Biology subjects

Weisz, C.

Publications and source records attributed to Weisz, C..

3 recordsLinked to original sources

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↗

bioRxiv2023

Fast inhibition slows and desynchronizes auditory efferent neuron activity

The encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem are well-suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that restrict MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation ( wedge-slice). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The in vivo-like timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivo-like timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hyper-suppression of cochlear activity. Significance StatementAuditory brainstem neurons are specialized for speed and fidelity to encode rapid features of sound. Extremely fast inhibition contributes to precise brainstem sound encoding. This circuit also projects to medial olivocochlear (MOC) efferent neurons that suppress cochlear function to enhance detection of signals in background sound. Using a novel brain slice preparation with intact ascending circuitry, we show that inhibition of MOC neurons can also be extremely fast, with the speed of the circuit localized to the cochlear nucleus. In contrast with the enhancement of precision afforded by fast inhibition in other brainstem auditory circuits, inhibition to MOC neurons instead has a variable onset that delays and desynchronizes activity, thus reducing precision for a slow, sustained response to background sounds.

neuroscience↗

bioRxiv2022

Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

Brainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage through unclear mechanisms. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize OCNs during postnatal development and after sound exposure. We identified markers for known OCN subtypes, medial (MOC) and lateral (LOC) OCNs, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.

neuroscience↗