The recent history of progress in other areas of medicine reminds us that transformative clinical applications can arise from basic science that is not targeting a specific disease or clinical need. This will be equally true in neuroscience, as demonstrated by studies of synaptic plasticity that have unexpectedly led to a new therapeutic approach to fragile X syndrome (Michalon et al., 2012). Indeed, given the fundamental role of nervous system plasticity across domains of function and the lifespan, it is clearly a key focus

for unraveling the causes of neuropsychiatric disorders and developing targeted and effective pre-emptive interventions, well beyond the KRX-0401 ic50 example of fragile X. We have made great strides in understanding how plasticity is regulated by biophysical and epigenetic mechanisms within cell compartments,

across cell types, and across circuits, but there are significant gaps that prevent the application of basic neuroscience insights to clinical application. As NIH institute directors, we have a growing concern about the tendency for every basic science grant application to mention a disease or to defend its translational impact. These “translational blurbs,” which seem JAK phosphorylation increasingly to be essential for some reviewers to assign a fundable score, are rarely substantive, may be misleading, and fail to recognize the large gap that remains between the state of our basic understanding and what is required for clinical application. Simply put, this gap requires more fundamental neurobiology. This gap will not be bridged Endonuclease by superficial associations between basic science and human disease or by assuming that transgenic mice are phenocopies of human disease. It has become abundantly clear that so-called “disease models” fall short when it comes to developing treatments and cures for human disorders. But the problems with “animal models” do not invalidate the use of “model animals”

(Insel, 2007). The value of using model systems is that we can learn about fundamental principles of brain organization. While most scientists think of translation as moving from bench to bedside or mouse to man, the future may belong more to reverse translation, moving from an observation in humans to experiments in a nonhuman species that can provide insights into fundamental mechanisms that are similar to or informatively different from humans. Studying the nervous system in model animals not only gives us insight into basic mechanisms but also helps us understand what makes us uniquely human. In considering what we need in 2013, one area that deserves special mention is human neurobiology. Human neurophysiology has begun to inform neuroprosthetics (Chadwick et al., 2011) and new interventions for epilepsy (Smart et al., 2012).