Biology subjects

Apostolides, P. F.

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

4 recordsLinked to original sources

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↗