Publications using the Medusa

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.

The frequency following response (FFR) arises from the sustained neural activity of a population of neurons that are phase locked to periodic acoustic stimuli. Determining the source of the FFR noninvasively may be useful for understanding the function of phase locking in the auditory pathway to the temporal envelope and fine structure of sounds. The current study compared the FFR recorded with a horizontally aligned (mastoid-to-mastoid) electrode montage and a vertically aligned (forehead-to-neck) electrode montage. Unlike previous studies, envelope and fine structure latencies were derived simultaneously from the same narrowband stimuli to minimize differences in cochlear delay. Stimuli were five amplitude-modulated tones centered at 576 Hz, each with a different modulation rate, resulting in different side-band frequencies across stimulus conditions. Changes in response phase across modulation frequency and side-band frequency (group delay) were used to determine the latency of the FFR reflecting phase locking to the envelope and temporal fine structure, respectively. For the FFR reflecting phase locking to the temporal fine structure, the horizontal montage had a shorter group delay than the vertical montage, suggesting an earlier generation source within the auditory pathway. For the FFR reflecting phase locking to the envelope, group delay was longer than that for the fine structure FFR, and no significant difference in group delay was found between montages. However, it is possible that multiple sources of FFR (including the cochlear microphonic) were recorded by each montage, complicating interpretations of the group delay.

There has been continued interest in clinical objective measures of binaural processing. One commonly proposed measure is the binaural interaction component (BIC), which is obtained typically by recording auditory brainstem responses (ABRs)—the BIC reflects the difference between the binaural ABR and the sum of the monaural ABRs (i.e., binaural − (left + right)). We have recently developed an alternative, direct measure of sensitivity to interaural time differences, namely, a following response to modulations in interaural phase difference (the interaural phase modulation following response; IPM-FR). To obtain this measure, an ongoing diotically amplitude-modulated signal is presented, and the interaural phase difference of the carrier is switched periodically at minima in the modulation cycle. Such periodic modulations to interaural phase difference can evoke a steady state following response. BIC and IPM-FR measurements were compared from 10 normal-hearing subjects using a 16-channel electroencephalographic system. Both ABRs and IPM-FRs were observed most clearly from similar electrode locations—differential recordings taken from electrodes near the ear (e.g., mastoid) in reference to a vertex electrode (Cz). Although all subjects displayed clear ABRs, the BIC was not reliably observed. In contrast, the IPM-FR typically elicited a robust and significant response. In addition, the IPM-FR measure required a considerably shorter recording session. As the IPM-FR magnitude varied with interaural phase difference modulation depth, it could potentially serve as a correlate of perceptual salience. Overall, the IPM-FR appears a more suitable clinical measure than the BIC.

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.

Noise pollution from anthropogenic sources is an increasingly problematic challenge faced by many taxa, including fishes. Recent studies demonstrate that road traffic noise propagates effectively from bridge crossings into surrounding freshwater ecosystems; yet, its effect on the stress response and auditory function of freshwater stream fishes is unexamined. The blacktail shiner (Cyprinella venusta) was used as a model to investigate the degree to which traffic noise impacts stress and hearing in exposed fishes. Fish were exposed to an underwater recording of traffic noise played at approximately 140 dB re 1 μPa. Waterborne cortisol samples were collected and quantified using enzyme immunoassay (EIA). Auditory thresholds were assessed in control and traffic exposed groups by measuring auditory evoked potentials (AEPs). After acute exposure to traffic noise, fish exhibited a significant elevation in cortisol levels. Individuals exposed to 2 hours of traffic noise playback had elevated hearing thresholds at 300 and 400 Hz, corresponding to the most sensitive bandwidth for this species.

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.

The kinase Akt is a key downstream mediator of the phosphoinositide-3-kinase signaling pathway and participates in a variety of cellular processes. Akt comprises three isoforms each encoded by a separate gene. There is evidence to indicate that Akt is involved in the survival and protection of auditory hair cells in vitro. However, little is known about the physiological role of Akt in the inner ear-especially in the intact animal. To elucidate this issue, we first analyzed the mRNA expression of the three Akt isoforms in the inner ear of C57/BL6 mice by real-time PCR. Next, we tested the susceptibility to gentamicin-induced auditory hair cell loss in isoform-specific Akt knockout mice compared to wild-types (C57/BL6) in vitro. To analyze the effect of gene deletion in vivo, hearing and cochlear microanatomy were evaluated in Akt isoform knockout animals. In this study, we found that all three Akt isoforms are expressed in the cochlea. Our results further indicate that Akt2 and Akt3 enhance hair cell resistance to ototoxicity, while Akt1 does not. Finally, we determined that untreated Akt1 and Akt2/Akt3 double knockout mice display significant hearing loss, indicating a role for these isoforms in normal hearing. Taken together, our results indicate that each of the Akt isoforms plays a distinct role in the mammalian inner ear.

A significant challenge in tinnitus research lies in explaining how acoustic insult leads to tinnitus in some individuals, but not others. One possibility is genetic variability in the expression and function of neuromodulators - components of neural signaling that alter the balance of excitation and inhibition in neural circuits. An example is nitric oxide (NO) - a free radical and potent neuromodulator in the mammalian brain - that regulates plasticity via both pre-synaptic and postsynaptic mechanisms. Changes in NO have previously been implicated in tinnitus generation, specifically in the ventral cochlear nucleus (VCN). Here, we examined nitric oxide synthase (NOS) - the enzyme responsible for NO production - in the guinea pig VCN following acoustic trauma. NOS was present in most cell types - including spherical and globular bushy cells, small, medium, and large multipolar cells, and octopus cells - spanning the entire extent of the VCN. The staining pattern was symmetrical in control animals. Unilateral acoustic over-exposure (AOE) resulted in marked asymmetries between ipsilateral and contralateral sides of the VCN in terms of the distribution of NOS across the cochlear nuclei in animals with behavioral evidence of tinnitus: fewer NOS-positive cells and a reduced level of NOS staining was present across the whole extent of the contralateral VCN, relative to the ipsilateral VCN. The asymmetric pattern of NOS-containing cells was observed as early as 1 day after AOE and was also present in some animals at 3, 7, and 21 days after AOE. However, it was not until 8 weeks after AOE, when tinnitus had developed, that asymmetries were significant overall, compared with control animals. Asymmetrical NOS expression was not correlated with shifts in the threshold hearing levels. Variability in NOS expression between animals may represent one underlying difference that can be linked to whether or not tinnitus develops after noise exposure.

Chronic tinnitus, or "ringing of the ears", affects upwards of 15% of the adult population. Identifying a cost-effective and objective measure of tinnitus is needed due to legal concerns and disability issues, as well as for facilitating the effort to assess neural biomarkers. We developed a modified gap-in-noise (GIN) paradigm to assess tinnitus in mice using the auditory brainstem response (ABR). We then compared the commonly used acoustic startle reflex gap-prepulse inhibition (gap-PPI) and the ABR GIN paradigm in young adult CBA/CaJ mice before and after administrating sodium salicylate (SS), which is known to reliably induce a 16 kHz tinnitus percept in rodents. Post-SS, gap-PPI was significantly reduced at 12 and 16 kHz, consistent with previous studies demonstrating a tinnitus-induced gap-PPI reduction in this frequency range. ABR audiograms indicated thresholds were significantly elevated post-SS, also consistent with previous studies. There was a significant increase in the peak 2 (P2) to peak 1 (P1) and peak 4 (P4) to P1 amplitude ratios in the mid-frequency range, along with decreased latency of P4 at higher intensities. For the ABR GIN, peak amplitudes of the response to the second noise burst were calculated as a percentage of the first noise burst response amplitudes to quantify neural gap processing. A significant decrease in this ratio (i.e. recovery) was seen only at 16 kHz for P1, indicating the presence of tinnitus near this frequency. Thus, this study demonstrates that GIN ABRs can be used as an efficient, non-invasive, and objective method of identifying the approximate pitch and presence of tinnitus in a mouse model. This technique has the potential for application in human subjects and also indicates significant, albeit different, deficits in temporal processing in peripheral and brainstem circuits following drug induced tinnitus.

Fragile X Syndrome (FXS), a neurodevelopmental disorder, is the most prevalent single-gene cause of autism spectrum disorder. Autism has been associated with impaired auditory processing, abnormalities in the auditory brainstem response (ABR), and reduced cell number and size in the auditory brainstem nuclei. FXS is characterized by elevated cortical responses to sound stimuli, with some evidence for aberrant ABRs. Here, we assessed ABRs and auditory brainstem anatomy in Fmr1-/- mice, an animal model of FXS. We found that Fmr1-/- mice showed elevated response thresholds to both click and tone stimuli. Amplitudes of ABR responses were reduced in Fmr1-/- mice for early peaks of the ABR. The growth of the peak I response with sound intensity was less steep in mutants that in wild type mice. In contrast, amplitudes and response growth in peaks IV and V did not differ between these groups. We did not observe differences in peak latencies or in interpeak latencies. Cell size was reduced in Fmr1-/- mice in the ventral cochlear nucleus (VCN) and in the medial nucleus of the trapezoid body (MNTB). We quantified levels of inhibitory and excitatory synaptic inputs in these nuclei using markers for presynaptic proteins. We measured VGAT and VGLUT immunolabeling in VCN, MNTB, and the lateral superior olive (LSO). VGAT expression in MNTB was significantly greater in the Fmr1-/- mouse than in wild type mice. Together, these observations demonstrate that FXS affects peripheral and central aspects of hearing and alters the balance of excitation and inhibition in the auditory brainstem.

While the timing of neuronal activity in the olfactory bulb (OB) relative to sniffing has been the object of many studies, the behavioral relevance of timing information generated by patterned activation within the bulbar response has not been explored. Here we show, using sniff-triggered, dynamic, 2-D, optogenetic stimulation of mitral/tufted cells, that virtual odors that differ by as little as 13 ms are distinguishable by mice. Further, mice are capable of discriminating a virtual odor movie based on an optically imaged OB odor response versus the same virtual odor devoid of temporal dynamics-independently of the sniff-phase. Together with studies showing the behavioral relevance of graded glomerular responses and the response timing relative to odor sampling, these results imply that the mammalian olfactory system is capable of very high transient information transmission rates.

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.

The neural substrate for the perception of vocalizations is relatively well described, but how their timing and specificity are tightly coupled with accompanying physiological changes and context-appropriate behaviors remains unresolved. We hypothesized that temporally integrated vocal and emotive responses, especially the expression of fear, vigilance and aggression, originate within the amygdala. To test this hypothesis, we performed electrical microstimulation at 461 highly restricted loci within the basal and central amygdala in awake mustached bats. At a subset of these sites, high frequency stimulation with weak constant current pulses presented at near-threshold levels triggered vocalization of either echolocation pulses or social calls. At the vast majority of locations, microstimulation produced a constellation of changes in autonomic and somatomotor outputs. These changes included widespread co-activation of significant tachycardia and hyperventilation and/or rhythmic ear pinna movements (PMs). In a few locations, responses were constrained to vocalization and/or PMs despite increases in the intensity of stimulation. The probability of eliciting echolocation pulses vs. social calls decreased in a medial-posterior to anterolateral direction within the centrobasal amygdala. Microinjections of kainic acid (KA) at stimulation sites confirmed the contribution of cellular activity rather than fibers-of-passage in the control of multimodal outputs. The results suggest that localized clusters of neurons may simultaneously modulate the activity of multiple central pattern generators (CPGs) present within the brainstem.

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.

Introduction: This study aimed to assess the top-down control of sound processing in the auditory brainstem of rats. Short latency evoked responses were analyzed after unilateral or bilateral ablation of auditory cortex. This experimental paradigm was also used towards analyzing the long-term evolution of post-lesion plasticity in the auditory system and its ability to self-repair. Method: Auditory cortex lesions were performed in rats by stereotactically guided fine-needle aspiration of the cerebrocortical surface. Auditory Brainstem Responses (ABR) were recorded at post-surgery day (PSD) 1, 7, 15 and 30. Recordings were performed under closed-field conditions, using click trains at different sound intensity levels, followed by statistical analysis of threshold values and ABR amplitude and latency variables. Subsequently, brains were sectioned and immunostained for GAD and parvalbumin to assess the location and extent of lesions accurately. Results: Alterations in ABR variables depended on the type of lesion and post-surgery time of ABR recordings. Accordingly, bilateral ablations caused a statistically significant increase in thresholds at PSD1 and 7 and a decrease in waves amplitudes at PSD1 that recover at PSD7. No effects on latency were noted at PSD1 and 7, whilst recordings at PSD15 and 30 showed statistically significant decreases in latency. Conversely, unilateral ablations had no effect on auditory thresholds or latencies, while wave amplitudes only decreased at PSD1 strictly in the ipsilateral ear. Conclusion: Post-lesion plasticity in the auditory system acts in two time periods: short-term period of decreased sound sensitivity (until PSD7), most likely resulting from axonal degeneration; and a long-term period (up to PSD7), with changes in latency responses and recovery of thresholds and amplitudes values. The cerebral cortex may have a net positive gain on the auditory pathway response to sound.

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.