The effect of 4-weeks exposure to music on social bonding between rats.

Interpersonal synchronization of movement induced by music is believed to facilitate social bonding between human beings, but it is unknown whether it also works in animals. We allowed rats to interact and develop social bonding with a specific subject for four weeks under one of the three acoustic conditions: playback of K.448 at its original tempo, playback at its double-tempo, and silence. The strength of social bonding between each pair of rats was then measured. The results showed an increase in preference for rats that had interacted under the original tempo playback compared to the other acoustic conditions. Considering that rats move in synchrony with the beat more robustly and consistently between subjects under the original tempo playback than under the double-tempo playback, this result suggests that motor synchronization between subjects through music may facilitate social bonding between rats.

Frequency-specific modulation of oscillatory activity in the rat auditory cortex by vagus nerve stimulation.

BACKGROUND: We previously found that vagus nerve stimulation (VNS) strengthened stimulus-evoked activity in the superficial layer of the sensory cortex but not in the deep layer, suggesting that VNS altered the balance between the feedforward (FF) and feedback (FB) pathways. Band-specific oscillatory activities in the cortex could serve as an index of the FF-FB balance, but whether VNS affects cortical oscillations along sensory pathways through neuromodulators remains unclear. HYPOTHESIS: VNS modulates the FF-FB balance through the cholinergic and noradrenergic systems, which modulate stimulus gain in the cortex. METHODS: We investigated the effects of VNS using electrocorticography in the auditory cortex of 34 Wistar rats under general anesthesia while presenting click stimuli. In the time-frequency analyses, the putative modulation of the FF and FB pathways was estimated using high- and low-frequency power. We assessed, using analysis of variance, how VNS modulates auditory-evoked activities and how the modulation changes with cholinergic and noradrenergic antagonists. RESULTS: VNS increased auditory cortical evoked potentials, consistent with results of our previous work. Furthermore, VNS increased auditory-evoked gamma and beta powers and decreased theta power. Local administration of cholinergic antagonists in the auditory cortex selectively disrupted the VNS-induced increase in gamma and beta power, while noradrenergic antagonists disrupted the decrease in theta power. CONCLUSIONS: VNS might strengthen the FF pathway through the cholinergic system and attenuate the FB pathway through the noradrenergic system in the auditory cortex. Cortical gain modulation through the VNS-induced neuromodulatory system provides new mechanistic insights into the effect of VNS on auditory processing.

Spontaneous beat synchronization in rats: Neural dynamics and motor entrainment.

Beat perception and synchronization within 120 to 140 beats/min (BPM) are common in humans and frequently used in music composition. Why beat synchronization is uncommon in some species and the mechanism determining the optimal tempo are unclear. Here, we examined physical movements and neural activities in rats to determine their beat sensitivity. Close inspection of head movements and neural recordings revealed that rats displayed prominent beat synchronization and activities in the auditory cortex within 120 to 140 BPM. Mathematical modeling suggests that short-term adaptation underlies this beat tuning. Our results support the hypothesis that the optimal tempo for beat synchronization is determined by the time constant of neural dynamics conserved across species, rather than the species-specific time constant of physical movements. Thus, latent neural propensity for auditory motor entrainment may provide a basis for human entrainment that is much more widespread than currently thought. Further studies comparing humans and animals will offer insights into the origins of music and dancing.

Oddball-irrelevant visual stimuli cross-modally attenuate auditory mismatch negativity in rats.

OBJECTIVE: To elaborate the recent theory of prediction models of the brain in light of actual neural activities, it is important to investigate the cross-modal interactions in the context of prediction construction. To this end, in this study, we assessed whether cross-modal disturbances would result in the attenuation of mismatch negativity in anesthetized animal models. METHODS: A surface electrode array recorded neural activities from the visual and auditory cortices of rats under isoflurane anesthesia, during an auditory oddball paradigm over the course of three audiovisual sequences. In the audiovisual sequences, the visual stimuli were simultaneously presented with the first, second, or third standard before the deviants. RESULTS: The interrupting visual stimuli decrease the amplitude of mismatch negativity in the auditory and visual cortices. In addition, the correlation coefficients between the amplitude of middle-latency potential for the interrupting visual stimuli and the amplitude of mismatch negativity to the following auditory deviant stimuli were smaller when the visual stimuli were presented alongside the third standards from the deviants. CONCLUSION: Such attenuation in mismatch negativity has been often associated with a top-down mechanism and the present anesthesia selectively attenuates top-down transmission. Taken together, our study's findings indicate that the cross-modal disturbances on prediction and deviation detection may also be mediated by bottom-up mechanisms, as well as previously reported top-down mechanisms.

Auditory, Visual, and Cross-Modal Mismatch Negativities in the Rat Auditory and Visual Cortices.

When the brain tries to acquire an elaborate model of the world, multisensory integration should contribute to building predictions based on the various pieces of information, and deviance detection should repeatedly update these predictions by detecting "errors" from the actual sensory inputs. Accumulating evidence such as a hierarchical organization of the deviance-detection system indicates that the deviance-detection system can be interpreted in the predictive coding framework. Herein, we targeted mismatch negativity (MMN) as a type of prediction-error signal and investigated the relationship between multisensory integration and MMN. In particular, we studied whether and how cross-modal information processing affected MMN in rodents. We designed a new surface microelectrode array and simultaneously recorded visual and auditory evoked potentials from the visual and auditory cortices of rats under anesthesia. Then, we mapped MMNs for five types of deviant stimuli: single-modal deviants in (i) the visual oddball and (ii) auditory oddball paradigms, eliciting single-modal MMN; (iii) congruent audio-visual deviants, (iv) incongruent visual deviants, and (v) incongruent auditory deviants in the audio-visual oddball paradigm, eliciting cross-modal MMN. First, we demonstrated that visual MMN exhibited deviance detection properties and that the first-generation focus of visual MMN was localized in the visual cortex, as previously reported in human studies. Second, a comparison of MMN amplitudes revealed a non-linear relationship between single-modal and cross-modal MMNs. Moreover, congruent audio-visual MMN exhibited characteristics of both visual and auditory MMNs-its latency was similar to that of auditory MMN, whereas local blockage of N-methyl-D-aspartic acid receptors in the visual cortex diminished it as well as visual MMN. These results indicate that cross-modal information processing affects MMN without involving strong top-down effects, such as those of prior knowledge and attention. The present study is the first electrophysiological evidence of cross-modal MMN in animal models, and future studies on the neural mechanisms combining multisensory integration and deviance detection are expected to provide electrophysiological evidence to confirm the links between MMN and predictive coding theory.

Mismatch-negativity (MMN) in animal models: Homology of human MMN?

Mismatch negativity (MMN) has long been considered to be one of the deviance-detecting neural characteristics. Animal models exhibit similar neural activities, called MMN-like responses; however, there has been considerable debate on whether MMN-like responses are homologous to MMN in humans. Herein, we reviewed several studies that compared the electrophysiological, pharmacological, and functional properties of MMN-like responses and adaptation-exhibiting middle-latency responses (MLRs) in animals with those in humans. Accumulating evidence suggests that there are clear differences between MMN-like responses and MLRs, in particular that MMN-like responses can be distinguished from mere effects of adaptation, i.e., stimulus-specific adaptation. Finally, we discuss a new direction for research on MMN-like responses by introducing our recent work, which demonstrated that MMN-like responses represent empirical salience of deviant stimuli, suggesting a new functional role of MMN beyond simple deviance detection.

Layer-specific representation of long-lasting sustained activity in the rat auditory cortex.

In the auditory system, distinct and reproducible transient activities responding to the onset of sound have long been the focus when characterizing the auditory cortex, i.e., tonotopic maps, subregions, and layer-specific representation. There is limited information on sustained activities because the rapid adaptation impairs reproducibility and the signal-to-noise ratio. We recently overcame this problem by focusing on neural synchrony and machine learning demonstrated that band-specific power and the phase locking value (PLV) represent sound information in a tonotopic and region-specific manner. Here, we attempted to reveal the layer-specific representation of sustained activities. A microelectrode array recorded sustained activities from layers 2/3, 4, and 5/6 of the rat auditory cortex. We characterized band-specific power and PLV patterns and applied sparse logistic regression (SLR) to discriminate (1) between the sound-induced and spontaneous activities and (2) five test frequencies from the sound-induced activities in each layer. SLR achieved the highest discrimination performance in high-gamma activities in layers 4 and 5/6, higher than in layer 2/3, indicating poor sound representation in layer 2/3. Moreover, the recording sites that contributed to the discrimination in layers 4 and 5/6 had a characteristic frequency similar to the test frequency and were often located in the belt area, indicating tonotopic and region-specific representation. These results indicate that information processing of sustained activities may depend on high-gamma oscillators, i.e., cortical inhibitory interneurons, and reflects layer-specific thalamocortical and corticocortical neural circuits in the auditory system, which may contribute to associative information processing beyond sound frequency in auditory perception.

Tone frequency representation beyond the tonotopic map: Cross-correlation between ongoing activity in the rat auditory cortex.

Functional maps play crucial roles in the neural representations of the sensory cortices, although such representations occasionally extend beyond these maps. For example, the auditory cortex exhibits distinct tonotopic activation at the onset of tone, which is followed by rapid decays in the majority of neuronal signals and ongoing activities in only a small number of neurons. Such ongoing activity should be maintained by the cortical states. To better understand maintenance of ongoing activity beyond that triggered directly by stimuli, we used a rat model. Here, we hypothesized that neural correlations between local field potentials (LFPs) within a local area of the auditory cortex may serve as a measure of the cortical state underlying ongoing activity. We densely mapped the auditory cortex of rats and demonstrated that cross-correlation patterns of ongoing activity were highly decodable. Informative features were widely distributed over the auditory cortex and across multiple frequency bands. Furthermore, acoustic trauma disrupted tonotopic representation at the onset but did not affect neural representations by the correlation of ongoing activities. These results suggest that cross-correlations of LFP within the auditory cortex represent frequencies of sustained auditory stimuli, and that these representations are made beyond direct tonotopic activation at stimulus onset.

Preference test of sound among multiple alternatives in rats.

Conditioned place preference (CPP) tests in rodents have been well established to measure preference induced by secondary reinforcing properties, but conventional assays are not sensitive enough to measure innate, weak preference, or the primary reinforcing property of a conditioned stimulus. We designed a novel CPP assay with better sensitivity and efficiency in quantifying and ranking preference of particular sounds among multiple alternatives. Each test tone was presented according to the location of free-moving rats in the arena, where assignment of location to each tone changed in every 20-s session. We demonstrated that our assay was able to rank tone preference among 4 alternatives within 12.5 min (125 s (habituation) + 25 s/sessions × 25 sessions). In order to measure and rank sound preference, we attempted to use sojourn times with each test sound ([Formula: see text]), and a preference index (PI) based on transition matrices of initial and end sounds in every session. Both [Formula: see text] and PI revealed similar trends of innate preference in which rats preferred test conditions in the following order: silence, 40-, 20-, then 10-kHz tones. Further, rats exhibited a change in preference after an classical conditioning of the 20-kHz tone with a rewarding microstimulation of the dopaminergic system. We also demonstrated that PI was a more robust and sensitive indicator than [Formula: see text] when the locomotion activity level of rats became low due to habituation to the assay repeated over sessions. Thus, our assay offers a novel method of evaluating auditory preference that is superior to conventional CPP assays, offering promising prospects in the field of sensory neuroscience.

Mismatch Negativity in Rat Auditory Cortex Represents the Empirical Salience of Sounds.

Mismatch negativity (MMN) is an N-methyl-D-aspartic acid-mediated component and thus has been widely considered a major candidate biomarker of schizophrenia. However, at present, no direct evidence has linked the MMN response and aberrant salience processing reported in schizophrenia patients, i.e., whether MMN represents empirical salience of the deviant stimulus. To test the eligibility of the MMN response as a biomarker of schizophrenia, we hypothesized and verified that the MMN in the rat auditory cortex encodes empirical salience, which depends on both empirical rarity of sound and association of sound with salient events through classical conditioning. We exposed rats to sound or appetitive or aversive classical conditioning and extinction training of aversive conditioning, then recorded MMN from the auditory cortex. We focused on the frequency-dependent asymmetry of the MMN amplitude; increment frequency changes elicit asymmetrically larger MMN amplitudes than do decremental frequency changes. We found that sound exposure reversed this asymmetry in rats, indicating that MMN encodes the empirical rarity of deviant sounds. The MMN amplitude was larger in the appetitive or aversive classical conditioning groups, and smaller after extinction training following aversive conditioning. These results indicate that the MMN response reflects the empirical salience of sound. The present work first linked MMN with empirical salience processing and expands the possibilities of MMN as a strong clinical biomarker of schizophrenia.

Microelectrode mapping of tonotopic, laminar, and field-specific organization of thalamo-cortical pathway in rat.

The rat has long been considered an important model system for studying neural mechanisms of auditory perception and learning, and particularly mechanisms involving auditory thalamo-cortical processing. However, the functional topography of the auditory thalamus, or medial geniculate body (MGB) has not yet been fully characterized in the rat, and the anatomically-defined features of field-specific, layer-specific and tonotopic thalamo-cortical projections have never been confirmed electrophysiologically. In the present study, we have established a novel technique for recording simultaneously from a surface microelectrode array on the auditory cortex, and a depth electrode array across auditory cortical layers and within the MGB, and characterized the rat MGB and thalamo-cortical projections under isoflurane anesthesia. We revealed that the ventral division of the MGB (MGv) exhibited a low-high-low CF gradient and long-short-long latency gradient along the dorsolateral-to-ventromedial axis, suggesting that the rat MGv is divided into two subdivisions. We also demonstrated that microstimulation in the MGv elicited cortical activation in layer-specific, region-specific and tonotopically organized manners. To our knowledge, the present study has provided the first and most compelling electrophysiological confirmation of the anatomical organization of the primary thalamo-cortical pathway in the rat, setting the groundwork for further investigation.

Cortical mapping of mismatch negativity with deviance detection property in rat.

Mismatch Negativity (MMN) is an N-methyl-d-aspartic acid (NMDA)-mediated, negative deflection in human auditory evoked potentials in response to a cognitively discriminable change. MMN-like responses have been extensively investigated in animal models, but the existence of MMN equivalent is still controversial. In this study, we aimed to investigate how closely the putative MMN (MMNp) in rats exhibited the comparable properties of human MMN. We used a surface microelectrode array with a grid of 10 × 7 recording sites within an area of 4.5 × 3.0 mm to densely map evoked potentials in the auditory cortex of anesthetized rats under the oddball paradigm. Firstly, like human MMN, deviant stimuli elicited negative deflections in auditory evoked potentials following the positive middle-latency response, termed P1. Secondly, MMNp exhibited deviance-detecting property, which could not be explained by simple stimulus specific adaptation (SSA). Thirdly, this MMNp occurred focally in the auditory cortex, including both the core and belt regions, while P1 activation focus was obtained in the core region, indicating that both P1 and MMNp are generated in the auditory cortex, yet the sources of these signals do not completely overlap. Fourthly, MMNp significantly decreased after the application of AP5 (D-(-)-2-amino-5-phosphonopentanoic acid), an antagonist at NMDA receptors. In stark contrast, AP5 affected neither P1 amplitude nor SSA of P1. These results provide compelling evidence that the MMNp we have examined in rats is functionally comparable to human MMN. The present work will stimulate translational research into MMN, which may help bridge the gap between electroencephalography (EEG)/magnetoencephalography (MEG) studies in humans and electrophysiological studies in animals.