Publications using TDT

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70–150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC. SIGNIFICANCE STATEMENT Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

Inhibition in the cerebral cortex is delivered by a variety of GABAergic interneurons. These cells have been categorized by their morphology, physiology, gene expression and connectivity. Many of these classes appear to be conserved across species, suggesting that the classes play specific functional roles in cortical processing. What these functions are, is still largely unknown. The largest group of interneurons in the upper layers of mouse primary visual cortex (V1) is formed by cells expressing the calcium-binding protein calretinin (CR). This heterogeneous class contains subsets of vasoactive intestinal polypeptide (VIP) interneurons and somatostatin (SOM) interneurons. Here we show, using in vivo two-photon calcium imaging in mice, that CR neurons can be sensitive to stimulus orientation, but that they are less selective on average than the overall neuronal population. Responses of CR neurons are suppressed by a surrounding stimulus, but less so than the overall population. In rats and primates, CR interneurons have been suggested to provide disinhibition, but we found that in mice their in vivo activation by optogenetics causes a net inhibition of cortical activity. Our results show that the average functional properties of CR interneurons are distinct from the averages of the parvalbumin, SOM and VIP interneuron populations.

Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

When stimuli from different sensory modalities are received, they may be combined by the brain to form a multisensory percept. One key mechanism for multisensory binding is the unity assumption under which multisensory stimuli that share certain physical properties like temporal and/or spatial correspondence are grouped together as deriving from one object. In humans, evidence for a role of the unity assumption has been found in spatial tasks and also in temporal tasks using stimuli that share physical properties (speech-related stimuli, musical and synesthetically congruent stimuli). In our study, we investigate the role of the unity assumption in an animal model in a temporal order judgment task. When subjects are asked to indicate which of two spatially separated visual stimuli appeared first in time, performance improves when the visual stimuli are paired (in time) with spatially non-informative acoustic cues, a phenomenon known as the temporal ventriloquism effect. Here, we show that European starlings perform better when one singleton acoustic cue is paired with the first visual stimulus as compared to pairing with the second visual stimulus. This shows, in combination with our previous study, that a non-informative singleton acoustic cue, when temporally paired with the first visual stimulus, triggers alerting while, when temporally pairing with the second visual stimulus, it prevents a temporal ventriloquism effect because the unity assumption is violated. Thus, the unity assumption influences sensory perception not only in humans but also in an animal model. The importance of the unity assumption in this task supports the idea that the temporal ventriloquism effect, similar to the spatial ventriloquism effect, is based on multisensory binding and integration but not on alerting effects.

Recent work has demonstrated that transmembrane channel-like 1 protein (TMC1) is an essential component of the sensory transduction complex in hair cells of the inner ear. A closely related homolog, TMC2, is expressed transiently in the neonatal mouse cochlea and can enable sensory transduction in Tmc1 -null mice during the first postnatal week. Both TMC1 and TMC2 are expressed at adult stages in mouse vestibular hair cells. The extent to which TMC1 and TMC2 can substitute for each other is unknown. Several biophysical differences between TMC1 and TMC2 suggest these proteins perform similar but not identical functions. To investigate these differences, and whether TMC2 can substitute for TMC1 in mature hair cells, we generated a knock-in mouse model allowing Cre -inducible expression of Tmc2 . We assayed for changes in hair cell sensory transduction and auditory and vestibular function in Tmc2 knockin mice ( Tm [ Tmc2 ]) in the presence or absence of endogenous Tmc1 , Tmc2 or both. Our results show that expression of Tm[TMC2] restores sensory transduction in vestibular hair cells and transiently in cochlear hair cells in the absence of TMC1. The cellular rescue leads to recovery of balance but not auditory function. We conclude that TMC1 provides some additional necessary function, not provided by TMC2.

Cortical mechanisms that regulate acute or chronic pain remain poorly understood. The prefrontal cortex (PFC) exerts crucial control of sensory and affective behaviors. Recent studies show that activation of the projections from the PFC to the nucleus accumbens (NAc), an important pathway in the brain's reward circuitry, can produce inhibition of both sensory and affective components of pain. However, it is unclear whether this circuit is endogenously engaged in pain regulation. To answer this question, we disrupted this circuit using an optogenetic strategy. We expressed halorhodopsin in pyramidal neurons from the PFC, and then selectively inhibited the axonal projection from these neurons to neurons in the NAc core. Our results reveal that inhibition of the PFC or its projection to the NAc, heightens both sensory and affective symptoms of acute pain in naïve rats. Inhibition of this corticostriatal pathway also increased nociceptive sensitivity and the aversive response in a chronic neuropathic pain model. Finally, corticostriatal inhibition resulted in a similar aversive phenotype as chronic pain. These results strongly suggest that the projection from the PFC to the NAc plays an important role in endogenous pain regulation, and its impairment contributes to the pathology of chronic pain.

Significance Early linguistic experience affects perception and cortical processing of speech, even in infants. The current study examined whether linguistic effects extend to brainstem speech encoding, where responses are rapid, automatic, and preattentive. We focused on transient consonants and measured perception behaviorally and the corresponding complex auditory brainstem response (cABR) onset using simultaneous electroencephalography/magnetoencephalography (EEG/MEG) in native Spanish and English speakers. We demonstrate that the latency of an EEG-cABR onset peak predicts consonant perception and that the perception differs according to language background. MEG-cABR analysis demonstrates deep sources for the onset, providing complimentary support for a brainstem origin. Effects of early linguistic experience on speech perception can be observed at the earlier stage of speech encoding at the brainstem.

Rats have the ability to learn and perform sophisticated behavioral tasks, making them very useful for investigating neural circuit functions. In contrast to the extensive mouse genetic toolkit, the paucity of recombinase-expressing rat models has limited the ability to monitor and manipulate molecularly-defined neural populations in this species. Here we report the generation and validation of two knock-in rat strains expressing either Cre or Flp recombinase under the control of Parvalbumin (Pvalb) , a gene expressed in the critical “fast-spiking” subset of inhibitory interneurons (FSIs). These strains were generated with CRISPR-Cas9 gene editing and show highly specific and penetrant labeling of Pvalb -expressing neurons, as demonstrated by in situ hybridization and immunohistochemistry. We validated these models in both prefrontal cortex and striatum using both ex vivo and in vivo approaches, including whole-cell recording, optogenetics, extracellular physiology and photometry. Our results demonstrate the utility of these new transgenic models for a wide range of neuroscience experiments.

Tonal working memory (WM) refers to the maintenance and the online manipulation of tonal information and has been suggested to involve different mechanisms than verbal WM. Previous research has suggested that verbal WM performance is determined by the duration instead of the number of verbal materials. We investigated in the present study to what degree that the number and the duration of notes in a sequence influence the tonal WM in participants with or without professional musical training. The forward tonal discrimination task in Experiment 1 tested the maintenance of the tonal information and the backward N-back tonal task in Experiment 2 probed the running memory span of tonal information. Results show that the number of notes, but not the duration of notes in a tone sequence significantly affects tonal WM performance for both musicians and non-musicians. In addition, within a minimum musical context, musicians outperformed non-musicians in the N-back tonal task but not the forward tone sequence discrimination task. These findings indicate that the capacity of tonal WM is determined by the number of notes but not the duration of notes in a sequence to be memorized, suggesting a different mechanism underlying tonal WM from verbal WM. Furthermore, the present study demonstrated that N-back tonal task is a quantitative and sensitive measure of the effect of musical training on tonal WM.

Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.

The ventriloquism aftereffect (VAE) refers to a shift in auditory spatial perception following exposure to a spatial disparity between auditory and visual stimuli. The VAE has been previously measured on two distinct time scales. Hundreds or thousands of exposures to a an audio-visual spatial disparity produces enduring VAE that persists after exposure ceases. Exposure to a single audio-visual spatial disparity produces immediate VAE that decays over seconds. To determine if these phenomena are two extremes of a continuum or represent distinct processes, we conducted an experiment with normal hearing listeners that measured VAE in response to a repeated, constant audio-visual disparity sequence, both immediately after exposure to each audio-visual disparity and after the end of the sequence. In each experimental session, subjects were exposed to sequences of auditory and visual targets that were constantly offset by +8° or -8° in azimuth from one another, then localized auditory targets presented in isolation following each sequence. Eye position was controlled throughout the experiment, to avoid the effects of gaze on auditory localization. In contrast to other studies that did not control eye position, we found both a large shift in auditory perception that decayed rapidly after each AV disparity exposure, along with a gradual shift in auditory perception that grew over time and persisted after exposure to the AV disparity ceased. We modeled the temporal and spatial properties of the measured auditory shifts using grey box nonlinear system identification, and found that two models could explain the data equally well. In the power model, the temporal decay of the ventriloquism aftereffect was modeled with a power law relationship. This causes an initial rapid drop in auditory shift, followed by a long tail which accumulates with repeated exposure to audio-visual disparity. In the double exponential model, two separate processes were required to explain the data, one which accumulated and decayed exponentially and the other which slowly integrated over time. Both models fit the data best when the spatial spread of the ventriloquism aftereffect was limited to a window around the location of the audio-visual disparity. We directly compare the predictions made by each model, and suggest additional measurements that could help distinguish which model best describes the mechanisms underlying the VAE.

Adaptation of learning and decision-making might depend on the regulation of activity in the prefrontal cortex. Here we examined how volatility of reward probabilities influences learning and neural activity in the primate prefrontal cortex. We found that animals selected recently rewarded targets more often when reward probabilities of different options fluctuated across trials than when they were fixed. Additionally, neurons in the orbitofrontal cortex displayed more sustained activity related to the outcomes of their previous choices when reward probabilities changed over time. Such volatility also enhanced signals in the dorsolateral prefrontal cortex related to the current but not the previous location of the previously rewarded target. These results suggest that prefrontal activity related to choice and reward is dynamically regulated by the volatility of the environment and underscore the role of the prefrontal cortex in identifying aspects of the environment that are responsible for previous outcomes and should be learned.

Age-related hearing decline typically includes threshold shifts as well as reduced wave I auditory brainstem response (ABR) amplitudes due to cochlear synaptopathy/neuropathy, which may compromise precise coding of suprathreshold speech envelopes. This is supported by findings with older listeners, who have difficulties in envelope and speech processing, especially in noise. However, separating the effects of threshold elevation, synaptopathy, and degradation by noise on physiological representations may be difficult. In the present study, the effects of notched, low- and high-pass noise on envelope-following responses (EFRs) in aging were compared when sound levels (aged: 85-dB SPL; young: 60- to 80-dB SPL) were matched between groups peripherally, by matching wave I ABR amplitudes, or centrally by matching EFR amplitudes. Low-level notched noise reduced EFRs to sinusoidally amplitude-modulated (SAM) tones in young animals for notch widths up to 2 octaves. High-pass noise above the carrier frequency reduced EFRs. Young animals showed EFR reductions at lower noise levels. Low-pass noise did not reduce EFRs in either young or aged animals. High-pass noise may affect EFR amplitudes in young animals more than aged by reducing the contributions of high-frequency-sensitive inputs. EFRs to SAM tones in modulated noise (NAM) suggest that neurons of young animals can synchronize to NAM at lower sound levels and maintain dual AM representations better than older animals. The overall results show that EFR amplitudes are strongly influenced by aging and the presence of a competing sound that likely reduces or shifts the pool of responsive neurons.

Stereocilia are mechanosensitive protrusions on the surfaces of sensory hair cells in the inner ear that detect sound, gravity, and head movement. Their cores are composed of parallel actin filaments that are cross-linked and stabilized by several actin-binding proteins, including fascin-2, plastin-1, espin, and XIRP2. The actin filaments are the most stable known, with actin turnover primarily occurring at the stereocilia tips. While stereocilia actin dynamics has been well studied, little is known about the behavior of the actin cross-linking proteins, which are the most abundant type of protein in stereocilia after actin and are critical for stereocilia morphogenesis and maintenance. Here, we developed a novel transgenic mouse to monitor EGFP-fascin-2 incorporation . In contrast to actin, EGFP-fascin-2 readily enters the stereocilia core. We also compared the effect of EGFP-fascin-2 expression on developing and mature stereocilia. When it was induced during hair cell development, we observed increases in both stereocilia length and width. Interestingly, stereocilia size was not affected when EGFP-fascin-2 was induced in adult stereocilia. Regardless of the time of induction, EGFP-fascin-2 displaced both espin and plastin-1 from stereocilia. Altering the actin cross-linker composition, even as the actin filaments exhibit little to no turnover, provides a mechanism for ongoing remodeling and repair important for stereocilia homeostasis.

Introduction: Injuries to the peripheral auditory system are among the most common results of high intensity impulsive acoustic exposure. Prior studies of high intensity sound transmission by the ossicular chain have relied upon measurements in animal models, measurements at more moderate sound levels (i.e. < 130 dB SPL), and/or measured responses to steady-state noise. Here, we directly measure intracochlear pressure in human cadaveric temporal bones, with fiber optic pressure sensors placed in scala vestibuli (SV) and tympani (ST), during exposure to shock waves with peak positive pressures between ∼7 and 83 kPa. Methods: Eight full-cephalic human cadaver heads were exposed, face-on, to acoustic shock waves in a 45 cm diameter shock tube. Specimens were exposed to impulses with nominal peak overpressures of 7, 28, 55, & 83 kPa (171, 183, 189, & 192 dB pSPL), measured in the free field adjacent to the forehead. Specimens were prepared bilaterally by mastoidectomy and extended facial recess to expose the ossicular chain. Ear canal (EAC), middle ear, and intracochlear sound pressure levels were measured with fiber-optic pressure sensors. Surface-mounted sensors measured SPL and skull strain near the opening of each EAC and at the forehead. Results: Measurements on the forehead showed incident peak pressures approximately twice that measured by adjacent free-field and EAC entrance sensors, as expected based on the sensor orientation (normal vs tangential to the shock wave propagation). At 7 kPa, EAC pressure showed gain, calculated from the frequency spectra, consistent with the ear canal resonance, and gain in the intracochlear pressures (normalized to the EAC pressure) were consistent with (though somewhat lower than) previously reported middle ear transfer functions. Responses to higher intensity impulses tended to show lower intracochlear gain relative to EAC, suggesting sound transmission efficiency along the ossicular chain is reduced at high intensities. Tympanic membrane (TM) rupture was observed following nearly every exposure 55 kPa or higher. Conclusions: Intracochlear pressures reveal lower middle-ear transfer function magnitudes (i.e. reduced gain relative to the ear canal) for high sound pressure levels, thus revealing lower than expected cochlear exposure based on extrapolation from cochlear pressures measured at more moderate sound levels. These results are consistent with lowered transmissivity of the ossicular chain at high intensities, and are consistent with our prior report measuring middle ear transfer functions in human cadaveric temporal bones with high intensity tone pips.

Acquired hearing loss is caused by complex interactions of multiple environmental risk factors, such as elevated levels of lead and noise, which are prevalent in urban communities. This study delineates the mechanism underlying lead-induced auditory dysfunction and its potential interaction with noise exposure. Young-adult C57BL/6 mice were exposed to: 1) control conditions; 2) 2 mM lead acetate in drinking water for 28 days; 3) 90 dB broadband noise 2 h/day for two weeks; and 4) both lead and noise. Blood lead levels were measured by inductively coupled plasma mass spectrometry analysis (ICP-MS) lead-induced cochlear oxidative stress signaling was assessed using targeted gene arrays, and the hearing thresholds were assessed by recording auditory brainstem responses. Chronic lead exposure downregulated cochlear Sod1, Gpx1, and Gstk1, which encode critical antioxidant enzymes, and upregulated ApoE, Hspa1a, Ercc2, Prnp, Ccl5, and Sqstm1, which are indicative of cellular apoptosis. Isolated exposure to lead or noise induced 8-12 dB and 11-25 dB shifts in hearing thresholds, respectively. Combined exposure induced 18-30 dB shifts, which was significantly higher than that observed with isolated exposures. This study suggests that chronic exposure to lead induces cochlear oxidative stress and potentiates noise-induced hearing impairment, possibly through parallel pathways.

Despite the common use of guinea pigs in investigations of the neural mechanisms of binaural and spatial hearing, their behavioral capabilities in spatial hearing tasks have surprisingly not been thoroughly investigated. To begin to fill this void, we tested the spatial hearing of adult male guinea pigs in several experiments using a paradigm based on the prepulse inhibition (PPI) of the acoustic startle response. In the first experiment, we presented continuous broadband noise from one speaker location and switched to a second speaker location (the "prepulse") along the azimuth prior to presenting a brief, ∼110 dB SPL startle-eliciting stimulus. We found that the startle response amplitude was systematically reduced for larger changes in speaker swap angle (i.e., greater PPI), indicating that using the speaker "swap" paradigm is sufficient to assess stimulus detection of spatially separated sounds. In a second set of experiments, we swapped low- and high-pass noise across the midline to estimate their ability to utilize interaural time- and level-difference cues, respectively. The results reveal that guinea pigs can utilize both binaural cues to discriminate azimuthal sound sources. A third set of experiments examined spatial release from masking using a continuous broadband noise masker and a broadband chirp signal, both presented concurrently at various speaker locations. In general, animals displayed an increase in startle amplitude (i.e., lower PPI) when the masker was presented at speaker locations near that of the chirp signal, and reduced startle amplitudes (increased PPI) indicating lower detection thresholds when the noise was presented from more distant speaker locations. In summary, these results indicate that guinea pigs can: 1) discriminate changes in source location within a hemifield as well as across the midline, 2) discriminate sources of low- and high-pass sounds, demonstrating that they can effectively utilize both low-frequency interaural time and high-frequency level difference sound localization cues, and 3) utilize spatial release from masking to discriminate sound sources. This report confirms the guinea pig as a suitable spatial hearing model and reinforces prior estimates of guinea pig hearing ability from acoustical and physiological measurements.

Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

Classic models of attention suggest that sustained neural firing constitutes a neural correlate of sustained attention. However, recent evidence indicates that behavioral performance fluctuates over time, exhibiting temporal dynamics that closely resemble the spectral features of ongoing, oscillatory brain activity. Therefore, it has been proposed that periodic neuronal excitability fluctuations might shape attentional allocation and overt behavior. However, empirical evidence to support this notion is sparse. Here, we address this issue by examining data from large-scale subdural recordings, using two different attention tasks that track perceptual ability at high temporal resolution. Our results reveal that perceptual outcome varies as a function of the theta phase even in states of sustained spatial attention. These effects were robust at the single-subject level, suggesting that rhythmic perceptual sampling is an inherent property of the frontoparietal attention network. Collectively, these findings support the notion that the functional architecture of top-down attention is intrinsically rhythmic.

The delivery of brain-controlled neuromodulation therapies during motor rehabilitation may augment recovery from neurological disorders. To test this hypothesis, we conceived a brain-controlled neuromodulation therapy that combines the technical and practical features necessary to be deployed daily during gait rehabilitation. Rats received a severe spinal cord contusion that led to leg paralysis. We engineered a proportional brain–spine interface whereby cortical ensemble activity constantly determines the amplitude of spinal cord stimulation protocols promoting leg flexion during swing. After minimal calibration time and without prior training, this neural bypass enables paralyzed rats to walk overground and adjust foot clearance in order to climb a staircase. Compared to continuous spinal cord stimulation, brain-controlled stimulation accelerates and enhances the long-term recovery of locomotion. These results demonstrate the relevance of brain-controlled neuromodulation therapies to augment recovery from motor disorders, establishing important proofs-of-concept that warrant clinical studies.