Expression of the Neuregulin Receptor ErbB4 in the Brain of the Rhesus Monkey (Macaca mulatta)

We demonstrated recently that frontal cortical expression of the Neuregulin (NRG) receptor ErbB4 is restricted to interneurons in rodents, macaques, and humans. However, little is known about protein expression patterns in other areas of the brain. In situ hybridization studies have shown high ErbB4 mRNA levels in various subcortical areas, suggesting that ErbB4 is also expressed in cell types other than cortical interneurons. Here, using highly-specific monoclonal antibodies, we provide the first extensive report of ErbB4 protein expression throughout the cerebrum of primates. We show that ErbB4 immunoreactivity is high in association cortices, intermediate in sensory cortices, and relatively low in motor cortices. The overall immunoreactivity in the hippocampal formation is intermediate, but is high in a subset of interneurons. We detected the highest overall immunoreactivity in distinct locations of the ventral hypothalamus, medial habenula, intercalated nuclei of the amygdala and structures of the ventral forebrain, such as the islands of Calleja, olfactory tubercle and ventral pallidum, and medium expression in the reticular thalamic nucleus. While this pattern is generally consistent with ErbB4 mRNA expression data, further investigations are needed to identify the exact cellular and subcellular sources of mRNA and protein expression in these areas. In contrast to in situ hybridization in rodents, we detected only low levels of ErbB4-immunoreactivity in mesencephalic dopaminergic nuclei but a diffuse pattern of immunofluorescence that was medium in the dorsal striatum and high in the ventral forebrain, suggesting that most ErbB4 protein in dopaminergic neurons could be transported to axons. We conclude that the NRG-ErbB4 signaling pathway can potentially influence many functional systems throughout the brain of primates, and suggest that major sites of action are areas of the “corticolimbic” network. This interpretation is functionally consistent with the genetic association of NRG1 and ERBB4 with schizophrenia

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

In vivo whole-cell recordings of stimulus-specific adaptation in the inferior colliculus

The inferior colliculus is an auditory structure where inputs from multiple lower centers converge, allowing the emergence of complex coding properties of auditory information such as stimulus-specific adaptation. Stimulus-specific adaptation is the adaptation of neuronal responses to a specific repeated stimulus, which does not entirely generalize to other new stimuli. This phenomenon provides a mechanism to emphasize saliency and potentially informative sensory inputs. Stimulus-specific adaptation has been traditionally studied analyzing the somatic spiking output. However, studies that correlate within the same inferior colliculus neurons their intrinsic properties, subthreshold responses and the level of acoustic stimulus-specific adaptation are still pending. For this, we recorded in vivo whole-cell patchclamp neurons in the mouse inferior colliculus while stimulating with current injections or the classic auditory oddball paradigm. Our data based on cases of ten neuron, suggest that although passive properties were similar, intrinsic properties differed between adapting and non-adapting neurons. Non-adapting neurons showed a sustained-regular firing pattern that corresponded to central nucleus neurons and adapting neurons at the inferior colliculus cortices showed variable firing patterns. Our current results suggest that synaptic stimulus-specific adaptation was variable and could not be used to predict the presence of spiking stimulus-specific adaptation. We also observed a small trend towards hyperpolarized membrane potentials in adapting neurons and increased synaptic inhibition with consecutive stimulus repetitions in all neurons. This finding indicates a more simple type of adaptation, potentially related to potassium conductances. Hence, these data represent a modest first step in the intracellular study of stimulusspecific adaptation in inferior colliculus neurons in vivo that will need to be expanded with pharmacological manipulations to disentangle specific ionic channels participatio

Prediction error signaling explains neuronal mismatch responses in the medial prefrontal cortex

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with “no-repetition” controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detectio

GABAA-Mediated Inhibition Modulates Stimulus-Specific Adaptation in the Inferior Colliculus

The ability to detect novel sounds in a complex acoustic context is crucial for survival. Neurons from midbrain through cortical levels adapt to repetitive stimuli, while maintaining responsiveness to rare stimuli, a phenomenon called stimulus-specific adaptation (SSA). The site of origin and mechanism of SSA are currently unknown. We used microiontophoretic application of gabazine to examine the role of GABAA-mediated inhibition in SSA in the inferior colliculus, the midbrain center for auditory processing. We found that gabazine slowed down the process of adaptation to high probability stimuli but did not abolish it, with response magnitude and latency still depending on the probability of the stimulus. Blocking GABAA receptors increased the firing rate to high and low probability stimuli, but did not completely equalize the responses. Together, these findings suggest that GABAA-mediated inhibition acts as a gain control mechanism that enhances SSA by modifying the responsiveness of the neuron

Neurons in the inferior colliculus of the rat show stimulus-specific adaptation for frequency, but not for intensity

Electrophysiological and psychophysical responses to a low-intensity probe sound tend to be suppressed by a preceding high-intensity adaptor sound. Nevertheless, rare low-intensity deviant sounds presented among frequent high-intensity standard sounds in an intensity oddball paradigm can elicit an electroencephalographic mismatch negativity (MMN) response. This has been taken to suggest that the MMN is a correlate of true change or “deviance” detection. A key question is where in the ascending auditory pathway true deviance sensitivity first emerges. Here, we addressed this question by measuring low-intensity deviant responses from single units in the inferior colliculus (IC) of anesthetized rats. If the IC exhibits true deviance sensitivity to intensity, IC neurons should show enhanced responses to low-intensity deviant sounds presented among high-intensity standards. Contrary to this prediction, deviant responses were only enhanced when the standards and deviants differed in frequency. The results could be explained with a model assuming that IC neurons integrate over multiple frequency-tuned channels and that adaptation occurs within each channel independently. We used an adaptation paradigm with multiple repeated adaptors to measure the tuning widths of these adaption channels in relation to the neurons’ overall tuning widths

Polarity-Dependent Transcranial Direct Current Stimulation Effects on Central Auditory Processing

Given the polarity dependent effects of transcranial direct current stimulation (tDCS) in facilitating or inhibiting neuronal processing, and tDCS effects on pitch perception, we tested the effects of tDCS on temporal aspects of auditory processing. We aimed to change baseline activity of the auditory cortex using tDCS as to modulate temporal aspects of auditory processing in healthy subjects without hearing impairment. Eleven subjects received 2mA bilateral anodal, cathodal and sham tDCS over auditory cortex in a randomized and counterbalanced order. Subjects were evaluated by the Random Gap Detection Test (RGDT), a test measuring temporal processing abilities in the auditory domain, before and during the stimulation. Statistical analysis revealed a significant interaction effect of time vs. tDCS condition for 4000 Hz and for clicks. Post-hoc tests showed significant differences according to stimulation polarity on RGDT performance: anodal improved 22.5% and cathodal decreased 54.5% subjects' performance, as compared to baseline. For clicks, anodal also increased performance in 29.4% when compared to baseline. tDCS presented polarity-dependent effects on the activity of the auditory cortex, which results in a positive or negative impact in a temporal resolution task performance. These results encourage further studies exploring tDCS in central auditory processing disorders

Structure of the Afferent Terminals in Terminal Ganglion of a Cricket and Persistent Homology

We use topological data analysis to investigate the three dimensional spatial structure of the locus of afferent neuron terminals in crickets Acheta domesticus. Each afferent neuron innervates a filiform hair positioned on a cercus: a protruding appendage at the rear of the animal. The hairs transduce air motion to the neuron signal that is used by a cricket to respond to the environment. We stratify the hairs (and the corresponding afferent terminals) into classes depending on hair length, along with position. Our analysis uncovers significant structure in the relative position of these terminal classes and suggests the functional relevance of this structure. Our method is very robust to the presence of significant experimental and developmental noise. It can be used to analyze a wide range of other point cloud data sets

Learning auditory space: generalization and long-term effects

Background: Previous findings have shown that humans can learn to localize with altered auditory space cues. Here we analyze such learning processes and their effects up to one month on both localization accuracy and sound externalization. Subjects were trained and retested, focusing on the effects of stimulus type in learning, stimulus type in localization, stimulus position, previous experience, externalization levels, and time. Method: We trained listeners in azimuth and elevation discrimination in two experiments. Half participated in the azimuth experiment first and half in the elevation first. In each experiment, half were trained in speech sounds and half in white noise. Retests were performed at several time intervals: just after training and one hour, one day, one week and one month later. In a control condition, we tested the effect of systematic retesting over time with post-tests only after training and either one day, one week, or one month later. Results: With training all participants lowered their localization errors. This benefit was still present one month after training. Participants were more accurate in the second training phase, revealing an effect of previous experience on a different task. Training with white noise led to better results than training with speech sounds. Moreover, the training benefit generalized to untrained stimulus-position pairs. Throughout the post-tests externalization levels increased. In the control condition the long-term localization improvement was not lower without additional contact with the trained sounds, but externalization levels were lower. Conclusion: Our findings suggest that humans adapt easily to altered auditory space cues and that such adaptation spreads to untrained positions and sound types. We propose that such learning depends on all available cues, but each cue type might be learned and retrieved differently. The process of localization learning is global, not limited to stimulus-position pairs, and it differs from externalization processes.Foundation for Science and TechnologyFEDE

Size constancy in bat biosonar?

Perception and encoding of object size is an important feature of sensory systems. In the visual system object size is encoded by the visual angle (visual aperture) on the retina, but the aperture depends on the distance of the object. As object distance is not unambiguously encoded in the visual system, higher computational mechanisms are needed. This phenomenon is termed "size constancy". It is assumed to reflect an automatic re-scaling of visual aperture with perceived object distance. Recently, it was found that in echolocating bats, the 'sonar aperture', i.e., the range of angles from which sound is reflected from an object back to the bat, is unambiguously perceived and neurally encoded. Moreover, it is well known that object distance is accurately perceived and explicitly encoded in bat sonar. Here, we addressed size constancy in bat biosonar, recruiting virtual-object techniques. Bats of the species Phyllostomus discolor learned to discriminate two simple virtual objects that only differed in sonar aperture. Upon successful discrimination, test trials were randomly interspersed using virtual objects that differed in both aperture and distance. It was tested whether the bats spontaneously assigned absolute width information to these objects by combining distance and aperture. The results showed that while the isolated perceptual cues encoding object width, aperture, and distance were all perceptually well resolved by the bats, the animals did not assign absolute width information to the test objects. This lack of sonar size constancy may result from the bats relying on different modalities to extract size information at different distances. Alternatively, it is conceivable that familiarity with a behaviorally relevant, conspicuous object is required for sonar size constancy, as it has been argued for visual size constancy. Based on the current data, it appears that size constancy is not necessarily an essential feature of sonar perception in bats