PART 1: CELLULAR AND MOLECULAR MECHANISMS OF MOTOR MEMORY By: Yue Yang, Ph.D., Department of Neurobiology at Northwestern University in Chicago
This discussion centered on the question of what molecular mechanism drives motor learning. It was determined that gene expression is important for neuron regulation in both early development and mature neurons, demonstrating the plasticity of both structure and function of chromatin. There is a specific order in proliferating vs. migrating vs. mature neurons. Calcium influx initiates a signaling cascade, triggering to start more genes to express, creating proteins that help restructure. Promoters and enhancers have a changing relationship during development in precursor cells as opposed to mature cells, affecting connectivity and changing genome regulation. Upon neurostimulation, gene enhancers are brought closer to gene promoters.
Cells studied were the anterior dorsal cerebellar vermis (ADCV) – where granular neurons have hundreds of genes that are expressed during a conditioned motor stimulus. Some genes are downregulated and others are upregulated, but the end result is that the chromatin remodels and is followed by changes in the genome architecture. Genome architecture is dynamic, leading to plasticity which rewires the neurological circuits. Experiments used a method of having antibodies to isolate gene promoters and label them, and see which part of a gene locus the promotor interacts with – usually the enhancer. Activation of the conditioned stimulus reorganizes gene enhancer and promotor interaction, thus showing the dynamic genome architecture.
Rather than using the antibodies, optogenetic stimulation demonstrated that the distance between enhancer and promoter changed to get closer or farther. Experiments worked with a head-fixed mouse and measured the avoidance (startle) reaction when a touch stimulus was introduced. The stimulus was coupled with lighting changes to create an associated conditioned response. The adaptive behavior was called Delay-Tactile startle conditioning and took 80% of the mice an average of 5 days to learn that association, because at first, the LED light did not elicit any startle response. More assessments were done to determine exactly where In the brain the link was that associated the light with the startle response. Researchers were looking at gene promoters that affect transcription and how they interact with gene enhancers (up to 500,000 base pairs) or a whole chromosome (hundreds of millions of base pairs). The researchers isolated a brain region important for plasticity and adaptive behavior, the section to acquire new memories.
Gene expression is important for plasticity and acquiring memories. The conditioned stimulus has more gene expression. Genome architectural mechanisms and interactions between promoter and enhancer plays powerful roles in learning and memory. Impaired acquisition of conditioned learning can also be affected by the induction of activity-dependent transcription. Learning can be impaired by disrupting transcription with a knockout of a transcription factor (in this case, Rad21). Doing the same experiment on the mice with a knocked out transcription factor only 40% could learn the conditioned startle response in 5 days.
Experience-dependent chromatin structural reorganization in cerebellar neurons influences motor learning. When the nuclear signaling is altered in the granule cell, chromatin remodeling is activated, so that the genome architecture forms loops, allowing the promoter and enhancer to come in close proximity, affecting RNA expression and changing motor learning circuitry and thus, behavior.