Recruitment of Replacement Cortico-spinal Motor Neurons via Induced Neurogenesis and Enhanced Survival
Macklis, Jeffrey D., MD, DHST
Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts

The long-term goal of this proposal is to repair "cortico-spinal" motor neuron circuitry (that along with "spinal" motor neurons is degenerated in ALS) via induction of the birth of new cortico-spinal neurons from resident "neural precursors." Recently, we have manipulated endogenous precursors to undergo neurogenesis -the birth of new neurons- in the adult cerebral cortex, where neurogenesis does not normally occur. Directly relevant to the goals of ALSA is our very recent finding that we can specifically induce endogenous precursors to develop into new cortico-spinal motor neurons (CSMN), suggesting that critical upper motor neuron circuitry might be rebuilt from the "inside-out". These experiments demonstrate that a combination of molecular signals exists by which the birth of new CSMN can be induced. We believe that we could recruit many more CSMN if we understood what molecules could help them survive while they connect to the spinal cord (which would then support their survival). We propose to take a goal-oriented approach: investigate what growth factors will make these new CSMN survive better and connect properly (Aim 1), enhance CSMN recruitment by infusing the factors in the brain (Aim 2), and investigate whether new CSMN connect and make functional synapses in the spinal cord (Aim 3).