Most studies of brain injury, such as stroke, have traditionally focused on preventing neurodegeneration and death of affected brain cells. Comparatively little has been done to maximize and optimize the plasticity processes involved in repair and recovery after brain injury. Our laboratory is involved in a new initiative directed at leveraging brain plasticity in efforts to enhance repair and recovery following brain injury. In particular, in collaboration with the Carmichael, Shohami and Dobkins laboratories, we are using manipulations that enhance learning and memory to accelerate and optimize recovery after brain injury.
In the last 10 years, we and others have discovered multiple genetic and viral manipulations that dramatically enhance learning and memory. We have used information obtained from these studies in efforts to develop therapies to facilitate repair and recovery. For example, viral manipulations that enhance CREB function enhance motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. CREB transfection enhances remapping of circuits disrupted by the stroke, and induces the formation of new connections within these circuits (PDF). Beyond the exciting clinical promise, these collaborative studies with the Carmichael lab showed that CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits.
Remarkably, collaborative studies (PDF) in our laboratory showed that the manipulations that we showed decreased CCR5 function and that consequently increased CREB activation and enhanced memory, were also shown to enhance recovery after stroke (studies with the Carmichael lab at UCLA), and after traumatic brain injury (studies with the Shohami lab). Our collaborative studies in humans (Bornstein lab) were consistent with these results in rodents, since individuals with a naturally occurring CCR5 null mutation (Delta 32 allele) were also shown to have better motor and cognitive recovery after stroke (PDF)!
Mary T. Joy, Einor Ben Assayag, Dalia Shabashov-Stone, Sigal Liraz-Zaltsman, Nikita S. Thareja,Marcela Arenas, Efrat Kliper, Amos D. Korczyn, Efrat L. Kesner, Miou Zho, Shan Huang2, Tawnie K. Silva2, Noomi, Katz, Natan M. Bornstein, Alcino J. Silva, Esther Shohami, Stanley T. Carmichael. CCR5 is a therapeutic target to stimulate recovery in stroke and traumatic brain injury. Cell (in press)(PDF)
Caracciolo, L., M. Marosi, J. Mazzitelli, S. Latifi, Y. Sano, L. Galvan, R. Kawaguchi, S. Holley, M. S. Levine, G. Coppola, C. Portera-Cailliau, A. J. Silva and S. T. Carmichael (2018). "CREB controls cortical circuit plasticity and functional recovery after stroke." Nat Commun 9(1): 2250 (PDF)
Kushner, S.A., Y. Elgersma, G.G. Murphy, D. Jaarsma, G.M. van Woerden, M.R. Hojjati, Y. Cui, J.C. LeBoutillier, D.F. Marrone, E.S. Choi, C.I. De Zeeuw, T.L. Petit, L. Pozzo-Miller, and A.J. Silva, Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway. J Neurosci, 2005. 25(42): p. 9721-34. (PDF)
Elgersma, Y., N. Fedorov, S. Ikonen, E. Choi, M. Elgersma, O. Carvalho, K. Giese, and A. Silva, Inhibitory autophosphorylation of CaMKII controls PSD association, plasticity and learning. Neuron, 2002. 36(3): p. 493-505.(PDF)
Murphy GG, Fedorov NB, Giese KP, Ohno M, Friedman E, Chen R, Silva AJ. Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice. Curr Biol. 2004 Nov 9;14(21):1907-15.(PDF)