Molecular Memory Systems

The neurorehabilitation of brain injury relies on treatment principles that have often existed unchanged through the many decades since their discovery. As many other major diseases benefit from advances in molecular medicine, rehabilitation of brain injury still utilizes traditional physical medicine principles within the domains of physical and occupational therapy. While these modalities have a clear role in promoting neurological recovery, there are no drugs that have been shown effective in stimulating neural repair after stroke and other brain injuries. There are several hints in the normal patterns of human recovery after CNS injury for a way forward to molecular treatment for stroke recovery. In cognitive terms, recovery after brain injury appears to rely on the normal learning of movement patters that were routine prior to the injury. This notion has led to the idea that formal learning and memory rules may be applied to brain injury rehabilitation. Indeed, this idea that some aspect of learning is the neuronal basis for recovery has led to ad hoc attempts to treat brain injured patients with any available drug that might also stimulate learning, memory or attention: including serotonin reuptake inhibitors, dopamine agonists, Ritalin, modafinil and amphetamines. Because these drugs were developed to treat conditions other than neurorehabilitation from brain injury, and because they act with less specificity on many neurotransmitter systems in the brain, these agents have not held up in clinical trials for stroke recovery. Research in this area within in the Carmichael lab determines how defined molecular memory systems might play a role in repair and recovery in stroke.

A second concept here is that memory formation occurs when groups of neurons are recruiting into co-active circuits. This is the concept of the memory engram: the set of cells that are active together in a specific and time-sensitive circuit that will store associations, such as two sensory inputs. In stroke, the brain circuits adjacent to the stroke in both humans and in animal models are hypoactive, and neurons that normally fire together during something like movement of the upper extremity do not fire together. This is reviewed here and here. We have found several molecular systems that influence neuronal excitability and appear to work by enhancing neuronal co-activity, the functional activity of motor circuits in recovering function that is lost after stroke. These molecular systems are tonic GABA activity, the transcription factor CREB, and small molecule approaches that enhance CREB signaling: CCR5 antagonism and PDE2a and PDE10a inhibition.

One way to study how neurons are active together in organized networks, or ensembles, is to image these neurons directly in the living mouse before and after stroke. This approach uses two-photon imaging to directly visualize neuronal activity using calcium sensors (GCaMPs) in motor cortex adjacent to the stroke site, and in more distant cortical areas. This work has been published.