Spontaneous hyperactivity in the auditory midbrain: Relationship to afferent input

Abstract

Hyperactivity in the form of increased spontaneous firing rates of single neurons develops in the guinea pig inferior colliculus (IC) after unilateral loud sound exposures that result in behavioural signs of tinnitus. The hyperactivity is found in those parts of the topographic frequency map in the IC where neurons possess characteristic frequencies (CFs) closely related to the region in the cochlea where lasting sensitivity changes occur as a result of the loud sound exposure. The observed hyperactivity could be endogenous to the IC, or it could be driven by hyperactivity at lower stages of the auditory pathway. In addition to the dorsal cochlear nucleus (DCN) hyperactivity reported by others, specific cell types in the ventral cochlear nucleus (VCN) also show hyperactivity in this animal model suggesting that increased drive from several regions of the lower brainstem could contribute to the observed hyperactivity in the midbrain. In addition, spontaneous afferent drive from the cochlea itself is necessary for the maintenance of hyperactivity up to about 8 weeks post cochlear trauma. After 8 weeks however, IC hyperactivity becomes less dependent on cochlear input, suggesting that central neurons transition from a state of hyperexcitability to a state in which they generate their own endogenous firing. The results suggest that there might be a “therapeutic window” for early-onset tinnitus, using treatments that reduce cochlear afferent firing.

Introduction

Elevated levels of spontaneous neural firing (spontaneous hyperactivity) have been described in a number of brain regions after treatments that are known to induce tinnitus in humans and that cause behavioural changes consistent with tinnitus in animal experiments. Numerous animal models have shown a consistent pattern of hyperactivity in the inferior colliculus (IC) after unilateral partial deafness induced by acoustic trauma and other forms of damage (Bauer et al., 2008, Dong et al., 2009, Dong et al., 2010b, Mulders and Robertson, 2009). This hyperactivity appears to be associated with altered patterns of gene expression in the IC, including reduced expression of elements of inhibitory, notably GABAergic synaptic machinery and of K⁺ ion channels that stabilize membrane potentials (Dong et al., 2009, Dong et al., 2010a, Dong et al., 2010b). Although a causal relationship between IC hyperactivity and behavioural tinnitus has not been definitively established, the central role of this structure in the ascending auditory pathways means that midbrain hyperactivity continues to be used as a promising model for the neural substrates of this potentially debilitating disorder.

An important question is to what extent the hyperactivity in the IC (and possibly therefore, that seen in even higher parts of the auditory pathway such as the auditory cortex) is a result of altered intrinsic properties of the IC neurons and their local circuitry, and how much is dependent on input from lower stages of the pathway, such as the cochlear nucleus and even the cochlea itself. There are numerous reports that cochlear trauma of the type that leads both to behavioural tinnitus and to midbrain hyperactivity, also produces hyperactivity in the dorsal subdivision of the cochlear nucleus (DCN) (Kaltenbach et al., 2000, Kaltenbach et al., 2004) but until recently, the ventral subdivision (VCN) had not been directly investigated. With regard to the role of the cochlea, little attention has been paid to the relationship between spontaneous cochlear neural activity, tinnitus and IC hyperactivity, aside from the fact that some loss of cochlear afferent drive to the CNS appears to be a common precipitating cause of tinnitus. Indeed there is a generally pervasive view that while cochlear trauma may initiate the chain of events that eventually leads to tinnitus and the associated abnormal central neural activity, tinnitus itself is essentially a central phenomenon, independent of ongoing background afferent input from the cochlea for its maintenance. In this paper, we review some of our recent published findings on hyperactivity in the brainstem and midbrain and also present some new data. We seek to address several questions: 1) how precise is the relationship between changes in cochlear afferent neural sensitivity and the features of hyperactivity in the IC? 2) is the VCN also a potential source of abnormal input to the IC? and 3) how dependent is central neural hyperactivity on the presence of ongoing spontaneous firing of cochlear primary afferent neurons?