Research Interests

Adult Neurogenesis

It is now well established that the adult brain maintains two discrete stem cell niches from which new neurons are born. One of these is the DG of the hippocampus, where self-renewing stem and transient-amplifying progenitor cells within a defined neurogenic niche produce immature neurons that migrate only a short distance into the granular layer of the DG. The exact molecular events that regulate neurogenesis are only beginning to be uncovered, however it is now believed that these newborn neurons can fully differentiate and integrate into the existing adult neural network and can participate in learning and memory. Damage to the hippocampus is often observed in numerous pathologies, including AlzheimerÍs disease, schizophrenia, epilepsy/seizures, stroke/ischemia, and after traumatic brain injury. In many of these instance changes in stem cell proliferation has been observed and this may reflect the brainÍs attempt to respond to the situation and repair the damage. I anticipate that a better understanding of the molecules regulating cell-cell interactions and controlling stem/progenitor cell proliferation, migration, and differentiation will provide important insight into the molecular basis of adult neurogenesis and its relationship with normal learning and memory. Such understanding will also provide novel ideas for future stem cell therapies to treat individuals suffering from neurological degeneration or injury.

My laboratory will continue to uncover the functional significance of adult neurogenesis, the mechanisms that regulate early neonatal and adult neurogenesis and the affect that damage to the brain plays on this process. We will initially focus on the following three areas:

1. The role of adult-derived neurons in learning and memory. The study proposed herein will investigate the functional significance of adult neurogenesis, the generations of new neurons, on learning and memory. It is clear that stem cells in the adult brain give rise to new neurons that can integrate into an area of the brain called the hippocampus. This structure is essential in learning and memory. However, it is unknown whether these newly integrated neurons themselves play a functional role in learning and memory. We will utilize a genetically engineered mouse in which the generation of these adult-derived neurons can be blocked using the common antiviral drug ganciclovir. Our investigations will compare the outcomes of learning and memory tests between control (untreated) animals and animals in which adult neurogenesis is blocked by the uptake of ganciclovir. Additionally, we will augment the degree of neurogenesis in the two groups by using treadmill running. The generation of new neurons in the adult brain is minimal in standard animal housing conditions. Fortunately, physical activity has been well documented to increase the production of new neurons in the adult brain. Ultimately, this work will allow us to understand the functional role of adult-derived neurons with regard to learning and memory.

2. The neurovascular niche. Here we will uncover the various molecular factors that set-up the architecture of the neurogenic niche around the microvasculature of the hippocampus. We will focus initially on the roles of EphB and ephrin-B proteins as we have shown they are important in neurogenesis. It is also important to mention that in the developing cardiovascular system, EphB and ephrin-B molecules control the angiogenic remodeling of blood vessels and lymphatic vessels and play essential roles in endothelial cells as well as in supporting pericytes and vascular smooth muscle cells. Recent evidence suggests that Ephs and ephrins may also be involved in pathological angiogenesis, in particular, the neovascularization of tumors. Because neurogenesis is intimately associated with the microvasculature of the hippocampus, and because modalities that induce vasculogenesis in the brain, such as exercise, also enhance neurogenesis, I feel these two processes are linked, and the Ephs and ephrins are prime candidates to regulate these processes.

3. Inflammatory effects on hippocampal neurogenesis. The brain, which is thought to be excluded from the peripheral immune system via the tightly regulated blood-brain barrier, is in all cases of neurodegenerative disorders, affected by inflammation. Further, site-specific inflammation in the hippocampus and peripheral systemic inflammation, are known to alter hippocampal neurogenesis. Interestingly, several Eph receptors and ephrin ligands are expressed on the surface of different leukocyte populations and likely play a role in their migration. It is my contention that the Eph-ephrin regulation of the inflammatory response may be partly responsible for the altered hippocampal neurogenesis, and in particular, modifies the normal composition and structure of the neurogenic niche. Central to this hypothesis are my preliminary findings that:

1. Animals lacking EphB3, and more profoundly EphB2 and EphB3, produce significantly more antigen-specific antibodies following immunization.

2. The acute inflammatory response of animals lacking the EphB3 receptor includes the production of significantly more pro-inflammatory cytokines, including IL-6, IL-1, IFN-g, TNF-a, and IL-12.

3. In the absence of EphB3, there is a more rapid migration of inflammatory cells (monocytes and neutrophils) into the peritoneal cavity following intraperitoneal immunization.

It is also important to note that a small body of published evidence also suggests that pro-inflammatory cytokines can alter the expression level of several Ephs and ephrins. Specifically, an animal model of fever induced by LPS injection caused changes in mRNA levels of several Ephs and ephrins in various tissues, including the brain.

The Role of Ephs and Ephrins in Inflammation

As mentioned above, we have previously determined that animals lacking EphB3, and more profoundly EphB2 and EphB3, produce significantly more antigen-specific antibodies following immunization. Furthermore, the acute inflammatory response of animals lacking the EphB3 receptor includes the production of significantly more pro-inflammatory cytokines, including IL-6, IL-1, IFN-g, TNF-a, and IL-12. The mechanistic role of Ephs and ephrins in the inflammatory respose is, however, unknown. Two possible mechanisms involve the role of Ephs and ephrins in the formation of, and maintenance of, the vasculature, and the role of Ephs and ephrins in cellular migration. My lab will address both of these possibilities using animals lacking the various Eph and ephrin cell surface proteins.