Electrophysiology publications

Loss of sensory input from peripheral organ damage, sensory deprivation, or brain damage can result in adaptive or maladaptive changes in sensory cortex. In previous research, we found that auditory cortical tuning and tonotopy were impaired by cross‐modal invasion of visual inputs. Sensory deprivation is typically associated with a loss of inhibition. To determine whether inhibitory plasticity is responsible for this process, we measured pre‐ and postsynaptic changes in inhibitory connectivity in ferret auditory cortex (AC) after cross‐modal plasticity. We found that blocking GABA A receptors increased responsiveness and broadened sound frequency tuning in the cross‐modal group more than in the normal group. Furthermore, expression levels of glutamic acid decarboxylase (GAD) protein were increased in the cross‐modal group. We also found that blocking inhibition unmasked visual responses of some auditory neurons in cross‐modal AC. Overall, our data suggest a role for increased inhibition in reducing the effectiveness of the abnormal visual inputs and argue that decreased inhibition is not responsible for compromised auditory cortical function after cross‐modal invasion. Our findings imply that inhibitory plasticity may play a role in reorganizing sensory cortex after cross‐modal invasion, suggesting clinical strategies for recovery after brain injury or sensory deprivation.

Hierarchical processing of sensory information requires interaction at multiple levels along the peripheral to central pathway. Recent evidence suggests that interaction between driving and modulating components can shape both top down and bottom up processing of sensory information. Here we show that a component inherited from extrinsic sources combines with local components to code sound intensity. By applying high concentrations of divalent cations to neurons in the nucleus of the inferior colliculus in the auditory midbrain, we show that as sound intensity increases, the source of synaptic efficacy changes from inherited inputs to local circuits. In neurons with a wide dynamic range response to intensity, inherited inputs increase firing rates at low sound intensities but saturate at mid-to-high intensities. Local circuits activate at high sound intensities and widen dynamic range by continuously increasing their output gain with intensity. Inherited inputs are necessary and sufficient to evoke tuned responses, however local circuits change peak output. Push-pull driving inhibition and excitation create net excitatory drive to intensity-variant neurons and tune neurons to intensity. Our results reveal that dynamic range and tuning re-emerge in the auditory midbrain through local circuits that are themselves variable or tuned.

Conspecific communication calls can be rhythmic or contain extended, discontinuous series of either constant or frequency modulated harmonic tones and noise bursts separated by brief periods of silence. In the guinea pig, rhythmic calls can produce isomorphic responses within the primary auditory cortex (AI) where single units respond to every call element. Other calls such as the chutter comprise a series of short irregular syllables that vary in their spectral content and are more like human speech. These calls can also evoke isomorphic responses, but may only do so in fields in the auditory belt and not in AI. Here we present evidence that cells in AI treat the individual elements within a syllable as separate auditory objects and respond selectively to one or a subset of them. We used a single chutter exemplar to compare single/multi-unit responses in the low-frequency portion of AI-AI(LF) and the low-frequency part of the thalamic medial geniculate body-MGB(LF) in urethane anaesthetized guinea pigs. Both thalamic and cortical cells responded with brief increases in firing rate to one, or more, of the 8 main elements present in the chutter call. Almost none of the units responded to all 8 elements. While there were many different combinations of responses to between one and five of the elements, MBG(LF) and AI(LF) neurons exhibited the same specific types of response combinations. Nearby units in the upper layers of the cortex tended to respond to similar combinations of elements while the deep layers were less responsive. Thus, the responses from a number of AI units would need to be combined in order to represent the entire chutter call. Our results don't rule out the possibility of constructive convergence but there was no evidence that a convergence of inputs within AI led to a complete representation of all eight elements.

Hierarchical processing of sensory information occurs at multiple levels between the peripheral and central pathway. Different extents of convergence and divergence in top down and bottom up projections makes it difficult to separate the various components activated by a sensory input. In particular, hierarchical processing at sub-cortical levels is little understood. Here we have developed a method to isolate extrinsic inputs to the inferior colliculus (IC), a nucleus in the midbrain region of the auditory system, with extensive ascending and descending convergence. By applying a high concentration of divalent cations (HiDi) locally within the IC, we isolate a HiDi-sensitive from a HiDi-insensitive component of responses evoked by afferent input in brain slices and in vivo during a sound stimulus. Our results suggest that the HiDi-sensitive component is a monosynaptic input to the IC, while the HiDi-insensitive component is a local polysynaptic circuit. Monosynaptic inputs have short latencies, rapid rise times, and underlie first spike latencies. Local inputs have variable delays and evoke long-lasting excitation. In vivo, local circuits have variable onset times and temporal profiles. Our results suggest that high concentrations of divalent cations should prove to be a widely useful method of isolating extrinsic monosynaptic inputs from local circuits in vivo.

The auditory midbrain implant (AMI) consists of a single shank array (20 sites) for stimulation along the tonotopic axis of the central nucleus of the inferior colliculus (ICC) and has been safely implanted in deaf patients who cannot benefit from a cochlear implant (CI). The AMI improves lip-reading abilities and environmental awareness in the implanted patients. However, the AMI cannot achieve the high levels of speech perception possible with the CI. It appears the AMI can transmit sufficient spectral cues but with limited temporal cues required for speech understanding. Currently, the AMI uses a CI-based strategy, which was originally designed to stimulate each frequency region along the cochlea with amplitude-modulated pulse trains matching the envelope of the bandpass-filtered sound components. However, it is unclear if this type of stimulation with only a single site within each frequency lamina of the ICC can elicit sufficient temporal cues for speech perception. At least speech understanding in quiet is still possible with envelope cues as low as 50 Hz. Therefore, we investigated how ICC neurons follow the bandpass-filtered envelope structure of natural stimuli in ketamine-anesthetized guinea pigs. We identified a subset of ICC neurons that could closely follow the envelope structure (up to ~100 Hz) of a diverse set of species-specific calls, which was revealed by using a peripheral ear model to estimate the true bandpass-filtered envelopes observed by the brain. Although previous studies have suggested a complex neural transformation from the auditory nerve to the ICC, our data suggest that the brain maintains a robust temporal code in a subset of ICC neurons matching the envelope structure of natural stimuli. Clinically, these findings suggest that a CI-based strategy may still be effective for the AMI if the appropriate neurons are entrained to the envelope of the acoustic stimulus and can transmit sufficient temporal cues to higher centers.

Age-related impairments in the primary auditory cortex (A1) include poor tuning selectivity, neural desynchronization, and degraded responses to low-probability sounds. These changes have been largely attributed to reduced inhibition in the aged brain, and are thought to contribute to substantial hearing impairment in both humans and animals. Since many of these changes can be partially reversed with auditory training, it has been speculated that they might not be purely degenerative, but might rather represent negative plastic adjustments to noisy or distorted auditory signals reaching the brain. To test this hypothesis, we examined the impact of exposing young adult rats to 8 weeks of low-grade broadband noise on several aspects of A1 function and structure. We then characterized the same A1 elements in aging rats for comparison. We found that the impact of noise exposure on A1 tuning selectivity, temporal processing of auditory signal and responses to oddball tones was almost indistinguishable from the effect of natural aging. Moreover, noise exposure resulted in a reduction in the population of parvalbumin inhibitory interneurons and cortical myelin as previously documented in the aged group. Most of these changes reversed after returning the rats to a quiet environment. These results support the hypothesis that age-related changes in A1 have a strong activity-dependent component and indicate that the presence or absence of clear auditory input patterns might be a key factor in sustaining adult A1 function.

It is not known how visual cortical neurons react to several moving objects and how their firing to the motion of one object is affected by neurons firing to another moving object. Here we combine imaging of voltage sensitive dye (VSD) signals, reflecting the population membrane potential from ferret visual areas 17, 18, 19, and 21, with laminar recordings of multiunit activity, (MUA), when two bars moved toward each other in the visual field, occluded one another, and continued on in opposite directions. Two zones of peak MUA, mapping the bars' motion, moved toward each other along the area 17/18 border, which in the ferret maps the vertical meridian of the field of view. This was reflected also in the VSD signal, at both the 17/18 border as well as at the 19/21 border with a short delay. After some 125 ms at the area 19/21 border, the VSD signal increased and became elongated in the direction of motion in front of both of the moving representations. This was directly followed by the phase of the signal reversing and travelling back from the 19/21 border toward the 17/18 border, seemingly without respect for retinotopic boundaries, where it arrived at 150 ms after stimulus onset. At this point the VSD signal in front of the moving bar representations along the 17/18 border also increased and became elongated in the direction of object motion; the signal now being the linear sum of what has been observed in response to single moving bars. When the neuronal populations representing the bars were some 600 μm apart on the cortex, the dye signal and laminar MUA decreased strongly, with the MUA scaling to that of a single bar during occlusion. Despite a short rebound of the dye signal and MUA, the MUA after the occlusion was significantly depressed. The interactions between the neuronal populations mapping the bars' position, and the neurons in between these populations were, apart from 19/21 to 17/18 interaction, mainly lateral-horizontal; first excitatory and inducing firing at the site of future occlusion, then inhibitory just prior to occlusion. After occlusion the neurons that had fired already to the first bar showed delayed and prolonged inhibition in response to the second bar. Thus, the interactions that were particular to the occlusion condition in these experiments were local and inhibitory at short cortical range, and delayed and inhibitory after the occlusion when the bars moved further apart.

The role of early auditory processing may be to extract some elementary features from an acoustic mixture in order to organize the auditory scene. To accomplish this task, the central auditory system may rely on the fact that sensory objects are often composed of spectral edges, i.e., regions where the stimulus energy changes abruptly over frequency. The processing of acoustic stimuli may benefit from a mechanism enhancing the internal representation of spectral edges. While the visual system is thought to rely heavily on this mechanism (enhancing spatial edges), it is still unclear whether a related process plays a significant role in audition. We investigated the cortical representation of spectral edges, using acoustic stimuli composed of multi-tone pips whose time-averaged spectral envelope contained suppressed or enhanced regions. Importantly, the stimuli were designed such that neural responses properties could be assessed as a function of stimulus frequency during stimulus presentation. Our results suggest that the representation of acoustic spectral edges is enhanced in the auditory cortex, and that this enhancement is sensitive to the characteristics of the spectral contrast profile, such as depth, sharpness and width. Spectral edges are maximally enhanced for sharp contrast and large depth. Cortical activity was also suppressed at frequencies within the suppressed region. To note, the suppression of firing was larger at frequencies nearby the lower edge of the suppressed region than at the upper edge. Overall, the present study gives critical insights into the processing of spectral contrasts in the auditory system.

Flowering plants employ a wide variety of signals, including scent, to attract the attention of pollinators. In this study we investigate the role of floral scent in mediating differential attraction between two species of monkeyflowers (Mimulus) reproductively isolated by pollinator preference. The emission rate and chemical identity of floral volatiles differ between the bumblebee-pollinated Mimulus lewisii and the hummingbird-pollinated M. cardinalis. M. lewisii flowers produce an array of volatiles dominated by D-limonene, β-myrcene, and E-β-ocimene. Of these three monoterpenes, M. cardinalis flowers produce only D-limonene, released at just 0.9% the rate of M. lewisii flowers. Using the Bombus vosnesenskii bumblebee, an important pollinator of M. lewisii, we conducted simultaneous gas chromatography with extracellular recordings in the bumblebee antennal lobe. Results from these experiments revealed that these three monoterpenes evoke significant neural responses, and that a synthetic mixture of the three volatiles evokes the same responses as the natural scent. Furthermore, the neural population shows enhanced responses to the M. lewisii scent over the scent of M. cardinalis. This neural response is reflected in behavior; in two-choice assays, bumblebees investigate artificial flowers scented with M. lewisii more frequently than ones scented with M. cardinalis, and in synthetic mixtures the three monoterpenes are necessary and sufficient to recapitulate responses to the natural scent of M. lewisii. In this system, floral scent alone is sufficient to elicit differential visitation by bumblebees, implying a strong role of scent in the maintenance of reproductive isolation between M. lewisii and M. cardinalis.

Daily our central nervous system receives inputs via several sensory modalities, processes them and integrates information in order to produce a suitable behavior. The amazing part is that such a multisensory integration brings all information into a unified percept. An approach to start investigating this property is to show that perception is better and faster when multimodal stimuli are used as compared to unimodal stimuli. This forms the first part of the present study conducted in a non-human primate's model (n = 2) engaged in a detection sensory-motor task where visual and auditory stimuli were displayed individually or simultaneously. The measured parameters were the reaction time (RT) between stimulus and onset of arm movement, successes and errors percentages, as well as the evolution as a function of time of these parameters with training. As expected, RTs were shorter when the subjects were exposed to combined stimuli. The gains for both subjects were around 20 and 40 ms, as compared with the auditory and visual stimulus alone, respectively. Moreover the number of correct responses increased in response to bimodal stimuli. We interpreted such multisensory advantage through redundant signal effect which decreases perceptual ambiguity, increases speed of stimulus detection, and improves performance accuracy. The second part of the study presents single-unit recordings derived from the premotor cortex (PM) of the same subjects during the sensory-motor task. Response patterns to sensory/multisensory stimulation are documented and specific type proportions are reported. Characterization of bimodal neurons indicates a mechanism of audio-visual integration possibly through a decrease of inhibition. Nevertheless the neural processing leading to faster motor response from PM as a polysensory association cortical area remains still unclear.

Research on the visual system of non-primates, such as birds and rodents, is increasing. Evidence that neural responses can differ dramatically between head-immobilized and freely behaving animals underlines the importance of studying visual processing in ethologically relevant contexts. In order to systematically study visual responses in freely behaving animals, an unobtrusive system for monitoring eye-in-orbit position in real time is essential. We describe a novel system for monitoring eye position that utilizes a head-mounted magnetic displacement sensor coupled with an eye-implanted magnet. This system is small, lightweight, and offers high temporal and spatial resolution in real time. We use the system to demonstrate the stability of the eye and the stereotypy of eye position during two different behavioral tasks in chickens. This approach offers a viable alternative to search coil and optical eye tracking techniques for high resolution tracking of eye-in-orbit position in behaving animals.

Invasive brain-computer interfaces (BCIs) may prove to be a useful rehabilitation tool for severely disabled patients. Although some systems have shown to work well in restricted laboratory settings, their usefulness must be tested in less controlled environments. Our objective was to investigate if a specific motor task could reliably be detected from multi-unit intra-cortical signals from freely moving animals. Four rats were trained to hit a retractable paddle (defined as a "hit"). Intra-cortical signals were obtained from electrodes placed in the primary motor cortex. First, the signal-to-noise ratio was increased by wavelet denoising. Action potentials were then detected using an adaptive threshold, counted in three consecutive time intervals and were used as features to classify either a "hit" or a "no-hit" (defined as an interval between two "hits"). We found that a "hit" could be detected with an accuracy of 75 ± 6% when wavelet denoising was applied whereas the accuracy dropped to 62 ± 5% without prior denoising. We compared our approach with the common daily practice in BCI that consists of using a fixed, manually selected threshold for spike detection without denoising. The results showed the feasibility of detecting a motor task in a less restricted environment than commonly applied within invasive BCI research.

Investigations into the biology of aquatic and semiaquatic species, including those involving sensory specialization, often require creative solutions to novel questions. We developed a technique for safely anesthetizing a semiaquatic chelonian species, the diamondback terrapin (Malaclemys terrapin), for measurement of auditory evoked potentials while animals were completely submerged in water. Custom-modified endotracheal tubes were used to obtain a watertight seal on both sides of the glottis and prevent aspiration of water during testing. No adverse effects were seen after the procedures, and assessment of venous blood-gas partial pressures and lactate concentrations indicated that sufficient gas exchange was maintained under anesthesia through manual ventilation.

Vocal communication is an important aspect of guinea pig behaviour and a large contributor to their acoustic environment. We postulated that some cortical areas have distinctive roles in processing conspecific calls. In order to test this hypothesis we presented exemplars from all ten of their main adult vocalizations to urethane anesthetised animals while recording from each of the eight areas of the auditory cortex. We demonstrate that the primary area (AI) and three adjacent auditory belt areas contain many units that give isomorphic responses to vocalizations. These are the ventrorostral belt (VRB), the transitional belt area (T) that is ventral to AI and the small area (area S) that is rostral to AI. Area VRB has a denser representation of cells that are better at discriminating among calls by using either a rate code or a temporal code than any other area. Furthermore, 10% of VRB cells responded to communication calls but did not respond to stimuli such as clicks, broadband noise or pure tones. Area S has a sparse distribution of call responsive cells that showed excellent temporal locking, 31% of which selectively responded to a single call. AI responded well to all vocalizations and was much more responsive to vocalizations than the adjacent dorsocaudal core area. Areas VRB, AI and S contained units with the highest levels of mutual information about call stimuli. Area T also responded well to some calls but seems to be specialized for low sound levels. The two dorsal belt areas are comparatively unresponsive to vocalizations and contain little information about the calls. AI projects to areas S, VRB and T, so there may be both rostral and ventral pathways for processing vocalizations in the guinea pig.

It was recently shown that rhythmic entrainment, long considered a human-specific mechanism, can be demonstrated in a selected group of bird species, and, somewhat surprisingly, not in more closely related species such as nonhuman primates. This observation supports the vocal learning hypothesis that suggests rhythmic entrainment to be a by-product of the vocal learning mechanisms that are shared by several bird and mammal species, including humans, but that are only weakly developed, or missing entirely, in nonhuman primates. To test this hypothesis we measured auditory event-related potentials (ERPs) in two rhesus monkeys (Macaca mulatta), probing a well-documented component in humans, the mismatch negativity (MMN) to study rhythmic expectation. We demonstrate for the first time in rhesus monkeys that, in response to infrequent deviants in pitch that were presented in a continuous sound stream using an oddball paradigm, a comparable ERP component can be detected with negative deflections in early latencies (Experiment 1). Subsequently we tested whether rhesus monkeys can detect gaps (omissions at random positions in the sound stream; Experiment 2) and, using more complex stimuli, also the beat (omissions at the first position of a musical unit, i.e. the 'downbeat'; Experiment 3). In contrast to what has been shown in human adults and newborns (using identical stimuli and experimental paradigm), the results suggest that rhesus monkeys are not able to detect the beat in music. These findings are in support of the hypothesis that beat induction (the cognitive mechanism that supports the perception of a regular pulse from a varying rhythm) is species-specific and absent in nonhuman primates. In addition, the findings support the auditory timing dissociation hypothesis, with rhesus monkeys being sensitive to rhythmic grouping (detecting the start of a rhythmic group), but not to the induced beat (detecting a regularity from a varying rhythm).

Sex steroids modulate vertebrate sensory processing, but the impact of circulating hormone levels on forebrain function remains unclear. We tested the hypothesis that circulating sex steroids modulate single-unit responses in the avian telencephalic auditory nucleus, field L. We mimicked breeding or nonbreeding conditions by manipulating plasma 17β-estradiol levels in wild-caught female Gambel's white-crowned sparrows ( Zonotrichia leucophrys gambelii ). Extracellular responses of single neurons to tones and conspecific songs presented over a range of intensities revealed that estradiol selectively enhanced auditory function in cells that exhibited monotonic rate level functions to pure tones. In these cells, estradiol treatment increased spontaneous and maximum evoked firing rates, increased pure tone response strengths and sensitivity, and expanded the range of intensities over which conspecific song stimuli elicited significant responses. Estradiol did not significantly alter the sensitivity or dynamic ranges of cells that exhibited non-monotonic rate level functions. Notably, there was a robust correlation between plasma estradiol concentrations in individual birds and physiological response properties in monotonic, but not non-monotonic neurons. These findings demonstrate that functionally distinct classes of anatomically overlapping forebrain neurons are differentially regulated by sex steroid hormones in a dose-dependent manner.

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.

Objective: It has been hypothesized that a vision prosthesis capable of evoking useful visual percepts can be based upon electrically stimulating the primary visual cortex (V1) of a blind human subject via penetrating microelectrode arrays. As a continuation of earlier work, we examined several spatial and temporal characteristics of V1 microstimulation. Approach: An array of 100 penetrating microelectrodes was chronically implanted in V1 of a behaving macaque monkey. Microstimulation thresholds were measured using a two-alternative forced choice detection task. Relative locations of electrically-evoked percepts were measured using a memory saccade-to-target task. Main results: The principal finding was that two years after implantation we were able to evoke behavioural responses to electric stimulation across the spatial extent of the array using groups of contiguous electrodes. Consistent responses to stimulation were evoked at an average threshold current per electrode of 204 ± 49 µA (mean ± std) for groups of four electrodes and 91 ± 25 µA for groups of nine electrodes. Saccades to electrically-evoked percepts using groups of nine electrodes showed that the animal could discriminate spatially distinct percepts with groups having an average separation of 1.6 ± 0.3 mm (mean ± std) in cortex and 1.0° ± 0.2° in visual space. Significance. These results demonstrate chronic perceptual functionality and provide evidence for the feasibility of a cortically-based vision prosthesis for the blind using penetrating microelectrodes.

Implantable neural microelectrodes that can record extracellular biopotentials from small, targeted groups of neurons are critical for neuroscience research and emerging clinical applications including brain-controlled prosthetic devices. The crucial material-dependent problem is developing microelectrodes that record neural activity from the same neurons for years with high fidelity and reliability. Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad. The resulting implants are an order of magnitude smaller than traditional recording electrodes, and more mechanically compliant with brain tissue. They were found to elicit much reduced chronic reactive tissue responses and enabled single-neuron recording in acute and early chronic experiments in rats. This technology, taking advantage of new composites, makes possible highly selective and stealthy neural interface devices towards realizing long-lasting implants.

Cerebrocortical injuries such as stroke are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, but the mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. In rats, we found that the thalamus, a structure that is remote from, but connected to, the injured cortex, was required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex underwent changes in HCN channel expression and became hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy revealed that reducing their activity in real-time was sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, as it spares cortical function between seizures, in contrast with existing treatments, such as surgical lesioning or drugs.