René Hen

Columbia University, New York, New York, United States

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Publications (338)2805.15 Total impact

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    ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.
    Nature Neuroscience 09/2015; 18(11). DOI:10.1038/nn.4116 · 16.10 Impact Factor
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    ABSTRACT: Degeneration of dopamine (DA) neurons in Parkinson's disease (PD) causes hypokinesia, but DA replacement therapy can elicit exaggerated voluntary and involuntary behaviors that have been attributed to enhanced DA receptor sensitivity in striatal projection neurons. Here we reveal that in hemiparkinsonian mice, striatal D1 receptor-expressing medium spiny neurons (MSNs) directly projecting to the substantia nigra reticulata (SNr) lose tonic presynaptic inhibition by GABAB receptors. The absence of presynaptic GABAB response potentiates evoked GABA release from MSN efferents to the SNr and drives motor sensitization. This alternative mechanism of sensitization suggests a synaptic target for PD pharmacotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 09/2015; 87(5):976-88. DOI:10.1016/j.neuron.2015.08.022 · 15.05 Impact Factor
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    Melody V Wu · Victor M Luna · René Hen ·
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    ABSTRACT: Normal aging and exercise exert extensive, often opposing, effects on the dentate gyrus (DG) of the hippocampus altering volume, synaptic function, and behaviors. The DG is especially important for behaviors requiring pattern separation-a cognitive process that enables animals to differentiate between highly similar contextual experiences. To determine how age and exercise modulate pattern separation in an aversive setting, young, aged, and aged mice provided with a running wheel were assayed on a fear-based contextual discrimination task. Aged mice showed a profound impairment in contextual discrimination compared to young animals. Voluntary exercise rescued this deficit to such an extent that behavioral pattern separation of aged-run mice was now similar to young animals. Running also resulted in a significant increase in the number of immature neurons with tertiary dendrites in aged mice. Despite this, neurogenesis levels in aged-run mice were still considerably lower than in young animals. Thus, mechanisms other than DG neurogenesis likely play significant roles in improving behavioral pattern separation elicited by exercise in aged animals.
    Frontiers in Systems Neuroscience 08/2015; 9:114. DOI:10.3389/fnsys.2015.00114
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    ABSTRACT: Behavioral studies have established a role for adult-born dentate granule cells in discriminating between similar memories. However, it is unclear how these cells mediate memory discrimination. Excitability is enhanced in maturing adult-born neurons, spurring the hypothesis that the activity of these cells “directly” encodes and stores memories.Analternative hypothesis posits that maturing neurons “indirectly” contribute to memory encoding by regulating excitation–inhibition balance. We evaluated these alternatives by using dentate-sensitive active place avoidance tasks to assess experience-dependent changes in dentate field potentials in the presence and absence of neurogenesis. Before training, X-ray ablation of adult neurogenesis-reduced dentate responses to perforant-path stimulation and shifted EPSP-spike coupling leftward. These differences were unchanged after place avoidance training with the shock zone in the initial location, which both groups learned to avoid equally well. In contrast, sham-treated mice decreased dentate responses and shifted EPSP-spike coupling leftward after the shock zone was relocated, whereas X-irradiated mice failed to show these changes in dentate function and were impaired on this test of memory discrimination. During place avoidance, excitation–inhibition coupled neural synchrony in dentate local field potentials was reduced in X-irradiated mice, especially in the θ band. The difference was most prominent during conflict learning, which is impaired in the X-irradiated mice. These findings indicate that maturing adult-born neurons regulate both functional network plasticity in response to memory discrimination and dentate excitation–inhibition coordination. The most parsimonious interpretation of these results is that adult neurogenesis indirectly regulates hippocampal information processing.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2015; 35(33):11656-66. DOI:10.1523/JNEUROSCI.0885-15.2015 · 6.34 Impact Factor
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    ABSTRACT: Background We examined the neurobiological mechanisms underlying stress susceptibility using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to determine neuroanatomical differences between stress-susceptible and resilient mice. We also examined synchronized anatomical differences between brain regions to gain insight into the plasticity of neural networks underlying stress susceptibility. Methods C57/Bl6 mice underwent 10 days of social defeat stress and were subsequently tested for social avoidance. For MRI, brains of stressed (susceptible n=11, resilient n=8) and control (n=12) mice were imaged ex vivo at 56µm resolution using a T2-weighted sequence. We tested for behavior-structure correlations by regressing social avoidance z-scores against local brain volume. For DTI, brains were scanned with a diffusion-weighted fast-spin echo sequence at 78μm isotropic voxels. Structural covariance was assessed by correlating local volume between brain regions. Results Social avoidance correlated negatively with local volume of the cingulate cortex, nucleus accumbens, thalamus, raphé nuclei and bed nucleus of the stria terminals. Social avoidance correlated positively with volume of the ventral tegmental area (VTA), habenula, periaqueductal grey, cerebellum, hypothalamus, and hippocampal CA3. Fractional anisotropy (FA) was increased in the hypothalamus and hippocampal CA3. We observed synchronized anatomical differences between the VTA and cingulate cortex, the hippocampus and VTA, hippocampus and cingulate cortex, and hippocampus and hypothalamus. These correlations revealed different structural covariance between brain regions in susceptible and resilient mice. Conclusions Stress-integrative brain regions shape the neural architecture underlying individual differences in susceptibility and resilience to chronic stress.
    Biological Psychiatry 08/2015; DOI:10.1016/j.biopsych.2015.08.009 · 10.26 Impact Factor
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    ABSTRACT: The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning, emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet the role of AHN in development of persistent pain has remained unexplored. Here we test the influence of AHN in post-injury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN mediated hippocampal learning mechanisms are involved in emergence of persistent pain.
    Pain 08/2015; DOI:10.1097/j.pain.0000000000000332 · 5.21 Impact Factor
  • Melody V Wu · Amar Sahay · Ronald S Duman · René Hen ·
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    ABSTRACT: Over the past several decades, the proliferation and integration of adult-born neurons into existing hippocampal circuitry has been implicated in a wide range of behaviors, including novelty recognition, pattern separation, spatial learning, anxiety behaviors, and antidepressant response. In this review, we suggest that the diversity in behavioral requirements for new neurons may be partly caused by separate functional roles of individual neurogenic niches. Growing evidence shows that the hippocampal formation can be compartmentalized not only along the classic trisynaptic circuit, but also along a longitudinal septotemporal axis. We suggest that subpopulations of hippocampal adult-born neurons may be specialized for distinct mnemonic- or mood-related behavioral tasks. We will examine the literature supporting a functional and anatomical dissociation of the hippocampus along the longitudinal axis and discuss techniques to functionally dissect the roles of adult-born hippocampal neurons in these distinct subregions. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 08/2015; 7(8). DOI:10.1101/cshperspect.a018978 · 8.68 Impact Factor
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    ABSTRACT: Stress exposure is one of the greatest risk factors for psychiatric illnesses like Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. Methods: Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine (K) could protect against depressive-like behavior. Mice were administered a single dose of saline (Sal) or ketamine and then one week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT. Results: SD robustly and reliably induced depressive-like behavior in control (Ctrl) mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test (FST) and in the dominant interaction (DI) test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training—and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the FST, novelty suppressed feeding (NSF) paradigm, and the sucrose splash test (ST). Conclusions: These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.
    Biological Psychiatry 05/2015; DOI:10.1016/j.biopsych.2015.04.022 · 10.26 Impact Factor
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    ABSTRACT: Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulates impulsive behavior during adulthood. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 04/2015; 86(3). DOI:10.1016/j.neuron.2015.03.041 · 15.05 Impact Factor
  • Alexis S Hill · Amar Sahay · René Hen ·
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    ABSTRACT: Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone, a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on HPA axis regulation, either at baseline or following chronic corticosterone administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects.Neuropsychopharmacology accepted article preview online, 02 April 2015. doi:10.1038/npp.2015.85.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2015; 40(10). DOI:10.1038/npp.2015.85 · 7.05 Impact Factor

  • Biological Psychiatry 02/2015; 77(3). DOI:10.1016/j.biopsych.2014.11.007 · 10.26 Impact Factor
  • Bradley R Miller · René Hen ·
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    ABSTRACT: Newborn neurons are continuously added to the adult hippocampus. Early studies found that adult neurogenesis is impaired in models of depression and anxiety and accelerated by antidepressant treatment. This led to the theory that depression results from impaired adult neurogenesis and restoration of adult neurogenesis leads to recovery. Follow up studies yielded a complex body of often inconsistent results, and the veracity of this theory is uncertain. We propose five criteria for acceptance of this theory, we review the recent evidence for each criterion, and we draw the following conclusions: Diverse animal models of depression and anxiety have impaired neurogenesis. Neurogenesis is consistently boosted by antidepressants in animal models only when animals are stressed. Ablation of neurogenesis in animal models impairs cognitive functions relevant to depression, but only a minority of studies find that ablation causes depression or anxiety. Recent human neuroimaging and postmortem studies are consistent with the neurogenic theory, but they are indirect. Finally, a novel drug developed based on the neurogenic theory is promising in animal models.
    Current Opinion in Neurobiology 02/2015; 30:51–58. DOI:10.1016/j.conb.2014.08.012 · 6.63 Impact Factor

  • 01/2015; 2(1):e1025180. DOI:10.1080/23262133.2015.1025180
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    Frank Scott Hall · Ichiro Sora · René Hen · George R Uhl ·
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    ABSTRACT: Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD) and that these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA) systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics.
    PLoS ONE 12/2014; 9(12):e115009. DOI:10.1371/journal.pone.0115009 · 3.23 Impact Factor
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    ABSTRACT: Selective serotonin reuptake inhibitors are the mostly widely used treatment for major depressive disorders and also are prescribed for several anxiety disorders. However, similar to most antidepressants, selective serotonin reuptake inhibitors suffer from two major problems: They only show beneficial effects after 2 to 4 weeks and only about 33% of patients show remission to first-line treatment. Thus, there is a considerable need for development of more effective antidepressants. There is a growing body of evidence supporting critical roles of 5-HT1A and 5-HT4 receptor subtypes in mediating successful depression treatments. In addition, appropriate activation of these receptors may be associated with a faster onset of the therapeutic response. This review will examine the known roles of 5-HT1A and 5-HT4 receptors in mediating both the pathophysiology of depression and anxiety and the treatment of these mood disorders. At the end of the review, the role of these receptors in the regulation of adult hippocampal neurogenesis will also be discussed. Ultimately, we propose that novel antidepressant drugs that selectively target these serotonin receptors could be developed to yield improvements over current treatments for major depressive disorders. © The Author(s) 2014.
    The Neuroscientist 12/2014; DOI:10.1177/1073858414561303 · 6.84 Impact Factor
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    ABSTRACT: Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4 hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21 hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30 min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA. Copyright © 2014. Published by Elsevier Inc.
    Experimental Neurology 12/2014; 264. DOI:10.1016/j.expneurol.2014.11.009 · 4.70 Impact Factor

  • 53rd Annual Meeting of the American-College-of-Neuropsychopharmacology; 12/2014
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    ABSTRACT: Innate behaviours are observed in naive animals without prior learning or experience, suggesting that the neural circuits that mediate these behaviours are genetically determined and stereotyped. The neural circuits that convey olfactory information from the sense organ to the cortical and subcortical olfactory centres have been anatomically defined, but the specific pathways responsible for innate responses to volatile odours have not been identified. Here we devise genetic strategies that demonstrate that a stereotyped neural circuit that transmits information from the olfactory bulb to cortical amygdala is necessary for innate aversive and appetitive behaviours. Moreover, we use the promoter of the activity-dependent gene arc to express the photosensitive ion channel, channelrhodopsin, in neurons of the cortical amygdala activated by odours that elicit innate behaviours. Optical activation of these neurons leads to appropriate behaviours that recapitulate the responses to innate odours. These data indicate that the cortical amygdala plays a critical role in generating innate odour-driven behaviours but do not preclude its participation in learned olfactory behaviours.
    Nature 11/2014; 515(7526). DOI:10.1038/nature13897 · 41.46 Impact Factor
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    ABSTRACT: Memory traces are believed to be ensembles of cells used to store memories. To visualize memory traces, we created a transgenic line that allows for the comparison between cells activated during encoding and expression of a memory. Mice re-exposed to a fear-inducing context froze more and had a greater percentage of reactivated cells in the dentate gyrus (DG) and CA3 than mice exposed to a novel context. Over time, these differences disappeared, in keeping with the observation that memories become generalized. Optogenetically silencing DG or CA3 cells that were recruited during encoding of a fear-inducing context prevented expression of the corresponding memory. Mice with reduced neurogenesis displayed less contextual memory and less reactivation in CA3 but, surprisingly, normal reactivation in the DG. These studies suggest that distinct memory traces are located in the DG and in CA3 but that the strength of the memory is related to reactivation in CA3. VIDEO ABSTRACT:
    Neuron 07/2014; 83(1):189-201. DOI:10.1016/j.neuron.2014.05.018 · 15.05 Impact Factor
  • Mazen A Kheirbek · René Hen ·
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    ABSTRACT: The adult brain generates neurons every day. These cells help us to distinguish one memory from another—a finding that could lead to novel treatments for anxiety disorders
    Scientific American 07/2014; 311(1):62-7. DOI:10.1038/scientificamerican0714-62 · 1.07 Impact Factor

Publication Stats

29k Citations
2,805.15 Total Impact Points


  • 1995-2015
    • Columbia University
      • • Department of Pharmacology
      • • Department of Psychiatry
      • • Department of Neuroscience
      • • Center for Neurobiology and Behavior
      New York, New York, United States
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 2004-2014
    • New York State Psychiatric Institute
      • Anxiety Disorders Clinic
      New York, New York, United States
    • CUNY Graduate Center
      New York, New York, United States
  • 2005
    • University of Tours
      Tours, Centre, France
  • 2002
    • The Children's Hospital of Philadelphia
      • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 2001
    • University of Nantes
      • Faculté de Médecine
      Nantes, Pays de la Loire, France
    • University of California, San Diego
      • Department of Psychiatry
      San Diego, California, United States
    • Université de Montréal
      • Department of Radiology, Radiation Oncology and Nuclear Medicine
      Montréal, Quebec, Canada
  • 1995-2001
    • Utrecht University
      • Division of Psychofarmacology
      Utrecht, Utrecht, Netherlands
  • 1998
    • Université Paris-Sud 11
      • Faculté de Pharmacie
      Paris, Ile-de-France, France
  • 1986-1995
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France