David Pérez-González

Novelty detector neurons in the mammalian auditory midbrain.

Novel stimuli in all sensory modalities are highly effective in attracting and focusing attention. Stimulus‐specific adaptation (SSA) and brain activity evoked by novel stimuli have been studied using population measures such as imaging and event‐related potentials, but there have been few studies at the single‐neuron level. In this study we compare SSA across different populations of neurons in the inferior colliculus (IC) of the rat and show that a subclass of neurons with rapid and pronounced SSA respond selectively to novel sounds. These neurons, located in the dorsal and external cortex of the IC, fail to respond to multiple repetitions of a sound but briefly recover their excitability when some stimulus parameter is changed. The finding of neurons that respond selectively to novel stimuli in the mammalian auditory midbrain suggests that they may contribute to a rapid subcortical pathway for directing attention and/or orienting responses to novel sounds.

A Discontinuous Tonotopic Organization in the Inferior Colliculus of the Rat

Audible frequencies of sound are encoded in a continuous manner along the length of the cochlea, and frequency is transmitted to the brain as a representation of place on the basilar membrane. The resulting tonotopic map has been assumed to be a continuous smooth progression from low to high frequency throughout the central auditory system. Here, physiological and anatomical data show that best frequency is represented in a discontinuous manner in the inferior colliculus, the major auditory structure of the midbrain. Multiunit maps demonstrate a distinct stepwise organization in the order of best frequency progression. Furthermore, independent data from single neurons show that best frequencies at octave intervals of approximately one-third are more prevalent than others. These data suggest that, in the inferior colliculus, there is a defined space of tissue devoted to a given frequency, and input within this frequency band may be pooled for higher-level processing.

The inferior colliculus of the rat : A quantitative analysis of monaural frequency response areas

Frequency response areas (FRAs) were measured for 237 single units in the inferior colliculus (IC) of urethane-anesthetized pigmented rats using monaural pure-tone stimulation. Based on qualitative criteria [J Neurosci 21 (2001) 7303], FRAs were classified as V-shaped in 69% of neurons, non-V-shaped in 29%, and unclassifiable in the remaining 2%. Non-V-shaped FRAs were heterogeneous, comprising a number of subtypes including narrow, closed, low- and high-tilt, multipeaked, U-shaped, mosaic and inhibitory. To complement this subjective classification, we applied quantitative measures used by others (e.g. [J Neurophysiol 84 (2000) 1012]), including the inverse slope of the upper and lower FRA borders, Q-values, and other measures of bandwidth. The results suggest that FRAs in the rat IC are best described as forming a continuous distribution among subtypes, rather than clustering into discrete categories. Moreover, there is a broad range of frequency tuning characteristics and FRA types across the entire frequency spectrum. Within this general pattern, however, there are some frequency-specific differences in FRA type distribution. The relative proportion of V-shaped FRAs was greatest at the high and low ends of the auditory range, with the highest proportion of non-V-shaped FRAs in the mid-range from 6 to 12 kHz. For most neurons with multipeaked FRAs, the peak frequencies were not harmonically related. Frequency tuning in the pigmented rat IC is generally similar to that in other species. Comparison of Q values across auditory nuclei shows little evidence that FRAs are sharpened at levels above the auditory nerve. Rather, there is a broad range of frequency tuning properties at each level.

Topographic Distribution, Frequency, and Intensity Dependence of Stimulus-Specific Adaptation in the Inferior Colliculus of the Rat

The ability to detect unexpected sounds within the environment is an important function of the auditory system, as a rapid response may be required for the organism to survive. Previous studies found a decreased response to repetitive stimuli (standard), but an increased response to rare or less frequent sounds (deviant) in individual neurons in the inferior colliculus (IC) and at higher levels. This phenomenon, known as stimulus-specific adaptation (SSA) has been suggested to underpin change detection. Currently, it is not known how SSA varies within a single neuron receptive field, i.e., it is unclear whether SSA is a unique property of the neuron or a feature that is frequency and/or intensity dependent. In the present experiments, we used the common SSA index (CSI) to quantify and compare the degree of SSA under different stimulation conditions in the IC of the rat. We calculated the CSI at different intensities and frequencies for each individual IC neuron to map the neuronal CSI within the receptive field. Our data show that high SSA is biased toward the high-frequency and low-intensity regions of the receptive field. We also find that SSA is better represented in the earliest portions of the response, and there is a positive correlation between the width of the frequency response area of the neuron and the maximum level of SSA. The present data suggest that SSA in the IC is not mediated by the intrinsic membrane properties of the neurons and instead might be related to an excitatory and/or inhibitory input segregation.

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.

Adaptation in the auditory system: an overview

The early stages of the auditory system need to preserve the timing information of sounds in order to extract the basic features of acoustic stimuli. At the same time, different processes of neuronal adaptation occur at several levels to further process the auditory information. For instance, auditory nerve fiber responses already experience adaptation of their firing rates, a type of response that can be found in many other auditory nuclei and may be useful for emphasizing the onset of the stimuli. However, it is at higher levels in the auditory hierarchy where more sophisticated types of neuronal processing take place. For example, stimulus-specific adaptation, where neurons show adaptation to frequent, repetitive stimuli, but maintain their responsiveness to stimuli with different physical characteristics, thus representing a distinct kind of processing that may play a role in change and deviance detection. In the auditory cortex, adaptation takes more elaborate forms, and contributes to the processing of complex sequences, auditory scene analysis and attention. Here we review the multiple types of adaptation that occur in the auditory system, which are part of the pool of resources that the neurons employ to process the auditory scene, and are critical to a proper understanding of the neuronal mechanisms that govern auditory perception.

Frequency discrimination and stimulus deviance in the inferior colliculus and cochlear nucleus

Auditory neurons that exhibit stimulus-specific adaptation (SSA) decrease their response to common tones while retaining responsiveness to rare ones. We recorded single-unit responses from the inferior colliculus (IC) where SSA is known to occur and we explored for the first time SSA in the cochlear nucleus (CN) of rats. We assessed an important functional outcome of SSA, the extent to which frequency discriminability depends on sensory context. For this purpose, pure tones were presented in an oddball sequence as standard (high probability of occurrence) or deviant (low probability of occurrence) stimuli. To study frequency discriminability under different probability contexts, we varied the probability of occurrence and the frequency separation between tones. The neuronal sensitivity was estimated in terms of spike-count probability using signal detection theory. We reproduced the finding that many neurons in the IC exhibited SSA, but we did not observe significant SSA in our CN sample. We concluded that strong SSA is not a ubiquitous phenomenon in the CN. As predicted, frequency discriminability was enhanced in IC when stimuli were presented in an oddball context, and this enhancement was correlated with the degree of SSA shown by the neurons. In contrast, frequency discrimination by CN neurons was independent of stimulus context. Our results demonstrated that SSA is not widespread along the entire auditory pathway, and suggest that SSA increases frequency discriminability of single neurons beyond that expected from their tuning curves.

Variability of the time course of stimulus-specific adaptation in the inferior colliculus

Stimulus-specific adaptation (SSA) is the ability of some neurons to respond better to rare than to frequent, repetitive stimuli. In the auditory system, SSA has been found at the level of the midbrain, thalamus, and cortex. While previous studies have used the whole overall neuronal response to characterize SSA, here we present a detailed analysis on the variations within the time course of the evoked responses. The extracellular activity of well isolated single neurons from the inferior colliculus (IC) was recorded during stimulation using an oddball paradigm, which is able to elicit SSA. At the same time, these responses were evaluated before, during, and after the microiontophoretic application of gabazine, a specific antagonist of GABAA receptors, to study the contribution of inhibition to the responses of these neurons. We then analyzed the difference signal (DS), which is the difference in the PSTH in response to rare and frequent stimuli. We found that, even in a sample of neurons showing strong SSA (i.e., showing larger preference for rare stimuli), the DS was variable and one third of the neurons contained portions that responded significantly better to the frequent stimuli than to the rare. This variability is not observed when averaging the responses of multiple cells. Furthermore, the blockade of GABAA receptors increased the number of neurons showing portions that responded better to the frequent stimuli, indicating that inhibition in the IC refines and sharpens SSA in the neural responses.

Stimulus-specific adaptation in the inferior colliculus: The role of excitatory, inhibitory and modulatory inputs

Patients suffering from pathologies such as schizophrenia, depression or dementia exhibit cognitive impairments, some of which can be reflected in event-related potential (ERP) measurements as the mismatch negativity (MMN). The MMN is one of the most commonly used ERPs and provides an electrophysiological index of auditory change or deviance detection. Moreover, MMN has been positioned as a potentially promising biomarker candidate for the diagnosis and prediction of the outcome of schizophrenia. Dysfunction of neural receptors has been linked to the etiopathology of schizophrenia or the induction of psychophysiological anomalies similar to those observed in schizophrenia. Stimulus-specific adaptation (SSA) is a neural mechanism that contributes to the upstream processing of auditory change detection. Auditory neurons that exhibit SSA specifically adapt their response to repetitive sounds but maintain their excitability to respond to rare ones. Thus, by studying the role of neuronal receptors on SSA, we can contribute to detangle the cellular bases of the impairments in deviance processing occurring in mental pathologies. Here, we review the current knowledge on the effect of GABAA-mediated inhibition and the modulation of acetylcholine on SSA in the inferior colliculus, and we add unpublished original data obtained blocking glutamate receptors. We found that the blockade of GABAA and glutamate receptors mediates an overall increase or decrease of the neural response, respectively, while acetylcholine affects only the response to the repetitive sounds. These results demonstrate that GABAergic, glutamatergic and cholinergic receptors play different and complementary roles on shaping SSA.

Extracellular Recording of Neuronal Activity Combined with Microiontophoretic Application of Neuroactive Substances in Awake Mice

Differences in the activity of neurotransmitters and neuromodulators, and consequently different neural responses, can be found between anesthetized and awake animals. Therefore, methods allowing the manipulation of synaptic systems in awake animals are required in order to determine the contribution of synaptic inputs to neuronal processing unaffected by anesthetics. Here, we present methodology for the construction of electrodes to simultaneously record extracellular neural activity and release multiple neuroactive substances at the vicinity of the recording sites in awake mice. By combining these procedures, we performed microiontophoretic injections of gabazine to selectively block GABAA receptors in neurons of the inferior colliculus of head-restrained mice. Gabazine successfully modified neural response properties such as the frequency response area and stimulus-specific adaptation. Thus, we demonstrate that our methods are suitable for recording single-unit activity and for dissecting the role of specific neurotransmitter receptors in auditory processing. The main limitation of the described procedure is the relatively short recording time (~3 hr), which is determined by the level of habituation of the animal to the recording sessions. On the other hand, multiple recording sessions can be performed in the same animal. The advantage of this technique over other experimental procedures used to manipulate the level of neurotransmission or neuromodulation (such as systemic injections or the use of optogenetic models), is that the drug effect is confined to the local synaptic inputs to the target neuron. In addition, the custom-manufacture of electrodes allows adjustment of specific parameters according to the neural structure and type of neuron of interest (such as the tip resistance for improving the signal-to-noise ratio of the recordings).