Auditory midbrain coding of statistical learning that results from discontinuous sensory stimulation.

Detecting regular patterns in the environment, a process known as statistical learning, is essential for survival. Neuronal adaptation is a key mechanism in the detection of patterns that are continuously repeated across short (seconds to minutes) temporal windows. Here, we found in mice that a subcortical structure in the auditory midbrain was sensitive to patterns that were repeated discontinuously, in a temporally sparse manner, across windows of minutes to hours. Using a combination of behavioral, electrophysiological, and molecular approaches, we found changes in neuronal response gain that varied in mechanism with the degree of sound predictability and resulted in changes in frequency coding. Analysis of population activity (structural tuning) revealed an increase in frequency classification accuracy in the context of increased overlap in responses across frequencies. The increase in accuracy and overlap was paralleled at the behavioral level in an increase in generalization in the absence of diminished discrimination. Gain modulation was accompanied by changes in gene and protein expression, indicative of long-term plasticity. Physiological changes were largely independent of corticofugal feedback, and no changes were seen in upstream cochlear nucleus responses, suggesting a key role of the auditory midbrain in sensory gating. Subsequent behavior demonstrated learning of predictable and random patterns and their importance in auditory conditioning. Using longer timescales than previously explored, the combined data show that the auditory midbrain codes statistical learning of temporally sparse patterns, a process that is critical for the detection of relevant stimuli in the constant soundscape that the animal navigates through.

Blocking c-Fos Expression Reveals the Role of Auditory Cortex Plasticity in Sound Frequency Discrimination Learning.

The behavioral changes that comprise operant learning are associated with plasticity in early sensory cortices as well as with modulation of gene expression, but the connection between the behavioral, electrophysiological, and molecular changes is only partially understood. We specifically manipulated c-Fos expression, a hallmark of learning-induced synaptic plasticity, in auditory cortex of adult mice using a novel approach based on RNA interference. Locally blocking c-Fos expression caused a specific behavioral deficit in a sound discrimination task, in parallel with decreased cortical experience-dependent plasticity, without affecting baseline excitability or basic auditory processing. Thus, c-Fos-dependent experience-dependent cortical plasticity is necessary for frequency discrimination in an operant behavioral task. Our results connect behavioral, molecular and physiological changes and demonstrate a role of c-Fos in experience-dependent plasticity and learning.

The hippocampus influences assimilation and accommodation of schemata that are not hippocampus-dependent.

Learning is facilitated when information can be incorporated into an already learned set of rules or 'mental schema'. The location of a new restaurant, for example, is learned more easily if the neighbourhood's general layout is already known. This type of information is processed by the hippocampus and stored as a schema in the cortex, but it is not known whether the hippocampus can also map new stimuli to cortical schemata that are hippocampus-independent, such as odour classification. Using a hippocampus-independent odour-rule task we found that animals without a functional hippocampus learnt which odours did not fit the rule faster than sham animals, which persistently applied the rule to all odours. Conversely, when non-fitting odours were linked to a new rule sham animals were faster to link these odours to the new rule. The hippocampus, thus, regulates the association of stimuli with existing schemata even when the schemata are hippocampus-independent. © 2016 Wiley Periodicals, Inc.

The emerging functions of oligodendrocytes in regulating neuronal network behaviour.

Myelin is required for efficient nerve conduction, but not all axons are myelinated to the same extent. Here we review recent studies that have revealed distinct myelination patterns of different axonal paths, suggesting that myelination is not an all or none phenomenon and that its presence is finely regulated in central nervous system networks. Whereas powerful reductionist biology has led to important knowledge of how oligodendrocytes function by themselves, little is known about their role in neuronal networks. We still do not understand how oligodendrocytes integrate information from neurons to adapt their function to the need of the system. An intricate cross talk between neurons and glia is likely to exist and to determine how neuronal circuits operate as a whole. Dissecting these mechanisms by using integrative systems biology approaches is one of the major challenges ahead.

Double dissociation between the contributions of the septal and temporal hippocampus to spatial learning: the role of prior experience.

The mammalian hippocampus is anatomically heterogeneous along its longitudinal axis, and there is evidence that distinct functions are executed by different septotemporal subregions. The best documented example is the dependency of spatial learning on the septal, but not the temporal, hippocampus. Here, we carried out a watermaze memory task in rats with partial lesions of the septal or temporal hippocampus made either before or after training. We then studied memory retention, reversal, and new spatial learning in a novel environment. This resulted in the surprising finding that spatial learning in a new environment is dependent on the temporal hippocampus in rats with preoperative experience of a different pool. Rats with septal hippocampal lesions made after learning not only retained the focused search strategy that was acquired during preoperative training, but were also capable of rapid spatial learning in a second pool. This demonstrates that once spatial information has been acquired in one context, related new learning in a different context can be mediated by the temporal hippocampus, a result that challenges the widely held view that spatial memory is an exclusive function of the septal hippocampus.

Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity.

Nedd4-2 is an E3 ubiquitin ligase in which missense mutation is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of the Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy.

Corrigendum: Listening loops and the adapting auditory brain.

[This corrects the article DOI: 10.3389/fnins.2023.1081295.].

The perceptual categorization of multidimensional stimuli is hierarchically organized.

As we interact with our surroundings, we encounter the same or similar objects from different perspectives and are compelled to generalize. For example, despite their variety we recognize dog barks as a distinct sound class. While we have some understanding of generalization along a single stimulus dimension (frequency, color), natural stimuli are identifiable by a combination of dimensions. Measuring their interaction is essential to understand perception. Using a 2-dimension discrimination task for mice and frequency or amplitude modulated sounds, we tested untrained generalization across pairs of auditory dimensions in an automatized behavioral paradigm. We uncovered a perceptual hierarchy over the tested dimensions that was dominated by the sound's spectral composition. Stimuli are thus not perceived as a whole, but as a combination of their features, each of which weights differently on the identification of the stimulus according to an established hierarchy, possibly paralleling their differential shaping of neuronal tuning.

Listening loops and the adapting auditory brain.

Analysing complex auditory scenes depends in part on learning the long-term statistical structure of sounds comprising those scenes. One way in which the listening brain achieves this is by analysing the statistical structure of acoustic environments over multiple time courses and separating background from foreground sounds. A critical component of this statistical learning in the auditory brain is the interplay between feedforward and feedback pathways-"listening loops"-connecting the inner ear to higher cortical regions and back. These loops are likely important in setting and adjusting the different cadences over which learned listening occurs through adaptive processes that tailor neural responses to sound environments that unfold over seconds, days, development, and the life-course. Here, we posit that exploring listening loops at different scales of investigation-from in vivo recording to human assessment-their role in detecting different timescales of regularity, and the consequences this has for background detection, will reveal the fundamental processes that transform hearing into the essential task of listening.

Subcortical coding of predictable and unsupervised sound-context associations.

Our environment is made of a myriad of stimuli present in combinations often patterned in predictable ways. For example, there is a strong association between where we are and the sounds we hear. Like many environmental patterns, sound-context associations are learned implicitly, in an unsupervised manner, and are highly informative and predictive of normality. Yet, we know little about where and how unsupervised sound-context associations are coded in the brain. Here we measured plasticity in the auditory midbrain of mice living over days in an enriched task-less environment in which entering a context triggered sound with different degrees of predictability. Plasticity in the auditory midbrain, a hub of auditory input and multimodal feedback, developed over days and reflected learning of contextual information in a manner that depended on the predictability of the sound-context association and not on reinforcement. Plasticity manifested as an increase in response gain and tuning shift that correlated with a general increase in neuronal frequency discrimination. Thus, the auditory midbrain is sensitive to unsupervised predictable sound-context associations, revealing a subcortical engagement in the detection of contextual sounds. By increasing frequency resolution, this detection might facilitate the processing of behaviorally relevant foreground information described to occur in cortical auditory structures.

Sound disrupts sleep-associated brain oscillations in rodents in a meaning-dependent manner.

Sleep is essential but places animals at risk. Filtering acoustic information according to its relevance, a process generally known as sensory gating, is crucial during sleep to ensure a balance between rest and danger detection. The mechanisms of this sensory gating and its specificity are not understood. Here, we tested the effect that sounds of different meaning have on sleep-associated ongoing oscillations. We recorded EEG and EMG from mice during REM and NREM sleep while presenting sounds with or without behavioural relevance. We found that sound presentation per se, in the form of a neutral sound, elicited a weak or no change in the power of sleep-state-dependent EEG during REM and NREM sleep. In contrast, the presentation of a sound previously conditioned in an aversive task, elicited a clear and fast decrease in the EEG power during both sleep phases, suggesting a transition to lighter sleep without awakening. The observed changes generally weakened over training days and were not present in animals that failed to learn. Interestingly, the effect could be generalized to unfamiliar neutral sounds if presented following conditioned training, an effect that depended on sleep phase and sound type. The data demonstrate that sounds are differentially gated during sleep depending on their meaning and that this process is reflected in disruption of sleep-associated brain oscillations without behavioural arousal.

jULIEs: nanostructured polytrodes for low traumatic extracellular recordings and stimulation in the mammalian brain.

Objective.Extracellular microelectrode techniques are the most widely used approach to interrogate neuronal populations. However, regardless of the manufacturing method used, damage to the vasculature and circuit function during probe insertion remains a concern. This issue can be mitigated by minimising the footprint of the probe used. Reducing the size of probes typically requires either a reduction in the number of channels present in the probe, or a reduction in the individual channel area. Both lead to less effective coupling between the probe and extracellular signals of interest.Approach.Here, we show that continuously drawn SiO2-insulated ultra-microelectrode fibres offer an attractive substrate to address these challenges. Individual fibres can be fabricated to >10 m continuous stretches and a selection of diameters below 30µm with low resistance (<100 Ω mm-1) continuously conductive metal core of <10µm and atomically flat smooth shank surfaces. To optimize the properties of the miniaturised electrode-tissue interface, we electrodeposit rough Au structures followed by ∼20 nm IrOx film resulting in the reduction of the interfacial impedance to <500 kΩ at 1 kHz.Main results. We demonstrate that these ultra-low impedance electrodes can record and stimulate both single and multi-unit activity with minimal tissue disturbance and exceptional signal-to-noise ratio in both superficial (∼40µm) and deep (∼6 mm) structures of the mouse brain. Further, we show that sensor modifications are stable and probe manufacturing is reproducible.Significance.Minimally perturbing bidirectional neural interfacing can reveal circuit function in the mammalian brainin vivo.

Ketogenic diet uncovers differential metabolic plasticity of brain cells.

To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type-specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease.

A role of oligodendrocytes in information processing.

Myelinating oligodendrocytes enable fast propagation of action potentials along the ensheathed axons. In addition, oligodendrocytes play diverse non-canonical roles including axonal metabolic support and activity-dependent myelination. An open question remains whether myelination also contributes to information processing in addition to speeding up conduction velocity. Here, we analyze the role of myelin in auditory information processing using paradigms that are also good predictors of speech understanding in humans. We compare mice with different degrees of dysmyelination using acute multiunit recordings in the auditory cortex, in combination with behavioral readouts. We find complex alterations of neuronal responses that reflect fatigue and temporal acuity deficits. We observe partially discriminable but similar deficits in well myelinated mice in which glial cells cannot fully support axons metabolically. We suggest a model in which myelination contributes to sustained stimulus perception in temporally complex paradigms, with a role of metabolically active oligodendrocytes in cortical information processing.

Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks.

Hippocampal sharp wave-ripple complexes (SPW-Rs) occur during slow-wave sleep and behavioral immobility and are thought to represent stored information that is transferred to the neocortex during memory consolidation. Here we show that stimuli that induce long-term potentiation (LTP), a neurophysiological correlate of learning and memory, can lead to the generation of SPW-Rs in rat hippocampal slices. The induced SPW-Rs have properties that are identical to spontaneously generated SPW-Rs: they originate in CA3, propagate to CA1 and subiculum and require AMPA/kainate receptors. Their induction is dependent on NMDA receptors and involves changes in interactions between clusters of neurons in the CA3 network. Their expression is blocked by low-frequency stimulation but not by NMDA receptor antagonists. These data indicate that induction of LTP in the recurrent CA3 network may facilitate the generation of SPW-Rs.

Wide sensory filters underlie performance in memory-based discrimination and generalization.

The way animals respond to a stimulus depends largely on an internal comparison between the current sensation and the memory of previous stimuli and outcomes. We know little about the accuracy with which the physical properties of the stimuli influence this type of memory-based discriminative decisions. Research has focused largely on discriminations between stimuli presented in quick succession, where animals can make relative inferences (same or different; higher or lower) from trial to trial. In the current study we used a memory-based task to explore how the stimulus' physical properties, in this case tone frequency, affect auditory discrimination and generalization in mice. Mice performed ad libitum while living in groups in their home quarters. We found that the frequency distance between safe and conditioned sounds had a constraining effect on discrimination. As the safe-to-conditioned distance decreased across groups, performance deteriorated rapidly, even for frequency differences significantly larger than reported discrimination thresholds. Generalization width was influenced both by the physical distance and the previous experience of the mice, and was not accompanied by a decrease in sensory acuity. In conclusion, memory-based discriminations along a single stimulus dimension are inherently hard, reflecting a high overlap between the memory traces of the relevant stimuli. Memory-based discriminations rely therefore on wide sensory filters.

IgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses.

Abnormalities in synaptic inhibition play a critical role in psychiatric disorders, and accordingly, it is essential to understand the molecular mechanisms linking components of the inhibitory postsynapse to psychiatrically relevant neural circuits and behaviors. Here we study the role of IgSF9b, an adhesion protein that has been associated with affective disorders, in the amygdala anxiety circuitry. We show that deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in mice lacking the synapse organizer Neuroligin-2 (Nlgn2), which was proposed to complex with IgSF9b. This normalization occurs through differential effects of Nlgn2 and IgSF9b at inhibitory synapses in the basal and centromedial amygdala (CeM), respectively. Moreover, deletion of IgSF9b in the CeM of adult Nlgn2 knockout mice has a prominent anxiolytic effect. Our data place IgSF9b as a key regulator of inhibition in the amygdala and indicate that IgSF9b-expressing synapses in the CeM may represent a target for anxiolytic therapies.

Forgetting, reminding, and remembering: the retrieval of lost spatial memory.

Retrograde amnesia can occur after brain damage because this disrupts sites of storage, interrupts memory consolidation, or interferes with memory retrieval. While the retrieval failure account has been considered in several animal studies, recent work has focused mainly on memory consolidation, and the neural mechanisms responsible for reactivating memory from stored traces remain poorly understood. We now describe a new retrieval phenomenon in which rats' memory for a spatial location in a watermaze was first weakened by partial lesions of the hippocampus to a level at which it could not be detected. The animals were then reminded by the provision of incomplete and potentially misleading information-an escape platform in a novel location. Paradoxically, both incorrect and correct place information reactivated dormant memory traces equally, such that the previously trained spatial memory was now expressed. It was also established that the reminding procedure could not itself generate new learning in either the original environment, or in a new training situation. The key finding is the development of a protocol that definitively distinguishes reminding from new place learning and thereby reveals that a failure of memory during watermaze testing can arise, at least in part, from a disruption of memory retrieval.

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy.

Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels.