Hearing Loss-induced Neural Plasticity and its Mechanism in the Temporal Lobe


Student thesis: Doctoral Thesis

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Award date27 Apr 2023


Hearing loss, mainly caused by loud noise exposure, prevails in modern society affecting not only other hearing disorders such as tinnitus, and hyperacusis but also psychiatric disorders such as enhanced anxiety, depression, and cognitive decline in humans. It has been well documented in animal research that loud noise exposure negatively affects physiology in brain regions in the temporal lobe that is known for its role in sound perception—the hippocampus and auditory cortex. However, it is not completely clear how hearing loss caused by excessive noise is related to changes in neural plasticity in those regions, resulting in altered cognitive behaviors. To address the question, therefore, this thesis consists of four chapters as summarized below.

The first chapter reviews the various synaptic circuitry within the hippocampus with a highlight on the longitudinal connections. The hippocampus is regarded as a cognition hub, particularly for learning and memory. Previously, neuronal mechanisms underlying various cognitive functions are delineated with the lamellar hippocampal circuitry, dentate gyrus (DG)—CA3 or CA2—CA1, within the transverse plane. More recently, interlamellar (often referred to as longitudinal) projections have received intensive attention to help understand signal convergence and divergence in cognition and behavior. Signal propagation along the longitudinal axis is evidenced by axonal arborization patterns and synaptic responses to electro‐ and photo‐stimulation, further demonstrating that information flow is more enriched in the longitudinal plane than the transverse plane. Therefore, this chapter emphasizes the significance of longitudinal connections for cognition, discusses a putative circuit mechanism of place coding, and suggests the reconceptualization of the hippocampal circuitry.

The next chapter focuses on the DG network in the hippocampus regarding how NIHL affects its synaptic plasticity and is related to behavioral changes. The behavior results show that the mouse model of noise-induced hearing loss (NIHL) enhances anxiety-like behaviors. The slice electrophysiology shows that these behaviors are concurrent with enhanced synaptic responsiveness and suppressed short- and long-term synaptic plasticity in the longitudinal DG-to-DG network but not in the transverse DG-to-CA3 connection just as it is with the chronic restraint stress mouse model. These findings suggest that the enhanced anxiety is typified by synaptic alteration in the longitudinal DG-to-DG network.

The third chapter explores a major complication of NIHL—tinnitus, a phantom perception of sound. The hearing loss (HL)-induced tinnitus is largely driven by irreversible damage of the peripheral auditory system which chronically leads to abnormal neural responses and disrupted frequency maps of the central auditory system. Yet, it remains speculative whether rehabilitating the neural abnormality can alleviate the tinnitus symptom and how to do so. For this, a graphene-based multichannel electrode is used to monitor and activate the surface of the auditory cortex in anesthetized mice. The results demonstrate that the surface stimulation increases cortical activities and reshapes the auditory maps, thereby alleviating HL-induced tinnitus-like behavior. Furthermore, the surface layer in brain slices possesses long-term synaptic potentiation (LTP) even in adult mice regardless of the presence of HL, being implied as a cellular mechanism underlying sensory map remodeling upon electrotherapy. Moreover, NIHL involves A-type voltage-gated K+ channels (IA) in N-methyl-D-aspartate receptor (NMDAR)-dependent LTP. This suggests that cortical surface map remodeling by surface stimulation can serve as an effective treatment method to facilitate functional recovery from sensory deprivation.

Finally, the last chapter gives an overview of the IA channels in the brain of humans and animals in terms of their distribution and function. The IA channels are one type of voltage-gated potassium channels known to shape excitability and firing properties of neurons by regulating synaptic potential and backpropagating action potential with its distinctively fast activation and inactivation. Thus, dysfunction and/or dysregulation of IA channels can easily result in neuronal hyperexcitability, the common symptom of several diseases in the brain. Therefore, this chapter summarizes how its expression and function are tightly related to various brain diseases such as Alzheimer’s disease, epilepsy, fragile X syndrome (FXS), Parkinson’s disease, chronic pain, tinnitus, and ataxia.

Overall, this thesis examines the importance of longitudinal connections in the hippocampus for cognition, especially longitudinal DG-to-DG connections for abnormal anxiety, explores the use of electrical rehabilitation in the surface area of the auditory cortex to alleviate tinnitus behavior upon NIHL, and provides an overview of IA channels in the brain and their relationship with various brain diseases including tinnitus.