Biology subjects

Di Guilmi, M. N.

Publications and source records attributed to Di Guilmi, M. N..

5 recordsLinked to original sources

bioRxiv2026

Medial Olivocochlear Activity Modulates Central Auditory Synapse Structure and Function

In many mammals, the auditory system is immature at birth and undergoes activity-dependent refinement. The medial olivocochlear system (MOC) contributes to the maturation of central auditory connectivity by shaping spontaneous activity in the developing inner ear. Although altered MOC activity has been linked to electrical and synaptic dysfunctions in different central auditory nuclei, an in-depth analysis of the same synapse under conditions of absent versus enhanced MOC activity is lacking. In this work, we set out a physiological and structural analysis of the calyx of Held and the principal neurons of the medial nucleus of the trapezoid body (CH-MNTB) synapse at postnatal days 12-14 in three mouse models of either sex: wild-type (WT), 9 knock-in (9KI; with enhanced MOC activity), and 9 knock-out (9KO; which lacks MOC activity). Electrophysiological recordings in brain slices revealed a reduced synaptic strength efficacy in 9KI compared to WT, including smaller excitatory postsynaptic current (EPSC) amplitudes, stronger short-term depression during repetitive stimulation and a decrease readily releasable pool size. In contrast, 9KO mice showed minimal synaptic differences relative to WT. Serial block-face electron microscopy (SBEM) reconstructions demonstrated morphological alterations of the CH in both MOC-manipulated mouse models. However, 9KI mice exhibited the largest deviations, including fewer morphologically complex CHs and increased poly-innervation of MNTB cells. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Moreover, the enhancement of MOC activity drives more pronounced developmental changes in brainstem auditory circuitry than its absence. Significance StatementBefore hearing onset, inner hair cells in altricial mammals show spontaneous electrical activity crucial for proper auditory pathway development. This activity is finely regulated by descending efferent nerves from the central nervous system during a critical developmental period, ensuring precise auditory circuit formation. Our study shows that genetically manipulating efferent function --either by eliminating it or enhancing it-- leads to structural alterations and severe synaptic dysfunction within the auditory brainstem. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Importantly, enhancing efferent peripheral activity causes more pronounced central synaptic changes than its absence, highlighting the importance of balanced efferent modulation during early auditory system development for normal brainstem auditory function.

neuroscience↗

bioRxiv2025

Early Noise Exposure and Changes in Medial Olivocochlear Strength Alters Auditory Pathway Development

The early onset of peripheral deafness significantly alters the proper development of the auditory system. Likewise, exposure to loud noise during early development produces a similar disruptive effect. Before hearing onset in altricial mammals, cochlear inner hair cells exhibit spontaneous electrical activity that drives auditory circuit development. This activity is modulated by medial olivocochlear (MOC) efferent feedback through 910 nicotinic cholinergic receptors in inner hair cells. In adults, these receptors are restricted to outer hair cells, where they mediate MOC feedback to regulate cochlear amplification. Although the MOC systems protective role to prevent noise-induced hearing loss in adulthood is well-established, its influence during early developmental stages-especially in response to exposure to loud noise-remains largely unexplored. In this study, we investigated the role of MOC feedback during early postnatal development using 9 knockout (KO) and 9 knock-in (KI) mice of either sex, which respectively lack or exhibit enhanced cholinergic activity. Our findings reveal that both increased and absent olivocochlear activity result in altered auditory sensitivity at the onset of hearing, along with long- range alterations in the number and morphology of ribbon synapses. Early noise exposure caused lasting auditory damage in both wild-type and 9KO mice, with deficits persisting into adulthood. In contrast, 9KI mice were protected from noise-induced damage, with no long-term effects on auditory function. These results highlight the increased susceptibility of the auditory system during early postnatal development. Moreover, they indicate that an enhanced MOC feedback shields the auditory system from noise damage during this period. SIGNIFICANCE STATEMENTEarly development represents a sensitive window for shaping auditory function. We show that the medial olivocochlear system is critical for establishing normal ribbon synapse density and size; key features for proper hearing onset. We also show that the developing auditory system is especially vulnerable to loud noise, with early exposure causing more severe and lasting effects than similar noise later in life. Notably, enhancing 910 nAChR receptor activity during this early stage offers protection against noise-induced damage, revealing a time-sensitive opportunity to safeguard auditory development.

neuroscience↗

bioRxiv2024

Co-release of GABA and ACh from medial olivocochlear neurons fine tunes cochlear efferent inhibition

During development, inner hair cells (IHCs) in the mammalian cochlea are unresponsive to acoustic stimuli but instead exhibit spontaneous activity. During this same period, neurons originating from the medial olivocochlear complex (MOC) transiently innervate IHCs, regulating their firing pattern which is crucial for the correct development of the auditory pathway. Although the MOC-IHC is a cholinergic synapse, previous evidence indicates the widespread presence of gamma-aminobutyric acid (GABA) signaling markers, including presynaptic GABAB receptors (GABABR). In this study, we explore the source of GABA by optogenetically activating either cholinergic or GABAergic fibers. The optogenetic stimulation of MOC terminals from GAD;ChR2-eYFP and ChAT;ChR2-eYFP mice evoked synaptic currents in IHCs that were blocked by -bungarotoxin. This suggests that GABAergic fibers release ACh and activate 910 nicotinic acetylcholine receptors (nAChRs). Additionally, MOC cholinergic fibers release not only ACh but also GABA, as the effect of GABA on ACh response amplitude was prevented by applying the GABAB-R blocker (CGP 36216). Using optical neurotransmitter detection and calcium imaging techniques, we examined the extent of GABAergic modulation at the single synapse level. Our findings suggest heterogeneity in GABA modulation, as only 15 out of 31 recorded synaptic sites were modulated by applying the GABABR specific antagonist, CGP (100-200 {micro}M). In conclusion, we provide compelling evidence that GABA and ACh are co-released from at least a subset of MOC terminals. In this circuit, GABA functions as a negative feedback mechanism, locally regulating the extent of cholinergic inhibition at certain efferent-IHC synapses during an immature stage. Significance statementBefore hearing onset, the medial olivocochlear (MOC) efferent system of the mammalian cochlea regulates the pattern of IHC spontaneous firing rate through the activation of 910 nAChRs. However, GABA is also known to have a modulatory role at the MOC-IHC synapse. Our results show that GABA is co-released from at least a subset of MOC terminals, working as a precise regulatory mechanism for ACh release. Furthermore, we demonstrate that not all synaptic contacts within a single IHC are equally modulated by GABA.

physiology↗

bioRxiv2021

Characterization of developmental changes in spontaneous electrical activity of superior olivary neurons before hearing onset under injectable or volatile anesthesia

In this work we studied the impact of two widely used anesthetics on the electrical activity of auditory brainstem neurons during development. The spontaneous electrical activity in neonate rats of either sex was analyzed under the injectable mix of ketamine/xylazine (K/X mix) and the volatile anesthetic isoflurane (ISO). We used a ventral craniotomy in mechanically ventilated pups to carry out electrophysiology recordings in the superior olivary complex (SOC) between birth (postnatal day 0, P0) and P12. To characterize neuronal activity of single and ensembles of neurons, we performed patch clamp and multi-electrode experiments under different anesthetic conditions. Our results provide the first study that compares K/X mix and ISO in the same rodent species. We demonstrate that electrical activity of SOC neurons ramps up during development, and that the firing pattern of single units recorded in K/X mix was similar to that reported in ISO anesthetized rat pups. However, ISO displayed a large scatter on its suppressing effects on electrical activity when delivered at 1.5% in the presence or the absence of K/X mix. Taken together, our results shed light on the use of anesthetics for future studies to enable electrophysiology or optical imaging studies in-vivo to obtain functional information on the activity of medial olivochoclear neurons and their role in auditory development.

neuroscience↗

bioRxiv2018

Strengthening of the efferent olivocochlear system leads to synaptic dysfunction and tonotopy disruption of a central auditory nucleus

The auditory system in many mammals is immature at birth but precisely organized in adults. Spontaneous activity in the inner ear plays a critical role in guiding this process. This is shaped by an efferent pathway that descends from the brainstem and makes transient direct synaptic contacts with inner hair cells (IHCs). In this work, we used an 9 cholinergic receptor knock-in mouse model (of either sex) with enhanced medial efferent activity (Chrna9L9T, L9T) to understand the role of the olivocochlear system in the correct establishment of auditory circuits. Wave III of auditory brainstem responses (which represents synchronized activity of synapses within the superior olivary complex) were smaller in L9T mice, suggesting a central dysfunction. The mechanism underlying this functional alteration was analysed in brain slices containing the medial nucleus of the trapezoid body (MNTB), where neurons are topographically organized along a medio-lateral axis. The topographic organization of MNTB physiological properties observed in WT mice was abolished in the L9T mice. Additionally, electrophysiological recordings in slices evidenced MNTB synaptic alterations, which were further supported by morphological alterations. The present results suggest that the transient cochlear efferent innervation to IHCs during the critical period before the onset of hearing is involved in the refinement of topographic maps as well as in setting the correct synaptic transmission at central auditory nuclei.\n\nSignificance StatementCochlear inner hair cells of altricial mammals display spontaneous electrical activity before hearing onset. The pattern and firing rate of these cells is crucial for the correct maturation of the central auditory pathway. A descending efferent innervation from the central nervous system contacts hair cells during this developmental window. The function of this transient efferent innervation remains an open question. The present work shows that the genetic enhancement of efferent function disrupts the orderly topographic distribution at the medial nucleus of the trapezoid body level and causes severe synaptic dysfunction. Thus, the transient efferent innervation to the cochlea is necessary for the correct establishment of the central auditory circuitry.

neuroscience↗