Egyes nucleus cochlearis neurontípusok jelentősége a hangingerek primér feldolgozásában és a hallás párhuzamos felszálló útvonalainak kialakításában = Role of some neurones of the cochlear nucleus in the primary processing of the auditory information and in determining the parallel ascending pathways serving the hearing function

A munka célja azon felszíni ioncsatornák, szignalizációs rendszerek és modulációs hatások tanulmányozása volt, amelyek lehetővé teszik a hallórendszer kezdeti szakaszán párhuzamosan működő neuronhálózatok kialakítását a hallási információ egyes jellemzőinek feldolgozása céljából. Mind a ganglion spirale, mind a nucleus cochlearis neuronjai expresszálják a depolarizáció-aktivált K+-áram fő komponenseiért (alacsony küszübű dendrotoxin-érzékeny, tranziens és késői egyenirányító áram) felelős Kv alegységeket, ezek megoszlása azonban jelentős sejtek közötti változékonyságot mutat. Különösen érdekes az a megállapítás, hogy nucleus cochlearis dorsalis részében található piramis- és óriásssejtek a morfológiai heterogenitás mellett valószínűleg funkcionálisan is eltérő alcsoportokat alkotnak. A cochlearis neuronok esetében jelentős eltérések mutathatók ki a citoplazmatikus kalciumkötő-fehérjék megoszlásában és mennyiségében. Megállapítottuk, hogy a nucleus cochlearis dorsalis részében levő projekciós neuronok elektromos ingerléssel kiváltott posztszinaptikus aktivitását muszkarinerg modulációs rendszerek jelentősen befolyásolhatják, többféle támadásponttal és következménnyel. Egyes muszkarinerg acetil-kolin-receptorok jelen vannak a cochlearis mag astrocytáiban is, aktiválásuk a sejtek egy részében intracelluláris Ca2+-koncentráció növekedést eredményez, aminek befolyása lehet a cochlearis neuronok közötti információátvitelre. | The main aim was to study those ionic channels, signalisation pathways and modulatory mechanisms that make possible the formation of parallel neuronal networks for decoding the various components of the acoustic information at the initial stages of the auditory pathway. The neurones of the spiral ganglion and the cochlear nucleus express the Kv subunits responsible for all major components of the depolarisation-activated K+ currents (low-threshold dendrotoxin-sensitive, transient and delayed rectifier currents). The distribution and amounts of these subunits, however, show cell-to-cell variability. It is especially noteworthy that the morphologically heterogeneous pyramidal and giant neurones of the dorsal cochlear nucleus seem to form functionally different subgroups. There were characteristic differences in the distribution and quantity of the cytoplasmic calcium-binding proteins in the cochlear neurones. It was found that various postsynaptic electrical phenomena could be elicited on the projection neurones of the dorsal cochlear nucleus using presynaptic electrical stimulation and these activity patterns could be influenced via muscarinergic modulatory mechanisms. Certain muscarinergic acetylcholine receptors are present in the cochelar astrocytes, too. In a fraction of these cells their activation resulted in increases of the cytoplasmic calcium concentration that might have influence on the interneuronal synaptic transmission

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

In light of the increasing evidence supporting a link between hearing loss and dementia, it is critical to gain a better understanding of the nature of this relationship. We have previously observed that following cochlear synaptopathy, the temporal auditory processing (e.g., auditory steady state responses, ASSRs), is sustained when reduced auditory input is centrally compensated. This central compensation process was linked to elevated hippocampal long-term potentiation (LTP). We further observed that, independently of age, central responsiveness to cochlear synaptopathy can differ, resulting in either a low or high capacity to compensate for the reduced auditory input. Lower central compensation resulted in poorer temporal auditory processing, reduced hippocampal LTP, and decreased recruitment of activity-dependent brain-derived neurotrophic factor (BDNF) expression in hippocampal regions (low compensators). Higher central compensation capacity resulted in better temporal auditory processing, higher LTP responses, and increased activity-dependent BDNF expression in hippocampal regions. Here, we aimed to identify modifying factors that are potentially responsible for these different central responses. Strikingly, a poorer central compensation capacity was linked to lower corticosterone levels in comparison to those of high compensators. High compensators responded to repeated placebo injections with elevated blood corticosterone levels, reduced auditory brainstem response (ABR) wave I amplitude, reduced inner hair cell (IHC) ribbon number, diminished temporal processing, reduced LTP responses, and decreased activity-dependent hippocampal BDNF expression. In contrast, the same stress exposure through injection did not elevate blood corticosterone levels in low compensators, nor did it reduce IHC ribbons, ABR wave I amplitude, ASSR, LTP, or BDNF expression as seen in high compensators. Interestingly, in high compensators, the stress-induced responses, such as a decline in ABR wave I amplitude, ASSR, LTP, and BDNF could be restored through the “memory-enhancing” drug phosphodiesterase 9A inhibitor (PDE9i). In contrast, the same treatment did not improve these aspects in low compensators. Thus, central compensation of age-dependent cochlear synaptopathy is a glucocorticoid and cyclic guanosine-monophosphate (cGMP)-dependent neuronal mechanism that fails upon a blunted stress response

Gα_i Proteins are Indispensable for Hearing

Background/Aims: From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary (“hair”) bundle, a requirement for the progression of mature hearing. We found that the lack of Gαi3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. Methods: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gαi proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Gαi isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons. Results: Here we report that lack of Gαi3 but not of the ubiquitously expressed Gαi2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Gαi2 or Gαi3 had no impact. In contrast, double-deficiency for Gαi2 and Gαi3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Gαi3-deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Gαi3 is selectively involved in generation of neural gain during auditory processing. Conclusion: We propose a so far unrecognized complexity of isoform-specific and overlapping Gαi protein functions particular during final differentiation processes