Regulation of neurogenesis and cognitive function by the aging systemic milieu [electronic resource]

Aging in mammals is associated with a decline in the function and regenerative capacity of tissue specific stem cells. In the adult central nervous system the age-related decline of these functional stem/progenitor cells (NPCs), and subsequently neurogenesis, is correlated with impairments in cognitive functions including learning and memory. Interestingly, changes occurring in the systemic milieu of an organism, such as those induced through increased exercise, have been shown to partially mitigate this cellular decline. While previous studies have examined intrinsic molecular mechanisms underlying NPC aging and decreased neurogenesis at the cellular level, a gap still exists in elucidating how age-dependent NPC function is impaired by systemic changes associated with aging. This dissertation addresses the role of the aging systemic milieu in the regulation of adult neurogenesis and cognition, and seeks to identify individual factors responsible in part for the age-related decline. Chapter 1 reviews the cellular process of adult neurogenesis and discusses its regulation during aging by intrinsic and extrinsic factors, as well as its contribution to synaptic plasticity and cognitive functions. Chapter 2 focuses on the age-related decrease in adult neurogenesis and asks whether systemic molecular changes naturally occurring with age contribute to this decline. Using heterochronic parabiosis, in which the circulatory systems of two animals are adjoined, we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age dependent fashion in mice. Furthermore, we demonstrate functional relevance for changes occurring in the systemic milieu, as exposing a young animal to an old systemic environment, or to plasma from old mice, decreased synaptic plasticity and impaired spatial learning and memory. Chapter 3 focuses on individual systemic factors and demonstrates that age-related changes in systemic chemokine levels negatively regulate neurogenesis and learning and memory. Using a targeted proteomic screen, we identified a conserved subset of blood borne chemokines - including CCL2/MCP-1 and CCL11/Eotaxin -- whose plasma levels correlate with reduced neurogenesis observed in normal and experimental (i.e. heterochronic parabiosis) aging. Additionally, mimicking an aged systemic environment by increasing the level of CCL11 in the periphery of young adult mice resulted in a decrease in neurogenesis and impaired spatial learning and memory. Chapter 4 focuses on [Beta]2-microglobulin (B2M), another identified systemic factor that increases with aging and negatively correlates with the age-related decline in neurogenesis, and examines its role in regulating adult hippocampal neurogenesis. Using primary cell models we show that exposure to recombinant B2M protein inhibits NPC function and neuronal differentiation in vitro. Furthermore, we show that local exposure of a young adult hippocampus to B2M decreases neurogenesis and impairs cognitive function in vivo. Additionally, we show that the inhibitory effects of B2M are mediated by MHCI. Lastly, using a genetic mouse model that lacks B2M expression we show that neurogenesis is improved in adult animals in an age-dependent manner. Chapter 5 contains a summary and conclusion of the results presented in this dissertation, highlighting the influence of the aging systemic milieu on neuroplasticity and cognition.

Advisor: Wyss-Coray Anton primary advisor. Thesis advisor
Andreasson Katrin advisor. Thesis advisor
Brunet Anne
Rando Thomas A.