Biology subjects

Apostolides, P. F.

Publications and source records attributed to Apostolides, P. F..

8 recordsLinked to original sources

bioRxiv2024

Population coding of auditory space in the dorsal inferior colliculus persists with altered binaural cues

Sound localization is critical for real-world hearing, such as segregating overlapping sound streams. For optimal flexibility, central representations of auditory space must adapt to peripheral changes in binaural cue availability, such as following asymmetric hearing loss in adulthood. However, whether the mature auditory system can reliably encode spatial auditory representations upon abrupt changes in binaural input is unclear. Here we use 2-photon Ca2+ imaging in awake head-fixed mice to determine how the higher-order "shell" layers of the inferior colliculus (IC) encode sound source location in the frontal azimuth, under binaural conditions and after acute monaural hearing loss induced by an ear plug ipsilateral to the imaged hemisphere. Spatial receptive fields were typically broad and not exclusively contralateral: Neurons responded reliably to multiple positions in the contra- and ipsi-lateral hemifields, with preferred positions tiling the entire frontal azimuth. Ear plugging broadened receptive fields and reduced spatial selectivity in a subset of neurons, in agreement with an inhibitory influence of ipsilateral sounds. However ear plugging also enhanced spatial tuning and/or unmasked receptive fields in other neurons, shifting the distribution of preferred angles ipsilaterally with minimal impact on the neuronal populations overall spatial resolution; these effects occurred within 2 hours of ear plugging. Consequently, linear classifiers trained on fluorescence data from control and ear-plugged conditions had similar classification accuracy when tested on held out data from within, but not across hearing conditions. Spatially informative neuronal population codes therefore arise rapidly following monaural hearing loss, in absence of overt experience.

neuroscience↗

bioRxiv2023

Mixed representations of sound and action in the auditory midbrain

Linking sensory input and its consequences is a fundamental brain operation. Accordingly, neural activity of neo-cortical and limbic systems often reflects dynamic combinations of sensory and behaviorally relevant variables, and these "mixed representations" are suggested to be important for perception, learning, and plasticity. However, the extent to which such integrative computations might occur in brain regions upstream of the forebrain is less clear. Here, we conduct cellular-resolution 2-photon Ca2+ imaging in the superficial "shell" layers of the inferior colliculus (IC), as head-fixed mice of either sex perform a reward-based psychometric auditory task. We find that the activity of individual shell IC neurons jointly reflects auditory cues and mices actions, such that trajectories of neural population activity diverge depending on mices behavioral choice. Consequently, simple classifier models trained on shell IC neuron activity can predict trial-by-trial outcomes, even when training data are restricted to neural activity occurring prior to mices instrumental actions. Thus in behaving animals, auditory midbrain neurons transmit a population code that reflects a joint representation of sound and action. Significance StatementNeurons in ICs superficial "shell" layers preferentially project to higher-order thalamic nuclei that are strongly activated by sounds and their behavioral consequences. This integrative computation is thought critical for a variety of behaviorally relevant functions, such as establishing learned sound valence. However, whether such "mixed representations" reflect unique properties of thalamocortical networks, or rather are inherited from afferent inputs, is unclear. We show that in behaving mice, many shell IC neurons are modulated by sounds and mices actions. Consequently, shell IC population activity suffices to predict behavioral outcomes even prior to the goal-directed action. Our data thus establish shell IC nuclei as a novel, ascending source of mixed representations for the thalamocortical system.

neuroscience↗

bioRxiv2023

Population coding of time-varying sounds in the non-lemniscal Inferior Colliculus

The inferior colliculus (IC) of the midbrain is important for complex sound processing, such as discriminating conspecific vocalizations and human speech. The ICs non-lemniscal, dorsal "shell" region is likely important for this process, as neurons in these layers project to higher-order thalamic nuclei that subsequently funnel acoustic signals to the amygdala and non-primary auditory cortices; forebrain circuits important for vocalization coding in a variety of mammals, including humans. However, the extent to which shell IC neurons transmit acoustic features necessary to discern vocalizations is less clear, owing to the technical difficulty of recording from neurons in the ICs superficial layers via traditional approaches. Here we use 2-photon Ca2+ imaging in mice of either sex to test how shell IC neuron populations encode the rate and depth of amplitude modulation, important sound cues for speech perception. Most shell IC neurons were broadly tuned, with a low neurometric discrimination of amplitude modulation rate; only a subset were highly selective to specific modulation rates. Nevertheless, neural network classifier trained on fluorescence data from shell IC neuron populations accurately classified amplitude modulation rate, and decoding accuracy was only marginally reduced when highly tuned neurons were omitted from training data. Rather, classifier accuracy increased monotonically with the modulation depth of the training data, such that classifiers trained on full-depth modulated sounds had median decoding errors of [~]0.2 octaves. Thus, shell IC neurons may transmit time-varying signals via a population code, with perhaps limited reliance on the discriminative capacity of any individual neuron. Significance StatementThe ICs shell layers originate a "non-lemniscal" pathway whose first- and second-order targets are thought important for perceiving conspecific vocalizations and human speech. However, prior studies suggest that individual shell IC neurons are broadly tuned and have high response thresholds, implying a limited reliability of efferent signals. Here we use Ca2+ imaging to test how shell IC neurons encode amplitude modulation, a key sound cue for speech perception and stream segregation. We show that the rate and depth of amplitude modulation is accurately represented in the ensemble activity of shell IC neuron populations. Thus, downstream targets can read out a sounds temporal envelope from a distributed rate code transmitted by populations of broadly tuned neurons.

neuroscience↗

bioRxiv2023

Calcium-sensitive subthreshold oscillations and electrical coupling in principal cells of mouse dorsal cochlear nucleus

In higher sensory brain regions, slow oscillations (0.5-5 Hz) associated with quiet wakefulness and attention modulate multisensory integration, predictive coding, and perception. Although often assumed to originate via thalamocortical mechanisms, the extent to which sub-cortical sensory pathways are independently capable of slow oscillatory activity is unclear. We find that in the first station for auditory processing, the cochlear nucleus, fusiform cells from juvenile mice (of either sex) generate robust 1-2 Hz oscillations in membrane potential and exhibit electrical resonance. Such oscillations were absent prior to the onset of hearing, intrinsically generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) and persistent Na+ conductances (NaP) interacting with passive membrane properties, and reflected the intrinsic resonance properties of fusiform cells. Cx36-containing gap junctions facilitated oscillation strength and promoted pairwise synchrony of oscillations between neighboring neurons. The strength of oscillations were strikingly sensitive to external Ca2+, disappearing at concentrations > 1.7 mM, due in part to the shunting effect of small-conductance calcium-activated potassium (SK) channels. This effect explains their apparent absence in previous in vitro studies of cochlear nucleus which routinely employed high-Ca2+ extracellular solution. In contrast, oscillations were amplified in reduced Ca2+ solutions, due to relief of suppression by Ca2+ of Na+ channel gating. Our results thus reveal mechanisms for synchronous oscillatory activity in auditory brainstem, suggesting that slow oscillations, and by extension their perceptual effects, may originate at the earliest stages of sensory processing. SIGNIFICANCE STATEMENT (120 words max.)Many studies show that electrical activity in higher brain regions is regulated by brain oscillations. Here we show that such oscillatory activity can arise even in the first levels of auditory processing in the cochlear nucleus of the brainstem (fusiform cells), and is generated not by neural networks but by the biophysical properties of individual neurons. Oscillations are highly sensitive to external Ca2+ due to interplay of multiple ionic conductances. Gap junctions between cells allows for amplification and synchrony of such activity. Oscillations are absent in pre-hearing neurons, suggesting that sound activity might be important for their emergence. We propose that such early-level oscillations may serve to enhance signaling associated with particular environmental stimuli.

neuroscience↗

bioRxiv2022

Auditory corticofugal neurons transmit non-auditory signals to support discriminative learning

Layer 5 pyramidal neurons of sensory cortices project "corticofugal" axons to myriad sub-cortical targets, thereby broadcasting high-level signals important for perception and learning. Recent studies suggest dendritic Ca2+ spikes as key biophysical mechanisms supporting corticofugal neuron function: These long-lasting events drive burst firing, thereby initiating uniquely powerful signals to modulate sub-cortical representations and trigger learning-related plasticity. However, the behavioral relevance of corticofugal dendritic spikes is poorly understood. We shed light on this issue using 2-photon Ca2+ imaging of auditory corticofugal dendrites as mice of either sex engage in a GO/NO-GO sound-discrimination task. Unexpectedly, only a minority of dendritic spikes were triggered by behaviorally relevant sounds under our conditions. Task related dendritic activity instead mostly followed sound cue termination and co-occurred with mices instrumental licking during the answer period of behavioral trials, irrespective of reward consumption. Temporally selective, optogenetic silencing of corticofugal neurons during the trial answer period impaired auditory discrimination learning. Thus, auditory corticofugal systems contribution to learning and plasticity may be partially non-sensory in nature. Significance StatementThe auditory cortex sends a massive "feedback" projection to the inferior colliculus (IC) which controls IC neuron plasticity and some types of perceptual learning. Precisely what signals are fed back during behavior is unclear. Using multiphoton imaging of auditory cortico-collicular neurons as mice engage in a sound discrimination task, we find that activity coincides more with mices instrumental actions rather than sound cues. Dendritic Ca2+ spikes and burst firing contributed to this non-auditory activity, which is notable given that dendritic spikes instruct synaptic plasticity in many other circuits. Accordingly, optogenetic silencing of corticofugal neurons during mices instrumental actions impaired discriminative learning. Auditory corticofugal neurons may thus transmit significant non-auditory information that contributes to learning-related plasticity.

neuroscience↗

bioRxiv2022

Kv7 channel antagonists block glycine receptors

XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone) is currently the most widely used and specific antagonist of the Kv7 (KCNQ) family of K+ channels. We report an unexpected antagonistic effect of this drug on ionotropic glycine receptors. In recordings of synaptic transmission in two brainstem nuclei (the medial nucleus of the trapezoid body and the dorsal cochlear nucleus), 10 M XE991, a concentration typical for Kv7 studies in brain tissue, inhibited evoked glycinergic inhibitory postsynaptic currents (IPSCs) without altering paired-pulse ratio, and also reduced the amplitude of glycinergic miniature IPSCs. These results are indicative of a direct effect of the drug on postsynaptic glycine receptors. XE991 also produced dose-dependent block of the response to exogenously applied glycine, to a degree comparable to the block of synaptic transmission. Moreover, the drug inhibited homomeric glycine receptors expressed on presynaptic membrane of the calyx of Held. The degree of block was independent of glycine concentration, suggesting an allosteric interaction. The effects of XE991 on glycine responses are not likely to reflect block of the glycine-activated Cl- channels themselves, because block was voltage independent, and because GABA-activated Cl- currents were resistant to XE991 at concentrations up to 100 {micro}M. Linopirdine, but not retigabine, also antagonized glycine receptor currents. Given the prevalence of glycine receptor signaling in the brain, these observations should be taken into account in studies of the roles of Kv7 channels in neural circuit function and disease.

neuroscience↗

bioRxiv2022

Recurrent circuits amplify corticofugal signals and drive feed-forward inhibition in the inferior colliculus

The inferior colliculus (IC) is a midbrain hub critical for perceiving complex sounds such as speech. In addition to processing ascending inputs from most auditory brainstem nuclei, the IC receives descending inputs from auditory cortex that control IC neuron feature selectivity, plasticity, and certain forms of perceptual learning. Although corticofugal synapses primarily release the excitatory transmitter glutamate, many physiology studies show that auditory cortical activity has a net inhibitory effect on IC neuron spiking. Perplexingly, anatomy studies imply that corticofugal axons primarily target glutamatergic IC neurons while only sparsely innervating IC GABA neurons. Corticofugal inhibition of the IC may thus occur largely independently of feedforward activation of local GABA neurons. We shed light on this paradox using in vitro electrophysiology in acute IC slices from fluorescent reporter mice of either sex. Using optogenetic stimulation of corticofugal axons, we find that excitation evoked with single light flashes is indeed stronger in presumptive glutamatergic neurons compared to GABAergic neurons. However, many IC GABA neurons fire tonically at rest, such that sparse and weak excitation suffices to significantly increase their spike rates. Furthermore, a subset of glutamatergic IC neurons fire spikes during repetitive corticofugal activity, leading to polysynaptic excitation in IC GABA neurons owing to a dense intra-collicular connectivity. Consequently, recurrent excitation amplifies corticofugal activity, drives spikes in IC GABA neurons, and generates substantial local inhibition in the IC. Thus, descending signals engage intra-collicular inhibitory circuits despite apparent constraints of monosynaptic connectivity between auditory cortex and IC GABA neurons. Significance StatementDescending "corticofugal" projections are ubiquitous across mammalian sensory systems, and enable the neocortex to control subcortical activity in a predictive or feedback manner. Although corticofugal neurons are glutamatergic, neocortical activity often inhibits subcortical neuron spiking. How does an excitatory pathway generate inhibition? Here we study the corticofugal pathway from auditory cortex to inferior colliculus (IC), a midbrain hub important for complex sound perception. Surprisingly, cortico-collicular transmission was stronger onto IC glutamatergic compared to GABAergic neurons. However, corticofugal activity triggered spikes in IC glutamate neurons with local axons, thereby generating strong polysynaptic excitation and feed-forward spiking of GABAergic neurons. Our results thus reveal a novel mechanism that recruits local inhibition despite limited monosynaptic convergence onto inhibitory networks.

neuroscience↗

bioRxiv2021

Synaptic Mechanisms of Top-Down Control by The Auditory Cortico-Collicular Pathway

Corticofugal projections to evolutionarily ancient, sub-cortical structures are ubiquitous across mammalian sensory systems. These "descending" pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor dependent, supra-linear EPSP summation, indicating that descending signals can non-linearly amplify IC neurons moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control, and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathways role in plasticity and perceptual learning.

neuroscience↗