Project 1

项目1

• 批准号: 10386840
• 负责人: Takao K Hensch
• 金额: $ 38.49万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386840
• 关键词: 3-Dimensional; Acoustics; Address; Adult; Age; Anatomy; Anxiety; Area; Attention; Behavior; Behavioral; Behavioral Paradigm; Biological; Biological Assay; Boston; Brain; Breathing; Calcium Chloride; Callithrix; Cell Maturation; Cell physiology; Cells; Chlorides; Cognition; Cognitive; Development; Dissection; Electrodes; Electroencephalography; Electrophysiology (science); Engineering; Equilibrium; Evolution; Exposure to; Foundations; Gait abnormality; Genes; Genetic; Grooming; Hindlimb; Human; Image; Impairment; Injections; Insula of Reil; Knock-out; Learning; Life; Litter Size; Locomotion; Longevity; Longitudinal Studies; Maps; Measures; Mental disorders; Methyl-CpG-Binding Protein 2; Modeling; Motor; Mus; Music; Mutant Strains Mice; Mutation; Neonatal; Neurologic; Neurologic Symptoms; Neurons; Organoids; Oxidation-Reduction; Parvalbumins; Patients; Pediatric Hospitals; Phase; Phenotype; Physiological; Physiology; Play; Prefrontal Cortex; Pregnancy; Primates; Recovery; Reversal Learning; Risk Factors; Role; Sampling; Sensory; Silicon; Stimulus; Structure; Symptoms; Tamoxifen; Testing; Time; Ultrasonics; Viral; Virus; Visual Cortex; Visual attention; Weight; Work; autism spectrum disorder; base; behavior test; circadian pacemaker; cognitive development; critical period; deprivation; designer receptors exclusively activated by designer drugs; early experience; experience; flexibility; gamma-Aminobutyric Acid; gene environment interaction; gene function; in vivo; inhibitory neuron; insight; multisensory; mutant; novel; preference; premature; reconstruction; restoration; risk variant; sensor; sensory cortex; sensory system; standard measure; tool; touchscreen; two-photon; vocalization

Abstract Mice – with their short gestation time, lifespan, large litter size, and above all, genetic tractability –are powerful experimental tools with which to explore mammalian brain development. One striking example is the reversible disruption of autism risk genes, like Mecp2 or Shank3. Switching on these genes after the emergence of fullblown phenotypes rescues several motor- related symptoms, including inertia, abnormal gait, weight, irregular breathing, repetitive grooming or hind-limb clasping. Instead, other neurological aspects are uncorrected in adulthood, such as anxiety or motor coordination. Of central relevance to human patients, it remains unknown to what extent higher cognition is impaired in Shank3 or Mecp2 mutant mice and whether recovery would also be limited to a critical period. The Hensch project will directly address sensitive periods and reversibility of dorsomedial prefrontal cortical (dmPFC) functions using novel behavioral tests of attention, cognitive flexibility and acoustic preference along with associated physiological measures from relevant areas. Pioneering work in the first phase of the Conte Center established the pivotal role of particular inhibitory neurons underlying critical period timing in mouse sensory systems. Parvalbumin (PV+) GABA circuit maturation dictates both the onset and closure of these windows of circuit refinement. Manipulations of psychiatric risk factors, such as circadian Clock gene disruption or redox dysregulation, can delay or extend developmental trajectories by upsetting the vulnerable PV+ component of local circuit excitatory-inhibitory balance. Recently, Hensch and Feng extended this principle to higher-order multi-sensory integration (MSI, commonly impaired in patients with autism) in the insular cortex. Shared MSI impairments in mice lacking either Shank3 (weak PV+) or Mecp2 (excessive PV+) suggest an optimal range of PV+ network function enables proper pruning of connections in the insula. Here, we will examine circuit physiology and anatomy before/after restoration of Shank3 or Mecp2 in mice, ultimately by full 3D EM circuit reconstruction with Lichtman also in marmosets carrying the same Shank3 deletion (from Feng). Further, our touchscreen two- choice visual attention assay, a multiple-choice foraging task to assess flexible rule learning, and preference for acoustic stimuli (music, ultrasonic calls) experienced early in life will probe dmPFC function in mutant and rescued mice. Electrophysiological recording and two-photon Calcium / Chloride imaging from the dmPFC in vivo will focus on PV+ networks in these areas across development, starting with comparison to Arlotta’s human organoids. Based on these many insights from mice, the impact of silencing/activating PV+ circuits in corresponding frontal cortical regions of PV-Cre marmosets (by Feng) using focal injections of viral DREADD constructs can be tested on analogous primate tasks of attention, cognitive flexibility and preference behavior at MIT. Our collective work will determine whether biological determinants of critical periods in sensory systems play a similar role in cognition, the corresponding circuit changes which are corrected when Shank3/Mecp2 symptoms are reversed and how much the mouse and primate brain differ.

抽象的 小鼠——妊娠时间短、寿命短、产仔数多，最重要的是，遗传易驯化 – 是探索哺乳动物大脑发育的强大实验工具。 一个引人注目的例子是自闭症风险基因的可逆破坏，例如 Mecp2 或 Shank3。 在成熟的表型出现后打开这些基因可以挽救一些运动功能 相关症状，包括惰性、步态异常、体重、呼吸不规则、重复 相反，其他神经方面的行为并未得到纠正。 成年期，例如焦虑或运动协调性，它与人类患者密切相关。 Shank3 或 Mecp2 突变小鼠的高级认知能力受损程度仍不清楚 以及复苏是否也将仅限于关键时期。 解决敏感期和背内侧前额皮质 (dmPFC) 功能的可逆性 使用注意力、认知灵活性和声音偏好的新颖行为测试以及 第一阶段相关领域的相关生理措施。 孔特中心确立了特定抑制性神经元在关键性神经元基础上的关键作用 小鼠感觉系统中的周期时间决定了小清蛋白 (PV+) GABA 电路的成熟。 这些回路细化窗口的开始和关闭。 风险因素，例如生物钟基因破坏或氧化还原失调，可能会延迟或延长 通过扰乱本地电路中脆弱的 PV+ 组件来实现发展轨迹 最近，Hensch 和 Feng 将这一原理扩展到更高阶。 岛叶皮质的多感觉统合（MSI，自闭症患者通常受损）。 缺乏 Shank3（弱 PV+）或 Mecp2（过度 PV+）的小鼠存在共同的 MSI 损伤 建议 PV+ 网络功能的最佳范围，以便能够适当修剪网络中的连接 在这里，我们将检查 Shank3 修复之前/之后的电路生理学和解剖学。 或小鼠中的 Mecp2，最终通过 Lichtman 的完整 3D EM 电路重建 狨猴携带相同的 Shank3 缺失（来自 Feng）此外，我们的触摸屏有两个-。 选择视觉注意分析，一项评估灵活规则学习的多项选择觅食任务， 以及对生命早期经历的声音刺激（音乐、超声波呼叫）的偏好将探索 突变小鼠和获救小鼠中的 dmPFC 功能。电生理记录和双光子。 体内 dmPFC 的钙/氯化物成像将重点关注这些区域的 PV+ 网络 跨越发展，从与 Arlotta 的人类类器官的比较开始。 来自小鼠的许多见解，沉默/激活 PV+ 电路对相应额叶的影响 PV-Cre 狨猴的皮质区域（冯）使用病毒 DREADD 的局部注射 可以在类似的灵长类动物注意力、认知灵活性和 麻省理工学院的偏好行为将决定生物决定因素。 感觉系统中的关键时期在认知中起着类似的作用，相应的电路 当 Shank3/Mecp2 症状逆转时，哪些变化会被纠正，以及有多少变化 老鼠和灵长类动物的大脑不同。