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Trabajo presentado en el 44th Annual MidWinter Meeting, celebrado en modalidad virtual del 20 al 24 de febrero de 2022., [Background]: Age-related loss of synaptic contacts between inner hair cells and auditory-nerve fibers (cochlear synaptopathy) has been linked to temporal processing deficits and impaired speech-in-noise recognition. In individual cases age-dependent temporal discrimination loss may be attenuated due to central compensation mechanism (neural gain). We hypothesize that cochlear synaptopathy, central neural gain and the ability for fast auditory temporal processing are connected to changes in hippocampal long-term potentiation (LTP) and brain-derived neurotrophic factor (BDNF) expression independent of the age. [Methods]: Here, we investigated middle-aged and old BDNF-live-exon-visualization (BLEV) reporter mice and analyzed auditory brainstem responses, auditory steady state responses and hippocampal field excitatory postsynaptic potentials. [Results]: In both, middle-aged and old groups, animals with lower or higher ability to centrally compensate reduced auditory nerve activity were found. The low compensators exhibited attenuated responses to amplitudemodulated tones and a reduction of hippocampal LTP and Bdnf transcript levels in comparison to high compensators. [Conclusions]: These results suggest that not the age itself but rather the diminished capacity for central compensation and LTP/BDNF recruitment play a key role in age-related loss of central auditory function caused by cochlear synaptopathy.

© 2021 Eckert, Marchetta, Manthey, Walter, Jovanovic, Savitska, Singer, Jacob, Rüttiger, Schimmang, Milenkovic, Pilz and Knipper., Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism., We acknowledge grants from the Deutsche Forschungsgemeins-chaft FOR 2060 project RU 713/3-2 (WS and LR), GRK 2381 (PM), SPP 1608 RU 316/12-1 (PE and LR), MI 954/3-1 (IM and SJ), KN 316/12-1 (MM and MK), BFU2016-76580-P (TS), and NIH NIMH 1R01MH106623 (MJ).

Trabajo presentado en el 43RD ANNUAL MidWinter MeetingAssociation for Otorhinolaryngology, celebrado en San José (Estados Unidos) del 25 al 29 de enero de 2020., Brain-derived neurotrophic factor (BDNF), a key modulator of synaptic plasticity is predicted to locally control cortical receptive field maturation and memory with sensory experience. BDNF`s main function for the adult central nervous system performance starts with sensory experience when local cortical BDNF is assumed to regulate the excitability of cortical circuits (Hong et al., 2008), a process leading to enhanced cortical auditory resolution. In the auditory system BDNF become gradually upregulated in cochlear neurons or glial cells and the ascending auditory path between P4 and P14 (Singer et al., 2014). Aiming to get a first insight in BDNF`s function from hearing onset onwards, Bdnf was deleted in lower level brain regions under the promoter of the paired-box transcription factor Pax2 (Zuccotti et al., 2012; Chumak et al., 2016). A striking novel role of BDNF in Pax2-expressing cells in the auditory periphery is identified that points to BDNF as trigger for rapid auditory processing, executive memorylinked functions, and normal social behavior., This work was supported by the Deutsche Forschungsgemeinschaft FOR 2060 project RU 713/3-2; GRK 2381; SPP 1608 RU 316/12-1 and KN 316/12-1; BFU2013-40944; NIH NIMH 1R01MH106623.

Trabajo presentado en el 42nd Annual MidWinter Meeting of the Association of Otorhinolaryngology, celebrado en Baltimore (Estados Unidos) del 9 al 13 de febrero de 2019., [Background]: While novel studies indicate that perceptional learning is not linked with permanent changes in cortical circuitry but rather with changes that are gated in a task- or context-dependent fashion, the molecular substrate of perceptional learning is still elusive. It is currently speculated that perhaps changes in synaptic weights restricted to a limited set of task-specific synapses play a crucial role (Irvine DRF Hearing Res. 2018, Zhang Y-X et al. Amitay S 2016, Plos One). BDNF is gradually upregulated in the cochlea and ascending auditory pathway onwards from prior hearing onset (postnatal day P4) (Singer et al., Knipper, Neuropharmacol 2014). Previously, we showed that peripheral BDNF in the cochlea or lower brainstem regions, but not in the central higher cortical brain regions is fundamental for improved and optimized auditory fidelity with hearing onset [Zuccotti A et al. Knipper, 2012, J Neuroscience, Chumak T et al., 2016, Mol Neurobiol]. This improved auditory fidelity included greater sensitivity of auditory fibers, lower hearing thresholds, and enlarged dynamic range and inhibitory strength in the inferior colliculus related to lowering of spontaneous firing rate. We here asked to what extend these BDNF driven changes in auditory fidelity may influence memory-related shaping of auditory skills and auditory perceptional learning., [Methods]: Using conditional BDNF Pax2 KO mice, lacking BDNF in the cochlea, DCN and IC, we compared auditory fine structure analysis, auditory steady state response (ASSR), LTP and LTP-dependent task performance in BDNF WT and mutant mice, and investigated changes in markers for excitatory and inhibitory neuronal activity using high-resolution confocal microscopy and quantitative westernblot approaches., [Results]: Fundamental differences were found between BDNF Pax2 WT and KO mice at the molecular, functional, and behavioral level. The findings are discussed in the context of a role of BDNF for auditory perceptional learning in lower auditory brainstem regions., This work was supported by the Deutsche Forschungsgemeinschaft DFG-Kni-316-10-1, FOR 2060 project RU 713/3-2, SPP 1608 RU 316/12-1; KN 316/12-1; the Brain & Behavior Research Foundation NARSAD Young Investigator Grant 20748, BFU2013-40944; DFG KFO134.

Activity-dependent BDNF (brain-derived neurotrophic factor) expression is hypothesized to be a cue for the context-specificity of memory formation. So far, activity-dependent BDNF cannot be explicitly monitored independently of basal BDNF levels. We used the BLEV (BDNF-live-exon-visualization) reporter mouse to specifically detect activity-dependent usage of Bdnf exon-IV and -VI promoters through bi-cistronic co-expression of CFP and YFP, respectively. Enriching acoustic stimuli led to improved peripheral and central auditory brainstem responses, increased Schaffer collateral LTP, and enhanced performance in the Morris water maze. Within the brainstem, neuronal activity was increased and accompanied by a trend for higher expression levels of Bdnf exon-IV-CFP and exon-VI-YFP transcripts. In the hippocampus BDNF transcripts were clearly increased parallel to changes in parvalbumin expression and were localized to specific neurons and capillaries. Severe acoustic trauma, in contrast, elevated neither Bdnf transcript levels, nor auditory responses, parvalbumin or LTP. Together, this suggests that critical sensory input is essential for recruitment of activity-dependent auditory-specific BDNF expression that may shape network adaptation., This work was supported by the Deutsche Forschungsgemeinschaft DFG-Kni-316-10-1 (RP-M, WS, H-SG, MK, and TO); FOR 2060 project RU 713/3-2 (LR and CH); SPP 1608 RU 316/12-1 (PE, KR, H-SG); KN 316/12-1 (MM, UZ, and MK); SPP 1608 FR 1784/17-1 (EF and NM); the Brain and Behavior Research Foundation NARSAD Young Investigator Grant 20748 (LM), BFU2013-40944 (TS); DFG KFO134 (PR and AB). We acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of University of Tübingen.

Resumen del póster presentado al 38th Annual MidWinter Meeting of the Association for Research in Otolaryngology, celebrado en Baltimore, Maryland (US) del 20 al 25 de febrero de 2015.-- et al., The accomplishment of spatial and temporal cortical resolution in the central auditory system is a process that is assumed to be initiated by the first auditory experience. Experience driven activity has been suggested to trigger increased intrinsic inhibition towards shaping the central sound resolution in dependency of brain-derived neurotrophic factor (BDNF). The experience dependent driving force for this process has so far not been specified further. Using mice with conditional deletion of BDNF under the Pax2 promotor and the TrkC promotor, we here demonstrate that the deletion of BDNF in the cochlea (BDNFPax2-KO) but not in the auditory cortex (BDNFTrkC-KO) or the inferior colliculus (BDNFPax2-KO, BDNFTrkC-KO) severely reduced dynamic range of sound sensitivity and noise vulnerability. Extracellular sound-evoked responses from IC neurons in BDNFPax2-WT and BDNFPax2-KO mice before and after acoustic trauma, moreover revealed that a BDNF dependent auditory fiber activity drives short response latency, low sound thresholds, and the narrow tuning of IC neurons including the generation regulatory high-frequency inhibitory sidebands. Analysis of further characteristic features within the ascending pathway of the mice mutants suggests that driving force for BDNF dependent intracortical inhibition itself may be a BDNF dependent process. The loss of the BDNF dependent intracortical inhibition has severe consequences for central sound processing. Data are discussed in the context of a novel role of cochlear BDNF for auditory processing and central auditory plasticity.

Resumen del póster presentado al 37th MidWinter Meeting of the Association for Research in Otorhinolaryngology celebrado en San Diego (US) del 22 al 26 de febrero de 2014.-- et al., [Background]: We recently showed that tissue-specific deletion of brain-derived neurotrophic factor (BDNF) in the cochlea prevents loss of thresholds and auditory brainstem response (ABR), and loss of inner hair cell (IHC) synaptic ribbons after exposure to traumatizing sound (Zuccotti et al., 2012; Journal of Neuroscience, 32, 25, 8545-53). These effects could be partly mimicked by the deletion of L-type voltage-gated calcium channel CaV1.2 in the cochlea (Zuccotti et al., 2013; Frontiers in molecular neuroscience, 6). The present study aimed to assess if deletion of BDNF or CaV1.2 in the cochlea alters the vulnerability of hearing over age. [Methods]: We compared the hearing function by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements on young and aged (1) conditional BDNFPax2 KO mice (Zuccotti et al., 2012) with the deletion of BDNF in the whole cochlea, the dorsal cochlear nucleus, and inferior colliculus, and (2) conditional CaV1.2Pax2 KO mice (Zuccotti et al., 2013) with deletion CaV1.2 in the same tissues as in the BDNFPax2 KO mice. We furthermore analyzed the influence of acoustic noise exposure on hearing loss., [Results]: Hearing function of both young and aged BDNFPax2KO and CaV1.2Pax2 KO mice were compared and related to outer hair cell (OHC) function and IHC synaptic structures. Suprathreshold ABR was analyzed in relation to young and aged mice. An interesting differential role of BDNF and CaV1.2 in the cochlea related to hair cell synaptic formation for sound processing became evident. [Conclusion]: We discuss the results in the context of a differential role of BDNF and CaV1.2 for hair cell and neuronal vulnerability during aging.

Resumen del trabajo presentado al 37th MidWinter Meeting of the Association for Research in Otorhinolaryngology celebrado en San Diego (US) del 22 al 26 de febrero de 2014.-- et al., [Background]: The precision of sound information transmitted to the brain depends on the transfer characteristics of the inner hair cell (IHC) ribbon synapse and its multiple contacting auditory fibers. Discharge rate and synchronicity of auditory fibers define the amplitude of sound induced brainstem responses. [Methods]: We used two mouse lines with either a cell specific deletion of brain-derived nerve growth factor (BDNF) in the cochlea and parts of the brainstem and midbrain (BDNF Pax2) or with deletion of BDNF within the entire brain (BDNF TrkC). We looked for molecular and functional differences pre and post acoustic trauma., [Results]: We found that BDNF is essential for maintaining exocytosis in IHC synapses in high frequency cochlear turns as well as for maintaining proper targeting of associated afferent fibers within this region (Zuccotti et al Knipper 2012 J. Neurosci.). Comparison of this BDNF Pax2 mice with the BDNF TrkC mice revealed that IHC response characteristics pre and post acoustic trauma were triggered by BDNF in the cochlea and not by BDNF in the brain. [Conclusion]: Extracellular recording of neurons in the inferior colliculus in BDNF Pax2 mice were performed. A surprising novel role of BDNF dependent steps for sound-processing was unraveled.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).-- et al., Voltage-gated L-type Ca2+ channels (L-VGCCs) like CaV1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, beside the well described L-VGCC CaV1.3, also CaV1.2 is expressed. Due to lethality of constitutive CaV1.2 KO mice, the function of this ion channel as well as its putative relationship to BDNF in the auditory system is entirely elusive. We recently described that BDNF plays a differential role for inner hair cell (IHC) vesicles release in normal and traumatized condition. To elucidate a presumptive role of CaV1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of CaV1.2 on the cochlea from that on feedback loops from higher auditory centers CaV1.2 was deleted, in one mouse line, under the Pax2 promoter (CaV1.2Pax2) leading to a deletion in the spiral ganglion neurons (SGN), dorsal cochlear nucleus (DCN), and inferior colliculus (IC). In the second mouse line, the Egr2 promoter was used for deleting CaV1.2 (CaV1.2Egr2) in auditory brainstem nuclei. In both mouse lines normal hearing threshold and equal number of IHC release sites were observed. We found a slight reduction of auditory brainstem response (ABR) wave I amplitudes in the CaV1.2Pax2 mice but not in the CaV1.2Egr2 mice. After noise exposure, CaV1.2Pax2 mice had less pronounced hearing loss that correlated with maintenance of ribbons in IHCs and less reduced activity in auditory nerve fibers, as well as in higher brain centers at supra-threshold sound stimulation. As reduced cochlear BDNF mRNA levels were found in CaV1.2Pax2 mice, we suggest that a CaV1.2 dependent step may participate in triggering part of the beneficial and deteriorating effects of cochlear BDNF in intact systems and during noise exposure through a pathway that is independent of Cav1.2 function in efferent circuits. © 2013 Zuccotti, Lee, Campanelli, Singer, Satheesh, Patriarchi, Geisler, Köpschall, Rohbock, Nothwang, Hu, Hell, Schimmang, Rüttiger and Knipper., This work was supported by the Marie Curie Research Training Network CavNET MRTN-CT-2006-035367, the Deutsche Forschungsgemeinschaft DFG-Kni-316-4-1 and Hahn Stiftung (Index AG), and the NIHR 01AG017502. We acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of Tübingen University.