Single Unit publications

Tonotopic map plasticity in the adult auditory cortex (AC) is a well established and oft-cited measure of auditory associative learning in classical conditioning paradigms. However, its necessity as an enduring memory trace has been debated, especially given a recent finding that the areal expansion of core AC tuned to a newly relevant frequency range may arise only transiently to support auditory learning. This has been reinforced by an ethological paradigm showing that map expansion is not observed for ultrasonic vocalizations (USVs) or for ultrasound frequencies in postweaning dams for whom USVs emitted by pups acquire behavioral relevance. However, whether transient expansion occurs during maternal experience is not known, and could help to reveal the generality of cortical map expansion as a correlate for auditory learning. We thus mapped the auditory cortices of maternal mice at postnatal time points surrounding the peak in pup USV emission, but found no evidence of frequency map expansion for the behaviorally relevant high ultrasound range in AC. Instead, regions tuned to low frequencies outside of the ultrasound range show progressively greater suppression of activity in response to the playback of ultrasounds or pup USVs for maternally experienced animals assessed at their pups’ postnatal day 9 (P9) to P10, or postweaning. This provides new evidence for a lateral-band suppression mechanism elicited by behaviorally meaningful USVs, likely enhancing their population-level signal-to-noise ratio. These results demonstrate that tonotopic map enlargement has limits as a construct for conceptualizing how experience leaves neural memory traces within sensory cortex in the context of ethological auditory learning.

Successful speech perception in real-world environments requires that the auditory system segregate competing voices that overlap in frequency and time into separate streams. Vowels are major constituents of speech and are comprised of frequencies (harmonics) that are integer multiples of a common fundamental frequency (F0). The pitch and identity of a vowel are determined by its F0 and spectral envelope (formant structure), respectively. When two spectrally overlapping vowels differing in F0 are presented concurrently, they can be readily perceived as two separate “auditory objects” with pitches at their respective F0s. A difference in pitch between two simultaneous vowels provides a powerful cue for their segregation, which in turn, facilitates their individual identification. The neural mechanisms underlying the segregation of concurrent vowels based on pitch differences are poorly understood. Here, we examine neural population responses in macaque primary auditory cortex (A1) to single and double concurrent vowels (/a/ and /i/) that differ in F0 such that they are heard as two separate auditory objects with distinct pitches. We find that neural population responses in A1 can resolve, via a rate-place code, lower harmonics of both single and double concurrent vowels. Furthermore, we show that the formant structures, and hence the identities, of single vowels can be reliably recovered from the neural representation of double concurrent vowels. We conclude that A1 contains sufficient spectral information to enable concurrent vowel segregation and identification by downstream cortical areas.

Auditory stream segregation describes the way that sounds are perceptually segregated into groups or streams on the basis of perceptual attributes such as pitch or spectral content. For sequences of pure tones, segregation depends on the tones' proximity in frequency and time. In the auditory cortex (and elsewhere) responses to sequences of tones are dependent on stimulus conditions in a similar way to the perception of these stimuli. However, although highly dependent on stimulus conditions, perception is also clearly influenced by factors unrelated to the stimulus, such as attention. Exactly how 'bottom-up' sensory processes and non-sensory 'top-down' influences interact is still not clear. Here, we recorded responses to alternating tones (ABAB …) of varying frequency difference (FD) and rate of presentation (PR) in the auditory cortex of anesthetized guinea-pigs. These data complement previous studies, in that top-down processing resulting from conscious perception should be absent or at least considerably attenuated. Under anesthesia, the responses of cortical neurons to the tone sequences adapted rapidly, in a manner sensitive to both the FD and PR of the sequences. While the responses to tones at frequencies more distant from neuron best frequencies (BFs) decreased as the FD increased, the responses to tones near to BF increased, consistent with a release from adaptation, or forward suppression. Increases in PR resulted in reductions in responses to all tones, but the reduction was greater for tones further from BF. Although asymptotically adapted responses to tones showed behavior that was qualitatively consistent with perceptual stream segregation, responses reached asymptote within 2 s, and responses to all tones were very weak at high PRs (>12 tones per second). A signal-detection model, driven by the cortical population response, made decisions that were dependent on both FD and PR in ways consistent with perceptual stream segregation. This included showing a range of conditions over which decisions could be made either in favor of perceptual integration or segregation, depending on the model 'decision criterion'. However, the rate of 'build-up' was more rapid than seen perceptually, and at high PR responses to tones were sometimes so weak as to be undetectable by the model. Under anesthesia, adaptation occurs rapidly, and at high PRs tones are generally poorly represented, which compromises the interpretation of the experiment. However, within these limitations, these results complement experiments in awake animals and humans. They generally support the hypothesis that 'bottom-up' sensory processing plays a major role in perceptual organization, and that processes underlying stream segregation are active in the absence of attention.

The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses.

Interaural level differences (ILDs) are the dominant cue for localizing the sources of high frequency sounds that differ in azimuth. Neurons in the primary auditory cortex (A1) respond differentially to ILDs of simple stimuli such as tones and noise bands, but the extent to which this applies to complex natural sounds, such as vocalizations, is not known. In sufentanil/N2O anesthetized marmosets, we compared the responses of 76 A1 neurons to three vocalizations (Ock, Tsik, and Twitter) and pure tones at cells' characteristic frequency. Each stimulus was presented with ILDs ranging from 20 dB favoring the contralateral ear to 20 dB favoring the ipsilateral ear to cover most of the frontal azimuthal space. The response to each stimulus was tested at three average binaural levels (ABLs). Most neurons were sensitive to ILDs of vocalizations and pure tones. For all stimuli, the majority of cells had monotonic ILD sensitivity functions favoring the contralateral ear, but we also observed ILD sensitivity functions that peaked near the midline and functions favoring the ipsilateral ear. Representation of ILD in A1 was better for pure tones and the Ock vocalization in comparison to the Tsik and Twitter calls; this was reflected by higher discrimination indices and greater modulation ranges. ILD sensitivity was heavily dependent on ABL: changes in ABL by ±20 dB SPL from the optimal level for ILD sensitivity led to significant decreases in ILD sensitivity for all stimuli, although ILD sensitivity to pure tones and Ock calls was most robust to such ABL changes. Our results demonstrate differences in ILD coding for pure tones and vocalizations, showing that ILD sensitivity in A1 to complex sounds cannot be simply extrapolated from that to pure tones. They also show A1 neurons do not show level-invariant representation of ILD, suggesting that such a representation of auditory space is likely to require population coding, and further processing at subsequent hierarchical stages.

Tinnitus is often identified in animal models by using the gap prepulse inhibition of acoustic startle. Impaired gap detection following acoustic over-exposure (AOE) is thought to be caused by tinnitus "filling in" the gap, thus, reducing its salience. This presumably involves altered perception, and could conceivably be caused by changes at the level of the neocortex, i.e., cortical reorganization. Alternatively, reduced gap detection ability might reflect poorer temporal processing in the brainstem, caused by AOE; in which case, impaired gap detection would not be a reliable indicator of tinnitus. We tested the latter hypothesis by examining gap detection in inferior colliculus (IC) neurons following AOE. Seven of nine unilaterally noise-exposed guinea pigs exhibited behavioral evidence of tinnitus. In these tinnitus animals, neural gap detection thresholds (GDTs) in the IC significantly increased in response to broadband noise stimuli, but not to pure tones or narrow-band noise. In addition, when IC neurons were sub-divided according to temporal response profile (onset vs. sustained firing patterns), we found a significant increase in the proportion of onset-type responses after AOE. Importantly, however, GDTs were still considerably shorter than gap durations commonly used in objective behavioral tests for tinnitus. These data indicate that the neural changes observed in the IC are insufficient to explain deficits in behavioral gap detection that are commonly attributed to tinnitus. The subtle changes in IC neuron response profiles following AOE warrant further investigation.

Animal models of tinnitus allow us to study the relationship between changes in neural activity and the tinnitus percept. Here, guinea pigs were subjected to unilateral noise trauma and tested behaviourally for tinnitus 8 weeks later. By comparing animals with tinnitus with those without, all of which were noise‐exposed, we were able to identify changes unique to the tinnitus group. Three physiological markers known to change following noise exposure were examined: spontaneous firing rates ( SFR s) and burst firing in the inferior colliculus ( IC ), evoked auditory brainstem responses ( ABR s), and the number of neurons in the cochlear nucleus containing nitric oxide synthase ( NOS ). We obtained behavioural evidence of tinnitus in 12 of 16 (75%) animals. Both SFR s and incidences of burst firing were elevated in the IC of all noise‐exposed animals, but there were no differences between tinnitus and no‐tinnitus animals. There were significant decreases in ipsilateral ABR latencies in tinnitus animals, contrary to what might be expected with a small hearing loss. Furthermore, there was an ipsilateral–contralateral asymmetry in NOS staining in the ventral cochlear nucleus ( VCN ) that was only apparent in tinnitus animals. Tinnitus animals had a significantly greater number of NOS ‐containing neurons on the noise‐exposed side, whereas no‐tinnitus animals did not. These data suggest that measuring NOS in the VCN and recording ABR s supplement behavioural methods for confirming tinnitus in animals, and that nitric oxide is involved in plastic neural changes associated with tinnitus.

Diabetic encephalopathy is one of the complications of diabetes. Cognitive dysfunction is the main consequence. Previous findings from neuroanatomical and in vitro electrophysiological studies showed that the structure and function of the hippocampus is impaired in diabetes, which may underlie the cognitive dysfunction induced by diabetes. However the study of electrophysiological abnormality of hippocampal neurons in intact networks is sparse. In the current study, we recorded the spontaneous firing of neurons in hippocampal CA1 area in anesthetized streptozotozin (STZ)-diabetic and age-matched control rats. Profound reduction in burst activity was found in diabetic rats. Compared to control rats, the intra-burst inter-spike intervals were prolonged significantly in diabetic rats, while the burst ratio and the mean number of spikes within a burst decreased significantly. Treatment with APP 17-mer peptide retarded the effects of diabetes on these parameters. In addition, the average PLV of diabetic rats was lower than that of control rats. These findings provide in vivo electrophysiological evidence for the impairment of hippocampal function in STZ-diabetic rats, and may have some implications in the mechanisms associated with cognitive deficits in diabetes.

Background The basal forebrain (BF) regulates cortical activity by the action of cholinergic projections to the cortex. At the same time, it also sends substantial GABAergic projections to both cortex and thalamus, whose functional role has received far less attention. We used deep brain stimulation (DBS) in the BF, which is thought to activate both types of projections, to investigate the impact of BF activation on V1 neural activity. Results BF stimulation robustly increased V1 single and multi-unit activity, led to moderate decreases in orientation selectivity and a remarkable increase in contrast sensitivity as demonstrated by a reduced semi-saturation contrast. The spontaneous V1 local field potential often exhibited spectral peaks centered at 40 and 70 Hz as well as reliably showed a broad γ-band (30-90 Hz) increase following BF stimulation, whereas effects in a low frequency band (1-10 Hz) were less consistent. The broad γ-band, rather than low frequency activity or spectral peaks was the best predictor of both the firing rate increase and contrast sensitivity increase of V1 unit activity. Conclusions We conclude that BF activation has a strong influence on contrast sensitivity in V1. We suggest that, in addition to cholinergic modulation, the BF GABAergic projections play a crucial role in the impact of BF DBS on cortical activity.

Detailed understanding of the haemodynamic changes that underlie non-invasive neuroimaging techniques such as blood oxygen level dependent functional magnetic resonance imaging is essential if we are to continue to extend the use of these methods for understanding brain function and dysfunction. The use of animal and in particular rodent research models has been central to these endeavours as they allow in-vivo experimental techniques that provide measurements of the haemodynamic response function at high temporal and spatial resolution. A limitation of most of this research is the use of anaesthetic agents which may disrupt or mask important features of neurovascular coupling or the haemodynamic response function. In this study we therefore measured spatiotemporal cortical haemodynamic responses to somatosensory stimulation in awake rats using optical imaging spectroscopy. Trained, restrained animals received non-noxious stimulation of the whisker pad via chronically implanted stimulating microwires whilst optical recordings were made from the contralateral somatosensory cortex through a thin cranial window. The responses we measure from un-anaesthetised animals are substantially different from those reported in previous studies which have used anaesthetised animals. These differences include biphasic response regions (initial increases in blood volume and oxygenation followed by subsequent decreases) as well as oscillations in the response time series of awake animals. These haemodynamic response features do not reflect concomitant changes in the underlying neuronal activity and therefore reflect neurovascular or cerebrovascular processes. These hitherto unreported hyperemic response dynamics may have important implications for the use of anaesthetised animal models for research into the haemodynamic response 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.

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.

We investigated how physiologically observed forward suppression interacts with stimulus frequency in neuronal responses in the guinea pig auditory cortex. The temporal order and frequency proximity of sounds influence both their perception and neuronal responses. Psychophysically, preceding sounds (conditioners) can make successive sounds (probes) harder to hear. These effects are larger when the two sounds are spectrally similar. Physiological forward suppression is usually maximal for conditioner tones near to a unit's characteristic frequency (CF), the frequency to which a neuron is most sensitive. However, in most physiological studies, the frequency of the probe tone and CF are identical, so the role of unit CF and probe frequency cannot be distinguished. Here, we systemically varied the frequency of the probe tone, and found that the tuning of suppression was often more closely related to the frequency of the probe tone than to the unit's CF, i.e. suppressed tuning was specific to probe frequency. This relationship was maintained for all measured gaps between the conditioner and the probe tones. However, when the probe frequency and CF were similar, CF tended to determine suppressed tuning. In addition, the bandwidth of suppression was slightly wider for off-CF probes. Changes in tuning were also reflected in the firing rate in response to probe tones, which was maximally reduced when probe and conditioner tones were matched in frequency. These data are consistent with the idea that cortical neurons receive convergent inputs with a wide range of tuning properties that can adapt independently.

Reversible inactivation of the cortex by surface cooling is a powerful method for studying the function of a particular area. Implanted cooling cryoloops have been used to study the role of individual cortical areas in auditory processing of awake-behaving cats. Cryoloops have also been used in rodents for reversible inactivation of the cortex, but recently there has been a concern that the cryoloop may also cool non-cortical structures either directly or via the perfusion of blood, cooled as it passed close to the cooling loop. In this study we have confirmed that the loop can inactivate most of the auditory cortex without causing a significant reduction in temperature of the auditory thalamus or other subcortical structures. We placed a cryoloop on the surface of the guinea pig cortex, cooled it to 2°C and measured thermal gradients across the neocortical surface. We found that the temperature dropped to 20-24°C among cells within a radius of about 2.5 mm away from the loop. This temperature drop was sufficient to reduce activity of most cortical cells and led to the inactivation of almost the entire auditory region. When the temperature of thalamus, midbrain, and middle ear were measured directly during cortical cooling, there was a small drop in temperature (about 4°C) but this was not sufficient to directly reduce neural activity. In an effort to visualize the extent of neural inactivation we measured the uptake of thallium ions following an intravenous injection. This confirmed that there was a large reduction of activity across much of the ipsilateral cortex and only a small reduction in subcortical structures.

Neurons in the primary visual cortex typically reach their highest firing rate after an abrupt image transition. Since the mutual information between the firing rate and the currently presented image is largest during this early firing period it is tempting to conclude this early firing encodes the current image. This view is, however, made more complicated by the fact that the response to the current image is dependent on the preceding image. Therefore we hypothesize that neurons encode a combination of current and previous images, and that the strength of the current image relative to the previous image changes over time. The temporal encoding is interesting, first, because neurons are, at different time points, sensitive to different features such as luminance, edges and textures; second, because the temporal evolution provides temporal constraints for deciphering the instantaneous population activity. To study the temporal evolution of the encoding we presented a sequence of 250 ms stimulus patterns during multiunit recordings in areas 17 and 18 of the anaesthetized ferret. Using a novel method we decoded the pattern given the instantaneous population-firing rate. Following a stimulus transition from stimulus A to B the decoded stimulus during the first 90ms was more correlated with the difference between A and B (B-A) than with B alone. After 90ms the decoded stimulus was more correlated with stimulus B than with B-A. Finally we related our results to information measures of previous (B) and current stimulus (A). Despite that the initial transient conveys the majority of the stimulus-related information; we show that it actually encodes a difference image which can be independent of the stimulus. Only later on, spikes gradually encode the stimulus more exclusively.

Psychophysical forward masking is an increase in threshold of detection of a sound (probe) when it is preceded by another sound (masker). This is reminiscent of the reduction in neuronal responses to a sound following prior stimulation. Studies in the auditory nerve and cochlear nucleus using signal detection theory techniques to derive neuronal thresholds showed that in centrally projecting neurons, increases in masked thresholds were significantly smaller than the changes measured psychophysically. Larger threshold shifts have been reported in the inferior colliculus of awake marmoset. The present study investigated the magnitude of forward masking in primary auditory cortical neurons of anaesthetised guinea-pigs. Responses of cortical neurons to unmasked and forward masked tones were measured and probe detection thresholds estimated using signal detection theory methods. Threshold shifts were larger than in the auditory nerve, cochlear nucleus and inferior colliculus. The larger threshold shifts suggest that central, and probably cortical, processes contribute to forward masking. However, although methodological differences make comparisons difficult, the threshold shifts in cortical neurons were, in contrast to subcortical nuclei, actually larger than those observed psychophysically. Masking was largely attributable to a reduction in the responses to the probe, rather than either a persistence of the masker responses or an increase in the variability of probe responses.

Background Magnetoencephalography (MEG) has become an increasingly popular technique for non-invasively characterizing neuromagnetic field changes in the brain at a high temporal resolution. To examine the reliability of the MEG signal, we compared magnetic and electrophysiological responses to complex natural stimuli from the same animals. We examined changes in neuromagnetic fields, local field potentials (LFP) and multi-unit activity (MUA) in macaque monkey primary somatosensory cortex that were induced by varying the rate of mechanical stimulation. Stimuli were applied to the fingertips with three inter-stimulus intervals (ISIs): 0.33s, 1s and 2s. Results Signal intensity was inversely related to the rate of stimulation, but to different degrees for each measurement method. The decrease in response at higher stimulation rates was significantly greater for MUA than LFP and MEG data, while no significant difference was observed between LFP and MEG recordings. Furthermore, response latency was the shortest for MUA and the longest for MEG data. Conclusion The MEG signal is an accurate representation of electrophysiological responses to complex natural stimuli. Further, the intensity and latency of the MEG signal were better correlated with the LFP than MUA data suggesting that the MEG signal reflects primarily synaptic currents rather than spiking activity. These differences in latency could be attributed to differences in the extent of spatial summation and/or differential laminar sensitivity.

When an object is introduced moving in the visual field of view, the object maps with different delays in each of the six cortical layers in many visual areas by mechanisms that are poorly understood. We combined voltage sensitive dye (VSD) recordings with laminar recordings of action potentials in visual areas 17, 18, 19 and 21 in ferrets exposed to stationary and moving bars. At the area 17/18 border a moving bar first elicited an ON response in layer 4 and then ON responses in supragranular and infragranular layers, identical to a stationary bar. Shortly after, the moving bar mapped as moving synchronous peak firing across layers. Complex dynamics evolved including feedback from areas 19/21, the computation of a spatially restricted pre-depolarization (SRP), and firing in the direction of cortical motion prior to the mapping of the bar. After 350 ms, the representations of the bar (peak firing and peak VSD signal) in areas 19/21 and 17/18 moved over the cortex in phase. The dynamics comprise putative mechanisms for automatic saliency of novel moving objects, coherent mapping of moving objects across layers and areas, and planning of catch-up saccades.

Neurons in the auditory midbrain are sensitive to differences in the timing of sounds at the two ears—an important sound localization cue. We used broadband noise stimuli to investigate the interaural-delay sensitivity of low-frequency neurons in two midbrain nuclei: the inferior colliculus (IC) and the dorsal nucleus of the lateral lemniscus. Noise-delay functions showed asymmetries not predicted from a linear dependence on interaural correlation: a stretching along the firing-rate dimension ( rate asymmetry), and a skewing along the interaural-delay dimension ( delay asymmetry). These asymmetries were produced by an envelope-sensitive component to the response that could not entirely be accounted for by monaural or binaural nonlinearities, instead indicating an enhancement of envelope sensitivity at or after the level of the superior olivary complex. In IC, the skew-like asymmetry was consistent with intermediate-type responses produced by the convergence of ipsilateral peak-type inputs and contralateral trough-type inputs. This suggests a stereotyped pattern of input to the IC. In the course of this analysis, we were also able to determine the contribution of time and phase components to neurons' internal delays. These findings have important consequences for the neural representation of interaural timing differences and interaural correlation—cues critical to the perception of acoustic space.