About

René Hen, PhD, is a Professor of Pharmacology (in Psychiatry) and Neuroscience at Columbia University Irving Medical Center. He serves as the Director of the Division of Systems Neuroscience. His research interests include models of psychiatric disorders and stem cell biology. Dr. Hen has contributed to understanding hippocampal neurogenesis, its role in stress resilience, memory modulation, and anxiety. His work explores how adult-born hippocampal neurons influence entorhinal inputs, modulate hippocampal memory traces, and affect behavior related to anxiety and depression. His research has advanced knowledge of neurogenesis and its implications for psychiatric conditions, emphasizing the importance of hippocampal neurogenesis in behavioral effects of antidepressants and in the mechanisms underlying pattern separation and stress resilience.

Research topics

• Neuroscience
• Psychology
• Medicine
• Computer Science
• Biology
• Internal medicine
• Algorithm
• Psychiatry

Selected publications

• Antidepressants reactivate developmental plasticity through remodeling of extracellular matrix

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-04 · 3 citations

  preprintOpen accessSenior authorCorresponding

  Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders, yet their molecular mechanisms of action remain poorly understood. Here, we show that chronic treatment with the SSRI fluoxetine reinstates a developmental plasticity program in the dentate gyrus (DG) by remodeling the extracellular matrix (ECM). Fluoxetine elicited a robust transcriptomic response in the DG, where mature granule cells adopted a juvenile-like profile. This shift was characterized by upregulation of the transcription factor SOX11 and the neurotrophic factor BDNF, as well as decreased ECM and enhanced structural remodeling of granule cell axon terminals. Direct enzymatic degradation of ECM in the DG reactivated SOX11 in mature granule cells. At the behavioral level, fluoxetine mitigated stress-induced fear generalization, an endophenotype of mood and anxiety disorders. This effect was phenocopied by ECM degradation, suggesting that ECM remodeling and granule cell rejuvenation are key mechanisms underlying the effects of fluoxetine, and possibly other antidepressants, on fear generalization.

  PublisherOA PDFDOI

• Distinct representations of an anxiogenic environment in different cell types of the ventral hippocampus

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-10

  preprintOpen access

  ABSTRACT In addition to its role in episodic memory and spatial navigation, the hippocampus has also been found to influence mood-related disorders such as anxiety and depression. These seemingly distinct roles are consistent with a functional dissociation between the two anatomical poles of the hippocampus: whereas the dorsal portion of the hippocampus in rodents is necessary for spatial tasks, the ventral portion controls affective behaviors. We have recently found that neurons in the ventral, but not dorsal, CA1 area of mice encode anxiety-related information (i.e. are “anxiety cells”) in diverse defensive and exploratory behaviors. Still it is unclear how general threat-related information is computed within the hippocampal circuit. In this work, we have examined how distinct hippocampal subregions and cell types encode anxiety-related information by imaging calcium activity in large populations of genetically-defined neurons in the ventral hippocampus while mice explore the elevated plus maze (EPM), a conflict-based anxiety test. We compared the neural encoding of task-related features within the ventral CA1 (vCA1) and ventral dentate gyrus (vDG) regions in order to examine the emergence of anxiety-related activity through the hippocampal circuit. We found that granule cells (vGCs) of the vDG represented similar valence information to neurons in vCA1 in the form of arm-type specific encoding in the EPM, which suggests that encoding of anxiety-related features is already present at this first stage of hippocampal processing. When compared with ventral granule cells (vGCs), ventral mossy cells (vMCs) underlying the DG had stronger spatial encoding and less valence encoding, suggesting that they may be more functionally connected with the highly spatially sensitive dorsal hippocampus. Together these findings will help to understand the encoding of anxiety-related information in the hippocampus and how it relates to neural circuit defects in mood-related disorders.

  PublisherOA PDFDOI

• Enhancing mental health and resilience in war-affected youth: The impact of virtual reality-induced awe experiences

  Computers in Human Behavior · 2025-05-21 · 4 citations

  articleSenior author
  PublisherDOI

• Prucalopride, a Serotonergic Type 4 (5HT4) Receptor Agonist, Alone or in Combination With a Selective Serotonin Reuptake Inhibitor, Induces Fast Anxiolytic/ Antidepressant-Like Activity

  Biological Psychiatry · 2025-04-09

  article
  PublisherDOI

• Synaptic Vesicle 2A (SV2A) Positron Emission Tomography (PET) Imaging as a Marker of Therapeutic Response in a Mouse Model of Depression

  ACS Pharmacology & Translational Science · 2025-01-28 · 5 citations

  articleOpen access

  In this preclinical pilot study, we used [11C]UCB-J PET imaging to monitor the synaptic modulation in depression and after fluoxetine. PET imaging was performed in a validated mouse model of depression/anxiety (CORT model), and the effect of 5-week treatment with fluoxetine was tested. Depression/anxiety phenotype and antidepressant action of fluoxetine were confirmed using the novelty-suppressed feeding test, previously validated in the CORT model. PET data showed significant decreases of volume of distribution (VT) of [11C]UCB-J in most brain regions of CORT mice compared with controls after 5 weeks of fluoxetine, and a trend toward restoration of VT values to control levels was observed, although it reached significance only in the olfactory bulb. These preliminary data support the use of [11C]UCB-J PET imaging and the CORT model to study the synaptic modulation of antidepressants. It provides excellent translational opportunities to study the relationship between synaptic plasticity and the clinical efficacy of antidepressants.

  PublisherOA PDFDOI

• A rare variant in <i>GPR156</i> associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice

  Proceedings of the National Academy of Sciences · 2025-04-14 · 1 citations

  articleOpen access

  Major depressive disorder (MDD) is a leading cause of disability worldwide. Risk for MDD is heritable, and the genetic structure of founder populations enables investigation of rare susceptibility alleles with large effect. In an extended Old Order Mennonite family cohort, we identified a rare missense variant in GPR156 (c.1599G&gt;T, p.Glu533Asp) associated with a two-fold increase in the relative risk of MDD. GPR156 is an orphan G protein–coupled receptor localized in the medial habenula, a region implicated in mood regulation. Insertion of a human sequence containing c.1599G&gt;T into the murine Gpr156 locus induced medial habenula hyperactivity and abnormal stress-related behaviors. This work reveals a human variant that is associated with depression, implicates GPR156 as a target for mood regulation, and introduces informative murine models for investigating the pathophysiology and treatment of affective disorders.

  PublisherDOI

• Hybrid Solid-Liquid Optics Enable Scalable, High-Resolution, Multi-Immersion Light-Sheet Microscopy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-04

  preprintOpen access

  Modern biology increasingly depends on data-driven discovery, requiring scalable and affordable high-content 3D imaging across molecular to organ scales. Although tissue clearing, expansion microscopy, and light-sheet microscopy (LSM) enable subcellular-resolution imaging of intact specimens, their scalability remains fundamentally limited by detection optics: immersion objectives deliver high-resolution, aberration-free imaging but with short working distances, high cost, and multi-immersion incompatibility, while air objectives offer long working distances and portability at lower cost but suffer from severe aberrations and reduced photon collection when imaging immersed samples. We introduce the Hybrid Solid-Liquid Immersion Lens (HySIL) framework, which pairs an off-the-shelf solid optical component with a refractive index-matched liquid to precompensate aberrations and enhance resolution. Building on HySIL, we developed SCOPE and Super-SCOPE, objective-agnostic imaging devices achieving submicron lateral resolution (<0.75 μm) across centimeter-scale samples using inexpensive air objectives with >30 mm working distances. Integration with a low-cost LSM platform yielded a compact, scalable system demonstrated for multi-immersion, multi-color, subcellular-resolution mapping of cleared or expanded mouse, salamander, and cavefish brains, human iPSC-derived organoids, and 3D histopathology of breast tissue. HySIL and SCOPE establish an accessible foundation for scalable, high-resolution volumetric imaging, advancing data-driven biological discovery.

  PublisherOA PDFDOI

• Psilocybin induces sex- and context-specific recruitment of the stress axis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-06 · 1 citations

  preprintOpen access

  ABSTRACT Psychedelics have reemerged as potential treatments for mental health disorders, yet their impact on stress-related brain regions remains poorly understood. Here, we provide the first real-time, in vivo evidence of psilocybin-induced neuronal activation, specifically in hypothalamic corticotropin-releasing hormone neurons. Notably, psilocybin elicited more pronounced responses in female mice and produced context-related alterations in threat assessment. Our findings provide valuable insight into the impact of psychedelics on a key stress center in the brain.

  PublisherOA PDFDOI

• Optimal sparsity in autoencoder memory models of the hippocampus

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-06

  preprintOpen access

  Storing complex correlated memories is significantly more efficient when memories are recoded to obtain compressed representations. Previous work has shown that compression can be implemented in a simple neural circuit, which can be described as a sparse autoencoder. The activity of the encoding units in these models recapitulates the activity of hippocampal neurons recorded in multiple experiments. However, these investigations have assumed that the level of sparsity is fixed and that inputs have the same statistics and, hence, that they are uniformly compressible. In contrast, biological agents encounter environments with vastly different memory demands and compressibility. Here, we investigate whether the compressibility of inputs determines optimal sparsity in sparse autoencoders. We find 1) that as the compressibility of inputs increases, the optimal coding level decreases, 2) that the desired coding level diverges from the observed coding level as a function of both memory demand and input compressibility, and 3) that optimal memory capacity is achieved when sparsity is weakly enforced. In addition, we characterize how sparsity and the strength of sparsity enforcement jointly control optimal performance. These results provide predictions for how sparsity in the hippocampus should change in response to environmental statistics and theoretical grounds for why sparsity is dynamically tuned in the brain.

  PublisherDOI

• Psilocybin Induces Sex- and Context-Specific Recruitment of the Stress Axis

  SSRN Electronic Journal · 2025-01-01 · 1 citations

  preprintOpen access
  PublisherDOI

Recent grants

• NIH Grant R37MH068542

  NIH · $4.1M · 2018

• NIH Grant P50MH050733

  NIH · $23.4M · 2005

• NIH Grant P50MH062185

  NIH · $30.0M · 2011

• Animal Models of Suicide: Behavior, Neurobiological and Molecular Phenotypes

  NIH · $47.0M · 2013–2026

• Translational Neuroscience Training Grant.

  NIH · $5.2M · 1977–2023

Frequent coauthors

• Denis J. David

  Centre de recherche en Epidémiologie et Santé des Populations

  164 shared

• Alain M. Gardier

  Centre de recherche en Epidémiologie et Santé des Populations

  136 shared

• Christine A. Denny

  Research Foundation For Mental Hygiene

  129 shared

• Indira Mendez‐David

  Centre de recherche en Epidémiologie et Santé des Populations

  116 shared

• Clay Lacefield

  New York State Psychiatric Institute

  93 shared

• Mazen A. Kheirbek

  University of California, San Francisco

  88 shared

• J. John Mann

  New York State Psychiatric Institute

  81 shared

• Pierre Chambon

  Institut de génétique et de biologie moléculaire et cellulaire

  74 shared

Labs

• Hen LabPI