Interdisciplinary Initiatives Program Round 9 - 2018
Keren Haroush, Neurobiology
Jin Hyung Lee, Neurology & Neurological Sciences, Bioengineering, and Neurosurgery
One of humanity’s greatest challenges is understanding the human brain and ameliorating its diseases. In particular, neuropsychiatric disorders alone are the leading causes of ill health and disability worldwide, affecting one in four people at some point in their lives. It is widely held that rodents, in particular mice, which today are used in 95% of neuroscience research, have major limitations in terms of translation of findings to human brain diseases, where the majority of translational research and drug discovery efforts fail. Indeed, our understanding and treatment of psychiatric and neurological disorders has been largely stagnant for decades, despite major technological revolutions, marking the need for a substantial paradigm shift in the scientific approach toward more human-relevant experimental-models. Luckily, the imminent availability of a wide range of genetic and molecular tools is swiftly making the common marmoset, a small primate, a particularly attractive intermediate model system, between rodents and humans, to bridge detailed circuit understanding of higher cognitive functions and disease models. Marmoset are cost-effective monkeys, that despite being smaller than rats, retain highly complex primate behavior and developed prefrontal functions, rendering them a promising model of human brain function. Moreover, marmosets breed well in captivity (with the shortest and highest yield reproductive-cycle of human-like primates), and share a high degree of genomic similarity to humans, thus are an ideal primate for genetic manipulations.
Marmosets hold enormous promise for bridging the gap between molecular and genetic approaches, systems neuroscience, and drug discovery for brain diseases. Already, there are world-wide coordinated efforts involving major capital investments to develop genetically based marmoset disease models. Transgenic marmosets in particular have high potential as effective disease models, due to their natural complex behaviors, which are a key prerequisite for a successful loss-of-function model.
Critically, the neural underpinnings of many of their behaviors of interest to mental health are thought to be supported by highly distributed computations, engaging many brain areas simultaneously. Therefore, to unlock the unique untapped potential of the marmoset model, a brain-wide approach is essential for mapping and targeting these circuits. Yet, the current state of technology available for linking brain-wide activity to complex behavior, are far behind the level required for such investigation. Here we propose an integrative solution by developing new approaches that allow for simultaneous tracking and perturbing brain-wide activity in behaving small animals. We expect the tools and approaches to be broadly applicable to studies of natural behavior to facilitate basic neuronal understanding of complex behaviors, a core challenge for modern neuroscience. At the same time, this research will advance the development of novel treatments of human disease.