Aging but not age-related hearing loss dominates the decrease of parvalbumin immunoreactivity in the primary auditory cortex of mice

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 usingin vitroelectrophysiology 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.

Successful navigation in complex acoustic scenes requires focusing on relevant sounds while ignoring irrelevant distractors. It has been argued that the ability to track stimulus statistics and generate predictions supports the choice of what to attend and what to ignore. However, the role of these predictions about future auditory events in drafting decisions remains elusive. While most psychophysical studies in humans indicate that expected stimuli are more easily detected, most work studying physiological auditory processing in animals highlights the detection of unexpected, surprising stimuli. Here, we tested whether in the mouse, high target probability results in enhanced detectability or whether detection is biased towards low-probability deviants using an auditory detection task. We implemented a probabilistic choice model to investigate whether a possible dependence on stimulus statistics arises from short-term serial correlations or from integration over longer periods. Our results demonstrate that target detectability in mice decreases with increasing probability, contrary to humans. We suggest that mice indeed track probability over a timescale of at least several minutes but do not use this information in the same way as humans do: instead of maximizing reward by focusing on high-probability targets, the saliency of a target is determined by surprise.

In patients with severe sensory impairment due to compromised peripheral function, partial restoration can be achieved by implantation of sensory prostheses for the electrical stimulation of the central nervous system. However, these state of the art approaches suffer from the drawback of limited spectral resolution. Electrical field spread depends on the impedance of the surrounding medium, impeding spatially focused electrical stimulation in neural tissue. To overcome these technical limitations, optogenetic excitation could be applied in such prostheses to achieve enhanced resolution through precise and differential stimulation of nearby neuronal ensembles within the central sensory pathway. Previous experiments have provided a first proof for behavioral detectability of optogenetic excitation in the rodent auditory system. However, little is known about the generation of complex and behaviorally relevant sensory patterns involving differential excitation. In this study, we developed an optogenetic implant to excite two spatially separated points along the tonotopy of the murine central inferior colliculus (ICc). Using a newly-devised reward-based operant Go/No-Go paradigm for the evaluation of optogenetic excitation of the auditory midbrain in freely moving, behaving mice, we demonstrate that differential optogenetic excitation of a sub-cortical sensory pathway is possible and efficient. Here we demonstrate how animals which were previously trained in a frequency discrimination paradigm a) rapidly generalize between sound and optogenetic excitation, b) generally detect optogenetic excitation at two different neuronal ensembles, and c) discriminate between them. Our results demonstrate for the first time that optogenetic excitation at different points of the ICc tonotopy elicits a stable response behavior over time periods of several months. With this study, we provide the first proof of principle for sub-cortical differential stimulation of sensory systems using complex artificial cues in freely moving animals.