シンポジウム
31 疾患脳における学習・記憶障害機構の多階層的理解とトランスレーショナルアプローチ
31 Multiscale perspectives on cognitive deficits in brain diseases and translational approaches to improve the deficits
座長：喜田 聡（東京大学大学院農学生命科学研究科）・Lee Yong-Seok（Seoul National University College of Medicine） |
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| 2022年7月3日 9:00～9:24 沖縄コンベンションセンター 会議場B5～7 第4会場
4S04m-01
Desipramine rescues memory deficit in the mouse model of Kabuki syndrome
*Weidong Li(1,2), Yuting Li(1), Lei Chen(1)
1. Shanghai Jiao Tong Univeristy, Shanghai, China, 2. WLA Laboratories, World Laureates Association, Shanghai,China
Keyword: Kabuki syndrome, Utx, histone demethylase, CaMKII
Kabuki syndrome is a rare developmental disorder characterized by multiple congenital anomalies and intellectual disability. Utx (also known as KMD6A), which encodes a histone demethylase, is the primary pathogenic risk genes of Kabuki syndrome type II. However, the mechanism of how Utx regulates the cognitive function in Kabuki syndrome remains unclear. We generated Utx conditional knockout mice and found that Utx deletion downregulates calmodulin transcription by disrupting H3K27me3 demethylation and decreasing phosphorylation of CaMKII. Moreover, Utx knockout mice showed impaired LTP and remote contextual fear memory deficits, which can be reversed by pharmacological activation of CaMKII with FDA-approved drug desipramine. The results reveal a crucial role of Utx in cognitive functions and suggest a potential therapeutic target for Kabuki syndrome. | | 2022年7月3日 9:24～9:48 沖縄コンベンションセンター 会議場B5～7 第4会場
4S04m-02
Oxytocin neurons: structural and functional connections
*Zhihua Gao(1)
1. Zhejiang University School of Medicine
Keyword: oxytocin , neuroendocrinology
The hypothalamo-neurohypophysial system (HNS), comprising hypothalamic magnocellular neuroendocrine cells (MNCs) and the neurohypophysis, plays a pivotal role in regulating reproduction and fluid homeostasis by releasing oxytocin and vasopressin into the bloodstream. However, its structure and contribution to the central actions of oxytocin and vasopressin remain incompletely understood. Using viral tracing and whole brain imaging, we reconstructed the three-dimensional architecture of the HNS and observed collaterals of MNCs within the brain. By dual viral tracing, we further uncovered that subsets of MNCs collaterally project to multiple extrahypothalamic regions. Selective activation of oxytocin neuroendocrine cells promoted peripheral oxytocin release and facilitated central oxytocin-mediated social interactions, whereas inhibition of these neurons elicited opposing effects. Our work reveals the previously unrecognized complexity of the HNS and provides structural and functional evidence for MNCs in coordinating both peripheral and central oxytocin-mediated actions, which will shed light on the mechanistic understanding of oxytocin-related psychiatric diseases. | | 2022年7月3日 9:48～10:12 沖縄コンベンションセンター 会議場B5～7 第4会場
4S04m-03
Targeting distinct cell types to improve learning and memory in mouse models of Rasopathy
*Yong-Seok Lee(1)
1. Seoul National University College of Medicine
Keyword: cognitive deficits, hippocampus, astrocyte, rasopathy
RAS-ERK signaling pathway regulates large numbers of biological processes. Thus, germline mutations in the RAS signaling pathway are associated with developmental disorders, collectively called RASopathy including Noonan syndrome (NS), neurofibromatosis (NF), and cardio-facio-cutaneous syndrome (CFCS). Considering that most of the mutations in Rasopathy are gain-of-function which can enhance RAS activation, RAS-MAPK inhibitors have been suggested as treatments. However, interestingly, RAS signaling is hyperactivated in a cell-type-specific manner in Rasopathy. For example, we and others have shown that NF affects the inhibitory synaptic transmission, whereas NS affects excitatory synaptic transmission. Therefore, the cell-type specificity in individual disorders should be considered to develop an efficient treatment strategy for cognitive impairments in Rasopathy rather than suppressing RAS activity in general. In this talk, I will present our recent findings on the cell type-specific manipulations of RAS signaling both in neurons and glia in mouse models of Rasopathy, which would shed light on developing an individualized treatment for cognitive deficits in Rasopathy. | | 2022年7月3日 10:12～10:36 沖縄コンベンションセンター 会議場B5～7 第4会場
4S04m-04
Frontolimbic circuitry underlying compulsive behaviors
*Anatol Kreitzer(1)
1. University of California, San Francisco
Keyword: obsessive-compulsive disorder
Patients with obsessive compulsive disorder (OCD) experience debilitating symptoms consisting of persistent and obtrusive thoughts, repetitive behaviors, and anxiety. Human neuroimaging, human neurosurgery, and mouse studies of neural circuit function indicate that OCD results broadly from dysfunction in cortico-basal-ganglia-thalamocortical circuitry. Despite this fundamental insight, effective treatments for OCD remain elusive. First-line treatments such as SSRIs and more invasive strategies such as deep-brain stimulation (DBS) only treat a fraction of patients successfully. One subregion of the amygdala, the intercalated nuclei (ITC), has several interesting features suggesting that it contributes to OCD circuit dysfunction. The ITC receives input from the prefrontal cortex and the ventral tegmental area, and sends dense inhibitory projections to both the CEA and BLA. The ITC is uniquely positioned to integrate signals from cortical and subcortical regions and, therefore, improper gating of neural activity at this interface could cause abnormal reinforcement learning and repetitive behavior. In addition, the ITC is required for negative reinforcement learning in mice, a behavior that is impaired in OCD patients. Using transgenic mice, we have undertaken a characterization of ITC circuits and their function in OCD- and anxiety-relevant behaviors, including grooming, platform-mediated avoidance, and elevated plus maze. Using a combination of fiber photometry, optogenetics, chemogenetics, ex vivo slice physiology, and quantitative behavioral analysis, we have examined the function of ITC amygdala in both wildtype mice, and in mouse models of compulsive behavior. | | 2022年7月3日 10:36～11:00 沖縄コンベンションセンター 会議場B5～7 第4会場
4S04m-05
Cell Type-Specific Translation in Memory and Neurodevelopmental Disorders
*Eric Klann(1)
1. New York University
Keyword: memory, fragile X syndrome, tuberous sclerosis complex, protein synthesis
De novo protein synthesis is required for long-lasting synaptic plasticity and long-term memory consolidation, reconsolidation, and extinction. We have developed inducible and conditional mouse models as well as viruses where translation initiation mediated by either eIF4E or eIF2 can be inhibited in a cell type-specific manner. Using these novel mouse lines, we have determined that auditory threat memory consolidation requires de novo translation in specific subtypes in neurons in the amygdala. We also have found that cell type-specific translation dysregulation contributes to behavioral phenotypes in mouse models of fragile X syndrome (FXS) and tuberous sclerosis complex (TSC), neurodevelopmental disorders with a high incidence of intellectual disability and autism spectrum disorder (ASD). Specifically, we have found that deletion of Fmr1 in specific subtypes of dopamine receptor-expressing neurons results in altered cortico-striatal synaptic plasticity, dendritic spine density, and repetitive behaviors that are consistent with ASD. Similarly, heterozygous deletion of Tsc2 in oxytocin receptor-expressing neurons gives rise to sexually dimorphic aberrations in social behavior and social isolation-induced anxiety-like behaviors. Collectively, our findings demonstrate that cell type-specific translation initiation is required for threat memory consolidation and cell type-specific disruption of translation contributes aberrant behaviors in mouse models of neurodevelopmental disorders. Supported by NIH grants NS034007, NS047384, and NS112316. | | | |
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