Disturbed Balance of Inhibitory Signaling Links Hearing Loss and Cognition

Abstract

Neuronal hyperexcitability in the central auditory pathway linked to reduced inhibitory activity is associated with numerous forms of hearing loss, including noise damage, age-dependent hearing loss, and deafness, as well as tinnitus or auditory processing deficits in autism spectrum disorder (ASD). In most cases, the reduced central inhibitory activity and the accompanying hyperexcitability are interpreted as an active compensatory response to the absence of synaptic activity, linked to increased central neural gain control (increased output activity relative to reduced input). We here suggest that hyperexcitability also could be related to an immaturity or impairment of tonic inhibitory strength that typically develops in an activity-dependent process in the ascending auditory pathway with auditory experience. In these cases, high-SR auditory nerve fibers, which are critical for the shortest latencies and lowest sound thresholds, may have either not matured (possibly in congenital deafness or autism) or are dysfunctional (possibly after sudden, stressful auditory trauma or age-dependent hearing loss linked with cognitive decline). Fast auditory processing deficits can occur despite maintained basal hearing. In that case, tonic inhibitory strength is reduced in ascending auditory nuclei, and fast inhibitory parvalbumin positive interneuron (PV-IN) dendrites are diminished in auditory and frontal brain regions. This leads to deficits in central neural gain control linked to hippocampal LTP/LTD deficiencies, cognitive deficits, and unbalanced extra-hypothalamic stress control. Under these conditions, a diminished inhibitory strength may weaken local neuronal coupling to homeostatic vascular responses required for the metabolic support of auditory adjustment processes. We emphasize the need to distinguish these two states of excitatory/inhibitory imbalance in hearing disorders: (i) Under conditions of preserved fast auditory processing and sustained tonic inhibitory strength, an excitatory/inhibitory imbalance following auditory deprivation can maintain precise hearing through a memory linked, transient disinhibition that leads to enhanced spiking fidelity (central neural gain⇑) (ii) Under conditions of critically diminished fast auditory processing and reduced tonic inhibitory strength, hyperexcitability can be part of an increased synchronization over a broader frequency range, linked to reduced spiking reliability (central neural gain⇓). This latter stage mutually reinforces diminished metabolic support for auditory adjustment processes, increasing the risks for canonical dementia syndromes.

Stress Affects Central Compensation of Neural Responses to Cochlear Synaptopathy in a cGMP-Dependent Way

“…The BLEV reporter mouse, which allows for visualization and identification of activity-dependent Bdnf exon-IV and -VI derived expression, is an ideal tool to study molecular correlates of plasticity changes in the hippocampus (Matt et al, 2018). As Bdnf exon-IV-CFP is expressed in blood vessels and Bdnf exon-VI-YFP is expressed in synaptic nerve terminals, differences in Bdnf exon-IV and -VI expression observed between high and low compensators (Figures 7H,I) may reflect differences in hemodynamic hippocampal responses, as has previously been suggested (Marchetta et al, 2020b;Knipper et al, 2022). Considering that specific neuronal activity may tightly regulate blood flow (Hillman, 2014), it was hypothesized that a critically reduced driving force of auditory nerve fibers could lead to less recruitment of activity-driven Bdnf exon-VI-YFP transcripts in nerve endings and of Bdnf exon-IV-CFP expression in capillaries in low compensators in comparison to high compensators (Singer et al, 2018b;Marchetta et al, 2020b), which might reveal a chronically lower level of neurovascular coupling in low compensators and an acutely depressed level of neurovascular coupling due to stress in high compensators.…”

“…A loss of fast auditory processing, as seen in high compensators after treatment with placebo (Figure 5A), is here also linked to reduced levels of PV-positive interneuron (PV-IN) staining in the hippocampus (Figure 7J). Recently, stress has been shown to cause impaired neurovascular coupling and attenuation of cerebral blood flow through a reduction in PV-IN GABAergic signaling, possibly through altered nitric oxide-induced vasodilation (Czeh et al, 2015(Czeh et al, , 2018Csabai et al, 2018;Han et al, 2019;Knipper et al, 2022). The differences between high and low compensators in Bdnf exon-IV-CFP expression in capillary vessels within the highly vascularized fissura region in conjunction with the altered PV-IN levels (Figure 7) may thus further point to differences in hemodynamic hippocampal responses.…”

“…Hearing loss has been identified as a common risk factor in cognitive decline and Alzheimer's disease (Lin et al, 2011;Livingston et al, 2017;Montero-Odasso et al, 2020). A direct link has not yet been established (Lin et al, 2011;Fortunato et al, 2016;Uchida et al, 2019;Johnson et al, 2021), although numerous studies on animals and humans point to an interaction of auditory processing and the hippocampus, the part of the limbic system engaged in memory, spatial navigation, and possibly also sensory gating (see for a review: Knipper et al, 2022;Zhang et al, 2022).…”

Olfactory, Auditory, and Vestibular Performance: Multisensory Impairment Is Significantly Associated With Incident Cognitive Impairment

“…In the context of hearing loss, loss of high-SR auditory fibers, as occurs in age-related hearing loss, is implicated in the development of imbalances in excitation and inhibition in ascending central pathways. This imbalance may lead to a decrease in central gain, dysregulation of the hypothalamic-pituitary axis, decrease in hippocampal long-term potentiation, and an overall decrease in signal-noise ratio ( 51 ).…”

Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling

“…We reconsidered that the coordinated function of central MR and GR are predominantly predicted to influence the extinction (MR) and consolidation (GR) of long-term potentiation (LTP; see for a review de Kloet et al, 2018). Any adaptive central auditory responses following sound enrichment or acoustic trauma were found to be accompanied by increased hippocampal LTP levels (Matt et al, 2018;Likhtik and Johansen, 2019;Knipper et al, 2020;Marchetta et al, 2020b;Knipper et al, 2022;Manohar et al, 2022;Savitska et al, 2022;Zhang et al, 2022). The association between adaptive central auditory responses following sound enrichment or auditory trauma and LTP changes is suggested to be triggered through corticothalamic feedforward and feedback circuits (Antunes and Malmierca, 2021;Knipper et al, 2022).…”