Making an Old Brain Young? From Developmental Critical Periods to Alzheimer’s Disease

The brain is the most incredible computational machine imaginable.  There are over one trillion nerve cells in the brain, and each cell can make 10,000 synaptic connections with other nerve cells.  How are connections wired up during development?  The wiring problem is solved sequentially first by forming a basic scaffold of connectivity according to genetic blueprints: strict molecular cues enable growing nerve connections to follow appropriate pathways to their correct target regions. Then, once this basic scaffold of connectivity forms, the exact details of each circuit emerge by pruning and sculpting synapses from the immature pattern of connections. The decision-making process that determines which synaptic connections remain and which are pruned is also genetically specified but in this case requires brain function. Even before birth, the brain generates its own internal neural activity patterns to jump-start the sculpting process. After birth once sensory systems, such as the eyes and ears, become mature enough, experience of the external world takes over to influence brain wiring during developmental critical periods. Neural activity and brain function regulate the expression of sets of genes including several previously thought to act only in the immune system. These activity-regulated genes- including Major Histocompatibility Class I family members and Paired immunoglobulin-like receptor B- are required in neurons for pruning and sculpting synapses during development, and they may also contribute to excessive synapse pruning in Alzheimer’s disease. Thus, the baby's brain is not a miniature version of the adult, but rather is a dynamically changing structure in which neural activity and experience ultimately select and stabilize essential details of neural circuitry that make each of us different from one another.