  Rutgers, The State University of New Jersey

  33 shared

• G. Miller Jonakait

  New Jersey Institute of Technology

  29 shared

• Danielle M. Dick

  Rutgers, The State University of New Jersey

  28 shared

Education

• Ph.D., Cell & Molecular Biology

  University of Michigan

  1981

• B.S., Biology

  University of Connecticut

  1977