Sculpting brain circuits with early experience

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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.