Publications using TDT

Neurobiological theories of memory posit that the neocortex is a storage site of declarative memories, a hallmark of which is the association of two arbitrary neutral stimuli. Early sensory cortices, once assumed uninvolved in memory storage, recently have been implicated in associations between neutral stimuli and reward or punishment. We asked whether links between neutral stimuli also could be formed in early visual or auditory cortices. Rats were presented with a tone paired with a light using a sensory preconditioning paradigm that enabled later evaluation of successful association. Subjects that acquired this association developed enhanced sound evoked potentials in their primary and secondary visual cortices. Laminar recordings localized this potential to cortical Layers 5 and 6. A similar pattern of activation was elicited by microstimulation of primary auditory cortex in the same subjects, consistent with a cortico-cortical substrate of association. Thus, early sensory cortex has the capability to form neutral stimulus associations. This plasticity may constitute a declarative memory trace between sensory cortices.

Behavioral improvement within the first hour of training is commonly explained as procedural learning (i.e., strategy changes resulting from task familiarization). However, it may additionally reflect a rapid adjustment of the perceptual and/or attentional system in a goal-directed task. In support of this latter hypothesis, we show feature-specific gains in performance for groups of participants briefly trained to use either a spectral or spatial difference between 2 vowels presented simultaneously during a vowel identification task. In both groups, the neuromagnetic activity measured during the vowel identification task following training revealed source activity in auditory cortices, prefrontal, inferior parietal, and motor areas. More importantly, the contrast between the 2 groups revealed a striking double dissociation in which listeners trained on spectral or spatial cues showed higher source activity in ventral ("what") and dorsal ("where") brain areas, respectively. These feature-specific effects indicate that brief training can implicitly bias top-down processing to a trained acoustic cue and induce a rapid recalibration of the ventral and dorsal auditory streams during speech segregation and identification.

The acoustic change complex (ACC) is an auditory-evoked potential elicited to changes within an ongoing stimulus that indicates discrimination at the level of the auditory cortex. Only a few studies to date have attempted to record ACCs in young infants. The purpose of the present study was to investigate the elicitation of ACCs to long-duration speech stimuli in English-learning 4-month-old infants. ACCs were elicited to consonant contrasts made up of two concatenated speech tokens. The stimuli included native dental-dental /dada/ and dental-labial /daba/ contrasts and a nonnative Hindi dental-retroflex /daDa/ contrast. Each consonant-vowel speech token was 410 ms in duration. Slow cortical responses were recorded to the onset of the stimulus and to the acoustic change from /da/ to either /ba/ or /Da/ within the stimulus with significantly prolonged latencies compared with adults. ACCs were reliably elicited for all stimulus conditions with more robust morphology compared with our previous findings using stimuli that were shorter in duration. The P1 amplitudes elicited to the acoustic change in /daba/ and /daDa/ were significantly larger compared to /dada/ supporting that the brain discriminated between the speech tokens. These findings provide further evidence for the use of ACCs as an index of discrimination ability.

The Mitogen-Activated Protein kinase, MAP3K1, plays an important role in a number of cellular processes, including epithelial migration during eye organogenesis. In addition, studies in keratinocytes indicate that MAP3K1 signaling through JNK is important for actin stress fibre formation and cell migration. However, MAP3K1 can also act independently of JNK in the regulation of cell proliferation and apoptosis. We have identified a mouse mutant, goya, which exhibits eyes-open-at-birth and microphthalmia phenotypes. In addition, these mice also have hearing loss. The goya mice carry a splice site mutation in the Map3k1 gene. We show that goya and kinase-deficient Map3k1 homozygotes initially develop supernumerary cochlear outer hair cells (OHCs) that subsequently degenerate, and a progressive profound hearing loss is observed by 9-weeks of age. Heterozygote mice also develop supernumerary OHCs, but no cellular degeneration or hearing loss is observed. MAP3K1 is expressed in a number of inner ear cell types, including outer and inner hair cells, stria vascularis and spiral ganglion. Investigation of targets downstream of MAP3K1 identified an increase in p38 phosphorylation (Thr180/Tyr182) in multiple cochlear tissues. We also show the extra OHCs do not arise from aberrant control of proliferation via p27KIP1. The identification of the goya mutant reveals a novel signaling molecule involved with hair cell development and survival. Mammalian hair cells do not have the ability to regenerate after damage, which can lead to irreversible sensorineural hearing loss. Given the observed goya phenotype, and the many diverse cellular processes MAP3K1 is known to act upon, further investigation of this model may help elaborate upon the mechanisms underlying sensory hair cell specification, and pathways important for their survival. In addition, MAP3K1 is revealed as a new candidate gene for human sensorineural hearing loss.

Although paternal ethanol (EtOH) abuse has been shown to affect the growth and behavior of offspring, the exact molecular and mechanistic basis remains largely unclear. Methylation alterations in imprinted genes may be related to well-documented teratogenic effects of ethanol. Here we show that chronic paternal ethanol exposure increases the susceptibility to abnormal behavior in offspring through male game epigenetic alteration. In our study, different doses of ethanol (0, 1.1, 3.3 g kg-1 ) were administered intra-gastrically to male mice and decreased sperm motility was found in the highest ethanol-exposed group compared with the controls. Data also showed a dose-dependent increase in deaf mice of the paternally ethanol-exposed groups. The methylation of H19, Peg3, Ndn and Snrpn was assessed in paternal spermatozoa and in the cerebral cortices of deaf mice. EtOH affected methylation of Peg3 (CpG 3, 7 and 9) in paternal spermatozoa and in the cerebral cortices of deaf mice, but the level of mRNA expression did not change, suggesting that other gene regulation may be involved in these processes. Overall, chronic paternal ethanol exposure could alter the methylation of imprinted genes in sire spermatozoa that could also be passed on to offspring, giving rise to developmental disorders. Our results provide possible epigenetic evidence for a paternal ethanol exposure contribution to Fetal Alcohol Syndrome (FAS).

MAP3K1 is a serine/threonine kinase that is activated by a diverse set of stimuli and exerts its effect through various downstream affecter molecules, including JNK, ERK1/2 and p38. In humans, mutant alleles of MAP3K1 are associated with 46, XY sex reversal. Until recently, the only phenotype observed in Map3k1tm1Yxia mutant mice was open eyelids at birth. Here, we report that homozygous Map3k1tm1Yxia mice have early-onset profound hearing loss accompanied by the progressive degeneration of cochlear outer hair cells. In the mouse inner ear, MAP3K1 has punctate localization at the apical surface of the supporting cells in close proximity to basal bodies. Although the cytoarchitecture, neuronal wiring and synaptic junctions in the organ of Corti are grossly preserved, Map3k1tm1Yxia mutant mice have supernumerary functional OHCs and Deiters' cells. Loss of MAP3K1 function resulted in the down-regulation of Fgfr3, Fgf8, Fgf10 and Atf3 expression in the inner ear. Fgfr3, Fgf8 and Fgf10 have a role in the otic placode induction or in otic epithelium development in mice and their functional deficits cause defects in cochlear morphogenesis and hearing loss. Our studies suggest that MAP3K1 has an essential role in the regulation of these key cochlear morphogenesis genes. Collectively, our data highlight the critical role of MAP3K1 in the development and function of the mouse inner ear and hearing.

Objective . The goal of this study was to begin to explore whether the beneficial auditory neural effects of early music training persist throughout life and influence age-related changes in neurophysiological processing of sound. Design . Cortical auditory evoked potentials (CAEPs) elicited by harmonic tone complexes were examined, including P1-N1-P2, mismatch negativity (MMN), and P3a. Study Sample . Data from older adult musicians ( n = 8 ) and nonmusicians ( n = 8 ) (ages 55–70 years) were compared to previous data from young adult musicians ( n = 40 ) and nonmusicians ( n = 20 ) (ages 18–33 years). Results . P1-N1-P2 amplitudes and latencies did not differ between older adult musicians and nonmusicians; however, MMN and P3a latencies for harmonic tone deviances were earlier for older musicians than older nonmusicians. Comparisons of P1-N1-P2, MMN, and P3a components between older and young adult musicians and nonmusicians suggest that P1 and P2 latencies are significantly affected by age, but not musicianship, while MMN and P3a appear to be more sensitive to effects of musicianship than aging. Conclusions . Findings support beneficial influences of musicianship on central auditory function and suggest a positive interaction between aging and musicianship on the auditory neural system.

Background and aims: The aim of this study was to evaluate the frontal intracortical connectivity during deep anaesthesia (burst-suppression). Methods: Experiments were carried out on 5 adult Sprague Dawley rats. The anaesthesia was induced and maintained with isoflurane. Following the induction of anaesthesia, rats were placed in a stereotactic instrument. A hole was drilled in the skull over the frontal cortex and electrodes were inserted in order to record the local field potentials. Rats were maintained in deep level anaesthesia (burst-suppression). The cortical connectivity was assessed by computing the coherence spectra. The frontal intracortical connectivity was calculated during burst, suppression (non-burst) and slow wave anaesthesia periods. Results: The global cortical connectivity (0.5-100 Hz) was 0.61 ± 0.078 during the burst periods compared to 0.55 ± 0.032 (p < 0.05) during the suppression periods and 0.55 ± 0.015 (p < 0.05) during slow wave anaesthesia. Conclusions: The global cortical connectivity increased during the burst periods compared to the suppression periods and slow wave anaesthesia. This increase in the cortical synchronization might be due to the subcortical origin of the bursts.

To explore the expression levels of T-type calcium channel receptors in spiral ganglion neurons of C57BL/6J mice and the effect of T-type calcium channel blockers on the spiral ganglion neurons of 42-44-W C57BL/6J mice. We first quantified the subunits of T-type calcium channel blockers in the spiral ganglion neurons of C57BL/6J mice in three groups (6-8 W, 24-26 W, 42-44 W) according to age via RT-PCR. Next, we administered three drugs (zonisamide, felodipine, saline) to the 42-44-W C57BL/6J mice by gavage for four weeks. We observed the changes in the hearing threshold of 42-44-W C57BL/6J mice after treatment. Meanwhile, we measured the expression of calcium-binding proteins of spiral ganglion neurons after treatment. Our results showed that three receptors were expressed in the spiral ganglion neurons of C57BL/6J mice. The expression level of α1H was stronger than that of α1G and α1I. The expression levels of three receptors especially for α1G and α1H significantly decreased with age. The hearing threshold at 24 kHz was significantly decreased after zonisamide administration. No significant difference in the expression level of calbindin in spiral ganglion neurons was noted. Interestingly, the expression level of calmodulin in spiral ganglion neurons was lower in the zonisamide-treated groups than in the felodipine- and saline-treated group. We concluded that the administration of T-type calcium channel blocker for four consecutive weeks can improve the hearing by ameliorating calcium overload on spiral ganglion neurons of 42-44-W C57BL/6J mice.

Nowadays the neuroscientific community is taking more and more advantage of the continuous interaction between engineers and computational neuroscientists in order to develop neuroprostheses aimed at replacing damaged brain areas with artificial devices. To this end, a technological effort is required to develop neural network models which can be fed with the recorded electrophysiological patterns to yield the correct brain stimulation to recover the desired functions. In this paper we present a machine learning approach to derive the input-output function of the olfactory-limbic pathway in the in vitro whole brain of guinea pig, less complex and more controllable than an in vivo system. We first experimentally characterized the neuronal pathway by delivering different sets of electrical stimuli from the lateral olfactory tract (LOT) and by recording the corresponding responses in the lateral entorhinal cortex (l-ERC). As a second step, we used information theory to evaluate how much information output features carry about the input. Finally we used the acquired data to learn the LOT-l-ERC “I/O function,” by means of the kernel regularized least squares method, able to predict l-ERC responses on the basis of LOT stimulation features. Our modeling approach can be further exploited for brain prostheses applications.

Audiovisual (AV) speech perception is the process by which auditory and visual sensory signals are integrated and used to understand what a talker is saying during face-to-face communication. This form of communication is markedly superior to speech perception in either sensory modality alone. However, there are additional lexical factors that are affected by age-related cognitive changes that may contribute to differences in AV perception. In the current study, we extended an existing model of spoken word identification to the AV domain, and examined the cognitive factors that contribute to age-related and individual differences in AV perception of words varying in lexical difficulty (i.e., on the basis of competing items). Young (n = 49) and older adults (n = 50) completed a series of cognitive inhibition tasks and a spoken word identification task. The words were presented in auditory-only, visual-only, and AV conditions, and were equally divided into lexically hard (words with many competitors) and lexically easy (words with few competitors). Overall, young adults demonstrated better inhibitory abilities and higher identification performance than older adults. However, whereas no relationship was observed between inhibitory abilities and AV word identification performance in young adults, there was a significant relationship between Stroop interference and AV identification of lexically hard words in older adults. These results are interpreted within the framework of existing models of spoken-word recognition with implications for how cognitive deficits in older adults contribute to speech perception.

The most common reason for sensorineural deafness is death of hair cells (HCs). Heat shock proteins (HSPs) are molecular chaperones that participate in folding, targeting, and degrading proteins. HSP expression is increased in response to various environmental stresses to protect cells from damage. Here, we tested whether viral-mediated overexpression of HSP70 can protect HCs and hearing from severe ototoxicity (kanamycin and furosemide) in guinea pigs. Adenovirus-HSP70 mCherry (Ad.HSP70-mCherry) was injected to experimental animals and adenovirus-mCherry to controls, 4 days before the ototoxic insult. Hearing thresholds were measured by auditory brainstem response before the insult and again before sacrificing the animals, 14 days after the insult. Epi-fluorescence immunocytochemistry showed that injection of Ad.HSP70-mCherry resulted in mCherry fluorescence in nonsensory cells of the organ of Corti. The ototoxic insult eliminated both outer HCs and inner HCs throughout most of the cochlea of control (adenovirus-mCherry-injected) ears and contralateral (uninjected) ears. Ad.HSP70-mCherry-injected ears exhibited a significant preservation of inner HCs compared to control and contralateral ears, but outer HCs were not protected. Auditory brainstem response thresholds were significantly better in Ad.HSP70-mCherry-injected ears than in control and contralateral ears. Our data show that HSP70 augmentation may represent a potential therapy attenuating ototoxic inner HC loss.

Novel ultra-soft neural microwire electrodes demonstrated excellent biocompatibility, high surface charge capacity, large electrochemical surface area, and sufficient electrical properties for recording single-unit activity from rodent visual cortex.

A novel PEDOT-ionic liquid polymer coating was synthesized for improving the performance of MEAs implanted in the brain.

Infants born prematurely are at risk for cardiovascular events causing hypoxia-ischemia (HI; reduced blood and oxygen to the brain). HI in turn can cause neuropathology, though patterns of damage are sometimes diffuse and often highly variable (with clinical heterogeneity further magnified by rapid development). As a result, though HI injury is associated with long-term behavioral and cognitive impairments in general, pathology indices for specific infants can provide only limited insight into individual prognosis. The current paper addresses this important clinical issue using a rat model that simulates unilateral HI in a late preterm infant coupled with long-term behavioral evaluation in two processing domains - auditory discrimination and spatial learning/memory. We examined the following: (1) whether deficits on one task would predict deficits on the other (suggesting that subjects with more severe injury perform worse across all cognitive domains) or (2) whether domain-specific outcomes among HI-injured subjects would be uncorrelated (suggesting differential damage to orthogonal neural systems). All animals (sham and HI) received initial auditory testing and were assigned to additional auditory testing (group A) or spatial maze testing (group B). This allowed within-task (group A) and between-task (group B) correlation. Anatomic measures of cortical, hippocampal and ventricular volume (indexing HI damage) were also obtained and correlated against behavioral measures. Results showed that auditory discrimination in the juvenile period was not correlated with spatial working memory in adulthood (group B) in either sham or HI rats. Conversely, early auditory processing performance for group A HI animals significantly predicted auditory deficits in adulthood (p = 0.05; no correlation in shams). Anatomic data also revealed significant relationships between the volumes of different brain areas within both HI and shams, but anatomic measures did not correlate with any behavioral measure in the HI group (though we saw a hippocampal/spatial correlation in shams, in the expected direction). Overall, current data provide an impetus to enhance tools for characterizing individual HI-related pathology in neonates, which could provide more accurate individual prognoses within specific cognitive/behavioral domains and thus improved patient-specific early interventions.

We study the feasibility and capability of the kernel temporal difference (KTD)( λ ) algorithm for neural decoding. KTD( λ ) is an online, kernel-based learning algorithm, which has been introduced to estimate value functions in reinforcement learning. This algorithm combines kernel-based representations with the temporal difference approach to learning. One of our key observations is that by using strictly positive definite kernels, algorithm’s convergence can be guaranteed for policy evaluation. The algorithm’s nonlinear functional approximation capabilities are shown in both simulations of policy evaluation and neural decoding problems (policy improvement). KTD can handle high-dimensional neural states containing spatial-temporal information at a reasonable computational complexity allowing real-time applications. When the algorithm seeks a proper mapping between a monkey’s neural states and desired positions of a computer cursor or a robot arm, in both open-loop and closed-loop experiments, it can effectively learn the neural state to action mapping. Finally, a visualization of the coadaptation process between the decoder and the subject shows the algorithm’s capabilities in reinforcement learning brain machine interfaces.

The robust representation of the environment from unreliable sensory cues is vital for the efficient function of the brain. However, how the neural processing captures the most reliable cues is unknown. The interaural time difference (ITD) is the primary cue to localize sound in horizontal space. ITD is encoded in the firing rate of neurons that detect interaural phase difference (IPD). Due to the filtering effect of the head, IPD for a given location varies depending on the environmental context. We found that, in barn owls, at each location there is a frequency range where the head filtering yields the most reliable IPDs across contexts. Remarkably, the frequency tuning of space-specific neurons in the owl's midbrain varies with their preferred sound location, matching the range that carries the most reliable IPD. Thus, frequency tuning in the owl's space-specific neurons reflects a higher-order feature of the code that captures cue reliability.

Some forms of tinnitus are believed to arise from abnormal central nervous system activity following a single or repeated noise exposure, for which there are no widely accepted pharmacological treatments. One central site that could be related to tinnitus awareness or modulation is the locus coeruleus, a brainstem structure associated with stress, arousal, and attention. In the present study, we evaluated the effects of cyclobenzaprine, a drug known to act on the rat locus coeruleus, on noise-induced tinnitus using Gap Prepulse Inhibition of the Acoustic Startle (GPIAS). In untreated rats, brief silent gaps presented prior to a 5-10-kHz bandpass startling stimulus produced robust GPIAS. Treatment with cyclobenzaprine alone had no effect on the ability of gaps to suppress the startle response. When animals were exposed to intense narrow-band (126 dB SPL, 16 kHz, 100 Hz BW) unilateral noise, GPIAS was significantly reduced, suggesting the presence of tinnitus. Following the noise exposure, a subset of rats that maintained a robust startle response continued to show GPIAS impairment at 6-20 kHz, 40 days post-noise, suggesting chronic tinnitus. When this subset of animals was treated with cyclobenzaprine, at a dose that had no significant effects on the startle response (0.5 mg/kg), GPIAS recovered partially or to near baseline levels at the affected frequencies. These results were consistent with the absence of tinnitus. By 48 h post-treatment, evidence of tinnitus re-emerged. Our results suggest that cyclobenzaprine was effective in transiently suppressing noise-induced tinnitus in rats.

Acoustic communication plays a key role for mate attraction in grasshoppers. Males use songs to advertise themselves to females. Females evaluate the song pattern, a repetitive structure of sound syllables separated by short pauses, to recognize a conspecific male and as proxy to its fitness. In their natural habitat females often receive songs with degraded temporal structure. Perturbations may, for example, result from the overlap with other songs. We studied the response behavior of females to songs that show different signal degradations. A perturbation of an otherwise attractive song at later positions in the syllable diminished the behavioral response, whereas the same perturbation at the onset of a syllable did not affect song attractiveness. We applied naïve Bayes classifiers to the spike trains of identified neurons in the auditory pathway to explore how sensory evidence about the acoustic stimulus and its attractiveness is represented in the neuronal responses. We find that populations of three or more neurons were sufficient to reliably decode the acoustic stimulus and to predict its behavioral relevance from the single-trial integrated firing rate. A simple model of decision making simulates the female response behavior. It computes for each syllable the likelihood for the presence of an attractive song pattern as evidenced by the population firing rate. Integration across syllables allows the likelihood to reach a decision threshold and to elicit the behavioral response. The close match between model performance and animal behavior shows that a spike rate code is sufficient to enable song pattern recognition.