BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury

Abstract

For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNFPax2-KO) versus the auditory cortex and hippocampus (BDNFTrkC-KO). We demonstrate that BDNFPax2-KO but not BDNFTrkC-KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNFPax2 mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNFPax2-KO, but not of BDNFTrkC-KO mice. Also, BDNFPax2-WT but not BDNFPax2-KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.

Gαi Proteins are Indispensable for Hearing

“…ABR to click and pure tone stimuli and the cubic 2*f1-f2 DPOAE for f2=1.24*f1 and L2=L1-10 dB were recorded in adult 1-to 8-month-old anesthetized mice. From click-evoked ABRs, consecutive wave components that reflect the summed neural activity along the ascending auditory pathway were analyzed as described [31][32][33]. In vivo electrocochleography (compound action potentials of the auditory nerve, CAP; summating potential of IHC receptor potentials, SP; receptor potential of OHCs, cochlear microphonic, CM) was performed in anesthetized mice as described [34].…”

Biomarkers for Hearing Dysfunction: Facts and Outlook

“…In conclusion, an increasing number of studies have now demonstrated that the counting of IHC ribbons after hearing loss, for example, in aged specimens [62,64] , or after an acoustic trauma [22,31,32,61,75,76] , or after intake of aminoglycoside [77,78] , can be a first indication of the loss of IHC synapses and AN integrity, independent of (elevated) hearing thresholds.…”

“…The resulting pressure waves from the motion of the epithelium, triggered by the active OHC process, are conducted (backwards) through the middle ear to the eardrum, which moves like a loudspeaker diaphragm to produce a sound pressure wave, which can be measured in the ear canal [26] . For technical details of DPOAE measurements in rodents, see [21,22,[30][31][32][33] .…”

“…7 ). Studies in laboratory rats and mice showed that reduction of ABR wave I, reflecting the summated response from the AN, to supra-threshold sound stimulation, correlated with the progressive loss of synaptic contacts of the AN fibers and AN degeneration after acoustic noise exposure (e.g., [21,22,31,32,61] . A reduced ABR wave I was also linked to a reduction of cochlear frequency selectivity (loss of sharpness of tuning) in noise-exposed adult chinchillas [84] .…”

“…In view of that, several studies analyzing the glutamate-decarboxylase (GAD67) protein, a marker for inhibitory neurons [123][124][125] , or parvalbumin, a marker for inhibitory interneurons [126] , find characteristic pattern changes in auditory nuclei with ageing [124,125,[127][128][129] , after cochlear trauma [31,110,130] or with auditory experience [31] . The use of parvalbumin as a biomarker for altered inhibitory circuity is particularly interesting because new findings link parvalbumin changes with characteristic electroencephalography signals.…”