Fetal and Postnatal Development of Visual Connections

胎儿和产后视觉连接的发育

• 批准号: 8369788
• 负责人: Carla J Shatz
• 金额: $ 48.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-01-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369788
• 关键词: Acute; Adolescent; Adult; Age; Aging; Alleles; Alzheimer' s Disease; Amblyopia; Apical; Autistic Disorder; Biochemical; Blocking Antibodies; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Cells; Childhood; Clinical; Dendrites; Dendritic Spines; Development; Drug Delivery Systems; Dyslexia; Effectiveness; Employee Strikes; Equilibrium; Etiology; Eye; Family; Genes; Genetic; Germ Lines; Goals; Histocompatibility; Human; Image; Immune system; Immunoglobulins; In Vitro; Label; Learning; Learning Disabilities; Life; Ligands; Link; Long-Term Depression; Long-Term Potentiation; Measures; Mediating; Memory Loss; Methods; Microscopy; Mitogen-Activated Protein Kinases; Molecular; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Ocular Dominance; Pathway interactions; Phosphorylation; Physiological; Proteins; Proto-Oncogene Proteins c-akt; Recombinants; Recovery; Repression; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Slice; Stroke; Synapses; Synaptic plasticity; System; T-Cell Receptor; Tamoxifen; Testing; Transgenic Mice; Transgenic Organisms; Vertebral column; Visual; Visual Cortex; Visual system structure; base; cell motility; cell type; critical developmental period; critical period; density; design; experience; fetal; hippocampal pyramidal neuron; human FRAP1 protein; in vivo; loss of function; member; monocular; monocular deprivation; novel; optical imaging; postnatal; receptor; relating to nervous system; repaired; research study; two-photon; vision development; white matter

DESCRIPTION (provided by applicant): What enables a baby's brain to learn so rapidly during early developmental critical periods? What cell and molecular mechanisms cause the decline in extensive plasticity by adulthood? The goal here is to enhance synaptic plasticity by discovering and then blocking endogenous mechanisms that function to suppress plasticity and circuit change. Specifically, can manipulations of the neuronal receptor PirB (Paired Immunoglobulin-like receptor B; Lilrb3 in humans) "release the brake" on ocular dominance (OD) plasticity, a form of experience-dependent synaptic plasticity in visual cortex? In the immune system PirB is a receptor for Major Histocompatibility Class I molecules, famous ligands for T-cell receptors. This Lab made the unexpected discovery that neurons express PirB and MHCI molecules at synapses. OD plasticity is enhanced in visual cortex of mice with germline deletion of PirB, consistent with PirB acting to brake synaptic plasticity. Three specific aims are proposed: 1) Determine if acute deletion of PirB postnatally enhances OD plasticity: A conditional allele of PirB (PirB flox/flox) has been made, allowing acute temporal and cell-type disruption of PirB by crossing mice with tamoxifen-inducible Cre transgenic lines. Direct blockade of PirB with recombinant soluble truncated PirB protein or function-blocking antibodies will also be used. These experiments should reveal when and in what cell types PirB acts. 2) Link enhanced OD plasticity in PirB-/- mice to cellular mechanisms of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) will be studied in vitro in visual cortex slices using physiological methods. Dendritic spine density of YFP-labeled layer 5 pyramidal neurons will be measured in PirB-/- vs WT mice reared with normal visual experience or with monocular eye closure; spine stability will be examined using two-photon microscopy. These experiments should broaden understanding of how PirB acts at synaptic and structural levels to suppress plasticity. 3) Identify PirB signal transduction pathways in mouse visual cortex: Candidate signaling pathways downstream of PirB will be identified and evaluated by comparing visually-driven signaling in WT vs germline PirB-/- mouse visual cortex during and after the critical period. Changes in expression and phosphorylation levels will be assessed in candidate pathways including MAP Kinase, AKT and mTOR signaling. Studies here will employ genetic, biochemical, electrophysiological, imaging and anatomical methods in mice to assess OD plasticity at the systems level and to understand cellular and molecular mechanisms of PirB function. Together, experiments should elucidate how PirB normally acts in neurons to suppress synaptic-plasticity signaling pathways during and beyond the critical period, as well as test feasibility of restoring OD plasticity by acute PirB blockade. They represent key steps in understanding mechanisms of developmental critical periods, as well as for designing new ways to enhance CNS function and repair by engaging the brain's inherent capacity for neural plasticity. PUBLIC HEALTH RELEVANCE: The idea that extensive synaptic plasticity might be restored to the brain by "releasing the brake" on mechanisms that act endogenously to suppress plasticity and circuit change has important clinical implications. If brain circuits can be restore to a more immature state in which synaptic plasticity can be easily engaged, it might be possible to facilitate recovery following damage or memory loss associated with Stroke, Alzheimer's or other neurodegenerative disorders of aging. Retraining the brain might also be applied post hoc for childhood learning disabilities including Dyslexia or Amblyopia in the developing visual system, and possibly even for treatment of Autism.

描述（由申请人提供）：是什么使婴儿的大脑在早期发育的关键时期学习如此迅速？什么样的细胞和分子机制导致了成年期广泛可塑性的下降？其目的是通过发现并阻断抑制可塑性和回路变化的内源性机制来增强突触可塑性。具体而言，神经元受体PirB（配对免疫球蛋白样受体B;人类Lilrb 3）的操纵是否能“释放”眼优势（OD）可塑性的刹车，这是视觉皮层中经验依赖性突触可塑性的一种形式？在免疫系统中，PirB是主要组织相容性I类分子（T细胞受体的著名配体）的受体。本实验室意外发现神经元在突触处表达PirB和MHCI分子。OD可塑性在具有PirB种系缺失的小鼠的视觉皮层中增强，与PirB作用于制动突触可塑性一致。提出了三个具体目标：1）确定PirB的急性缺失是否在出生后增强OD可塑性：已经制备了PirB的条件等位基因（PirB flox/flox），通过将小鼠与他莫昔芬诱导的Cre转基因系杂交，允许PirB的急性时间和细胞类型破坏。还将使用重组可溶性截短PirB蛋白或功能阻断抗体直接阻断PirB。这些实验应该揭示PirB何时以及在何种细胞类型中起作用。2)PirB-/-小鼠中OD可塑性增强与突触可塑性的细胞机制相关。长时程增强（LTP）和长时程抑制（LTD）将使用生理学方法在体外视觉皮层切片中进行研究。将在以正常视觉经验或单眼闭眼饲养的PirB-/- vs WT小鼠中测量YFP标记的第5层锥体神经元的树突棘密度;将使用双光子显微镜检查棘稳定性。这些实验应该拓宽PirB如何在突触和结构水平上抑制可塑性的理解。3)鉴定小鼠视觉皮层中的PirB信号转导途径：将通过比较WT与种系PirB-/-小鼠视觉皮层中在关键期期间和之后的视觉驱动的信号传导来鉴定和评价PirB下游的候选信号传导途径。将在候选途径（包括MAP激酶、AKT和mTOR信号传导）中评估表达和磷酸化水平的变化。这里的研究将采用遗传，生物化学，电生理学，成像和解剖学方法在小鼠中评估OD可塑性在系统水平上，并了解PirB功能的细胞和分子机制。总之，实验应该阐明PirB通常如何在神经元中起作用，以抑制突触可塑性信号通路期间和之后的关键时期，以及测试的可行性恢复OD可塑性急性PirB封锁。它们代表了理解发育关键期机制的关键步骤，以及通过利用大脑固有的神经可塑性来设计新的方法来增强CNS功能和修复。 公共卫生关系：通过对内源性抑制可塑性和回路变化的机制“释放制动”，大脑可能恢复广泛的突触可塑性，这一想法具有重要的临床意义。如果大脑回路可以恢复到一个更不成熟的状态，突触可塑性可以很容易地参与，它可能有助于恢复与中风，阿尔茨海默氏症或其他衰老的神经退行性疾病相关的损伤或记忆丧失。再训练大脑也可以事后应用于儿童学习障碍，包括视觉系统发育中的阅读障碍或弱视，甚至可能用于自闭症的治疗。