Corticothalamic Pathways in Auditory Processing: Recent Advances and Insights From Other Sensory Systems.

The corticothalamic (CT) pathways emanate from either Layer 5 (L5) or 6 (L6) of the neocortex and largely outnumber the ascending, thalamocortical pathways. The CT pathways provide the anatomical foundations for an intricate, bidirectional communication between thalamus and cortex. They act as dynamic circuits of information transfer with the ability to modulate or even drive the response properties of target neurons at each synaptic node of the circuit. L6 CT feedback pathways enable the cortex to shape the nature of its driving inputs, by directly modulating the sensory message arriving at the thalamus. L5 CT pathways can drive the postsynaptic neurons and initiate a transthalamic corticocortical circuit by which cortical areas communicate with each other. For this reason, L5 CT pathways place the thalamus at the heart of information transfer through the cortical hierarchy. Recent evidence goes even further to suggest that the thalamus via CT pathways regulates functional connectivity within and across cortical regions, and might be engaged in cognition, behavior, and perceptual inference. As descending pathways that enable reciprocal and context-dependent communication between thalamus and cortex, we venture that CT projections are particularly interesting in the context of hierarchical perceptual inference formulations such as those contemplated in predictive processing schemes, which so far heavily rely on cortical implementations. We discuss recent proposals suggesting that the thalamus, and particularly higher order thalamus via transthalamic pathways, could coordinate and contextualize hierarchical inference in cortical hierarchies. We will explore these ideas with a focus on the auditory system.

Role of GluA3 AMPA Receptor Subunits in the Presynaptic and Postsynaptic Maturation of Synaptic Transmission and Plasticity of Endbulb-Bushy Cell Synapses in the Cochlear Nucleus.

The AMPA receptor (AMPAR) subunit GluA3 has been suggested to shape synaptic transmission and activity-dependent plasticity in endbulb-bushy cell synapses (endbulb synapses) in the anteroventral cochlear nucleus, yet the specific roles of GluA3 in the synaptic transmission at endbulb synapses remains unexplored. Here, we compared WT and GluA3 KO mice of both sexes and identified several important roles of GluA3 in the maturation of synaptic transmission and short-term plasticity in endbulb synapses. We show that GluA3 largely determines the ultrafast kinetics of endbulb synapses glutamatergic currents by promoting the insertion of postsynaptic AMPARs that contain fast desensitizing flop subunits. In addition, GluA3 is also required for the normal function, structure, and development of the presynaptic terminal which leads to altered short term-depression in GluA3 KO mice. The presence of GluA3 reduces and slows synaptic depression, which is achieved by lowering the probability of vesicle release, promoting efficient vesicle replenishment, and increasing the readily releasable pool of synaptic vesicles. Surprisingly, GluA3 also makes the speed of synaptic depression rate-invariant. We propose that the slower and rate-invariant speed of depression allows an initial response window that still contains presynaptic firing rate information before the synapse is depressed. Because this response window is rate-invariant, GluA3 extends the range of presynaptic firing rates over which rate information in bushy cells can be preserved. This novel role of GluA3 may be important to allowing the postsynaptic targets of spherical bushy cells in mice use rate information for encoding sound intensity and sound localization.SIGNIFICANCE STATEMENT We report novel roles of the glutamate receptor subunit GluA3 in synaptic transmission in synapses between auditory nerve fibers and spherical bushy cells (BCs) in the cochlear nucleus. We show that GluA3 contributes to the generation of ultrafast glutamatergic currents at these synapses, which is important to preserve temporal information about the sound. Furthermore, we demonstrate that GluA3 contributes to the normal function and development of the presynaptic terminal, whose properties shape short-term plasticity. GluA3 slows and attenuates synaptic depression, and makes it less dependent on the presynaptic firing rates. This may help BCs to transfer information about the high rates of activity that occur at the synapse in vivo to postsynaptic targets that use rate information for sound localization.

Conductive Hearing Loss Has Long-Lasting Structural and Molecular Effects on Presynaptic and Postsynaptic Structures of Auditory Nerve Synapses in the Cochlear Nucleus.

UNLABELLED: Sound deprivation by conductive hearing loss increases hearing thresholds, but little is known about the response of the auditory brainstem during and after conductive hearing loss. Here, we show in young adult rats that 10 d of monaural conductive hearing loss (i.e., earplugging) leads to hearing deficits that persist after sound levels are restored. Hearing thresholds in response to clicks and frequencies higher than 8 kHz remain increased after a 10 d recovery period. Neural output from the cochlear nucleus measured at 10 dB above threshold is reduced and followed by an overcompensation at the level of the lateral lemniscus. We assessed whether structural and molecular substrates at auditory nerve (endbulb of Held) synapses in the cochlear nucleus could explain these long-lasting changes in hearing processing. During earplugging, vGluT1 expression in the presynaptic terminal decreased and synaptic vesicles were smaller. Together, there was an increase in postsynaptic density (PSD) thickness and an upregulation of GluA3 AMPA receptor subunits on bushy cells. After earplug removal and a 10 d recovery period, the density of synaptic vesicles increased, vesicles were also larger, and the PSD of endbulb synapses was larger and thicker. The upregulation of the GluA3 AMPAR subunit observed during earplugging was maintained after the recovery period. This suggests that GluA3 plays a role in plasticity in the cochlear nucleus. Our study demonstrates that sound deprivation has long-lasting alterations on structural and molecular presynaptic and postsynaptic components at the level of the first auditory nerve synapse in the auditory brainstem. SIGNIFICANCE STATEMENT: Despite being the second most prevalent form of hearing loss, conductive hearing loss and its effects on central synapses have received relatively little attention. Here, we show that 10 d of monaural conductive hearing loss leads to an increase in hearing thresholds, to an increased central gain upstream of the cochlear nucleus at the level of the lateral lemniscus, and to long-lasting presynaptic and postsynaptic structural and molecular effects at the endbulb of the Held synapse. Knowledge of the structural and molecular changes associated with decreased sensory experience, along with their potential reversibility, is important for the treatment of hearing deficits, such as hyperacusis and chronic otitis media with effusion, which is prevalent in young children with language acquisition or educational disabilities.

The cortical modulation of stimulus-specific adaptation in the auditory midbrain and thalamus: a potential neuronal correlate for predictive coding.

To follow an ever-changing auditory scene, the auditory brain is continuously creating a representation of the past to form expectations about the future. Unexpected events will produce an error in the predictions that should "trigger" the network's response. Indeed, neurons in the auditory midbrain, thalamus and cortex, respond to rarely occurring sounds while adapting to frequently repeated ones, i.e., they exhibit stimulus specific adaptation (SSA). SSA cannot be explained solely by intrinsic membrane properties, but likely involves the participation of the network. Thus, SSA is envisaged as a high order form of adaptation that requires the influence of cortical areas. However, present research supports the hypothesis that SSA, at least in its simplest form (i.e., to frequency deviants), can be transmitted in a bottom-up manner through the auditory pathway. Here, we briefly review the underlying neuroanatomy of the corticofugal projections before discussing state of the art studies which demonstrate that SSA present in the medial geniculate body (MGB) and inferior colliculus (IC) is not inherited from the cortex but can be modulated by the cortex via the corticofugal pathways. By modulating the gain of neurons in the thalamus and midbrain, the auditory cortex (AC) would refine SSA subcortically, preventing irrelevant information from reaching the cortex.

Intracellular correlates of stimulus-specific adaptation.

Stimulus-specific adaptation (SSA) is the reduction in response to a common stimulus that does not generalize, or only partially generalizes, to rare stimuli. SSA is strong and widespread in primary auditory cortex (A1) of rats, but is weak or absent in the main input station to A1, the ventral division of the medial geniculate body. To study SSA in A1, we recorded neural activity in A1 intracellularly using sharp electrodes. We studied the responses to tone pips of the same frequency in different contexts: as Standard and Deviants in Oddball sequences; in equiprobable sequences; in sequences consisting of rare tone presentations; and in sequences composed of many different frequencies, each of which was rare. SSA was found both in subthreshold membrane potential fluctuations and in spiking responses of A1 neurons. SSA for changes in frequency was large at a frequency difference of 44% between Standard and Deviant, and clearly present with tones separated by as little as 4%, near the behavioral frequency difference limen in rats. When using equivalent measures, SSA in spiking responses was generally larger than the SSA at the level of the membrane potential. This effect can be traced to the nonlinearity of the transformation between membrane potential to spikes. Using the responses to the same tone in different contexts made it possible to demonstrate that cortical SSA could not be fully explained by adaptation in narrow frequency channels, even at the level of the membrane potential. We conclude that local processing significantly contributes to the generation of cortical SSA.

An overview of stimulus-specific adaptation in the auditory thalamus.

In the auditory brain, some populations of neurons exhibit stimulus-specific adaptation (SSA), whereby they adapt to frequently occurring stimuli but retain sensitivity to stimuli that are rare. SA has been observed in auditory structures from the midbrain to the primary auditory cortex (A1) and has been proposed to be a precursor to the generation of deviance detection. SSA is strongly expressed in non-lemniscal regions of the medial geniculate body (MGB), the principal nucleus of the auditory thalamus. In this account we review the state of the art of SSA research in the MGB, highlighting the importance of this auditory centre in detecting sounds that may be relevant for survival.

Effect of auditory cortex deactivation on stimulus-specific adaptation in the medial geniculate body.

An animal's survival may depend on detecting new events or objects in its environment, and it is likely that the brain has evolved specific mechanisms to detect such changes. In sensory systems, neurons often exhibit stimulus-specific adaptation (SSA) whereby they adapt to frequently occurring stimuli, but resume firing when "surprised" by rare or new ones. In the auditory system, SSA has been identified in the midbrain, thalamus, and auditory cortex (AC). It has been proposed that the SSA observed subcortically originates in the AC as a higher-order property that is transmitted to the subcortical nuclei via corticofugal pathways. Here we report that SSA in the auditory thalamus of the rat remains intact when the AC is deactivated by cooling, thus demonstrating that the AC is not necessary for the generation of SSA in the thalamus. The AC does, however, modulate the responses of thalamic neurons in a way that strongly indicates a gain modulation mechanism. The changes imposed by the AC in thalamic neurons depend on the level of SSA that they exhibit.

Stimulus-specific adaptation in the auditory thalamus of the anesthetized rat.

The specific adaptation of neuronal responses to a repeated stimulus (Stimulus-specific adaptation, SSA), which does not fully generalize to other stimuli, provides a mechanism for emphasizing rare and potentially interesting sensory events. Previous studies have demonstrated that neurons in the auditory cortex and inferior colliculus show SSA. However, the contribution of the medial geniculate body (MGB) and its main subdivisions to SSA and detection of rare sounds remains poorly characterized. We recorded from single neurons in the MGB of anaesthetized rats while presenting a sequence composed of a rare tone presented in the context of a common tone (oddball sequences). We demonstrate that a significant percentage of neurons in MGB adapt in a stimulus-specific manner. Neurons in the medial and dorsal subdivisions showed the strongest SSA, linking this property to the non-lemniscal pathway. Some neurons in the non-lemniscal regions showed strong SSA even under extreme testing conditions (e.g., a frequency interval of 0.14 octaves combined with a stimulus onset asynchrony of 2000 ms). Some of these neurons were able to discriminate between two very close frequencies (frequency interval of 0.057 octaves), revealing evidence of hyperacuity in neurons at a subcortical level. Thus, SSA is expressed strongly in the rat auditory thalamus and contribute significantly to auditory change detection.

Divergent and point-to-point connections in the commissural pathway between the inferior colliculi.

The commissure of the inferior colliculus interconnects the left and right sides of the auditory midbrain and provides the final opportunity for interaction between the two sides of the auditory pathway at the subcortical level. Although the functional properties of the commissure are beginning to be revealed, the topographical organization of its connections is unknown. A combination of neuroanatomical tracing studies, 3D reconstruction, and neuronal density maps was used to study the commissural connections in rat. The results demonstrate that commissural neurons in the central nucleus of the inferior colliculus send a divergent projection to the equivalent frequency-band laminae in the central nucleus and dorsal and lateral cortices on the opposite side. The density of this projection, however, is weighted toward a point that matches the position of the tracer injection; consistent with a point-to-point emphasis in the wiring pattern. In the dorsal cortex of the inferior colliculus there may be two populations of neurons that project across the commissure, one projecting exclusively to the frequency-band laminae in the central nucleus and the other projecting diffusely to the dorsal cortex. Neurons in the lateral cortex of the inferior colliculus make only a very weak contribution to the commissural pathway. The point-to-point pattern of connections permits interactions between specific regions of corresponding frequency-band laminae, whereas the divergent projection pattern could subserve integration across the lamina.

A monosynaptic pathway from dorsal cochlear nucleus to auditory cortex in rat.

Of the three major subdivisions of the auditory thalamus, the medial subdivision is the only one that receives a direct projection from the dorsal cochlear nucleus. Those cells in the medial auditory thalamus that receive the projection from the dorsal cochlear nucleus continue to the auditory cortex. A combination of anterograde and retrograde anatomical tracer injections made in the dorsal cochlear nucleus and the auditory cortex respectively, revealed terminal boutons which were directly apposed onto the dendrites and cell bodies of neurons in the medial auditory thalamus. The presence of a monosynaptic pathway, which transfers information from the first relay in the auditory system to the last, suggests that this pathway may rapidly convey very basic information to the auditory cortex.