Graduation Date

Summer 8-18-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

STEPHEN J. BONASERA

Abstract

The aging process is accompanied by functional impairments, including reduced locomotor function, fragmentation of active states, and alterations in energy balance. Our lab has demonstrated that immune proteins are increased in specific regions of the mouse brain that correlate with strain specific deficits. These immune proteins include toll-like receptors (Tlr), class I major histocompatibility complex proteins (MHC I), and complement proteins. There is an increasing appreciation for the role of immune proteins in neurodevelopment; however, their involvement in age-associated deficits is poorly understood. Here, we present data demonstrating that 1) activation of a specific immune receptor (Tlr2) leads to changes in cell signaling that may underlie age related functional deficits, and 2) loss of specific immune proteins (Tlr2 and C3) and mutation of MHC I H2-Kb lead to impairments in behaviors commonly effected by aging.

First, we present data demonstrating that activation of toll-like receptor 2 by a synthetic agonists leads to activation of NF-κB signaling in cerebellar granule cells. Our data, among others, suggests that NF-κB signaling is dysregulated in the aging brain. Additionally, we suggest that accumulation of amyloid β in the aging brain may act as an endogenous agonist for Tlr2 activation. This data reveals that a less appreciated pathway, neuronal immune receptor signaling, may play a role in age related NF-κB dysregulation.

Second, analysis of mice lacking specific immune proteins revealed that loss of complement protein 3 leads to deficits in locomotor function characterized by reduced gait speed and markers of gait ataxia. Additionally, loss of complement 3 leads to changes in cerebellar granule cell synapse density and excitability in vitro. Loss of toll-like receptor 2 results in consolidation of active and inactive states in young mice, suggesting that toll-like receptor 2 may play a role in hypothalamic functions. Mutation of major histocompatibility complex isoform H2-Kb leads to a progressive obesity phenotype characterized by reduced activity and deficits in orexin neuron function. Collectively, this data demonstrates the involvement of immune proteins in regulating behaviors often disrupted in aging, including locomotor function, active state regulation, and energy balance.

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