Susumu Tonegawa

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Organization: Howard Hughes Medical Institute , Japan

Department: and Departments of Biology and Brain and Cognitive Sciences

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References

Direct Medial Entorhinal Cortex Input to Hippocampal CA1 Is Crucial for Extended Quiet Awake Replay

Co-reporter:Jun Yamamoto, Susumu Tonegawa

Neuron 2017 Volume 96, Issue 1(Volume 96, Issue 1) pp:

Publication Date(Web):27 September 2017

DOI:10.1016/j.neuron.2017.09.017

•Ripple bursts co-occur in CA1 and MEC in quiet awake with alternating ripples•MECIII blockade to CA1 reduces ripple bursts and extended replays in quiet awake•MECIII blockade to CA1 does not affect ripple bursts or extended replays in sleep•CA3 blockade to CA1 suppresses ripples and replays in both quiet awake and sleepHippocampal replays have been demonstrated to play a crucial role in memory. Chains of ripples (ripple bursts) in CA1 have been reported to co-occur with long-range place cell sequence replays during the quiet awake state, but roles of neural inputs to CA1 in ripple bursts and replays are unknown. Here we show that ripple bursts in CA1 and medial entorhinal cortex (MEC) are temporally associated. An inhibition of MECIII input to CA1 during quiet awake reduced ripple bursts in CA1 and restricted the spatial coverage of replays to a shorter distance corresponding to single ripple events. The reduction did not occur with MECIII input inhibition during slow-wave sleep. Inhibition of CA3 activity suppressed ripples and replays in CA1 regardless of behavioral state. Thus, MECIII input to CA1 is crucial for ripple bursts and long-range replays specifically in quiet awake, whereas CA3 input is essential for both, regardless of behavioral state.

Co-reporter:Takashi Kitamura;Sachie K. Ogawa;Dheeraj S. Roy;Teruhiro Okuyama;Mark D. Morrissey;Lillian M. Smith;Roger L. Redondo

Science 2017 Volume 356(Issue 6333) pp:

Publication Date(Web):

DOI:10.1126/science.aam6808

The representation of contextual fear memories evolves over time in the hippocampus, amygdala, and prefrontal cortex.

Manipulating memory in space and time

Co-reporter:Dheeraj S Roy, Susumu Tonegawa

Current Opinion in Behavioral Sciences 2017 Volume 17(Volume 17) pp:

Publication Date(Web):1 October 2017

DOI:10.1016/j.cobeha.2017.05.020

•Identification and manipulations of memory engrams and engram cells.•Creating false memory by manipulating engram cells.•Countering depression-like behaviors by stimulating positive valence engram cells.•Restoring memory in early Alzheimer’s mouse models by engineering engram cells.One of the most fascinating aspects of an animal’s brain is its ability to acquire new information from experience and retain this information over time as memory. The search for physical correlates of memory, the memory engram, has been a longstanding endeavor in modern neurobiology. Recent advances in transgenic and optogenetic tools have enabled the identification, visualization, and manipulations of natural, sensory-evoked, engram cells for a specific memory residing in specific brain regions. These studies are paving the way not only to understand memory mechanisms in unprecedented detail, but also to repair the abnormal state of mind associated with memory by engineering.

Dorsal Raphe Serotonergic Neurons Control Intertemporal Choice under Trade-off

Co-reporter:Sangyu Xu, Gishnu Das, Emily Hueske, Susumu Tonegawa

Current Biology 2017 Volume 27, Issue 20(Volume 27, Issue 20) pp:

Publication Date(Web):23 October 2017

DOI:10.1016/j.cub.2017.09.008

•Mice performed a novel odor-guided intertemporal choice task•Manipulations of DR serotonergic neurons at the decision point regulated impulsive choice•Effects of manipulations were most prominent under trade-off conditions•The nucleus accumbens is a target for DR serotonergic neurons in regulating choiceAppropriate choice about delayed reward is fundamental to the survival of animals. Although animals tend to prefer immediate reward, delaying gratification is often advantageous. The dorsal raphe (DR) serotonergic neurons have long been implicated in the processing of delayed reward, but it has been unclear whether or when their activity causally directs choice. Here, we transiently augmented or reduced the activity of DR serotonergic neurons, while mice decided between differently delayed rewards as they performed a novel odor-guided intertemporal choice task. We found that these manipulations, precisely targeted at the decision point, were sufficient to bidirectionally influence impulsive choice. The manipulation specifically affected choices with more difficult trade-off. Similar effects were observed when we manipulated the serotonergic projections to the nucleus accumbens (NAc). We propose that DR serotonergic neurons preempt reward delays at the decision point and play a critical role in suppressing impulsive choice by regulating decision trade-off.

Distinct Neural Circuits for the Formation and Retrieval of Episodic Memories

Co-reporter:Dheeraj S. Roy, Takashi Kitamura, Teruhiro Okuyama, Sachie K. Ogawa, ... Susumu Tonegawa

Cell 2017 Volume 170, Issue 5(Volume 170, Issue 5) pp:

Publication Date(Web):24 August 2017

DOI:10.1016/j.cell.2017.07.013

•dSub and the circuit, CA1→dSub→EC5, are required for hippocampal memory retrieval•The direct CA1→EC5 circuit is essential for hippocampal memory formation•The dSub→MB circuit regulates memory-retrieval-induced stress hormone responses•The dSub→EC5 circuit contributes to context-dependent memory updatingThe formation and retrieval of a memory is thought to be accomplished by activation and reactivation, respectively, of the memory-holding cells (engram cells) by a common set of neural circuits, but this hypothesis has not been established. The medial temporal-lobe system is essential for the formation and retrieval of episodic memory for which individual hippocampal subfields and entorhinal cortex layers contribute by carrying out specific functions. One subfield whose function is poorly known is the subiculum. Here, we show that dorsal subiculum and the circuit, CA1 to dorsal subiculum to medial entorhinal cortex layer 5, play a crucial role selectively in the retrieval of episodic memories. Conversely, the direct CA1 to medial entorhinal cortex layer 5 circuit is essential specifically for memory formation. Our data suggest that the subiculum-containing detour loop is dedicated to meet the requirements associated with recall such as rapid memory updating and retrieval-driven instinctive fear responses.Download high-res image (170KB)Download full-size image

Ventral CA1 neurons store social memory

Co-reporter:Teruhiro Okuyama;Takashi Kitamura;Dheeraj S. Roy;Shigeyoshi Itohara

Science 2016 Vol 353(6307) pp:1536-1541

Publication Date(Web):30 Sep 2016

DOI:10.1126/science.aaf7003

Abstract

The medial temporal lobe, including the hippocampus, has been implicated in social memory. However, it remains unknown which parts of these brain regions and their circuits hold social memory. Here, we show that ventral hippocampal CA1 (vCA1) neurons of a mouse and their projections to nucleus accumbens (NAc) shell play a necessary and sufficient role in social memory. Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse. Optogenetic reactivation of vCA1 neurons that respond to the familiar mouse enabled memory retrieval and the association of these neurons with unconditioned stimuli. Thus, vCA1 neurons and their NAc shell projections are a component of the storage site of social memory.

Rehebbilitating Memory

Co-reporter:Tomás J Ryan and Susumu Tonegawa

Neuropsychopharmacology 2016 41(1) pp:370-371

Publication Date(Web):2016-01-01

DOI:10.1038/npp.2015.264

Amnesia is a deficit of memory function that can result from trauma, stress, disease, drug use, or ageing. Though efforts are being made to prevent and treat the various causes of amnesia, there remains no treatment for the symptom of memory loss itself. Because the defining feature of amnesia is an inability to recall memory, any given case may be due to the possibility that the memory is gone, or the alternative that it is present but irretrievable (Squire, 1982). Discriminating between these two scenarios would be of scientific value, because the neurobiology of memory formation is anchored in experimental amnesia. From a clinical perspective, pathological cases of amnesia that are due to retrieval deficits may in principle be treatable rather than merely preventable. Amnesia could be attributed to a retrieval deficit if the ostensible ‘lost’ memory could be evoked through brain stimulation. The challenge here is to identify exactly where in the brain a particular memory is stored.Our strategy to meet this challenge was based on Richard Semon’s 100 and some year-old memory engram theory (Semon, 1904). In the contemporary version of this theory, formation of memory starts with learning-induced activation of a specific population of neurons, followed by an establishment of enduring physical or chemical changes in these neurons, referred to as an engram, which is the brain representation of the acquired memory. Furthermore, subsequent recall of the memory is evoked by reactivation of these engram-holding neurons by recall cues. Our approach took advantage of the activation of an immediate early gene, c-fos, in a specific population of neurons upon experiencing a certain episode. These neurons can be labelled upon learning with a light-sensitive protein like channelrhodopsin-2 (ChR2) in a transgenic mouse in which the promotor of the c-fos promoter controls the expression of ChR2 (Liu et al, 2012). Using this genetic technology, the memory engram cell population in the hippocampus could be identified, and their subsequent reactivation by light of a specific wavelength was sufficient for eliciting recall of the specific memory. Furthermore, these engram cell populations were shown to be essential for natural memory recall (Tonegawa et al, 2015).We employed engram technology to investigate retrograde amnesia due to disrupted memory consolidation (Ryan et al, 2015). Memory consolidation is the process whereby a newly formed memory is temporally susceptible to disruption by interventions such as protein synthesis inhibitors (PSIs), and represents the dominant neurobiological paradigm for memory formation. We found that contextual fear memories could be retrieved from a range of cases of amnesia due to disrupted consolidation, by direct optogenetic activation of amnesic memory engram cells. These findings provide positive evidence that retrograde amnesia due to disrupted consolidation is a deficit of memory retrievability.If a memory survives amnesia, what causes the retrieval deficit? We observed an engram cell-specific plasticity of enhanced dendritic spine density and synaptic strength that was abolished by PSI administration. How then are memories stored in amnesic engram cells? A transynaptic engram cell connectivity pattern across brain regions was observed in normal mice and it persisted in the amnesic case, being unaffected by PSIs. Thus, the engram cell circuit is a plausible candidate mechanism for robust and persistent storage of memory. These data lead to a hypothesis that engram cell-specific enhanced synaptic plasticity is necessary for the efficient retrieval of the memory, and that amnesia is caused by inefficient access of natural recall cues to the engram cell somata due to the lack of enhanced synaptic density and strength (Ryan et al, 2015; Tonegawa et al, 2015).The experimental design employed here may be expanded to clinical cases of amnesia, including early stages of Alzheimer’s disease and other neurodegenerative disorders. If memory content endures in engram circuits of clinical amnesia, then seemingly lost memories may be reinvigorated by targeted stimulation of amnesic engram cells. Indeed, when an amnesic contextual engram was artificially updated with a fear association, the amnesic contextual memory became accessible to natural recall (Ryan et al, 2015). Beyond amnesia, affective disorders such as depression might be ameliorated by potentiating access to positive engrams (Ramirez et al, 2015). A paradox of memory is that it is simultaneously an enduring biological property, and yet one that is intrinsically fragile. Embracing a theoretical dissociation of the dual features of storage and access may account for this discrepancy and should lead to novel lines of research into the neurobiological mechanisms of memory storage and memory retrieval.The authors declare no conflict of interest.This work was supported by the RIKEN Brain Science Institute, Howard Hughes Medical Institute, and the JPB Foundation (to ST).

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells

Co-reporter:Lacey J. Kitch;Jared Martin;Takashi Kitamura;Mark J. Schnitzer;Jun Yamamoto;Michele Pignatelli;Chen Sun

PNAS 2015 Volume 112 (Issue 30 ) pp:9466-9471

Publication Date(Web):2015-07-28

DOI:10.1073/pnas.1511668112

Entorhinal–hippocampal circuits in the mammalian brain are crucial for an animal’s spatial and episodic experience, but the neural basis for different spatial computations remain unknown. Medial entorhinal cortex layer II contains pyramidal island and stellate ocean cells. Here, we performed cell type-specific Ca2+ imaging in freely exploring mice using cellular markers and a miniature head-mounted fluorescence microscope. We found that both oceans and islands contain grid cells in similar proportions, but island cell activity, including activity in a proportion of grid cells, is significantly more speed modulated than ocean cell activity. We speculate that this differential property reflects island cells’ and ocean cells’ contribution to different downstream functions: island cells may contribute more to spatial path integration, whereas ocean cells may facilitate contextual representation in downstream circuits.

Engram cells retain memory under retrograde amnesia

Co-reporter:Dheeraj S. Roy;Autumn Arons;Michele Pignatelli;Tomás J. Ryan

Science 2015 Volume 348(Issue 6238) pp:1007-1013

Publication Date(Web):29 May 2015

DOI:10.1126/science.aaa5542

Experimental recovery from retrograde amnesia

When memory researchers induce amnesia, they normally assume that the manipulations prevent the memory engram from effective encoding at consolidation. In accordance with this, Ryan et al. found that after the injection of protein synthesis inhibitors, animals could not retrieve a memory. However, to their surprise, the memory could nevertheless be reactivated by light-induced activation of the neurons tagged during conditioning. Increased synaptic strength that is the result of cellular consolidation is thus not a critical requisite for storing a memory.

Science, this issue p. 1007

Island Cells Control Temporal Association Memory

Co-reporter:Takashi Kitamura;Michele Pignatelli;Junghyup Suh;Keigo Kohara;Atsushi Yoshiki;Kuniya Abe

Science 2014 Vol 343(6173) pp:896-901

Publication Date(Web):21 Feb 2014

DOI:10.1126/science.1244634

Entorhinal Cell Clusters

There is considerable interest in understanding the function of neurons in layer 2 of the medial entorhinal cortex and how they generate their unique firing patterns, which are important in the recall of facts and past events (see the Perspective by Blair). Ray et al. (p. 891, published online 23 January) investigated principal cells in layer 2 by immunoreactivity, projection patterns, microcircuit analysis, and assessment of temporal discharge properties in awake, freely moving animals. In tangential sections, pyramidal neurons were clustered into patches arranged in a hexagonal grid—very similar to the patterns observed in grid cell spatial firing. These patches received selective cholinergic innervation, which is critical for sustaining grid cell activity. Kitamura et al. (p. 896, published online 23 January) found that these cells drive a hippocampal circuit by projecting directly to the hippocampal CA1 area and synapsing with a distinct class of inhibitory neurons. This circuit provides feed-forward inhibition in combination with excitatory inputs from layer 3 cells of the medial entorhinal cortex, projecting to CA1 pyramidal cells to determine the strength and time window of temporal associative inputs.

Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory

Co-reporter:Joshua Sariñana;Takashi Kitamura;Patrik Künzler;Lisa Sultzman

PNAS 2014 Volume 111 (Issue 22 ) pp:8245-8250

Publication Date(Web):2014-06-03

DOI:10.1073/pnas.1407395111

Activation of the hippocampal dopamine 1-class receptors (D1R and D5R) are implicated in contextual fear conditioning (CFC). However, the specific role of the D1R versus D5R in hippocampal dependent CFC has not been investigated. Generation of D1R- and D5R-specific in situ hybridization probes showed that D1R and D5R mRNA expression was greatest in the dentate gyrus (DG) of the hippocampus. To identify the role of each receptor in CFC we generated spatially restricted KO mice that lack either the D1R or D5R in DG granule cells. DG D1R KOs displayed significant fear memory deficits, whereas DG D5R KOs did not. Furthermore, D1R KOs but not D5R KOs, exhibited generalized fear between two similar but different contexts. In the familiar home cage context, c-Fos expression was relatively low in the DG of control mice, and it increased upon exposure to a novel context. This level of c-Fos expression in the DG did not further increase when a footshock was delivered in the novel context. In DG D1R KOs, DG c-Fos levels in the home cage was higher than that of the control mice, but it did not further increase upon exposure to a novel context and remained at the same level upon a shock delivery. In contrast, the levels of DG c-Fos expression was unaffected by the deletion of DG D5R neither in the home cage nor upon a shock delivery. These results suggest that DG D1Rs, but not D5Rs, contribute to the formation of distinct contextual representations of novel environments.

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486

Co-reporter:David A. Campbell;Benedikt Vollrath;Hui-Yeon Ko;Sergio G. Duron;B. S. Shankaranarayana Rao;Gregory G. Lin;Bridget M. Dolan;Arvind Govindarajan;Se-Young Choi

PNAS 2013 Volume 110 (Issue 14 ) pp:5671-5676

Publication Date(Web):2013-04-02

DOI:10.1073/pnas.1219383110

Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition—including hyperactivity, repetitive behaviors, and seizures—as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor—which we call FRAX486—also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

Distinct preplay of multiple novel spatial experiences in the rat

Co-reporter:George Dragoi

PNAS 2013 Volume 110 (Issue 22 ) pp:9100-9105

Publication Date(Web):2013-05-28

DOI:10.1073/pnas.1306031110

The activity of ensembles of hippocampal place cells represents a hallmark of an animal’s spatial experience. The neuronal mechanisms that enable the rapid expression of novel place cell sequences are not entirely understood. Here we report that during sleep or rest, distinct sets of hippocampal temporal sequences in the rat preplay multiple corresponding novel spatial experiences with high specificity. These findings suggest that the place cell sequence of a novel spatial experience is determined, in part, by an online selection of a subset of cellular firing sequences from a larger repertoire of preexisting temporal firing sequences in the hippocampal cellular assembly network that become rapidly bound to the novel experience. We estimate that for the given context, the recorded hippocampal network activity has the capacity to preplay an extended repertoire of at least 15 future spatial experiences of similar distinctiveness and complexity.

Creating a False Memory in the Hippocampus

Co-reporter:Steve Ramirez;Xu Liu;Pei-Ann Lin;Junghyup Suh;Michele Pignatelli;Roger L. Redondo;Tomás J. Ryan

Science 2013 Vol 341(6144) pp:387-391

Publication Date(Web):26 Jul 2013

DOI:10.1126/science.1239073

Can You Trust Your Memory?

Being highly imaginative animals, humans constantly recall past experiences. These internally generated stimuli sometimes get associated with concurrent external stimuli, which can lead to the formation of false memories. Ramirez et al. (p. 387; see the cover) identified a population of cells in the dentate gyrus of the mouse hippocampus that encoded a particular context and were able to generate a false memory and study its neural and behavioral interactions with true memories. Optogenetic reactivation of memory engram–bearing cells was not only sufficient for the behavioral recall of that memory, but could also serve as a conditioned stimulus for the formation of an associative memory.

Entorhinal Cortex Layer III Input to the Hippocampus Is Crucial for Temporal Association Memory

Co-reporter:Alexander J. Rivest;Junghyup Suh;Toshiaki Nakashiba;Takashi Tominaga

Science 2011 Volume 334(Issue 6061) pp:1415-1420

Publication Date(Web):09 Dec 2011

DOI:10.1126/science.1210125

A specific neural circuit integrates temporally dispersed stimuli into a coherent memory episode.

Presynaptic m1 muscarinic receptors are necessary for mGluR long-term depression in the hippocampus

Co-reporter:Ariel Kamsler;Thomas J. McHugh;David Gerber;Shu Ying Huang

PNAS 2010 107 (4 ) pp:1618-1623

Publication Date(Web):2010-01-26

DOI:10.1073/pnas.0912540107

To investigate the role of M1 muscarininc acetylcholine receptors (m1 receptors) in metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), we produced mouse lines in which deletion of the m1 gene is restricted to the forebrain (FB–m1KO) or hippocampal CA3 pyramidal neurons (CA3–m1KO). Stimulation in FB–m1KO hippocampal slices resulted in excitatory postsynaptic potentials and long-term synaptic plasticity (long-term potentiation and LTD) similar to controls. The mice were deficient in (S)-3,5-dihydroxyphenylglycine hydrate (DHPG)-induced mGluR LTD, which correlated with a presynaptic increase in the release of neurotransmitters. Protein kinase C (PKC) activity, which is downstream from both mGluRs and m1 receptors, was reduced in CA3 but not in CA1. The presynaptic requirement of m1 receptors was confirmed by the lack of DHPG-induced mGluR LTD in the CA1 of slices from CA3–m1KO mice. mGluR LTD was rescued by stimulating PKC activity pharmacologically in CA3–m1KO mice. These data confirm a role for PKC activation in presynaptic induction of mGluR LTD and distinguish between the roles of mGluRs and m1 receptors.

Transgenic Inhibition of Synaptic Transmission Reveals Role of CA3 Output in Hippocampal Learning

Co-reporter:Toshiaki Nakashiba;Thomas J. McHugh;Jennie Z. Young;Derek L. Buhl

Science 2008 Volume 319(Issue 5867) pp:1260-1264

Publication Date(Web):29 Feb 2008

DOI:10.1126/science.1151120

Abstract

The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex → dentate gyrus → CA3 → CA1 → entorhinal cortex) and the monosynaptic pathway (entorhinal cortex → CA1 → entorhinal cortex). We developed a generally applicable tetanus toxin–based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion–based memory recall, and for spatial tuning of CA1 cells.

Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice

Co-reporter:Mansuo L. Hayashi;B. S. Shankaranarayana Rao;Jin-Soo Seo;Han-Saem Choi;Bridget M. Dolan;Se-Young Choi;Sumantra Chattarji;

Proceedings of the National Academy of Sciences 2007 104(27) pp:11489-11494

Publication Date(Web):June 25, 2007

DOI:10.1073/pnas.0705003104

Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.

Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia

Co-reporter:Kazuo Yamada;David J. Gerber;Yoshimi Iwayama;Tetsuo Ohnishi;Hisako Ohba;Tomoko Toyota;Jun Aruga;Yoshio Minabe;Takeo Yoshikawa

PNAS 2007 Volume 104 (Issue 8 ) pp:2815-2820

Publication Date(Web):2007-02-20

DOI:10.1073/pnas.0610765104

The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. To replicate and extend our previously reported association between the PPP3CC gene, encoding the calcineurin catalytic γ-subunit, and schizophrenia, we examined 84 SNPs from 14 calcineurin-related candidate genes for genetic association by using 124 Japanese schizophrenic pedigrees. Four of these genes (PPP3CC, EGR2, EGR3, and EGR4) showed nominally significant association with schizophrenia. In a postmortem brain study, EGR1, EGR2, and EGR3 transcripts were shown to be down-regulated in the prefrontal cortex of schizophrenic, but not bipolar, patients. These findings raise a potentially important role for EGR genes in schizophrenia pathogenesis. Because EGR3 is an attractive candidate gene based on its chromosomal location close to PPP3CC within 8p21.3 and its functional link to dopamine, glutamate, and neuregulin signaling, we extended our analysis by resequencing the entire EGR3 genomic interval and detected 15 SNPs. One of these, IVS1 + 607A→G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene.

Dentate Gyrus NMDA Receptors Mediate Rapid Pattern Separation in the Hippocampal Network

Co-reporter:Thomas J. McHugh;Bradford B. Lowell;Joel K. Elmquist;Nina Balthasar;Roberto Coppari;Jennifer J. Quinn;Matthew W. Jones;Michael S. Fanselow;Matthew A. Wilson

Science 2007 Volume 317(Issue 5834) pp:94-99

Publication Date(Web):06 Jul 2007

DOI:10.1126/science.1140263

Abstract

Forming distinct representations of multiple contexts, places, and episodes is a crucial function of the hippocampus. The dentate gyrus subregion has been suggested to fulfill this role. We have tested this hypothesis by generating and analyzing a mouse strain that lacks the gene encoding the essential subunit of the N-methyl-d-aspartate (NMDA) receptor NR1, specifically in dentate gyrus granule cells. The mutant mice performed normally in contextual fear conditioning, but were impaired in the ability to distinguish two similar contexts. A significant reduction in the context-specific modulation of firing rate was observed in the CA3 pyramidal cells when the mutant mice were transferred from one context to another. These results provide evidence that NMDA receptors in the granule cells of the dentate gyrus play a crucial role in the process of pattern separation.

A clustered plasticity model of long-term memory engrams

Co-reporter:Arvind Govindarajan, Raymond J. Kelleher and Susumu Tonegawa

Nature Reviews Neuroscience 2006 7(7) pp:575

Publication Date(Web):

DOI:10.1038/nrn1937

Long-term memory and its putative synaptic correlates the late phases of both long-term potentiation and long-term depression require enhanced protein synthesis. On the basis of recent data on translation-dependent synaptic plasticity and on the supralinear effect of activation of nearby synapses on action potential generation, we propose a model for the formation of long-term memory engrams at the single neuron level. In this model, which we call clustered plasticity, local translational enhancement, along with synaptic tagging and capture, facilitates the formation of long-term memory engrams through bidirectional synaptic weight changes among synapses within a dendritic branch.

Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep

Co-reporter:Matthew P. Anderson;Takatoshi Mochizuki;Jinghui Xie;Walter Fischler;Jules P. Manger;Edmund M. Talley;Thomas E. Scammell;

Proceedings of the National Academy of Sciences 2005 102(5) pp:1743-1748

Publication Date(Web):January 26, 2005

DOI:10.1073/pnas.0409644102

It has long been suspected that sensory signal transmission is inhibited in the mammalian brain during sleep. We hypothesized that Ca_v3.1 T-type Ca²⁺ channel currents inhibit thalamic sensory transmission to promote sleep. We found that T-type Ca²⁺ channel activation caused prolonged inhibition (>9 s) of action-potential firing in thalamic projection neurons of WT but not Ca_v3.1 knockout mice. Inhibition occurred with synaptic transmission blocked and required an increase of intracellular Ca²⁺. Furthermore, focal deletion of the gene encoding Ca_v3.1 from the rostral–midline thalamus by using Cre/loxP recombination led to frequent and prolonged arousal, which fragmented and reduced sleep. Interestingly, sleep was not disturbed when Ca_v3.1 was deleted from cortical pyramidal neurons. These findings support the hypothesis that thalamic T-type Ca²⁺ channels are required to block transmission of arousal signals through the thalamus and to stabilize sleep.

NMDA receptors, place cells and hippocampal spatial memory

Co-reporter:Kazu Nakazawa, Thomas J. McHugh, Matthew A. Wilson & Susumu Tonegawa

Nature Reviews Neuroscience 2004 5(5) pp:361

Publication Date(Web):

DOI:10.1038/nrn1385

N-methyl-D-aspartate receptors (NMDARs) in the rodent hippocampus have been shown to be essential for spatial learning and memory, and for the induction of long-term synaptic plasticity at various hippocampal synapses. In this review, we examine the evidence concerning the role of NMDARs in hippocampal memory processes, with an emphasis on the function of NMDARs in area CA1 of the hippocampus in memory acquisition, and the unique role of NMDARs in area CA3 in the rapid acquisition and associative retrieval of spatial information. Finally, we discuss the data that have emerged from in vivo hippocampal recording studies that indicate that the activity of hippocampal place cells during behaviour is an expression of a memory trace.

Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit

Co-reporter:David J. Gerber;Diana Hall;Tsuyoshi Miyakawa;Sandra Demars;Joseph A. Gogos;Maria Karayiorgou

PNAS 2003 100 (15 ) pp:8993-8998

Publication Date(Web):2003-07-22

DOI:10.1073/pnas.1432927100

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurin-related genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin γ catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis.

Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia

Co-reporter:Tsuyoshi Miyakawa;Lorene M. Leiter;David J. Gerber;Raul R. Gainetdinov;Tatyana D. Sotnikova;Hongkui Zeng;Marc G. Caron

PNAS 2003 Volume 100 (Issue 15 ) pp:8987-8992

Publication Date(Web):2003-07-22

DOI:10.1073/pnas.1432926100

Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.

Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice

Co-reporter:Tatyana D. Sotnikova;Raul R. Gainetdinov;David J. Gerber;Marc G. Caron;Shu Ying Huang

PNAS 2001 Volume 98 (Issue 26 ) pp:15312-15317

Publication Date(Web):2001-12-18

DOI:10.1073/pnas.261583798

Acetylcholine serves an important modulatory role in the central nervous system. Pharmacological evidence has suggested that cholinergic activity can modulate central dopaminergic transmission; however, the nature of this interaction and the receptors involved remain undefined. In this study we have generated mice lacking the M1 muscarinic acetylcholine receptor and examined the effects of M1 deletion on dopaminergic transmission and locomotor behavior. We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity. M1-deficient mice also have an increased response to the stimulatory effects of amphetamine. Our results provide direct evidence for regulation of dopaminergic transmission by the M1 receptor and are consistent with the idea that M1 dysfunction could be a contributing factor in psychiatric disorders in which altered dopaminergic transmission has been implicated.

CA1-specific N-methyl-d-aspartate receptor knockout mice are deficient in solving a nonspatial transverse patterning task

Co-reporter:Laure Rondi-Reig;Megan Libbey;Howard Eichenbaum

PNAS 2001 Volume 98 (Issue 6 ) pp:3543-3548

Publication Date(Web):2001-03-13

DOI:10.1073/pnas.041620798

In both humans and animals, the hippocampus is critical to memory across modalities of information (e.g., spatial and nonspatial memory) and plays a critical role in the organization and flexible expression of memories. Recent studies have advanced our understanding of cellular basis of hippocampal function, showing that N-methyl-d-aspartate (NMDA) receptors in area CA1 are required in both the spatial and nonspatial domains of learning. Here we examined whether CA1 NMDA receptors are specifically required for the acquisition and flexible expression of nonspatial memory. Mice lacking CA1 NMDA receptors were impaired in solving a transverse patterning problem that required the simultaneous acquisition of three overlapping odor discriminations, and their impairment was related to an abnormal strategy by which they failed to adequately sample and compare the critical odor stimuli. By contrast, they performed normally, and used normal stimulus sampling strategies, in the concurrent learning of three nonoverlapping concurrent odor discriminations. These results suggest that CA1 NMDA receptors play a crucial role in the encoding and flexible expression of stimulus relations in nonspatial memory.

Memory engram storage and retrieval

Co-reporter:Susumu Tonegawa, Michele Pignatelli, Dheeraj S Roy, Tomás J Ryan

Current Opinion in Neurobiology (December 2015) Volume 35() pp:101-109

Publication Date(Web):1 December 2015

DOI:10.1016/j.conb.2015.07.009

•We review the history of research into putative memory storage mechanisms.•We highlight recent advances catalyzed by memory engram labeling technology.•We discuss the physiological properties of engram cells in memory consolidation.•We describe a novel investigation into the nature of retrograde amnesia.•We propose a differentiation between the mechanism of memory storage and retrieval.A great deal of experimental investment is directed towards questions regarding the mechanisms of memory storage. Such studies have traditionally been restricted to investigation of the anatomical structures, physiological processes, and molecular pathways necessary for the capacity of memory storage, and have avoided the question of how individual memories are stored in the brain. Memory engram technology allows the labeling and subsequent manipulation of components of specific memory engrams in particular brain regions, and it has been established that cell ensembles labeled by this method are both sufficient and necessary for memory recall. Recent research has employed this technology to probe fundamental questions of memory consolidation, differentiating between mechanisms of memory retrieval and the true neurobiology of memory storage.

The Ins and Outs of Hippocampal Circuits

Co-reporter:Susumu Tonegawa, Thomas J. McHugh

Neuron (24 January 2008) Volume 57(Issue 2) pp:175-177

Publication Date(Web):24 January 2008

DOI:10.1016/j.neuron.2008.01.005

The anatomy of the entorhinal-hippocampal circuit suggests how spatial information may flow into and out of the CA1 region. In this issue of Neuron, two groups use in vivo physiology to make predictions about the circuit mechanisms involved in the encoding and maintenance of spatial memory. Brun et al. show that lesions of the cells providing direct input from the mEC to CA1 lead to a decrease in spatial tuning, while Cheng and Frank report that the exploration of novel space leads to a transient increase in the temporally correlated firing of pairs of CA1 cells outside of their place fields specifically during ripple-like high-frequency events in the local field potential.

Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory

Co-reporter:Takashi Kitamura, Chen Sun, Jared Martin, Lacey J. Kitch, ... Susumu Tonegawa

Neuron (23 September 2015) Volume 87(Issue 6) pp:1317-1331

Publication Date(Web):23 September 2015

DOI:10.1016/j.neuron.2015.08.036

•Ocean cells rapidly form a distinct representation of a novel context•Ocean cells drive context-specific CA3 activation and context-specific fear memory•Ocean cells are dispensable for temporal association learning•Island cells are indifferent to context-specific encoding or memoryForming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions, but the role of the entorhinal cortex (EC) is poorly understood. Here, we show that Ocean cells, excitatory stellate neurons in the medial EC layer II projecting into DG and CA3, rapidly form a distinct representation of a novel context and drive context-specific activation of downstream CA3 cells as well as context-specific fear memory. In contrast, Island cells, excitatory pyramidal neurons in the medial EC layer II projecting into CA1, are indifferent to context-specific encoding or memory. On the other hand, Ocean cells are dispensable for temporal association learning, for which Island cells are crucial. Together, the two excitatory medial EC layer II inputs to the hippocampus have complementary roles in episodic memory.

Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors

Co-reporter:Joshua Kim, Xiangyu Zhang, Shruti Muralidhar, Sarah A. LeBlanc, Susumu Tonegawa

Neuron (22 March 2017) Volume 93(Issue 6) pp:1464-1479.e5

Publication Date(Web):22 March 2017

DOI:10.1016/j.neuron.2017.02.034

•Several genetically distinct CeA neurons mediate appetitive behaviors•BLA Ppp1r1b+ neurons project to CeA neurons that mediate appetitive behaviors•BLA Rspo2+ neurons project to CeA neurons that suppress appetitive behaviors•BLA-to-CeA pathways are analogous to corticostriatal direct and indirect pathwaysBasolateral amygdala (BLA) principal cells are capable of driving and antagonizing behaviors of opposing valence. BLA neurons project to the central amygdala (CeA), which also participates in negative and positive behaviors. However, the CeA has primarily been studied as the site for negative behaviors, and the causal role for CeA circuits underlying appetitive behaviors is poorly understood. Here, we identify several genetically distinct populations of CeA neurons that mediate appetitive behaviors and dissect the BLA-to-CeA circuit for appetitive behaviors. Protein phosphatase 1 regulatory subunit 1B+ BLA pyramidal neurons to dopamine receptor 1+ CeA neurons define a pathway for promoting appetitive behaviors, while R-spondin 2+ BLA pyramidal neurons to dopamine receptor 2+ CeA neurons define a pathway for suppressing appetitive behaviors. These data reveal genetically defined neural circuits in the amygdala that promote and suppress appetitive behaviors analogous to the direct and indirect pathways of the basal ganglia.Video AbstractDownload video (54MB)Help with mp4 files

Memory Engram Cells Have Come of Age

Co-reporter:Susumu Tonegawa, Xu Liu, Steve Ramirez, Roger Redondo

Neuron (2 September 2015) Volume 87(Issue 5) pp:918-931

Publication Date(Web):2 September 2015

DOI:10.1016/j.neuron.2015.08.002

The idea that memory is stored in the brain as physical alterations goes back at least as far as Plato, but further conceptualization of this idea had to wait until the 20th century when two guiding theories were presented: the “engram theory” of Richard Semon and Donald Hebb’s “synaptic plasticity theory.” While a large number of studies have been conducted since, each supporting some aspect of each of these theories, until recently integrative evidence for the existence of engram cells and circuits as defined by the theories was lacking. In the past few years, the combination of transgenics, optogenetics, and other technologies has allowed neuroscientists to begin identifying memory engram cells by detecting specific populations of cells activated during specific learning epochs and by engineering them not only to evoke recall of the original memory, but also to alter the content of the memory.

The Dendritic Branch Is the Preferred Integrative Unit for Protein Synthesis-Dependent LTP

Co-reporter:Arvind Govindarajan, Inbal Israely, Shu-Ying Huang, Susumu Tonegawa

Neuron (13 January 2011) Volume 69(Issue 1) pp:132-146

Publication Date(Web):13 January 2011

DOI:10.1016/j.neuron.2010.12.008

The late-phase of long-term potentiation (L-LTP), the cellular correlate of long-term memory, induced at some synapses facilitates L-LTP expression at other synapses receiving stimulation too weak to induce L-LTP by itself. Using glutamate uncaging and two-photon imaging, we demonstrate that the efficacy of this facilitation decreases with increasing time between stimulations, increasing distance between stimulated spines and with the spines being on different dendritic branches. Paradoxically, stimulated spines compete for L-LTP expression if stimulated too closely together in time. Furthermore, the facilitation is temporally bidirectional but asymmetric. Additionally, L-LTP formation is itself biased toward occurring on spines within a branch. These data support the Clustered Plasticity Hypothesis, which states that such spatial and temporal limits lead to stable engram formation, preferentially at synapses clustered within dendritic branches rather than dispersed throughout the dendritic arbor. Thus, dendritic branches rather than individual synapses are the primary functional units for long-term memory storage.Highlights► Synaptic tagging and capture (STC) at single spines is temporally asymmetric ► STC efficiency decreases with increasing distance and across branches ► Spines compete for L-LTP expression due to limiting protein availability ► The induction of L-LTP requires multiple spines and is branch biased