Regulation of Auditory System Plasticity

Abstract

Plasticity is defined as the brain’s ability to change in response to intrinsic and extrinsic stimuli by reorganizing its structure function and connections. Plasticity is a feature of brain function that underlies complex mechanisms such as learning and memory, neural development and disease pathogenesis. Plasticity levels throughout the brain are highest during a discrete time early in development known as the critical period. During this time, the high levels of plasticity facilitate experience-dependent wiring of our sensory cortices to ensure proper adaptation to the external environment. Following the critical period, plasticity levels in the brain drop precipitously, leading to different requirements for the induction of plasticity. During the critical period, plasticity can be induced via passive exposure to sensory stimuli, while in adulthood, plasticity induction requires sustained attention towards the sensory stimuli. In the auditory system, this takes form as frequency map plasticity. Exposing animals to a pure tone of a specific frequency increases the area dedicated to that frequency within primary auditory cortex (Figure 1.1). This passive exposure-based plasticity does not occur in adulthood. The significant difference in requirements for plasticity induction underscores the importance of understanding the factors that promote plasticity during the critical period and the factors that restrict plasticity in adulthood. A deeper understanding of these factors is vital for understanding how plasticity is regulated within the cortex. The introduction of this dissertation will explore our current understanding of the mechanisms that progress the critical period. The critical period itself is a dynamic epoch in development that is controlled both by environmental and genetic factors. A detailed mechanistic understanding of the cellular, molecular and physiological processes that progressively shifts the brain from a plastic, to a non-plastic state will provide the context for the experiments discussed in later chapters. In the second chapter, I clarify the relationship between DNA methylation (DNA-ME) dynamics and the progression of the critical period. I show that as animals progress from the critical period into adulthood, their auditory cortices accumulate DNA-ME. Furthermore, removing DNA-ME from adult mice, via pharmacological injections of a DNA methylation inhibitor, re-established the capacity for frequency map plasticity in the auditory cortex of adult mice. These results correlate with results showing that reduction of DNA methylation in adulthood reversed characteristics of gene expression and synaptic transmission back to levels seen during the critical period. Together, these results implicate accumulation DNA-ME as a crucial mechanism for progression of the critical period. In the conclusion, I will discuss how these results influence our understanding of certain developmental disorders such as Rett Syndrome. In the third chapter, I show that homeostatic plasticity, a form of plasticity that regulates synaptic strength off a certain baseline, plays an important role in closing the critical period. Animals deficient in Tumor-necrosis factor-alpha (TNF-α), an important mediator of homeostatic plasticity in the central nervous system, retain frequency map plasticity into adulthood. Furthermore, TNF-α deficient animals display reduced Parvalbumin positive (PV) neuron density, increased excitatory synaptic transmission, and signatures of elevated cortical excitation levels. Together these results show that without the contributions of TNF-α the brain fails to progress out of the critical period, thus implicating homeostatic plasticity in the regulation of critical period plasticity. In the fourth chapter, I explore the relationship between central nervous system damage and cortical plasticity. I show that under normal conditions, the contralateral auditory pathway transmits signal faster, contains larger bandwidth receptive fields, and elicits stronger auditory evoked responses than the ipsilateral auditory pathway. Following unilateral hearing lesion, latencies along the ipsilateral pathway decrease, while receptive field bandwidth increases. Furthermore, unilateral hearing lesion re-stablishes frequency map plasticity along the ipsilateral auditory pathway. Together, these results indicate that in the presence of noise-induced neural damage, the brain engages plasticity mechanisms to re-map damaged areas of cortex and shift hearing bias from the contralateral to the ipsilateral auditory pathway.