The development of the brain is a highly orchestrated series of events resulting in the formation of a complex network, the cerebral cortex. Disturbances in this developmental process, especially with regards to inhibitory neurons, can result in neuropsychiatric disorders, such as epilepsy and autism spectrum disorders. Inhibitory neurons, or interneurons, are a subgroup of neurons that regulates the synchronization of neuronal activity and the overall balance of excitation-inhibition in the brain. It was previously believed that most young neurons had arrived at their final cortical destinations by birth. However, recent data, most especially in primates, now point to the contrary. I present evidence of a novel population of migratory neurons, likely interneurons, within the postnatal human cortex. The goal of this proposal is to define this group of late- migrating interneurons in the developing human cortex during the postnatal period, and how they contribute to the inhibitory network at their cortical destinations. Our group recently characterized a population of cells wit migratory morphology in the early postnatal human sub ventricular zone (SVZ), a site along the lateral ventricular (LV) wall where neural stem cells and progenitors are believed to generate new neurons. Cells expressing the migratory marker, doublecortin (DCX), were found in two separate collections in the infant human brain: a rostral migratory stream (RMS), with cells migrating through the olfactory tract, and a medial migratory stream (MMS) linking the SVZ with the most anterior part of the brain at the prefrontal cortex. I have now identified a new population of DCX+ migratory cells in the postnatal cortex, a dorsolateral migratory stream, or DLS, at the LV dorsolateral wall. I propose that the DLS (i) corresponds to a distinct stream of young migrating interneurons in the early postnatal human brain and (ii) is a population that is incorporated into the frontal and cingulate cortices, regions important in executive function, abstract thought, and emotional behavior. Thus late-migrating interneurons contribute to important neural circuits during early infant life. I will map the cortical targets of late-arrivig DCX+ cells and characterize their molecular identities. I will also investigate how neurons in the DLS change the inhibitory network in the human brain. Finally, I will analyze the dynamics of postnatal interneuron migratory behavior in human cortical slice cultures with time- lapse microscopy. These experiments are important to accurately assess their dynamic properties, migratory attributes, and potentially identify features that are unique to human interneurons. The proposed studies are the core components of Mentored Clinical Scientist Training Grant (the K08) and will be under the mentorship of Drs. Arturo Alvarez-Buylla and Eric Huang.
The aims will implement a multi-disciplinary approach to reveal the basic cellular changes during the postnatal period for the inhibitory circuit in the human. This information is fundamental to understanding the pathogenesis of neuropsychiatric diseases with defects in interneuron development. The grant is also a training vehicle for me to achieve additional scientific training in stereological analysis and live imaging. To achieve these goals, I have devised a 5-year career development plan and assembled multidisciplinary collaborations with scientists and clinicians specializing in developmental neuroscience, interneuron development, and neuropathology. The studies proposed in this grant and the ideal training environment at UCSF will ensure that I meet the proposed milestones and have a successful transition to an independent physician-scientist in developmental and regenerative neuroscience.

Public Health Relevance

Fundamental questions remain about how the human brain develops, especially with regards to inhibitory neurons. This project seeks to characterize a newly-identified population of young migrating interneurons that reach important cortical regions, including the cingulate cortex, late in brain development. By better understanding the basic steps in how the inhibitory system is formed, we can more effectively direct our efforts in therapies for neuropsychiatric diseases, such as epilepsy and autism spectrum disorders, where interneuron development has gone awry.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Lavaute, Timothy M
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Sorrells, Shawn F; Paredes, Mercedes F; Cebrian-Silla, Arantxa et al. (2018) Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555:377-381
Priya, Rashi; Paredes, Mercedes Francisca; Karayannis, Theofanis et al. (2018) Activity Regulates Cell Death within Cortical Interneurons through a Calcineurin-Dependent Mechanism. Cell Rep 22:1695-1709
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