Publications using TDT

Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington’s disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.

Embodied theories of cognition emphasize the central role of sensorimotor transformations in the representation of others' actions. Support for these theories is derived from the discovery of the mirror neuron system (MNS) in primates, from noninvasive techniques in humans, and from a limited number of intracranial studies. To understand the neural dynamics of the human MNS, more studies with precise spatial and temporal resolutions are essential. We used electrocorticography to define activation patterns in sensorimotor, parietal and/or frontal neuronal populations, during a viewing and grasping task. Our results show robust high gamma activation for both conditions in classic MNS sites. Furthermore, we provide novel evidence for 2 different populations of neurons: sites that were only active for viewing and grasping ("pure mirroring") and sites that were also active between viewing and grasping, and perhaps serve a more general attentional role. Lastly, a subgroup of parietal electrodes showed earlier peaks than all other regions. These results highlight the complexity of spatial-temporal patterns within the MNS and provide a critical link between single-unit research in monkeys and noninvasive techniques in human.

Echolocating bats face the challenge of actively sensing their environment through their own emissions, while also hearing calls and echoes of nearby conspecifics. How bats mitigate interference is a long-standing question that has both ecological and technological implications, as biosonar systems continue to outperform man-made sonar systems in noisy, cluttered environments. We recently showed that perched bats decreased calling rates in groups, displaying a behavioral strategy resembling the back-off algorithms used in artificial communication networks to optimize information throughput at the group level. We tested whether free-tailed bats ( Tadarida brasiliensis ) would employ such a coordinated strategy while performing challenging flight maneuvers, and report here that bats navigating obstacles lowered emission rates when hearing artificial playback of another bat’s calls. We measured the impact of acoustic interference on navigation performance and show that the calculated reductions in interference rates are sufficient to reduce interference and improve obstacle avoidance. When bats flew in pairs, each bat responded to the presence of the other as an obstacle by increasing emissions, but hearing the sonar emissions of the nearby bat partially suppressed this response. This behavior supports social cohesion by providing a key mechanism for minimizing mutual interference.

The subthalamic nucleus (STN) and globus pallidus internus (GPi) have recently been shown to encode reward, but few studies have been performed in humans. We investigated STN and GPi encoding of reward and loss (i.e., valence) in humans with Parkinson's disease. To test the hypothesis that STN and GPi neurons would change their firing rate in response to reward‐ and loss‐related stimuli, we recorded the activity of individual neurons while participants performed a behavioral task. In the task, action choices were associated with potential rewarding, punitive, or neutral outcomes. We found that STN and GPi neurons encode valence‐related information during action control, but the proportion of valence‐responsive neurons was greater in the STN compared to the GPi. In the STN, reward‐related stimuli mobilized a greater proportion of neurons than loss‐related stimuli. We also found surprising limbic overlap with the sensorimotor regions in both the STN and GPi, and this overlap was greater than has been previously reported. These findings may help to explain alterations in limbic function that have been observed following deep brain stimulation therapy of the STN and GPi. Hum Brain Mapp 38:1952–1964, 2017 . © 2017 Wiley Periodicals, Inc.

A general principle of sensory processing is that neurons adapt to sustained stimuli by reducing their response over time. Most of our knowledge on adaptation in single cells is based on experiments in anesthetized animals. How responses adapt in awake animals, when stimuli may be behaviorally relevant or not, remains unclear. Here we show that contrast adaptation in mouse primary visual cortex depends on the behavioral relevance of the stimulus. Cells that adapted to contrast under anesthesia maintained or even increased their activity in awake naïve mice. When engaged in a visually guided task, contrast adaptation re-occurred for stimuli that were irrelevant for solving the task. However, contrast adaptation was reversed when stimuli acquired behavioral relevance. Regulation of cortical adaptation by task demand may allow dynamic control of sensory-evoked signal flow in the neocortex.

Perceptual constancy requires neural representations that are selective for object identity, but also tolerant for identity-preserving transformations. How such representations arise in the brain and contribute to perception remains unclear. Here we studied tolerant representations of sound identity in the auditory system by recording multi-unit activity in tonotopic auditory cortex of ferrets discriminating the identity of vowels which co-varied across orthogonal stimulus dimensions (fundamental frequency, sound level, location and voicing). We found that neural decoding of vowel identity was most successful across the same orthogonal dimensions over which animals generalized their behavior. We also decoded orthogonal sound features and behavioral variables including choice and accuracy to show a behaviorally-relevant, multivariate and multiplexed representation of sound, with each variable represented over a distinct time-course. Finally, information content and timing of sound feature encoding was modulated by task-engagement and training, suggesting that tolerant representations during perceptual constancy are attentionally and experience-dependent.

The pulvinar complex is interconnected extensively with brain regions involved in spatial processing and eye movement control. Recent inactivation studies have shown that the dorsal pulvinar (dPul) plays a role in saccade target selection; however, it remains unknown whether it exerts effects on visual processing or at planning/execution stages. We used electrical microstimulation of the dPul while monkeys performed saccade tasks toward instructed and freely chosen targets. Timing of stimulation was varied, starting before, at, or after onset of target(s). Stimulation affected saccade properties and target selection in a time-dependent manner. Stimulation starting before but overlapping with target onset shortened saccadic reaction times (RTs) for ipsiversive (to the stimulation site) target locations, whereas stimulation starting at and after target onset caused systematic delays for both ipsiversive and contraversive locations. Similarly, stimulation starting before the onset of bilateral targets increased ipsiversive target choices, whereas stimulation after target onset increased contraversive choices. Properties of dPul neurons and stimulation effects were consistent with an overall contraversive drive, with varying outcomes contingent upon behavioral demands. RT and choice effects were largely congruent in the visually-guided task, but stimulation during memory-guided saccades, while influencing RTs and errors, did not affect choice behavior. Together, these results show that the dPul plays a primary role in action planning as opposed to visual processing, that it exerts its strongest influence on spatial choices when decision and action are temporally close, and that this choice effect can be dissociated from motor effects on saccade initiation and execution. SIGNIFICANCE STATEMENT Despite a recent surge of interest, the core function of the pulvinar, the largest thalamic complex in primates, remains elusive. This understanding is crucial given the central role of the pulvinar in current theories of integrative brain functions supporting cognition and goal-directed behaviors, but electrophysiological and causal interference studies of dorsal pulvinar (dPul) are rare. Building on our previous studies that pharmacologically suppressed dPul activity for several hours, here we used transient electrical microstimulation at different periods while monkeys performed instructed and choice eye movement tasks, to determine time-specific contributions of pulvinar to saccade generation and decision making. We show that stimulation effects depend on timing and behavioral state and that effects on choices can be dissociated from motor effects.

Cellular asymmetries play crucial roles in development and organ function. The planar cell polarity (PCP) signaling pathway is involved in the establishment of cellular asymmetry within the plane of a cell sheet. Inner ear sensory hair cells (HCs), which have several rows of staircase-like stereocilia and one kinocilium located at the vertex of the stereocilia protruding from the apical surface of each HC, exhibit a typical form of PCP. Although connections between cilia and PCP signaling in vertebrate development have been reported, their precise nature is not well understood. During inner ear development, several ciliary proteins are known to play a role in PCP formation. In the current study, we investigated a functional role for intestinal cell kinase (Ick), which regulates intraflagellar transport (IFT) at the tip of cilia, in the mouse inner ear. A lack of Ick in the developing inner ear resulted in PCP defects in the cochlea, including misorientation or misshaping of stereocilia and aberrant localization of the kinocilium and basal body in the apical and middle turns, leading to auditory dysfunction. We also observed abnormal ciliary localization of Ift88 in both HCs and supporting cells. Together, our results show that Ick ciliary kinase is essential for PCP formation in inner ear HCs, suggesting that ciliary transport regulation is important for PCP signaling. SIGNIFICANCE STATEMENT The cochlea in the inner ear is the hearing organ. Planar cell polarity (PCP) in hair cells (HCs) in the cochlea is essential for mechanotransduction and refers to the asymmetric structure consisting of stereociliary bundles and the kinocilium on the apical surface of the cell body. We reported previously that a ciliary kinase, Ick, regulates intraflagellar transport (IFT). Here, we found that loss of Ick leads to abnormal localization of the IFT component in kinocilia, PCP defects in HCs, and hearing dysfunction. Our study defines the association of ciliary transport regulation with PCP formation in HCs and hearing function.

Short-term training can lead to improvements in behavioral discrimination of auditory and visual stimuli, as well as enhanced EEG responses to those stimuli. In the auditory domain, fluency with tonal languages and musical training has been associated with long-term cortical and subcortical plasticity, but less is known about the effects of shorter-term training. This study combined electroencephalography (EEG) and behavioral measures to investigate short-term learning and neural plasticity in both auditory and visual domains. Forty adult participants were divided into four groups. Three groups trained on one of three tasks, involving discrimination of auditory fundamental frequency (F0), auditory amplitude modulation rate (AM), or visual orientation (VIS). The fourth (control) group received no training. Pre- and post-training tests, as well as retention tests 30 days after training, involved behavioral discrimination thresholds, steady-state visually evoked potentials (SSVEP) to the flicker frequencies of visual stimuli, and auditory envelope-following responses simultaneously evoked and measured in response to rapid stimulus F0 (EFR), thought to reflect subcortical generators, and slow amplitude modulation (ASSR), thought to reflect cortical generators. Enhancement of the ASSR was observed in both auditory-trained groups, not specific to the AM-trained group, whereas enhancement of the SSVEP was found only in the visually-trained group. No evidence was found for changes in the EFR. The results suggest that some aspects of neural plasticity can develop rapidly and may generalize across tasks but not across modalities. Behaviorally, the pattern of learning was complex, with significant cross-task and cross-modal learning effects.

The neural substrates by which speech sounds are perceptually segregated into distinct streams are poorly understood. Here, we recorded high-density scalp event-related potentials (ERPs) while participants were presented with a cyclic pattern of three vowel sounds (/ee/-/ae/-/ee/). Each trial consisted of an adaptation sequence, which could have either a small, intermediate, or large difference in first formant (Δ f 1 ) as well as a test sequence, in which Δ f 1 was always intermediate. For the adaptation sequence, participants tended to hear two streams (“streaming”) when Δ f 1 was intermediate or large compared to when it was small. For the test sequence, in which Δ f 1 was always intermediate, the pattern was usually reversed, with participants hearing a single stream with increasing Δ f 1 in the adaptation sequences. During the adaptation sequence, Δ f 1 -related brain activity was found between 100–250 ms after the /ae/ vowel over fronto-central and left temporal areas, consistent with generation in auditory cortex. For the test sequence, prior stimulus modulated ERP amplitude between 20–150 ms over left fronto-central scalp region. Our results demonstrate that the proximity of formants between adjacent vowels is an important factor in the perceptual organization of speech, and reveal a widely distributed neural network supporting perceptual grouping of speech sounds.

In a multi-talker situation, spatial separation between talkers reduces cognitive processing load: this is the "spatial release of cognitive load". The present study investigated the role played by the relative levels of the talkers on this spatial release of cognitive load. During the experiment, participants had to report the speech emitted by a target talker in the presence of a concurrent masker talker. The spatial separation (0° and 120° angular distance in azimuth) and the relative levels of the talkers (adverse, intermediate, and favorable target-to-masker ratio) were manipulated. The cognitive load was assessed with a prefrontal functional near-infrared spectroscopy. Data from 14 young normal-hearing listeners revealed that the target-to-masker ratio had a direct impact on the spatial release of cognitive load. Spatial separation significantly reduced the prefrontal activity only for the intermediate target-to-masker ratio and had no effect on prefrontal activity for the favorable and the adverse target-to-masker ratios. Therefore, the relative levels of the talkers might be a key point to determine the spatial release of cognitive load and more specifically the prefrontal activity induced by spatial cues in multi-talker situations.

The objective of this study was to demonstrate the efficacy of acute inactivation of brain areas by cooling in the behaving ferret and to demonstrate that cooling auditory cortex produced a localisation deficit that was specific to auditory stimuli. The effect of cooling on neural activity was measured in anesthetized ferret cortex. The behavioural effect of cooling was determined in a benchmark sound localisation task in which inactivation of primary auditory cortex (A1) is known to impair performance. Cooling strongly suppressed the spontaneous and stimulus-evoked firing rates of cortical neurons when the cooling loop was held at temperatures below 10°C, and this suppression was reversed when the cortical temperature recovered. Cooling of ferret auditory cortex during behavioural testing impaired sound localisation performance, with unilateral cooling producing selective deficits in the hemifield contralateral to cooling, and bilateral cooling producing deficits on both sides of space. The deficit in sound localisation induced by inactivation of A1 was not caused by motivational or locomotor changes since inactivation of A1 did not affect localisation of visual stimuli in the same context.

Significance Harmonicity is a fundamental element of music, speech, and animal vocalizations. How the brain extracts harmonic structures embedded in complex sounds remains largely unknown. We have discovered a unique population of harmonic template neurons in the core region of auditory cortex of marmosets, a highly vocal primate species. Responses of these neurons show nonlinear facilitation to harmonic complex sounds over inharmonic sounds and selectivity for particular harmonic structures. Such neuronal selectivity may form the basis of harmonic processing by the brain and has important implications for music and speech processing.

Whether the auditory and visual systems use a similar coding strategy to represent motion direction is an open question. We investigated this question in the barn owl's optic tectum ( OT ) testing stimulus‐specific adaptation ( SSA ) to the direction of motion. SSA , the reduction of the response to a repetitive stimulus that does not generalize to other stimuli, has been well established in OT neurons. SSA suggests a separate representation of the adapted stimulus in upstream pathways. So far, only SSA to static stimuli has been studied in the OT . Here, we examined adaptation to moving auditory and visual stimuli. SSA to motion direction was examined using repeated presentations of moving stimuli, occasionally switching motion to the opposite direction. Acoustic motion was either mimicked by varying binaural spatial cues or implemented in free field using a speaker array. While OT neurons displayed SSA to motion direction in visual space, neither stimulation paradigms elicited significant SSA to auditory motion direction. These findings show a qualitative difference in how auditory and visual motion is processed in the OT and support the existence of dedicated circuitry for representing motion direction in the early stages of visual but not the auditory system.

Auditory nerve fibers (ANFs) transmit acoustic information from the sensory hair cells to the cochlear nuclei. In experimental and clinical audiology, probing the whole ANF population remains a difficult task, as the ANFs differ greatly in their threshold and onset response to sound. Thus, low spontaneous rate (SR) fibers, which have rather higher thresholds, delay and larger jitter in their first spike latency are not detectable in the far-field compound action potential of the auditory nerve. Here, we developed a new protocol of acoustic stimulation together with electrophysiological signal processing to track the steady state activity of ANFs. Mass potentials at the round window were recorded in response to repetitive 300-ms bursts of 1/3 octave band noise centered on a frequency probe. Analysis was assessed during the last 200-ms of the response to capture the steady-state response of ANFs. To eliminate the microphonic component reflecting the sensory cells activity, repetitive pairs of sounds of opposite polarities were used. The spectral analysis was calculated on the average of two consecutive responses, and the neural gain was calculated by dividing point-by-point the spectrum to sound over unstimulated condition. In response to low-sound-level stimulation, neural gain predominated in the low-frequency cochlear regions, while a second component of responses centered on higher cochlear frequency regions appeared beyond 30 dB SPL. At 60 dB SPL, neural gain showed a bimodal shape, with a notch near 5.6 kHz. In addition to correlate with the functional mapping of ANFs along the tonotopic axis, the deletion of low-SR fibers leads to a reduction in the high-frequency response, where the low-SR fibers are preferentially located. Thus, mass potentials at the round window may provide a useful tool to probe the SR-based distribution of ANFs in humans and in other species in which direct single-unit recordings are difficult to achieve or not feasible.

We report on the superior electrochemical properties, in-vivo performance and long term stability under electrical stimulation of a new electrode material fabricated from lithographically patterned glassy carbon. For a direct comparison with conventional metal electrodes, similar ultra-flexible, micro-electrocorticography (μ-ECoG) arrays with platinum (Pt) or glassy carbon (GC) electrodes were manufactured. The GC microelectrodes have more than 70% wider electrochemical window and 70% higher CTC (charge transfer capacity) than Pt microelectrodes of similar geometry. Moreover, we demonstrate that the GC microelectrodes can withstand at least 5 million pulses at 0.45 mC/cm 2 charge density with less than 7.5% impedance change, while the Pt microelectrodes delaminated after 1 million pulses. Additionally, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) was selectively electrodeposited on both sets of devices to specifically reduce their impedances for smaller diameters (<60 μm). We observed that PEDOT-PSS adhered significantly better to GC than Pt, and allowed drastic reduction of electrode size while maintaining same amount of delivered current. The electrode arrays biocompatibility was demonstrated through in-vitro cell viability experiments, while acute in vivo characterization was performed in rats and showed that GC microelectrode arrays recorded somatosensory evoked potentials (SEP) with an almost twice SNR (signal-to-noise ratio) when compared to the Pt ones.

Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.

Extensive research on humans has improved our understanding of how the brain integrates information from our different senses, and has begun to uncover the brain regions and large-scale neural activity that contributes to an observer's ability to perceive the relative timing of auditory and visual stimuli. In the present study, we developed the first behavioral tasks to assess the perception of audiovisual temporal synchrony in rats. Modeled after the parameters used in human studies, separate groups of rats were trained to perform: (1) a simultaneity judgment task in which they reported whether audiovisual stimuli at various stimulus onset asynchronies (SOAs) were presented simultaneously or not; and (2) a temporal order judgment task in which they reported whether they perceived the auditory or visual stimulus to have been presented first. Furthermore, using in vivo electrophysiological recordings in the lateral extrastriate visual (V2L) cortex of anesthetized rats, we performed the first investigation of how neurons in the rat multisensory cortex integrate audiovisual stimuli presented at different SOAs. As predicted, rats (n = 7) trained to perform the simultaneity judgment task could accurately (~80%) identify synchronous vs. asynchronous (200 ms SOA) trials. Moreover, the rats judged trials at 10 ms SOA to be synchronous, whereas the majority (~70%) of trials at 100 ms SOA were perceived to be asynchronous. During the temporal order judgment task, rats (n = 7) perceived the synchronous audiovisual stimuli to be "visual first" for ~52% of the trials, and calculation of the smallest timing interval between the auditory and visual stimuli that could be detected in each rat (i.e., the just noticeable difference (JND)) ranged from 77 ms to 122 ms. Neurons in the rat V2L cortex were sensitive to the timing of audiovisual stimuli, such that spiking activity was greatest during trials when the visual stimulus preceded the auditory by 20-40 ms. Ultimately, given that our behavioral and electrophysiological results were consistent with studies conducted on human participants and previous recordings made in multisensory brain regions of different species, we suggest that the rat represents an effective model for studying audiovisual temporal synchrony at both the neuronal and perceptual level.

Auditory selective attention paradigms are powerful tools for elucidating the various stages of speech processing. This study examined electrocorticographic activation during target detection tasks within and beyond auditory cortex. Subjects were nine neurosurgical patients undergoing chronic invasive monitoring for treatment of medically refractory epilepsy. Four subjects had left hemisphere electrode coverage, four had right coverage and one had bilateral coverage. Stimuli were 300 ms complex tones or monosyllabic words, each spoken by a different male or female talker. Subjects were instructed to press a button whenever they heard a target corresponding to a specific stimulus category (e.g., tones, animals, numbers). High gamma (70-150 Hz) activity was simultaneously recorded from Heschl's gyrus (HG), superior, middle temporal and supramarginal gyri (STG, MTG, SMG), as well as prefrontal cortex (PFC). Data analysis focused on: (1) task effects (non-target words in tone detection vs. semantic categorization task); and (2) target effects (words as target vs. non-target during semantic classification). Responses within posteromedial HG (auditory core cortex) were minimally modulated by task and target. Non-core auditory cortex (anterolateral HG and lateral STG) exhibited sensitivity to task, with a smaller proportion of sites showing target effects. Auditory-related areas (MTG and SMG) and PFC showed both target and, to a lesser extent, task effects, that occurred later than those in the auditory cortex. Significant task and target effects were more prominent in the left hemisphere than in the right. Findings demonstrate a hierarchical organization of speech processing during auditory selective attention.

Brain imaging techniques that use vascular signals to map changes in neuronal activity rely on the coupling between electrophysiology and hemodynamics, a phenomenon referred to as “neurovascular coupling” (NVC). It is unknown whether this relationship remains reliable under altered brain states associated with acetylcholine (ACh) levels, such as attention and arousal and in pathological conditions such as Alzheimer's disease. We therefore assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex, measured by cerebral blood flow (CBF) and neurophysiological recordings (local field potentials, LFPs). We found that acutely enhanced ACh tone significantly potentiated whisker-evoked CBF responses through muscarinic ACh receptors and concurrently facilitated neuronal responses, as illustrated by increases in the amplitude and power in high frequencies of the evoked LFPs. However, the cellular identity of the activated neuronal network within the responsive barrel was unchanged, as characterized by c-Fos upregulation in pyramidal cells and GABA interneurons coexpressing vasoactive intestinal polypeptide. In contrast, chronic ACh deprivation hindered whisker-evoked CBF responses and the amplitude and power in most frequency bands of the evoked LFPs and reduced the rostrocaudal extent and area of the activated barrel without altering its identity. Correlations between LFP power and CBF, used to estimate NVC, were enhanced under high ACh tone and disturbed significantly by ACh depletion. We conclude that ACh is not only a facilitator but also a prerequisite for the full expression of sensory-evoked NVC responses, indicating that ACh may alter the fidelity of hemodynamic signals in assessing changes in evoked neuronal activity. SIGNIFICANCE STATEMENT Neurovascular coupling, defined as the tight relationship between activated neurons and hemodynamic responses, is a fundamental brain function that underlies hemodynamic-based functional brain imaging techniques. However, the impact of altered brain states on this relationship is largely unknown. We therefore investigated how acetylcholine (ACh), known to drive brain states of attention and arousal and to be deficient in pathologies such as Alzheimer's disease, would alter neurovascular coupling responses to sensory stimulation. Whereas acutely increased ACh enhanced neuronal responses and the resulting hemodynamic signals, chronic loss of cholinergic input resulted in dramatic impairments in both types of sensory-evoked signals. We conclude that ACh is not only a potent modulator but also a requirement for the full expression of sensory-evoked neurovascular coupling responses.