About

John A. Dani, Ph.D., is the David J. Mahoney Professor of Neurological Sciences and the Chair of the Department of Neuroscience at the University of Pennsylvania. He is also the Scientific Director of the UPENN CNS Consortium and the Director of the Mahoney Institute for Neurosciences (MINS). Dr. Dani's research interests encompass addiction, neural mechanisms of learning and memory, and the cellular biophysics underlying brain communication and adaptability. His work has demonstrated that addictive drugs induce synaptic changes in the brain similar to those involved in learning, and that antidepressant therapies can alter neurotransmitter signaling relationships related to mood regulation. He received his Ph.D. in Physiology from the University of Minnesota and completed postdoctoral training at Yale University, where he worked in the Section of Molecular Neurobiology. His academic career includes positions at Baylor College of Medicine, where he served as Professor and held administrative roles such as Chair of the Neuroscience Appointments, Promotion, and Tenure Committee, and Director of the Center on Addiction, Learning, and Memory. Dr. Dani has also been a Visiting Scholar at MIT and a Wiersma Visiting Professor at Caltech. His research employs techniques such as systems neurophysiology, in vivo recording, electrophysiology, behavioral tasks, and brain slices to explore the signaling and dysfunction of neurotransmitter systems, with a focus on addiction, neurodegenerative diseases, mood disorders, and memory functions during drug exposure, stress, or degenerative conditions.

Research topics

• Neuroscience
• Chemistry
• Psychology
• Pharmacology
• Biology

Selected publications

• ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

  Proceedings of the National Academy of Sciences · 2026-01-09 · 1 citations

  articleOpen access

  Epigenetic mechanisms, including histone acetylation, regulate learning and memory and underlie Alzheimer's disease and related dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme generating acetyl-CoA, locally regulates histone acetylation and gene expression in neuronal nuclei. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously, we showed that systemic ACSS2 knockout mice, although largely normal in physiology, exhibit memory deficits. Here, we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Additionally, boosting histone acetylation through ACSS2 countered age-related memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. These findings position ACSS2 as a key epigenetic regulator of cognitive aging and ADRD, highlighting its potential for targeted therapeutics to enhance brain resilience and function.

  PublisherDOI

• Ventral Tegmental Area Glutamatergic Neurons Suppress Hippocampal Sharp-wave Ripples and Induce Head Movements in Mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-26

  preprintOpen accessSenior author

  Sharp-wave ripples are brief, high-frequency hippocampal oscillations crucial for memory consolidation, occurring predominantly during the non-rapid-eye-movement (NREM) sleep. While ripples are generated intrinsically within the hippocampus, growing evidence suggests that their occurrence is modulated by subcortical regions. Whether the ventral tegmental area (VTA)-a subcortical region that directly projects to the hippocampus-regulates ripple activity remains unknown. To investigate this, we optogenetically activated VTA neurons during NREM sleep and recorded ripple activity in the dorsal hippocampus via field recording electrodes. Using cell-type specific excitatory opsin expression in the VTA, we found that activation of glutamatergic (vGlut2+) neurons strongly suppressed ripple incidence. In contrast, activation of GABAergic (vGAT+) neurons produced weak suppression, and activation of dopaminergic (DAT+) neurons showed no effect. During ripple suppression by glutamatergic activation, we observed small but consistent head movements. Trial-by-trial analysis revealed no correlation between head movement and ripple suppression. Furthermore, glutamatergic activation during wakefulness also led to head movement, suggesting that ripple suppression and head movement could be dissociated. Overall, our results suggest that VTA vGlut2+ neurons play a role in head movement and that their activation suppresses hippocampal sharp-wave ripples during NREM sleep, offering a potential way to alter memory consolidation.

  PublisherOA PDFDOI

• Paradoxical ventral tegmental area GABA signaling drives enhanced morphine reward after adolescent nicotine

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-11

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Background An important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction. Methods Male and female adolescent mice received two-weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent three morphine tests: conditioned place preference (CPP), locomotor sensitization, and two-bottle choice. Ex vivo ventral tegmental area (VTA) brain slices were assessed via patch clamp for GABA and dopamine (DA) neuron morphine responses. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP. Results In adulthood, Adol Nic mice had greater morphine CPP, more morphine locomotor sensitization, and more choice-based oral morphine consumption vs. Adol Water mice. In contrast, adult mice given nicotine vs. water had similar morphine CPP. Patch clamp analysis of VTA neurons from adult Adol Water mice showed canonical cell-type responses to bath-applied morphine: fewer action potentials in GABA neurons and more in DA neurons. Paradoxically, VTA GABA and DA neurons from adult Adol Nic mice did not show these morphine responses. In support of a causal relationship between GABA neuron firing and reward behavior, chemogenetic inhibition of VTA GABA neurons in Adol Water mice during pairing increased morphine CPP. In contrast, inhibition of VTA GABA neurons in Adol Nic mice brought morphine CPP down to control levels. Conclusions These data reveal an electrophysiological mechanism by which adolescent nicotine intake promotes morphine reward later in life, showing that adolescent nicotine exposure alters reward circuitry well into adulthood.

  PublisherOA PDFDOI

• Paradoxical Ventral Tegmental Area GABA Signaling Drives Enhanced Morphine Reward After Adolescent Nicotine

  Biological Psychiatry · 2025-06-24 · 3 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-29 · 1 citations

  preprintOpen access

  ABSTRACT Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimer’s disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function. Summary ACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.

  PublisherOA PDFDOI

• Protracted opioid withdrawal behaviors are reduced by nitric oxide inhibition in mice

  Addiction Neuroscience · 2024-07-18 · 6 citations

  articleOpen accessSenior authorCorresponding

  Following opioid cessation, patients with opioid use disorder experience physical and psychological withdrawal symptoms. Prolonged negative affect, including anxiety and heightened stress reactivity, continues after physical withdrawal symptoms subside, contributing to the high relapse rates. The nitric oxide system plays a role in synaptic plasticity downstream of the mu opioid receptor pathway, and nitric oxide synthase inhibitors attenuate physical opioid withdrawal signs. We hypothesized that N(gamma)-nitro-l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, would reduce negative affect after protracted opioid withdrawal. Therefore, we first modeled withdrawal in male and female mice using 5 days of morphine injections followed by behavioral tests after one week of forced abstinence from morphine. One week of morphine withdrawal caused altered responses to tests of affective behavior in both male and female mice. There were, however, both subtle and significant sex differences among many of the behavioral measures of negative affect. Males and females had differences in immobility during the tail suspension test during morphine withdrawal, while only females had altered grooming in the sucrose splash test. Forced l-NAME in the animals’ drinking water during withdrawal attenuated all physical and affective measures of withdrawal in males and females but there were subtle differences. Together, these results suggest that the nitric oxide system may be a target to ameliorate the different behavioral manifestations of negative affect in males and females.

  PublisherDOI

• Dopaminergic regulation of hippocampal plasticity, learning, and memory

  Frontiers in Behavioral Neuroscience · 2023-01-27 · 63 citations

  reviewOpen accessSenior authorCorresponding

  The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus . Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.

  PublisherOA PDFDOI

• CHRNA5 gene variation affects the response of VTA dopaminergic neurons during chronic nicotine exposure and withdrawal

  Neuropharmacology · 2023-04-27 · 8 citations

  articleOpen accessCorresponding
  PublisherOA PDFDOI

• Sex differences in VTA GABA transmission and plasticity during opioid withdrawal

  Scientific Reports · 2023-05-25 · 22 citations

  articleOpen accessSenior author

  Abstract The effectiveness of current treatments for opioid use disorder (OUD) varies by sex. Our understanding of the neurobiological mechanisms mediating negative states during withdrawal is lacking, particularly with regard to sex differences. Based on preclinical research in male subjects, opioid withdrawal is accompanied by increased gamma-aminobutyric acid (GABA) release probability at synapses onto dopamine neurons in the ventral tegmental area (VTA). It is unclear, however, if the physiological consequences of morphine that were originally elucidated in male rodents extend to females. The effects of morphine on the induction of future synaptic plasticity are also unknown. Here, we show that inhibitory synaptic long-term potentiation (LTP GABA ) is occluded in the VTA in male mice after repeated morphine injections and 1 day of withdrawal, while morphine-treated female mice maintain the ability to evoke LTP GABA and have basal GABA activity similar to controls. Our observation of this physiological difference between male and female mice connects previous reports of sex differences in areas upstream and downstream of the GABA-dopamine synapse in the VTA during opioid withdrawal. The sex differences highlight the mechanistic distinctions between males and females that can be targeted when designing and implementing treatments for OUD.

  PublisherOA PDFDOI

• A common SNP in Chrna5 enhances morphine reward in female mice

  Neuropharmacology · 2022-08-13 · 8 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant R01NS048505

  NIH · $1.1M · 2009

• Dopaminergic regulation of in vivo plasticity & memory retention

  NIH · $7.2M · 1987–2023

• NIH Grant R37NS021229

  NIH · $2.1M · 2007

• Acute Nicotine Decreases Alcohol-induced Dopamine Response & Increases Drinking

  NIH · $5.5M · 1997–2019

• Adolescent Exposure to Stress or Nicotine Increases Rodent Alcohol Self-Administration

  NIH · $2.4M · 2019–2025

Frequent coauthors

• William M. Doyon

  University of Pennsylvania

  24 shared

• Mariella De Biasi

  University of Pennsylvania

  21 shared

• Alexey Ostroumov

  Georgetown University Medical Center

  14 shared

• Ramiro Salas

  Baylor College of Medicine

  11 shared

• Fu-Ming Zhou

  Naval University of Engineering

  10 shared

• Lifen Zhang

  Zhengzhou University

  9 shared

• Kechun Yang

  University of Pennsylvania

  9 shared

• Volodymyr I. Pidoplichko

  Uniformed Services University of the Health Sciences

  9 shared

Labs

• Dani LabPI

Education

• Ph.D., Physiology

  University of Minnesota

  1980