Publications using TDT

Nowadays, the majority of the progress in the development of implantable neuroprostheses has been achieved by improving the knowledge of brain functions so as to restore sensorial impairments. Intracortical microstimulation (ICMS) is a widely used technique to investigate site-specific cortical responses to electrical stimuli. Herein, we investigated the neural modulation induced in the primary auditory cortex (A1) by an acousto-electric transduction of ultrasonic signals using a bio-inspired intracortical microstimulator. The developed electronic system emulates the transduction of ultrasound signals in the cochlea, providing bio-inspired electrical stimuli. Firstly, we identified the receptive fields in the primary auditory cortex devoted to encoding ultrasonic waves at different frequencies, mapping each area with neurophysiological patterns. Subsequently, the activity elicited by bio-inspired ICMS in the previously identified areas, bypassing the sense organ, was investigated. The observed evoked response by microstimulation resulted as highly specific to the stimuli, and the spatiotemporal dynamics of neural oscillatory activity in the alpha, beta, and gamma waves were related to the stimuli preferred by the neurons at the stimulated site. The alpha waves modulated cortical excitability only during the activation of the specific tonotopic neuronal populations, inhibiting neural responses in unrelated areas. Greater neuronal activity in the posterior area of A1 was observed in the beta band, whereas a gamma rhythm was induced in the anterior A1. The results evidence that the proposed bio-inspired acousto-electric ICMS triggers high-frequency oscillations, encoding information about the stimulation sites and involving a large-scale integration in the brain.

Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.

The nucleus accumbens (NAc) contributes to behavioral inhibition and compulsions, but circuit mechanisms are unclear. Recent evidence suggests that amygdala and thalamic inputs exert opposing control over behavior, much like direct and indirect pathway output neurons. Accordingly, opponent processes between these NAc inputs or cell types may underlie efficient reward seeking. We assess the contributions of these circuit elements to mouse operant behavior during recurring conditions when reward is and is not available. Although direct pathway stimulation is rewarding and indirect pathway stimulation aversive, the activity of both cell types is elevated during periods of behavioral suppression, and the inhibition of either cell-type selectively increases unproductive reward seeking. Amygdala and thalamic inputs are also necessary for behavioral suppression, even though they both support self-stimulation and innervate different NAc subregions. These data suggest that efficient reward seeking relies on complementary activity across NAc cell types and inputs rather than opponent processes between them.

Previous research has shown that musical beat perception is a surprisingly complex phenomenon involving widespread neural coordination across higher-order sensory, motor and cognitive areas. However, the question of how low-level auditory processing must necessarily shape these dynamics, and therefore perception, is not well understood. Here, we present evidence that the auditory cortical representation of music, even in the absence of motor or top-down activations, already favours the beat that will be perceived. Extracellular firing rates in the rat auditory cortex were recorded in response to 20 musical excerpts diverse in tempo and genre, for which musical beat perception had been characterized by the tapping behaviour of 40 human listeners. We found that firing rates in the rat auditory cortex were on average higher on the beat than off the beat. This ‘neural emphasis’ distinguished the beat that was perceived from other possible interpretations of the beat, was predictive of the degree of tapping consensus across human listeners, and was accounted for by a spectrotemporal receptive field model. These findings strongly suggest that the ‘bottom-up’ processing of music performed by the auditory system predisposes the timing and clarity of the perceived musical beat.

Observer-based procedures are used to assess auditory behavior in infants, often incorporating adaptive tracking algorithms. These procedures are reliable, but effects of modifications made to accommodate infant testing are not fully understood. One modification is that observation intervals are undefined for the listener, introducing signal-temporal uncertainty and increasing the likelihood that listener response bias will influence estimates of performance. The effect of these factors was evaluated by comparing threshold estimates obtained from adults using two tasks: (1) single-interval, yes/no and (2) two-interval, forced-choice. Detection thresholds were estimated adaptively for a 1000-Hz FM tone in quiet and for a word presented in two-talker speech masking. Trials were initiated and judged by the observer (observer-based) or the listener (listener-based). Thus, listening intervals were temporally uncertain in observer-based procedures and temporally defined in listener-based procedures. Thresholds were higher for observer-based relative to corresponding listener-based procedures. The magnitude of this difference was similar across the yes/no and two-interval tasks, and was larger for masked word detection than tone detection in quiet. Listeners adopted a conservative criterion when tested using the observer-based, yes/no procedure, but modeling results suggest that signal-temporal uncertainty accounts for the largest portion of the threshold difference between observer-based and listener-based procedures.

During critical periods, neural circuits develop to form receptive fields that adapt to the sensory environment and enable optimal performance of relevant tasks. We hypothesized that early exposure to background noise can improve signal-in-noise processing, and the resulting receptive field plasticity in the primary auditory cortex can reveal functional principles guiding that important task. We raised rat pups in different spectro-temporal noise statistics during their auditory critical period. As adults, they showed enhanced behavioral performance in detecting vocalizations in noise. Concomitantly, encoding of vocalizations in noise in the primary auditory cortex improves with noise-rearing. Significantly, spectro-temporal modulation plasticity shifts cortical preferences away from the exposed noise statistics, thus reducing noise interference with the foreground sound representation. Auditory cortical plasticity shapes receptive field preferences to optimally extract foreground information in noisy environments during noise-rearing. Early noise exposure induces cortical circuits to implement efficient coding in the joint spectral and temporal modulation domain.

Visual search performance varies with stimulus and response history. Priming of pop-out refers to increased accuracy and reduced response time with repeated presentation of particular singleton and distractor features (e.g., a red target among green distractor stimuli), which are abruptly impaired when singleton and distractor features swap (e.g., green target among red distractors). Meanwhile, inhibition of return refers to the slowing of response time when target location repeats. Neurophysiological correlates of both these phenomena have been reported in the frontal eye field (FEF), an area in the frontal lobe contributing to attentional selection and eye movement planning. To understand the mechanistic origin of these adaptive behaviors, we investigated visual cortical area V4, an area providing input to and receiving feedback from FEF, during feature-based priming of pop-out and location-based inhibition of return. Performing a color pop-out task, monkeys exhibited pronounced priming of pop-out and inhibition of return. Neural spiking from V4 revealed earlier target selection associated with priming of pop-out and delayed selection associated with inhibition of return. These results demonstrate substantial involvement of extrastriate visual cortex in behavioral priming and inhibition of return.

In the auditory system, the spectrotemporal structure of acoustic signals determines the temporal pattern of spikes. Here, we investigated this effect in neurons of the barn owl’s auditory midbrain ( Tyto furcata ) that are selective for auditory space and whether it can influence the coding of sound direction. We found that in the nucleus where neurons first become selective to combinations of sound localization cues, reproducibility of spike trains across repeated trials of identical sounds, a metric of across-trial temporal fidelity of spiking patterns evoked by a stimulus, was maximal at the sound direction that elicited the highest firing rate. We then tested the hypothesis that this stimulus-dependent patterning resulted in rate co-modulation of cells with similar frequency and spatial selectivity, driving stimulus-dependent synchrony of population responses. Tetrodes were used to simultaneously record multiple nearby units in the optic tectum (OT), where auditory space is topographically represented. While spiking of neurons in OT showed lower reproducibility across trials compared with upstream nuclei, spike-time synchrony between nearby OT neurons was highest for sounds at their preferred direction. A model of the midbrain circuit explained the relationship between stimulus-dependent reproducibility and synchrony, and demonstrated that this effect can improve the decoding of sound location from the OT output. Thus, stimulus-dependent spiking patterns in the auditory midbrain can have an effect on spatial coding. This study reports a functional connection between spike patterning elicited by spectrotemporal features of a sound and the coding of its location.

Inhibition plays a key role in shaping sensory processing in the central auditory system and has been implicated in sculpting receptive field properties such as sound intensity coding and also in shaping temporal patterns of neuronal firing such as onset- or offset-evoked responses. There is substantial evidence supporting a decrease in inhibition throughout the ascending auditory pathway in geriatric animals. We therefore examined intensity coding of onset (ON) and offset (OFF) responses in auditory cortex of aged and young monkeys. A large proportion of cells in the primary auditory cortex (A1) and the caudolateral field (CL) displayed nonmonotonic rate-level functions for OFF responses in addition to nonmonotonic coding of ON responses. Aging differentially affected ON and OFF responses; the magnitude of effects was generally greater for ON responses. In addition to higher firing rates, neurons in old monkeys exhibited a significant increase in the proportion of monotonic rate-level functions and had higher best intensities than those in young monkeys. OFF responses in young monkeys displayed a range of intensity coding relationships with ON responses of the same cells, ranging from highly similar to highly dissimilar. Dissimilarity in ON/OFF coding was greater in CL and was reduced with aging, which was largely explained by a preferential decrease in the percentage of cells with nonmonotonic coding of ON and OFF responses. The changes we observed are consistent with previously demonstrated alterations in inhibition in the ascending auditory pathway of primates and could be involved in age-related deficits in the temporal processing of sounds. NEW & NOTEWORTHY Aging has a major impact on intensity coding of neurons in auditory cortex of rhesus macaques. Neural responses to sound onset and offset were affected to different extents, and their rate-level functions became more mutually similar, which could be accounted for by the loss of nonmonotonic intensity coding in geriatric monkeys. These findings were consistent with weakened inhibition in the central auditory system and could contribute to auditory processing deficits in elderly subjects.

The ventral pallidum (VP) is critical for invigorating reward seeking and is also involved in punishment avoidance, but how it contributes to such opposing behavioral actions remains unclear. Here, we show that GABAergic and glutamatergic VP neurons selectively control behavior in opposing motivational contexts. In vivo recording combined with optogenetics in mice revealed that these two populations oppositely encode positive and negative motivational value, are differentially modulated by animal's internal state, and determine the behavioral response during motivational conflict. Furthermore, GABAergic VP neurons are essential for movements toward reward in a positive motivational context but suppress movements in an aversive context. In contrast, glutamatergic VP neurons are essential for movements to avoid a threat but suppress movements in an appetitive context. Our results indicate that GABAergic and glutamatergic VP neurons encode the drive for approach and avoidance, respectively, with the balance between their activities determining the type of motivational behavior.

Objective: Intracortical microelectrode implants can generate a tissue response hallmarked by glial scarring and neuron cell death within 100-150 μm of the biomaterial device. Many have proposed that any performance decline in intracortical microstimulation (ICMS) due to this foreign body tissue response could be offset by increasing the stimulation amplitude. The mechanisms of this approach are unclear, however, as there has not been consensus on how increasing amplitude affects the spatial and temporal recruitment patterns of ICMS. Approach: We clarify these unknowns using in vivo two-photon imaging of mice transgenically expressing the calcium sensor GCaMP6s in Thy1 neurons or virally expressing the glutamate sensor iGluSnFr in neurons. Calcium and neurotransmitter activity are tracked in the neuronal somas and neuropil during long-train stimulation in Layer II/III of somatosensory cortex. Main results: Neural calcium activity and glutamate release are dense and strongest within 20-40 μm around the electrode, falling off with distance from the electrode. Neuronal calcium increases with higher amplitude stimulations. During prolonged stimulation trains, a sub-population of somas fail to maintain calcium activity. Interestingly, neuropil calcium activity is 3-fold less correlated to somatic calcium activity for cells that drop-out during the long stimulation train compared to cells that sustain activity throughout the train. Glutamate release is apparent only within 20 μm of the electrode and is sustained for at least 10s after cessation of the 15 and 20 μA stimulation train, but not lower amplitudes. Significance: These results demonstrate that increasing amplitude can increase the radius and intensity of neural recruitment, but it also alters the temporal response of some neurons. Further, dense glutamate release is highest within the first 20 μm of the electrode site even at high amplitudes, suggesting that there may be spatial limitations to the amplitude parameter space. The glutamate elevation outlasts stimulation, suggesting that high-amplitude stimulation may affect neurotransmitter re-uptake. This ultimately suggests that increasing the amplitude of ICMS device stimulation may fundamentally alter the temporal neural response, which could have implications for using amplitude to improve the ICMS effect or "offset" the effects of glial scarring.

Oxidative stress is a major contributor to noise-induced hearing loss, the most common cause of hearing loss among military personnel and young adults. HK-2 is a potent, orally-active, multifunctional, redox-modulating drug that has been shown to protect against a wide range of neurological disorders with no observed side effects. HK-2 protected cochlear HEI-OC1 cells against various forms of experimentally-induced oxidative stressors similar to those observed during and after intense noise exposure. The mechanisms by which HK-2 protects cells is twofold, first by its ability to reduce oxidative stress generated by free radicals, and second, by its ability to complex biologically active transition metals such as Fe+2, thus reducing their availability to participate in the Fenton reaction where highly toxic hydroxyl radicals are generated. For the rat in vivo studies, HK-2 provided significant protection against noise-induced hearing loss and hair cell loss. Noise-induced hearing loss was induced by an 8-16 kHz octave band noises presented for 8 h/d for 21 days at an intensity of 95 dB SPL. In the Prevention study, HK-2 was administered orally beginning 5 days before the start of the noise and ending 10 days after the noise. Treatment with HK-2 dose-dependently reduced the amount of noise-induced hearing impairment, reflected in the cochlear compound action potential, and noise-induced hair cell loss. In a subsequent Rescue experiment in which HK-2 was administered for 10 days starting after the noise was turned off, HK-2 also significantly reduced the amount of hearing impairment, but the effect size was substantially less than in the Prevention studies. HK-2 alone did not adversely affect HEI-OC1 cell viability, nor did it cause any adverse changes in rat body weight, behavior, cochlear function or hair cell integrity. Thus, HK-2 is a novel, safe, orally-deliverable and highly effective otoprotective compound with considerable potential for preventing hearing loss from noise and other hearing disorders linked to excessive oxidative stress.

The underlying causes of age-related hearing loss (ARHL) are not well understood, but it is clear from heritability estimates that genetics plays a role in addition to environmental factors. Genome-wide association studies (GWAS) in human populations can point to candidate genes that may be involved in ARHL, but follow-up analysis is needed to assess the role of these genes in the disease process. Some genetic variants may contribute a small amount to a disease, while other variants may have a large effect size, but the genetic architecture of ARHL is not yet well-defined. In this study, we asked if a set of 17 candidate genes highlighted by early GWAS reports of ARHL have detectable effects on hearing by knocking down expression levels of each gene in the mouse and analysing auditory function. We found two of the genes have an impact on hearing. Mutation of Dclk1 led to late-onset progressive increase in ABR thresholds and the A430005L14Rik (C1orf174) mutants showed worse recovery from noise-induced damage than controls. We did not detect any abnormal responses in the remaining 15 mutant lines either in thresholds or from our battery of suprathreshold ABR tests, and we discuss the possible reasons for this.

Phasic dopamine activity is evoked by reliable predictors of food reward and plays a role in cue-triggered, goal-directed behavior. While this important signal is modulated by physiological state (e.g. hunger, satiety), the mechanisms by which physiological state is integrated by dopamine neurons is only beginning to be elucidated. Activation of central receptors for glucagon-like peptide-1 (GLP-1R) via long-acting agonists (e.g., Exendin-4) suppresses food intake and food-directed motivated behavior, in part, through action in regions with dopamine cell bodies, terminals, and/or neural populations that directly target the mesolimbic dopamine system. However, the effects of GLP-1R activation on cue-evoked, phasic dopamine signaling remain unknown. Here, in vivo fiber photometry was used to capture real-time signaling dynamics selectively from dopamine neurons in the ventral tegmental area of male and female transgenic (tyrosine hydroxylase-Cre; TH:Cre+) rats trained to associate an audio cue with the brief availability of a sucrose solution. Cue presentation evoked a brief spike in dopamine activity. Administration of Exendin-4 (Ex4; 0, 0.05, 0.1 μg) to the lateral ventricle both dose-dependently suppressed sucrose-directed behaviors and the magnitude of cue-evoked dopamine activity. Moreover, the amplitude of cue evoked dopamine activity was significantly correlated with subsequent sucrose-directed behaviors. While female rats exhibited overall reduced dopamine responses to the sucrose-paired cue relative to males, there was no significant interaction with Ex4. Together, these findings support a role for central GLP-1Rs in modulating a form of dopamine signaling that influences approach behavior and provide a potential mechanism whereby GLP-1 suppresses food-directed behaviors.

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

We investigated whether the categorical perception (CP) of speech might also provide a mechanism that aids its perception in noise. We varied signal-to-noise ratio (SNR) [clear, 0 dB, -5 dB] while listeners classified an acoustic-phonetic continuum (/u/ to /a/). Noise-related changes in behavioral categorization were only observed at the lowest SNR. Event-related brain potentials (ERPs) differentiated category vs. category-ambiguous speech by the P2 wave (~180-320 ms). Paralleling behavior, neural responses to speech with clear phonetic status (i.e., continuum endpoints) were robust to noise down to -5 dB SNR, whereas responses to ambiguous tokens declined with decreasing SNR. Results demonstrate that phonetic speech representations are more resistant to degradation than corresponding acoustic representations. Findings suggest the mere process of binning speech sounds into categories provides a robust mechanism to aid figure-ground speech perception by fortifying abstract categories from the acoustic signal and making the speech code more resistant to external interferences.

Sound localization plays a critical role in animal survival. Three cues can be used to compute sound direction: interaural timing differences (ITDs), interaural level differences (ILDs) and the direction-dependent spectral filtering by the head and pinnae (spectral cues). Little is known about how spectral cues contribute to the neural encoding of auditory space. Here we report on auditory space encoding in the mouse superior colliculus (SC). We show that the mouse SC contains neurons with spatially-restricted receptive fields (RFs) that form an azimuthal topographic map. We found that frontal RFs require spectral cues and lateral RFs require ILDs. The neurons with frontal RFs have frequency tunings that match the spectral structure of the specific head and pinna filter for sound coming from the front. These results demonstrate that patterned spectral cues in combination with ILDs give rise to the topographic map of azimuthal auditory space.

Accumulation of amyloid β oligomers (AβO) in Alzheimer’s disease (AD) impairs hippocampal theta and gamma oscillations. These oscillations are important in memory functions and depend on distinct subtypes of hippocampal interneurons such as somatostatin-positive (SST) and parvalbumin-positive (PV) interneurons. Here, we investigated whether AβO causes dysfunctions in SST and PV interneurons by optogenetically manipulating them during theta and gamma oscillations in vivo in AβO-injected SST-Cre or PV-Cre mice. Hippocampal in vivo multi-electrode recordings revealed that optogenetic activation of channelrhodopsin-2 (ChR2)-expressing SST and PV interneurons in AβO-injected mice selectively restored AβO-induced reduction of the peak power of theta and gamma oscillations, respectively, and resynchronized CA1 pyramidal cell (PC) spikes. Moreover, SST and PV interneuron spike phases were resynchronized relative to theta and gamma oscillations, respectively. Whole-cell voltage-clamp recordings in CA1 PC in ex vivo hippocampal slices from AβO-injected mice revealed that optogenetic activation of SST and PV interneurons enhanced spontaneous inhibitory postsynaptic currents (IPSCs) selectively at theta and gamma frequencies, respectively. Furthermore, analyses of the stimulus–response curve, paired-pulse ratio, and short-term plasticity of SST and PV interneuron-evoked IPSCs ex vivo showed that AβO increased the initial GABA release probability to depress SST/PV interneuron’s inhibitory input to CA1 PC selectively at theta and gamma frequencies, respectively. Our results reveal frequency-specific and interneuron subtype-specific presynaptic dysfunctions of SST and PV interneurons’ input to CA1 PC as the synaptic mechanisms underlying AβO-induced impairments of hippocampal network oscillations and identify them as potential therapeutic targets for restoring hippocampal network oscillations in early AD.

The increasing awareness of the impact of spontaneous movements on neuronal activity has raised the need to track behavior. We present FreiPose, a versatile learning-based framework to directly capture 3D motion of freely definable points with high precision (median error < 3.5% body length, 41.9% improvement compared to state-of-the-art) and high reliability (82.8% keypoints within < 5% body length error boundary, 72.0% improvement). The versatility of FreiPose is demonstrated in two experiments: (1) By tracking freely moving rats with simultaneous electrophysiological recordings in motor cortex, we identified neuronal tuning to behavioral states and individual paw trajectories. (2) We inferred time points of optogenetic stimulation in rat motor cortex from the measured pose across individuals and attributed the stimulation effect automatically to body parts. The versatility and accuracy of FreiPose open up new possibilities for quantifying behavior of freely moving animals and may lead to new ways of setting up experiments.

Acid-base homeostasis is critical for normal growth, development, and hearing function. The sodium–hydrogen exchanger 6 (NHE6), a protein mainly expressed in early and recycling endosomes, plays an important role in regulating organellar pH. Mutations in NHE6 cause complex, slowly progressive neurodegeneration. Little is known about NHE6 function in the mouse cochlea. Here, we found that all NHE isoforms were expressed in wild-type (WT) mouse cochlea. Nhe6 knockout (KO) mice showed significant hearing loss compared to WT littermates. Immunohistochemistry in WT mouse cochlea showed that Nhe6 was localized in the organ of Corti (OC), spiral ganglion (SG), stria vascularis (SV), and afferent nerve fibres. The middle and the inner ears of WT and Nhe6 KO mice were not different morphologically. Given the putative role of NHE6 in early endosomal function, we examined Rab GTPase expression in early and late endosomes. We found no change in Rab5, significantly lower Rab7, and higher Rab11 levels in the Nhe6 KO OC, compared to WT littermates. Because Rabs mediate TrkB endosomal signalling, we evaluated TrkB phosphorylation in the OCs of both strains. Nhe6 KO mice showed significant reductions in TrkB and Akt phosphorylation in the OC. In addition, we examined genes used as markers of SG type I ( Slc17a7 , Calb1 , Pou4f1 , Cal2 ) and type II neurons ( Prph , Plk5 , Cacna1g ). We found that all marker gene expression levels were significantly elevated in the SG of Nhe6 KO mice, compared to WT littermates. Anti-neurofilament factor staining showed axon loss in the cochlear nerves of Nhe6 KO mice compared to WT mice. These findings indicated that BDNF/TrkB signalling was disrupted in the OC of Nhe6 KO mice, probably due to TrkB reduction, caused by over acidification in the absence of NHE6. Thus, our findings demonstrated that NHEs play important roles in normal hearing in the mammalian cochlea.