Sculpting brain circuits with early experience

用早期经验塑造大脑回路

• 批准号: RGPIN-2014-05791
• 负责人: Pittman, Quentin
• 金额: $ 3.57万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=689795
• 关键词: Sculpting; brain; circuits; early; experience

There is now overwhelming evidence that the neonatal brain is in a very plastic state, whereby even relatively innocuous interventions can have long-lasting effects upon adult physiology. In our previous NSERC supported research program, we studied the long-term effects of experimental neonatal febrile convulsions to cause long lasting changes in excitability of the brain. We learned that inflammation alone, caused by peripheral administration of the pyrogen, lipopolysaccharide (LPS), caused similar changes to those resulting from the febrile convulsion. This may be because a number of pro-inflammatory molecules including pro-inflammatory cytokines and prostaglandins are generated in the brain and regulate the activity of a number of signaling molecules such as endocannabinoids. Pro-inflammatory molecules such as cytokines and prostaglandins, as well as endocannabinoids, play a role in the normal developmental processes in the immature brain. It is likely that excess signalling by pro-inflammatory and related molecules in early life has the potential to interfere with normal developmental processes. To determine if excess signaling by these molecules during the neonatal period affects development, I am seeking funding to discover underlying evidence for, and mechanisms for long term altered central nervous system (CNS) function and behavior after neonatal inflammation. I will focus upon an important brain nucleus, the amygdala, where we have preliminary evidence for both behavioral and electrophysiological changes in adults. My overall hypothesis is that: *Neonatal inflammation produces cytokine-mediated, long-term molecular, electrophysiological and behavioral changes in adults.*The long term objectives of my research program are to better understand how neonatal stressors affect the brain. My specific short term objectives focus upon delineating how increased inflammatory signaling in the neonate affects amygdala function in the adult:*1. Determine if synaptic and neuronal membrane properties in the amygdala are altered by neonatal inflammation? Neonatal mice of both sexes will be given lipopolysaccharide to induce inflammation. Brain slices of the amygdala will be collected from these subjects at 60 days age and intrinsic excitability, pre- and postsynaptic properties and endocannabinoid signaling will be assessed. *2. Determine if neonatal inflammation alters amygdala-dependent behaviors. Aversive learning is thought to be a reliable test for amygdala function; thus mice that were inflamed as neonates will be subjected, as adults to fear conditioning and acquisition and extinction of learned behavior compares with saline treated animals.*3. Determine the key inflammatory changes that precipitate the altered adult behavior and electrophysiological changes? To determine causal mechanisms underlying long-term changes we will determine which cells are activated and which molecules are released in the neonatal amygdala after inflammation. To determine which of these are causal for the long-term changes, I will intervene with pharmacological agents, or make use of genetically modified animals to validate the pharmacology, in the neonate after inflammation and determine if the electrophysiological and behavioral alterations caused by inflammation are reversed in the adult.*We will pursue these questions by using well-controlled neonatal mouse inflammatory models and a combination of in vivo behavioral, in vitro electrophysiological and molecular approaches that are well established in the lab.

现在有压倒性的证据表明，新生儿的大脑处于非常可塑的状态，即使是相对无害的干预措施也会对成人的生理机能产生长期持续的影响。在我们以前的NSERC支持的研究计划中，我们研究了实验性新生儿热性惊厥的长期影响，以引起大脑兴奋性的长期持续变化。我们了解到，由外周给予热原脂多糖（LPS）引起的炎症单独引起的变化与热性惊厥引起的变化相似。这可能是因为在大脑中产生了许多促炎分子，包括促炎细胞因子和大麻素，并调节了许多信号分子如内源性大麻素的活性。促炎分子，如细胞因子和肾上腺素，以及内源性大麻素，在未成熟大脑的正常发育过程中发挥作用。早期生命中促炎分子和相关分子的过度信号传导可能会干扰正常的发育过程。为了确定这些分子在新生儿时期的过度信号传导是否会影响发育，我正在寻求资金，以发现新生儿炎症后长期改变中枢神经系统（CNS）功能和行为的潜在证据和机制。我将集中在一个重要的大脑核，杏仁核，我们有初步的证据表明，在成年人的行为和电生理变化。 我的总体假设是：* 新生儿炎症在成年人中产生尼古丁介导的长期分子，电生理和行为变化。我的研究计划的长期目标是更好地了解新生儿压力源如何影响大脑。我的具体短期目标集中在描述新生儿炎症信号的增加如何影响成年人的杏仁核功能：*1。确定新生儿炎症是否改变了杏仁核中突触和神经元膜的特性？将给予两种性别的新生小鼠脂多糖以诱导炎症。在60日龄时从这些受试者收集杏仁核的脑切片，并评估内在兴奋性、突触前和突触后特性以及内源性大麻素信号传导。（注2） 确定新生儿炎症是否改变杏仁核依赖行为。厌恶性学习被认为是杏仁核功能的可靠测试;因此，与盐水处理的动物相比，在新生儿时发炎的小鼠在成年后将受到恐惧条件反射以及学习行为的获得和消失。3.确定促使成年人行为改变和电生理变化的关键炎症变化？为了确定长期变化背后的因果机制，我们将确定炎症后新生儿杏仁核中哪些细胞被激活，哪些分子被释放。为了确定哪些是长期变化的原因，我将在炎症后的新生儿中使用药理学试剂进行干预，或者使用转基因动物来验证药理学，并确定炎症引起的电生理和行为改变是否在成人中逆转。我们将通过使用控制良好的新生小鼠炎症模型和在实验室中建立良好的体内行为，体外电生理和分子方法的组合来追求这些问题。