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The impact of Tsc-mTOR signaling on basal ganglia function

Tsc-mTOR信号对基底神经节功能的影响

基本信息

批准号：
10371870
负责人：
Helen S. Bateup
金额：
$ 32.06万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371870
关键词：
Affect Basal Ganglia Behavior Behavioral Biological Assay Brain Brain region Caregivers Cell physiology Cells Cognitive Complex Corpus striatum structure Data Development Disease Dopamine Electrophysiology (science)Epilepsy FRAP1 gene Fire - disasters Genes Genetic Habits High Prevalence Impaired cognition Intervention Knockout Mice Knowledge Learning Lifestyle-related condition Mental disorders Midbrain structure Motor Mus Mutation Neurobiology Neurodevelopmental Disorder Neurologic Neuromodulator Neurons Outcome Output Pathway interactions Patients Pattern Pharmacology Phenotype Physiology Population Prevalence Process Proteins Research Reversal Learning Role Signal Transduction Slice Synapses Synaptic Transmission Synaptic plasticity Syndrome TSC1 gene TSC1/2 gene TSC2 gene Testing Therapeutic Tuberous Sclerosis Up-Regulation autism spectrum disorder base brain cell cell growth cell type dopaminergic neuron experimental study flexibility habit learning improved loss of function mutation motor learning mouse model nervous system disorder neuropsychiatry novel therapeutic intervention prevent repetitive behavior synaptic function transmission process

项目摘要

PROJECT SUMMARY Tuberous Sclerosis Complex is a neurodevelopmental disorder caused by mutations in the TSC1 or 2 genes that encode negative regulators of mTOR complex 1 signaling. TSC is associated with a high prevalence of autism spectrum disorder (ASD) and other neuropsychiatric conditions, which are debilitating for patients and caregivers. Despite their prevalence in TSC, relatively little is known about the neurobiology of these manifestations including the cell types responsible. We propose that a core aspect of ASD, repetitive, inflexible patterns of behavior, is caused by synaptic changes in the basal ganglia, a brain region responsible for the selection and learning of appropriate actions. Here we will investigate this in the context of TSC by determining how mutations in Tsc1 affect the cellular physiology and behavioral output of neurons comprising key basal ganglia circuits. To isolate specific cell types, we will use genetic mouse models in which Tsc1 is selectively deleted from defined cell populations. The experiments in Aim 1 will determine how Tsc1 loss affects synaptic transmission and plasticity in the two classes of striatal projection neurons that initiate the primary output pathways of the basal ganglia. We will test the idea that increased cortical synaptic drive of direct pathway striatal neurons leads to altered learning and increased propensity for motor habit formation. Striatal activity is dynamically regulated by dopamine signaling, which exerts powerful control over behavior. In Aim 2, we will determine how selective deletion of Tsc1 from dopamine neurons affect their physiology and output. We will test the hypothesis that loss of Tsc1 causes hypofunctional striatal dopamine signaling leading to impaired cognitive flexibility in reversal learning tasks. This strategy represents a key step towards dissecting the cellular and circuit basis of TSC, and may ultimately inform new therapeutic strategies for this and related ASDs.

项目总结

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.

DOI：
10.1016/j.celrep.2021.109511
发表时间：
2021-08-10
期刊：
Cell reports
影响因子：
8.8
作者：
Benthall KN;Cording KR;Agopyan-Miu AHCW;Wong CD;Chen EY;Bateup HS
通讯作者：
Bateup HS

Altered motor learning and coordination in mouse models of autism spectrum disorder.

DOI：
10.3389/fncel.2023.1270489
发表时间：
2023
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
通讯作者：

The Convergence of Two Signaling Pathways Within the Striatum Reveals Potential Mechanisms of Neuropsychiatric Disease.

纹状体内两条信号通路的融合揭示了神经精神疾病的潜在机制。

DOI：
10.1016/j.biopsych.2021.03.019
发表时间：
2021
期刊：
Biological psychiatry
影响因子：
10.6
作者：
Cording,KatherineR;Bateup,HelenS
通讯作者：
Bateup,HelenS

Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models.

综合症自闭症谱系疾病中的多巴胺能失调：遗传小鼠模型的见解。

DOI：
10.3389/fncir.2021.700968
发表时间：
2021
期刊：
Frontiers in neural circuits
影响因子：
3.5
作者：
Kosillo P;Bateup HS
通讯作者：
Bateup HS

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Helen S. Bateup其他文献

Implementation and validation of single-cell genomics experiments in neuroscience

神经科学中单细胞基因组学实验的实施与验证

DOI：
10.1038/s41593-024-01814-0
发表时间：
2024-12-03
期刊：
NATURE NEUROSCIENCE
影响因子：
20.000
作者：
Marco Colonna;Genevieve Konopka;Shane A. Liddelow;Tomasz Nowakowski;Rajeshwar Awatramani;Helen S. Bateup;Cathryn R. Cadwell;Emre Caglayan;Jerry L. Chen;Jesse Gillis;Martin Kampmann;Fenna Krienen;Samuel E. Marsh;Michelle Monje;Michael R. O’Dea;Rickie Patani;Alex A. Pollen;Francisco J. Quintana;Marissa Scavuzzo;Matthew Schmitz;Steven A. Sloan;Paul J. Tesar;Jessica Tollkuhn;Maria Antonietta Tosches;Madeleine E. Urbanek;Jonathan M. Werner;Omer A. Bayraktar;Ozgun Gokce;Naomi Habib
通讯作者：
Naomi Habib

The Differential Contribution of Striatonigral and Striatopallidal Neurons in Mediating Responses to Therapeutic Agents and Drugs of Abuse: A Dual Role for DARPP-32

DOI：
发表时间：
2008
期刊：
影响因子：
0
作者：
Helen S. Bateup
通讯作者：
Helen S. Bateup

STAT3 regulates the generation of astroglia in human brain organoids with high mTORC1 activity

STAT3 调节具有高 mTORC1 活性的人脑类器官中星形胶质细胞的生成

DOI：
发表时间：
2023
期刊：
bioRxiv
影响因子：
0
作者：
B. K. Deb;Thomas L. Li;John D. Blair;D. Hockemeyer;Helen S. Bateup
通讯作者：
Helen S. Bateup

Maternal separation suppresses TGF alpha mRNA expression in the prefrontal cortex of male and female neonatal C57BL/6 mice.

母体分离抑制雄性和雌性新生 C57BL/6 小鼠前额皮质中 TGF α mRNA 的表达。

DOI：
10.1016/j.devbrainres.2004.05.007
发表时间：
2004
期刊：
Brain research. Developmental brain research
影响因子：
0
作者：
R. Romeo;J. Fossella;Helen S. Bateup;H. Sisti;W. Brake;B. McEwen
通讯作者：
B. McEwen

A framework for neural organoids, assembloids and transplantation studies

用于神经类器官、类组装体和移植研究的框架

DOI：
10.1038/s41586-024-08487-6
发表时间：
2024-12-09
期刊：
NATURE
影响因子：
48.500
作者：
Sergiu P. Pașca;Paola Arlotta;Helen S. Bateup;J. Gray Camp;Silvia Cappello;Fred H. Gage;Jürgen A. Knoblich;Arnold R. Kriegstein;Madeline A. Lancaster;Guo-Li Ming;Gaia Novarino;Hideyuki Okano;Malin Parmar;In-Hyun Park;Orly Reiner;Hongjun Song;Lorenz Studer;Jun Takahashi;Sally Temple;Giuseppe Testa;Barbara Treutlein;Flora M. Vaccarino;Pierre Vanderhaeghen;Tracy Young-Pearse
通讯作者：
Tracy Young-Pearse