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A neuron model with unbalanced synaptic weights explains the asymmetric effects of anaesthesia on the auditory cortex [1]

['Luciana López-Jury', 'Institute For Cell Biology', 'Neuroscience', 'Goethe University', 'Frankfurt Am Main', 'Francisco García-Rosales', 'Ernst Strüngmann Institute', 'Esi', 'For Neuroscience In Cooperation With Max Planck Society', 'Eugenia González-Palomares']

Date: 2023-02

Substantial progress in the field of neuroscience has been made from anaesthetized preparations. Ketamine is one of the most used drugs in electrophysiology studies, but how ketamine affects neuronal responses is poorly understood. Here, we used in vivo electrophysiology and computational modelling to study how the auditory cortex of bats responds to vocalisations under anaesthesia and in wakefulness. In wakefulness, acoustic context increases neuronal discrimination of natural sounds. Neuron models predicted that ketamine affects the contextual discrimination of sounds regardless of the type of context heard by the animals (echolocation or communication sounds). However, empirical evidence showed that the predicted effect of ketamine occurs only if the acoustic context consists of low-pitched sounds (e.g., communication calls in bats). Using the empirical data, we updated the naïve models to show that differential effects of ketamine on cortical responses can be mediated by unbalanced changes in the firing rate of feedforward inputs to cortex, and changes in the depression of thalamo-cortical synaptic receptors. Combined, our findings obtained in vivo and in silico reveal the effects and mechanisms by which ketamine affects cortical responses to vocalisations.

The main aim of this study was to determine if echolocation and communication acoustic contexts drive similar context-dependent effects in awake and KX-anaesthetized bats. Previous studies have shown that ketamine reduces responses to vocalisations [ 11 , 12 ] and increases adaptation in cortical regions [ 24 , 25 ]. Considering these findings, we modified the neuron model previously constructed for awake data and simulated the expected KX effects. We called this first in silico experiment “naïve modelling.” Naïve modelling predicted that known effects of KX would have significant effects on the context-mediated modulation of neural responses, independent on the type of the context that precedes the target sounds (echolocation or communication). Surprisingly, electrophysiological recordings contradicted the naïve model prediction and showed that under KX, context effects were asymmetrical: Only the sound responses after communication context were affected by anaesthesia. A new set of in vivo experiments allowed us to determine that such asymmetries were due to stimulus frequency-specific effects of anaesthesia. The naïve model was updated based on the findings obtained in vivo. From the updated models, the one that succeeded at reproducing all in vivo experimental observations was one in which anaesthesia affected only high-frequency (HF) tuned inputs and their respective synapses, creating a compensation of the effects and causing the apparent absence of effect of anaesthesia after echolocation context.

( A ) A representative spectrogram of natural bat vocalisations obtained from a group of bats. The audio recording is composed of a mixture of echolocation pulses and social calls uttered by several conspecifics roosting together. The colour bar indicates sound amplitude (arbitrary units). ( B ) Response of one cortical neuron to playbacks of echolocation and communication calls heard in silence (left) and after acoustic contexts (right). The responses were recorded in the awake state. Data from [ 23 ]. ( C ) Top left: Location of the bat auditory cortex (AC). The HF cortical fields that contain multifunctional neurons (such as that represented in B) are highlighted in red. Below: A characteristic multipeaked frequency tuning curve (FTC) from these neurons is shown. Right: An integrate-and-fire neuron model reproduces the context-dependent processing observed experimentally in awake bats. In theory, the known effects of ketamine on evoked responses can be used to predict ketamine effects on context-dependent processing in the bat cortex. Data supporting panel B can be found in “all_psth.mat” and the underlying code in “Fig 1B.m,” both in “Ephys data” folder in https://gin.g-node.org/Luciana/anesthesia_bats .

Bats represent a good mammalian model to study vocal communication [ 13 , 14 ]. In addition to their own sonar pulses, which enable bats to navigate in the dark, bats are constantly processing echolocation pulses and social calls from conspecifics [ 15 ]. These two types of vocalisations differ in terms of their frequency composition: Social calls often have lower fundamental frequencies than echolocation ( Fig 1A ) [ 16 ]. In the auditory cortex of bats, there are specialised neurons that respond well to both types of signals, echolocation and communication, suggesting a multifunction theory of cortical processing [ 17 ]. Bat multifunctional neurons have been well characterised in terms of their location within the auditory cortex, responses to pure tones, and even to natural sounds [ 18 – 22 ]. It has been shown that multifunctional neurons increase their discrimination between echolocation and communication calls when the vocalisations are preceded by natural acoustic contexts ( Fig 1B ) [ 23 ]. Multifunctional neurons present a good opportunity to investigate the effects of anaesthesia on sensory processing of vocalisations because (i) they constitute a well-characterised neuronal population; (ii) they are thought to play an important role for communication in complex acoustic environments; and (iii) the synaptic mechanisms underlying the effects of anaesthesia can be studied in silico, since a neuron model that explains responses to individual sounds and sound mixtures in the awake state is now available ( Fig 1C ) [ 23 ].

The mixture of KX is widely used in electrophysiological studies in mammals to ensure the absence of pain and the animal’s unconsciousness. Interestingly, in the last decade, clinical studies have demonstrated that ketamine is also useful as an antidepressant [ 7 , 8 ]. Ketamine mainly affects glutamatergic transmission inhibiting NMDA receptors [ 9 ]. Its effect in the cortex is characterised by increasing low-frequency (LF) oscillations and reducing ongoing “spontaneous” activity [ 10 ]. However, the effects of KX on stimulus-evoked activity are difficult to generalise across cortical neurons, particularly to complex sounds such as vocalisations [ 11 , 12 ].

In the past decades, substantial progress has been made in the field of sensory processing of vocalisations. Work on anaesthetized animals has contributed tremendously to the current body of knowledge on how behaviourally relevant sounds are represented in the brain [ 1 – 6 ]. Yet, our understanding of how anaesthetics influence responses to sounds is limited. In this article, we combined computational modelling and in vivo electrophysiological recordings from awake and anaesthetized bats (species: Carollia perspicillata) to study the effects of ketamine-xylazine (KX) anaesthesia on the processing of conspecifics vocalisations.

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002013

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