About

Lief Fenno, M.D., Ph.D., FAPA, is a physician-scientist and clinician whose work bridges basic neuroscience, bioengineering, and addiction medicine. He holds faculty appointments in Dell Medical School’s Department of Psychiatry and Behavioral Sciences, the College of Natural Sciences’ Department of Neuroscience, and a courtesy appointment in the Department of Biomedical Engineering at the Cockrell School of Engineering. Dr. Fenno directs the Fenno Lab, which develops and applies new molecular, genetic, and viral technologies for precisely defining, monitoring, and controlling neural circuits. His research focuses on creating next-generation tools for understanding brain function and therapeutically manipulating dysfunctional neural systems relevant to psychiatric and neurologic disease. His laboratory investigates biological questions related to neural-circuit mechanisms of psychedelic therapeutics, the roles of non-neuronal cell types in addiction, and approaches to causally link human GWAS findings to circuit dysfunction. Dr. Fenno is an inventor on multiple patents arising from his work, and his technologies are widely used in academia and industry. He has played founding and advisory roles in companies focused on neurotechnology and gene-based therapeutics. Clinically, he specializes in the management of addiction, with a focus on office-based treatment of opioid use disorder and harm-reduction-oriented care. He is board-certified in adult psychiatry and addiction medicine, and serves as chair of the American Psychiatric Association’s Council on Addiction Psychiatry, as well as a voting member of the Texas Opioid Abatement Fund Council. Dr. Fenno earned his B.S. in Neurobiology from Harvard University, and both his M.D. and Ph.D. in neuroscience from Stanford University School of Medicine, followed by residency training in adult psychiatry and postdoctoral training in bioengineering at Stanford.

Research topics

• Biology
• Neuroscience
• Cell biology
• Artificial Intelligence
• Computer Science
• Genetics
• Computational biology
• Biochemistry
• Chemistry
• Nanotechnology
• Endocrinology
• Evolutionary biology
• Materials science

Selected publications

• It’s not all DAT: harnessing the potential of organic cation transporter 3 inhibition to selectively attenuate amphetamine reinforcement and dopamine release

  Neuropsychopharmacology · 2026-03-26

  articleOpen access

  Afflicting over 50 million people worldwide and demonstrating growing global trends of abuse, amphetamine-type stimulant abuse poses a significant public health burden. No effective pharmacological treatments exist for amphetamine-type stimulant use disorders, underscoring a critical need to identify novel, effective therapeutic targets. Amphetamine exerts its actions in part by targeting high-affinity, low-capacity monoamine transporters, particularly the dopamine transporter (DAT). However, therapeutic interventions targeting DAT have been so far unsuccessful. Emerging evidence supports a role for the low-affinity, high-capacity organic cation transporter 3 (OCT3) in the actions of amphetamine. Here we use in vivo electrochemical and behavioral approaches, as well as constitutive and temporally-inducible OCT3 knockout mice, to establish OCT3 as a critical mediator of neurochemical and behavioral actions of amphetamine. We demonstrate that OCT3 substantially contributes to amphetamine-evoked dopamine efflux in dorsal striatum and is key to reinforcing effects of amphetamine in intravenous self-administration assays. Our novel findings provide convergent evidence to suggest that OCT3 plays a central role in mediating abuse-related effects of amphetamine, establishing OCT3 as a potential novel target for the development of therapeutics to treat amphetamine-type stimulant use disorders.

  PublisherDOI

• Aging-related vulnerability in dopamine–glutamate neurons weakens entorhinal dopamine signaling and underlies novelty discrimination deficits

  Research Square · 2026-04-26

  preprintOpen access
  PublisherOA PDFDOI

• Transcriptional and functional divergence in lateral hypothalamic glutamate neurons projecting to the lateral habenula and ventral tegmental area

  UNC Libraries · 2026-02-04

  articleOpen access
  PublisherDOI

• A Knock-in Ntsr1-Flp Driver Enables Intersectional and Systemic Targeting of Heterogeneous Midbrain Dopamine Circuits

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-12

  articleOpen access

  Abstract Precise genetic access to molecularly defined neuronal subpopulations is essential for dissecting circuit heterogeneity. We report the development and validation of a knock-in neurotensin receptor 1 (Ntsr1)-FlpO mouse line enabling intersectional targeting of Ntsr1-expressing neurons. Following Flp-dependent adeno-associated viral (AAV) reporter delivery, we observed robust recombination in the substantia nigra and ventral tegmental area, revealing that midbrain Ntsr1 populations include both dopaminergic and non-dopaminergic neurons. Systemic retro-orbital delivery of a Cre- and Flp-dependent Con/Fon reporter in complementary dual-recombinase configurations demonstrated orientation-dependent differences in dopaminergic targeting specificity. Cis-gene controls defined the maximal achievable dopaminergic ceiling and demonstrated that persistent non-dopaminergic populations exceed expectations from recombinase inefficiency alone. Finally, a dual-recombinase-dependent taCaspase-3 construct enabled intersectional ablation of midbrain dopamine neurons in vivo. Together, these findings establish Ntsr1 Flp as a physiologically neutral, intersectionally compatible driver line supporting scalable Boolean targeting using local and systemic AAV strategies.

  PublisherOA PDFDOI

• Ultrasound-activated drug release with extracellular vesicles

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-14 · 1 citations

  preprintOpen access

  Abstract Precise, noninvasive targeting and controlled drug release to the nervous system could transform both basic research and clinical therapy. In this work, we developed a focused ultrasound–responsive delivery system based on extracellular vesicles (EVs), which are naturally occurring and biocompatible phospholipid nanocarriers. To enable the ultrasound responsiveness, a lipid–gas phase transition material Perfluoropentane (PFP) was co-encapsulated with therapeutic agents into EVs via low-temperature sonication. The resulting EVs had a size of 100–200 nm and demonstrated efficient, on-demand release upon ultrasound stimulation. In primary cultured neurons, EVs loaded with lidocaine successfully suppressed calcium activity and showed minimum cytotoxicity. Finally, we demonstrated in vivo application of this system for modulation pain sensitivity in rats. Our EVs-drugs platform demonstrated a safe, and ultrasound-activated drug delivery with high spatiotemporal control, showing strong potential therapeutic applications.

  PublisherOA PDFDOI

• Hydrogen-bonded organic framework nanotransducers enabled sono-optogenetics for Parkinsonian rats

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-04 · 4 citations

  preprintOpen access

  Cell-type-specific activation of parvalbumin (PV)-expressing neurons in the external globus pallidus (GPe) through optogenetics has shown promise in facilitating long-lasting movement dysfunction recovery in mice with Parkinson's disease. However, its translational potential is hindered by adverse effects stemming from the invasive implantation of optical fibers into the brain. In this study, we have developed a non-invasive optogenetics approach, utilizing focused ultrasound-triggered mechanoluminescent nanotransducers to enable remote photon delivery deep in the brain for genetically targeted neuromodulation. These mechanoluminescent nanotransducers consist of sonosensitized hydrogen-bonded frameworks and chemiluminescent L012, serving as a nanoscale light source through ultrasound-induced cascade reactions. This system offers high ultrasound-triggered brightness and long-lasting light emission, facilitating repeatable deep brain stimulation. Our sono-optogenetics technology demonstrated effective modulation in the mouse motor cortex for limb motion control and activation of PV-GPe neurons for rescuing movement dysfunction over time in dopamine-depleted Parkinson's disease rats. This approach demonstrates the pathway for achieving genetically targeted and non-invasive neuromodulation for long-lasting treatment of Parkinson's disease, towards non-human primate models and clinical applications.

  PublisherOA PDFDOI

• Optogenetics and Related Technologies for Psychiatric Disease Research

  2025-01-01

  book-chapter1st authorCorresponding

  Abstract Causal study of brain function in model organisms is a central goal of neuroscience, and this work is critical to opening new frontiers in the management of psychiatric disease. Optogenetics—the use of light-activated proteins to directly control the activity of defined populations of neurons in awake, behaving animals—has revolutionized neuroscience and is being investigated for clinical use for the direct treatment of human neurological disease. This chapter serves as an introduction to the development of optogenetics, describes the use of this tool class in modern systems neuroscience and applications to understanding mental illness, and outlines current efforts to further develop this technology. Readers can expect to gain a sufficient mechanistic understanding of optogenetics to understand current primary neuroscience research, become familiar with this class of molecular techniques, and to be able to use the text as a reference for further reading.

  PublisherDOI

• eLife Assessment: Generation of knock-in Cre and FlpO mouse lines for precise targeting of striatal projection neurons and dopaminergic neurons

  2025-10-09

  peer-reviewOpen access1st authorCorresponding

  The basal ganglia and midbrain dopaminergic systems are critical for motor control, reward processing, and reinforcement learning, with dysfunction in these systems implicated in numerous neurodegenerative and neuropsychiatric disorders. To enable precise genetic targeting of key neuronal populations, we generated and characterized five knock-in mouse lines: Drd1-Cre, Adora2a-Cre, Drd1-FlpO, Adora2a-FlpO, and DAT-FlpO. These lines allow for Cre-or FlpO-mediated recombination in dopamine D1 receptor-expressing spiny projection neurons (SPNs), adenosine A2a receptor-expressing SPNs, and dopamine transporter (DAT)-expressing neurons in the midbrain. Histological analyses confirmed recombinase activity in expected brain regions, and whole-cell electrophysiological recordings validated the intrinsic excitability profiles of each neuronal subpopulation. These tools provide high specificity and reliability for studying basal ganglia circuitry and dopaminergic neurons. By enabling targeted manipulations, these openly available knock-in lines will advance research into the neural mechanisms underlying motor control, reward, and neuropsychiatric diseases.

  PublisherDOI

• Selective Vulnerability of Dopamine-Glutamate Neurons in Aging Weakens Entorhinal Dopamine Signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-07

  preprintOpen access

  The lateral entorhinal cortex (LEC) is selectively vulnerable to age-related decline and is essential for novelty detection and episodic memory. While DAergic (DAergic) input is known to modulate LEC function, how aging impacts this circuitry remains unclear. Here, we used two viral labeling strategies to investigate projections from the ventral tegmental area (VTA) to the LEC. First, we employed an INTRSECT dual-recombinase approach in TH-Flp::VGLUT2-Cre mice to selectively label dopamine-only (DA-only) and dopamine-glutamate co-releasing (DA-GLU) neurons. Next, we used a DAT-Cre-driven ChR2-YFP strategy to broadly label all DA axons. We found that both DA-only and DA-GLU populations innervate the LEC. With age, we observed a selective reduction in tyrosine hydroxylase (TH) signal within DA axons in the LEC, despite preserved axonal structure as revealed by YFP labeling. VGLUT2 signal within DA-GLU terminals appeared less affected. In the VTA, TH+ neuron density declined with age, with distinct spatial patterns along the anterior-posterior axis. These findings reveal an age-related vulnerability of DAergic projections to the LEC and suggest a circuit-level mechanism may contribute to memory impairments in aging.

  PublisherOA PDFDOI

• Salience Signaling and Stimulus Scaling of Ventral Tegmental Area Glutamate Neuron Subtypes

  Journal of Neuroscience · 2025-06-05 · 3 citations

  articleOpen access

  Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of these neurons cotransmit glutamate and GABA (VGluT2 + VGaT + neurons), transmit glutamate without GABA (VGluT2 + VGaT − neurons), or cotransmit glutamate and dopamine (VGluT2 + TH + neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified in male and female mice that VGluT2 + subpopulations are sensitive to the reward value in unique ways. VGluT2 + VGaT + neurons increased maximum activity with increased sucrose concentration, whereas VGluT2 + VGaT − neurons increased maximum and sustained activity with increased sucrose concentration, and VGluT2 + TH + neurons increased sustained but not maximum activity with increased sucrose concentration. VGluT2 + subpopulations also uniquely signaled consumption of sweet/noncaloric (saccharine) and nonsweet/high-calorie rewards (fat). VGluT2 + VGaT + neurons uniquely signaled lower-calorie sucrose over fat, whereas both VGluT2 + VGaT − neurons and VGluT2 + TH + neurons showed a signaling preference for higher-calorie fat over sucrose but in temporally distinct ways. Further experiments suggested that VGluT2 + VGaT + consummatory reward-related activity was related to sweetness, partially modulated by prefeeding, and not dependent on caloric content. Additionally, aversive stimuli increased activity for each VGluT2 + subpopulation, but VGluT2 + VGaT + neurons uniquely scaled their magnitude and sustained activity with footshock intensity. Optogenetic activation of VGluT2 + VGaT + neurons during low-intensity footshock enhanced fear-related behavior without inducing place preference or aversion. About half of VGluT2 + VGaT + sucrose-sensitive neurons were transcriptionally activated by footshock. We interpret these data such that VTA glutamatergic subpopulations signal different elements of rewarding and aversive experiences and highlight the unique role of VTA VGluT2 + VGaT + neurons in salience signaling.

  PublisherOA PDFDOI

Frequent coauthors

• Karl Deisseroth

  Stanford University

  136 shared

• Charu Ramakrishnan

  Stanford University

  60 shared

• Ofer Yizhar

  Weizmann Institute of Science

  18 shared

• Yoon Seok Kim

  16 shared

• Yoon Seok Kim

  Stanford University

  14 shared

• Feng Zhang

  11 shared

• Wyatt J. Woodson

  Stanford University

  9 shared

• Gary K. Steinberg

  Stanford Medicine

  9 shared

Awards & honors

• American Psychiatric Association fellow