Showing papers by "Susumu Tonegawa published in 2016"

Ventral CA1 neurons store social memory

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.

Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

What is memory? The present state of the engram

Abstract: The mechanism of memory remains one of the great unsolved problems of biology Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous “excitations”, whose precise physical nature and consequences were out of reach of the biology of his day Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today

Antagonistic negative and positive neurons of the basolateral amygdala

Abstract: The authors identify two genetic markers defining non-overlapping populations of principal cells in the amygdala that respond to stimuli of opposite valence. These two populations of cells contribute to behavioral responses to aversive or rewarding experiences, are distributed along antero-posterior gradients that run in opposite directions, and synaptically suppress each other.

Differentiation of forebrain and hippocampal dopamine 1‐class receptors, D1R and D5R, in spatial learning and memory

Abstract: Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1-class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water-maze spatial learning task remains unknown. D1R- and D5R-specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F-D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F-D1R/D5R KO mice were given water-maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F-D1R KO) and D5R KO (F-D5R KO) mice were trained on the water-maze task. F-D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F-D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F-D5R KO animals did not present observable deficits on the water-maze task. Because F-D1R KO mice showed water-maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG-D1R KO) mice on the water-maze task. DG-D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory. © 2015 Wiley Periodicals, Inc.

Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

Antagonistic negative and positive neurons of the basolateral amygdala

Abstract: The authors identify two genetic markers defining non-overlapping populations of principal cells in the amygdala that respond to stimuli of opposite valence These two populations of cells contribute to behavioral responses to aversive or rewarding experiences, are distributed along antero-posterior gradients that run in opposite directions, and synaptically suppress each other

Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma

Abstract: Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/β1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/β1i expression, that is up-regulated by interferon-γ (IFNγ), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFNγ signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/β1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1 arrest via PSMB9/β1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

Functional and inducible expression of a transfected murine class II major histocompatibility complex gene (antigen presentation/cosmid clones/y-interferon/protoplast fusion/T-helper hybridoma)

Abstract: Using the spheroplast fusion technique, we have introduced the cloned E beta b gene into two d haplotype cell lines, the B lymphoma line A20-2J and the macrophage tumor line P388D1. Analysis with a monoclonal antibody indicates that the product of the transfected E beta b gene associates with the endogenous E alpha chain to form an E alpha dE beta b complex. While expression of E alpha dE beta b is constitutive in A20-2J cells transfected with the E beta b gene, surface expression of E alpha dE beta b is detected in transfected macrophage cells only after treatment of cells with culture supernatants from concanavalin A (Con A)-stimulated T cells. Transfected B lymphoma cells and transfected Con A supernatant-treated macrophage cells have acquired the ability to present antigen to E alpha dE beta b-restricted T-cell hybridomas. The observed inducible expression of the transfected gene in the macrophage host indicates that sequences responsible for regulated expression of the E beta b gene may be associated with the transfected gene. In combination with directed mutagenesis, the system described here provides a means to study (i) E beta b sequences that are important in determining the restriction specificity of the E molecule and (ii) sequences associated with the E beta gene that may be important in the regulation of E beta chain expression.

Methods and compositions for treating alzheimer's disease and other memory-associated disorders and conditions

Abstract: The invention, in part, relates to the use of optogenetic methods to increase dendritic spine density on DG memory engram cells in treatment methods for memory-impairment-associated diseases and conditions.

The Identification of Somatic Mutations in Interferon-g Signal Molecules in Human Uterine Leiomyosarcoma

Abstract: Human uterine leiomyosarcoma (LMS) is neoplastic malignancy that typically arises in tissues of mesenchymal origin. The identification of novel molecular mechanism leading to human uterine LMS formation and the establishment of new therapies has been hampered by several critical points. We earlier reported that mice with a homozygous deficiency for proteasome beta subunit 9 (PSMB9)/b1i, an interferon (IFN)-g inducible factor, spontaneously develop uterine LMS. The use of research findings of the experiment with mouse model has been successful in increasing our knowledge and understanding of how alterations, in relevant oncogenic, tumour suppressive, and signaling pathways directly impact sarcomagenesis. The IFN-g pathway is important for control of tumour growth and invasion and, has been implicated in several malignant tumours. In this study, experiments with human tissues revealed a defective PSMB9/b1i expression in human uterine LMS that was traced to the IFN-g pathway and the specific effect of somatic mutations of Janus kinase (JAK1) molecule or promoter region on the transcriptional activation of PSMB9/b1i gene. Understanding the molecular mechanisms of human uterine LMS may lead to identification of new diagnostic candidates or therapeutic targets in human uterine LMS. DOI : 10.14302/issn2572-3030.jcgb-16-1276 Freely Available Online www.openaccesspub.org | JCGB CC-license DOI : 10.14302/issn2572-3030.jcgb-16-1276 Vol-1 Issue 1 Pg. no.30 Introduction Uterine mesenchymal tumours have been traditionally divided into benign tumour leiomyomas (LMA) and malignant tumour leiomyosarcomas (LMS) based on cytological atypia, mitotic activity and other criteria. Uterine LMS, which are some of the most common neoplasms of the female genital tract, are relatively rare uterine mesenchymal tumour, having an estimated annual incidence of 0.64 per 100,000 women (1). They account for approximately one-third of uterine sarcomas, of only 53% for tumours confined to the uterus (2,3). Generally, patients with uterine LMS typically present with vaginal bleeding, pain, and a pelvic mass. Gynecological cancer, for instance breast cancer and endometrial carcinomas, are strongly promoted by female hormones, but the rate of hormone receptor expression is reported to be significantly less in human uterine LMS compared with normal myometrium. These low receptor expressions were found to not correlate with the promotion of initial disease development or with the overall survival of patients with uterine LMS. As uterine LMS is resistant to chemotherapy and radiotherapy, and thus surgical intervention is virtually the only means of treatment for this disease (4,5,6), however, molecular targeting therapies against tumours have recently shown remarkable achievements (7,8). It is noteworthy that, when adjusting for stage and mitotic count, uterine LMS has a significantly worse prognosis than carcinosarcoma (9); developing an efficient adjuvant therapy is expected to improve the prognosis of the disease. A trend towards prolonged disease-free survival is seen in patients with matrix metalloproteinase (MMP)-2-negative tumours (10). Although typical presentations with hypercalcemia or eosinophilia have been reported, this clinical abnormality is not an initial risk factor for uterine LMS. To the best of our knowledge, little is known regarding the biology of uterine LMS; therefore, the risk factors that promote the initial development of uterine LMS and regulate their growth in vivo remain poorly understood. The mice with a targeted disruption of proteasome beta subunit 9 (PSMB9)/b1i, which is interferon (IFN)-g -inducible proteasome subunit, exhibited a defect in tissueand substratedependent proteasome function, and female PSMB9-deficient mice shown to develop uterine LMS, with a disease prevalence of 37% by 14 months of age (11,12). Defective PSMB9/b1i expression is likely to be one of the risk factors for the development of human uterine LMS, as it is in PSMB9/b1i-deficient mice (12). Recent report shows that stable PSMB9/b1i expression contributes to cell proliferation, which directly correlates to the progressive deterioration with increasing stage and grade of the tumour. As the importance and involvement of the IFN-g signal pathway in the transcriptional regulation of the transporter associated with antigen processing (TAP1) and PSMB9/b1i promoter have been established, it is demonstrated that the defective PSMB9/b1i expression was attributable to G871E somatic mutation in the ATPbinding region of JAK1 molecule in SKN cell line, which is established from patient with uterine LMS. It is (Continued on page 31) Corresponding Author: Takuma Hayashi, Dept. of Obstetrics and Gynecology, Shinshu University School of Medicine, Japan, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. Tel: 81-263-37-2719, e-mail: takumah@shinshu-u.ac.jp

Methods and compositions for treating mental disorders and conditions

Abstract: The invention, in some aspects, relates to methods to alter activity in cells and the use of such method to treat disorders and conditions The methods involve, in part, expressing stimulus-activated opsin polypeptides in neurons involved in memory and behavior and activating the opsin polypeptides to modulate activity of cells in which they are expressed and/or cells to which the cells that express the opsin polypeptides project

Molecular approaches of sarcomagenesis for establishment of clinical therapy

Abstract: Sarcomas are neoplastic malignancies that typically arise in tissues of a mesenchymal origin. The identification of novel molecular mechanisms leading to sarcoma formation and the establishment of new therapies and biomarkers have been hampered by several critical factors. This type of cancer is rarely observed in clinical settings, with fewer than 15,000 newly cases being diagnosed each year in the United States. Another complicating factor is that sarcomas are extremely heterogeneous as they arise in a multitude of tissues from many different cell lineages. The scarcity of clinical samples coupled with its inherent heterogeneity creates a challenging experimental environment for clinicians and scientists. Faced with these challenges, there have been extremely limited advances in treatment options available to patients with sarcomas than in those for patients with other cancers. In order to glean insight into the pathobiology of sarcomas, scientists are now using mouse models whose genomes have been specifically tailored to carry gene deletions, gene amplifications, and point mutations commonly observed in human sarcomas. The use of these model organisms has been successful in increasing our knowledge and understanding of how alterations in relevant oncogenic, tumor suppressive, and signaling pathways directly impact sarcomagenesis. It is the goal of many in the biological community that the use of these mouse models will serve as powerful in vivo tools to further our understanding of sarcomagenesis and potentially identify new biomarkers and develop therapeutic strategies.