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Memory Mechanisms and Mental Disorders

记忆机制和精神障碍

基本信息

批准号：
8628216
负责人：
TYRONE D CANNON
金额：
$ 18.23万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-05 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628216
关键词：
Memory Mechanisms Mental Disorders

项目摘要

Schizophrenia (SZ) and bipolar disorder (BP) are the most chronic and debilitating of psychiatric syndromes, each with lifetime prevalence of about 1%. Existing pharmacologic treatments are partially effective in reducing symptom severity but do not ameliorate the underlying disease processes, cognitive deficits, or functional disabilities associated with these syndromes. Given that both SZ and BP are substantially heritable, gene discovery represents our best hope for identifying new molecular targets for interventions. However, the highly polygenic and heterogeneous nature of these syndromes substantially reduces the effectiveness of traditional genetic linkage and association designs. In addition, recent evidence suggests that some genetic overlaps between these conditions. Our approach is based on the premise that SZ and BP are best conceptualized as sets of quantitative traits that reflect intermediate phenotypes between predisposing genes and syndromal expression (CEendophenotypes1). Here we will screen 300,000 SNP markers - distributed so as to enable the detection of linkage disequilibrium in most parts of the genome - for association with memory and sociability phenotypes previously associated with risk for SZ and BP in a sample of 2,000 subjects from the greater Los Angeles area (LA2K sample). Followup studies of patients with SZ and BP will be performed to specify the impact of the genes identified in the LA2K sample on neuroanatomical and neurophysiological indicators of the pathophysiology of SZ and BP. Because nearly half of the genome is expressed in the brain, and considering the central importance of memory and sociability to adaptive behavioral function, there are likely dozens to hundreds of genes of small to moderate effect influencing these phenotypes in the general population. We hypothesize that many of these genes contribute to susceptibility to SZ and BP through their impacts on the brain systems mediating memory systems and social function and that most of these have been undetected by previous studies using syndromal status as the phenotypic target. In parallel with this whole genome strategy, and to illustrate our translational approach, we will use rodent transgenic models of two promising candidate genes DISC1 and Dysbindin to specify the cellular mechanisms underlying the associations of these genes with memory, sociabiliy, and susceptibility to SZ and BP.

精神分裂症（SZ）和双相情感障碍（BP）是最慢性和最衰弱的精神综合征，每种疾病的终生患病率都在1%左右。现有的药物治疗在以下方面部分有效：减轻症状严重程度，但不改善基础疾病过程、认知缺陷，或与这些综合征相关的功能障碍。鉴于SZ和BP都是遗传基因的发现是我们确定新的干预分子靶点的最大希望。然而，这些综合征的高度多基因和异质性实质上降低了其遗传多样性。传统遗传连锁和关联设计的有效性。此外，最近的证据表明，这些病症之间存在遗传重叠我们的方法是基于这样的前提，即SZ和 BP最好被概念化为反映中间表型的数量性状集，易感基因和综合征表达（CE内表型1）。在这里，我们将筛选30万个SNP 标记-分布以使得能够检测基因组的大多数部分中的连锁不平衡-用于与先前与SZ和BP风险相关的记忆和社交表型相关，来自大洛杉矶地区的2，000名受试者的样本（LA 2K样本）。患者随访研究将进行SZ和BP，以详细说明LA 2K样本中鉴定的基因对 SZ和BP病理生理学的神经解剖学和神经生理学指标。因为几乎基因组的一半在大脑中表达，考虑到记忆的核心重要性，从社会性到适应性行为功能，可能有几十到几百个小到中等的基因。影响这些表型在一般人群中的作用。我们假设这些基因中的许多基因通过影响调节记忆系统和社会功能的大脑系统，其中大部分已经被以前的研究使用综合征状态作为表型目标未检测到。与此同时为了说明我们的翻译方法，我们将使用两种啮齿动物转基因模型，有希望的候选基因DISC 1和Dysbindin指定的细胞机制，这些基因与记忆力、社交能力以及对SZ和BP的易感性相关。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recognition deficits in mice carrying mutations of genes encoding BLOC-1 subunits pallidin or dysbindin.

携带编码 BLOC-1 亚基 pallidin 或 Dysbindin 基因突变的小鼠的识别缺陷。

DOI：
10.1111/gbb.12240
发表时间：
2015
期刊：
Genes, brain, and behavior
影响因子：
0
作者：
Spiegel,S;Chiu,A;James,AS;Jentsch,JD;Karlsgodt,KH
通讯作者：
Karlsgodt,KH

Memory systems in schizophrenia: Modularity is preserved but deficits are generalized.

DOI：
10.1016/j.schres.2015.08.014
发表时间：
2015-10
期刊：
Schizophrenia research
影响因子：
4.5
作者：
Haut KM;Karlsgodt KH;Bilder RM;Congdon E;Freimer NB;London ED;Sabb FW;Ventura J;Cannon TD
通讯作者：
Cannon TD

Differences in neural activation as a function of risk-taking task parameters.

DOI：
10.3389/fnins.2013.00173
发表时间：
2013
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Congdon E;Bato AA;Schonberg T;Mumford JA;Karlsgodt KH;Sabb FW;London ED;Cannon TD;Bilder RM;Poldrack RA
通讯作者：
Poldrack RA

Decomposing decision components in the stop-signal task: a model-based approach to individual differences in inhibitory control.

DOI：
10.1162/jocn_a_00567
发表时间：
2014-08
期刊：
Journal of cognitive neuroscience
影响因子：
3.2
作者：
White CN;Congdon E;Mumford JA;Karlsgodt KH;Sabb FW;Freimer NB;London ED;Cannon TD;Bilder RM;Poldrack RA
通讯作者：
Poldrack RA

Potential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice.