The NINDS Advanced Postdoctoral Career Transition Award to Promote Diversity in Neuroscience Research (K22) will significantly facilitate the candidate's ability to begin a career as an independent scientist, by extending and developing his postdoctoral training and expertise in stem cell transplantation methods and sophisticated methods to measure plasticity. Most forebrain interneurons originate in the developing medial ganglionic eminence (MGE), from where they migrate into cortex, hippocampus, striatum, and amygdala to form local inhibitory circuits. When transplanted into the juvenile or adult mouse cortex, MGE cells retain the ability for migration, functional integration, and differentiation primarily into parvalbumin (PV) and somatostatin (SOM) expressing GABAergic cortical interneurons. Previous work has shown that GABAergic inhibition is required for the induction of cortical plasticity and brain repair. Recent work in the laboratory showed that transplantation of MGE cells into the neonatal or juvenile mouse visual cortex can induce a new period of ocular dominance plasticity (ODP). The ability of these cells to induce plasticity de novo also offers a powerful tool to study the mechanisms and limits of cortical plasticity. The present proposal has four Aims.
In Aim 1, we will determine which type of cortical interneuron is responsible for the induction of cortical plasticity. We have developed and validated genetic tools to ablate PV, SOM, or both cell types from the MGE grafts. Previous research suggests that PV cells may be responsible for the induction of ODP, but this hypothesis has not been formally tested. Surprisingly, our preliminary studies suggest that ODP can still be opened, even when most PV cells are eliminated from MGE grafts. We will determine if SOM interneuron depletion is sufficient for the elimination of ODP, or whether both populations have the capacity to induce ODP.
In Aim 2, we will determine if the transplantation of cortical interneurons can be extended to the adult brain to induce ODP and contribute to recovery of function. We have developed and validated optical recording techniques to study ODP induction in adult mice. The laboratory also has preliminary evidence that MGE cells grafted into the adult mouse cortex migrate and integrate, suggesting that they could also modify cortical circuits and possibly induce ODP. The independent phase of the Award, will focus on the study of activity-dependent mechanisms of transplant- induced cortical plasticity.
In Aim 3, we will explore whether potent GABAergic transmission from transplanted MGE cells is necessary for de novo cortical plasticity. We will use genetic tools to block synaptic transmission and reduce by half GABAergic transmission in specific transplanted MGE cells.
In Aim 4, we will use genetically encoded calcium indicators to measure the changes in visual responses to the two eyes in transplanted and endogenous PV+ and SOM+ interneurons during de novo competitive cortical plasticity. The identification of cortical interneurons responsible for the induction of plasticity, the age range and types of cortical plasticity that can be induced, the role of GABAergic transmission, and how transplanted MGE cells change during plasticity will provide valuable new information for the therapeutic use of MGE cells in brain repair. In summary, the research proposed in this Career Transition Award will prepare the candidate to develop a fully independent research program capable of integrating a wide range of cellular and molecular and systems approaches in a technically advanced and high impact manner, including: (i) cell transplantation methods to open new periods of cortical plasticity in juvenile and adult mice, (ii) multisite microelectrode recordingsin vivo to measure neuronal responses and plasticity in all cortical layers, (iii) genetic methods to manipulate synaptic transmission of specific inhibitory microcircuits, and (iv) a model system to study the mechanisms of cortical plasticity and their therapeutic potential.
The objective of this project is to prepare Dr. Juan Sebastian Espinosa to transition to a position as an independent, tenure-track academic investigator. The project will establish which type(s) of inhibitory interneurons are responsible for regulating cortical plasticity in mice, investigate whether inhibitory interneuron transplantation into the fuly mature adult mouse brain can also induce a new period of cortical plasticity and contribute to recovery of function, and investigate the mechanisms that allow inhibitory interneurons to regulate cortical plasticity. This work will suggest key cellular components required for cortical plasticity that can be targeted to improve the course of progression and the functional outcome of neurological injury and disease.