Publications using the OpenEx

Sodium salicylate (SS) is a widely used medication with side effects on hearing. In order to understand these side effects, we recorded sound-driven local-field potentials in a neural structure, the dorsal cortex of the inferior colliculus (ICd). Using a microiontophoretic technique, we applied SS at sites of recording and studied how auditory responses were affected by the drug. Furthermore, we studied how the responses were affected by combined local application of SS and an agonists/antagonist of the type-A or type-B γ-aminobutyric acid receptor (GABAA or GABAB receptor). Results revealed that SS applied alone enhanced auditory responses in the ICd, indicating that the drug had local targets in the structure. Simultaneous application of the drug and a GABAergic receptor antagonist synergistically enhanced amplitudes of responses. The synergistic interaction between SS and a GABAA receptor antagonist had a relatively early start in reference to the onset of acoustic stimulation and the duration of this interaction was independent of sound intensity. The interaction between SS and a GABAB receptor antagonist had a relatively late start, and the duration of this interaction was dependent on sound intensity. Simultaneous application of the drug and a GABAergic receptor agonist produced an effect different from the sum of effects produced by the two drugs released individually. These differences between simultaneous and individual drug applications suggest that SS modified GABAergic inhibition in the ICd. Our results indicate that SS can affect sound-driven activity in the ICd by modulating local GABAergic inhibition.

The adult central nervous system is capable of significant reorganization and adaptation following neurotrauma. After a thoracic contusive spinal cord injury (SCI) neuropathways that innervate the cord below the epicenter of injury are damaged, with minimal prospects for functional recovery. In contrast, pathways above the site of injury remain intact and may undergo adaptive changes in response to injury. We used cortical somatosensory evoked potentials (SSEPs) to evaluate changes in intact forelimb pathways. Rats received a midline contusion SCI, unilateral contusion SCI, or laminectomy with no contusion at the T8 level and were monitored for 28 days post-injury. In the midline injury group, SSEPs recorded from the contralateral forelimb region of the primary somatosensory cortex were 59.7% (CI 34.7%, 84.8%; c(2) = 21.9; dof = 1; p = 2.9 ×10(-6)) greater than the laminectomy group; SSEPs from the ipsilateral somatosensory cortex were 47.6% (CI 18.3%, 77%; c(2) = 10.1; dof = 1; p = 0.001) greater. Activation of the ipsilateral somatosensory cortex was further supported by BOLD-fMRI, which showed increased oxygenation at the ipsilateral hemisphere at day seven post-injury. In the unilateral injury group, ipsilesional side was compared to the contralesional side. SSEPs on day 14 (148%; CI 111%, 185%) and day 21 (137%; CI 110%, 163%) for ipsilesional forelimb stimulation were significantly increased over baseline (100%). SSEPs recorded from the hindlimb sensory cortex upon ipsilesional stimulation were 33.9% (CI 14.3%, 53.4%; c(2) = 11.6; dof = 1; p = 0.0007) greater than contralesional stimulation. Therefore, these results demonstrate the ability of SSEPs to detect significant enhancements in the activation of forelimb sensory pathways following both midline and unilateral contusive SCI at T8. Reorganization of forelimb pathways may occur after thoracic SCI, which SSEPs can monitor to aid the development of future therapies.

Tinnitus has a complex etiology that involves auditory and non-auditory factors and may be accompanied by hyperacusis, anxiety and cognitive changes. Thus far, investigations of the interrelationship between tinnitus and auditory and non-auditory impairment have yielded conflicting results. To further address this issue, we noise exposed rats and assessed them for tinnitus using a gap detection behavioral paradigm combined with statistically-driven analysis to diagnose tinnitus in individual rats. We also tested rats for hearing detection, responsivity, and loss using prepulse inhibition and auditory brainstem response, and for spatial cognition and anxiety using Morris water maze and elevated plus maze. We found that our tinnitus diagnosis method reliably separated noise-exposed rats into tinnitus((+)) and tinnitus((-)) groups and detected no evidence of tinnitus in tinnitus((-)) and control rats. In addition, the tinnitus((+)) group demonstrated enhanced startle amplitude, indicating hyperacusis-like behavior. Despite these results, neither tinnitus, hyperacusis nor hearing loss yielded any significant effects on spatial learning and memory or anxiety, though a majority of rats with the highest anxiety levels had tinnitus. These findings showed that we were able to develop a clinically relevant tinnitus((+)) group and that our diagnosis method is sound. At the same time, like clinical studies, we found that tinnitus does not always result in cognitive-emotional dysfunction, although tinnitus may predispose subjects to certain impairment like anxiety. Other behavioral assessments may be needed to further define the relationship between tinnitus and anxiety, cognitive deficits, and other impairments.

Background: Mice produce ultrasonic vocalizations in various inter-individual encounters and with high call rates. However, it is so far virtually unknown how these vocal patterns are generated. On the one hand, these vocal patterns could be embedded into the normal respiratory cycle, as happens in bats and other mammals that produce similar call rates and frequencies. On the other, mice could possess distinct vocal pattern generating systems that are capable of modulating the respiratory cycle, which is what happens in non-human and human primates. In the present study, we investigated the temporal call patterns of two different mammalian species, bats and mice, in order to differentiate between these two possibilities for mouse vocalizations. Our primary focus was on comparing the mechanisms for the production of rapid, successive ultrasound calls of comparable frequency ranges in the two species. Results: We analyzed the temporal call pattern characteristics of mice, and we compared these characteristics to those of ultrasonic echolocation calls produced by horseshoe bats. We measured the distributions of call durations, call intervals, and inter-call intervals in the two species. In the bat, and consistent with previous studies, we found that call duration was independent of corresponding call intervals, and that it was negatively correlated with the corresponding inter-call interval. This indicates that echolocation call production mechanisms in the bat are highly correlated with the respiratory cycle. In contrast, call intervals in the mouse were directly correlated with call duration. Importantly, call duration was not, or was only slightly, correlated with inter-call intervals, consistent with the idea that vocal production in the mouse is largely independent of the respiratory cycle. Conclusions: Our findings suggest that ultrasonic vocalizations in mice are produced by call-pattern generating mechanisms that seem to be similar to those that have been found in primates. This is in contrast to the production mechanisms of ultrasonic echolocation calls in horseshoe bats. These results are particularly interesting, especially since mouse vocalizations have recently attracted increased attention as potential indicators for the degree of progression of several disease patterns in mouse models for neurodegenerative and neurodevelopmental disorders of humans.

The consolidation of newly acquired memories involves the temporal transition from a recent, less stable trace to a more permanent consolidated form. Opiates possess potent rewarding effects and produce powerful associative memories. The activation of these memories is associated with opiate abuse relapse phenomena and the persistence of compulsive opiate dependence. However, the neuronal, molecular and temporal mechanisms by which associative opiate reward memories are consolidated are not currently understood. We report that the consolidation of associative opiate reward memories involves a temporal and molecular switch between the basolateral nucleus of the amygdala (BLA) (early consolidation phase) to the medial prefrontal cortex (mPFC) (late consolidation phase). We demonstrate at the molecular, behavioral and neuronal levels that the consolidation of a recently acquired opiate reward memory involves an extracellular signal-related kinase (ERK)-dependent phosphorylation process within the BLA. In contrast, later-stage consolidation of a newly acquired memory is dependent upon a calcium-calmodulin-dependent (CaMKII), ERK-independent, mechanism in the mPFC, over a 12 hr temporal gradient. In addition, using in vivo multi-unit neuronal recordings in the mPFC, we report that protein synthesis within the BLA modulates the consolidation of opiate-reward memory in neuronal mPFC sub-populations, via the same temporal dynamic.

How bats adapt their sonar behavior to accommodate the noisiness of a crowded day roost is a mystery. Some bats change their pulse acoustics to enhance the distinction between theirs and another bat's echoes, but additional mechanisms are needed to explain the bat sonar system's exceptional resilience to jamming by conspecifics. Variable pulse repetition rate strategies offer one potential solution to this dynamic problem, but precisely how changes in pulse rate could improve sonar performance in social settings is unclear. Here we show that bats decrease their emission rates as population density increases, following a pattern that reflects a cumulative mutual suppression of each other's pulse emissions. Playback of artificially-generated echolocation pulses similarly slowed emission rates, demonstrating that suppression was mediated by hearing the pulses of other bats. Slower emission rates did not support an antiphonal emission strategy but did reduce the relative proportion of emitted pulses that overlapped with another bat's emissions, reducing the relative rate of mutual interference. The prevalence of acoustic interferences occurring amongst bats was empirically determined to be a linear function of population density and mean emission rates. Consequently as group size increased, small reductions in emission rates spread across the group partially mitigated the increase in interference rate. Drawing on lessons learned from communications networking theory we show how modest decreases in pulse emission rates can significantly increase the net information throughput of the shared acoustic space, thereby improving sonar efficiency for all individuals in a group. We propose that an automated acoustic suppression of pulse emissions triggered by bats hearing each other's emissions dynamically optimizes sonar efficiency for the entire group.

Age-related impairments in the primary auditory cortex (A1) include poor tuning selectivity, neural desynchronization, and degraded responses to low-probability sounds. These changes have been largely attributed to reduced inhibition in the aged brain, and are thought to contribute to substantial hearing impairment in both humans and animals. Since many of these changes can be partially reversed with auditory training, it has been speculated that they might not be purely degenerative, but might rather represent negative plastic adjustments to noisy or distorted auditory signals reaching the brain. To test this hypothesis, we examined the impact of exposing young adult rats to 8 weeks of low-grade broadband noise on several aspects of A1 function and structure. We then characterized the same A1 elements in aging rats for comparison. We found that the impact of noise exposure on A1 tuning selectivity, temporal processing of auditory signal and responses to oddball tones was almost indistinguishable from the effect of natural aging. Moreover, noise exposure resulted in a reduction in the population of parvalbumin inhibitory interneurons and cortical myelin as previously documented in the aged group. Most of these changes reversed after returning the rats to a quiet environment. These results support the hypothesis that age-related changes in A1 have a strong activity-dependent component and indicate that the presence or absence of clear auditory input patterns might be a key factor in sustaining adult A1 function.

Excessive exposure to loud noise can damage the cochlea and create a hearing loss. These pathologies coincide with a range of CNS changes including reorganisation of frequency representation, alterations in the pattern of spontaneous activity and changed expression of excitatory and inhibitory neurotransmitters. Moreover, damage to the cochlea is often accompanied by acoustic disorders such as hyperacusis and tinnitus, suggesting that one or more of these neuronal changes may be involved in these disorders, although the mechanisms remain unknown. We tested the hypothesis that excessive noise exposure increases expression of markers of excitation and plasticity, and decreases expression of inhibitory markers over a 32-day recovery period. Adult rats (n = 25) were monaurally exposed to a loud noise (16 kHz, 1/10(th) octave band pass (115 dB SPL)) for 1-hour, or left as non-exposed controls (n = 5). Animals were euthanased at either 0, 4, 8, 16 or 32 days following acoustic trauma. We used Western Blots to quantify protein levels of GABA(A) receptor subunit α1 (GABA(A)α1), Glutamic-Acid Decarboxylase-67 (GAD-67), N-Methyl-D-Aspartate receptor subunit 2A (NR2A), Calbindin (Calb1) and Growth Associated Protein 43 (GAP-43) in the Auditory Cortex (AC), Inferior Colliculus (IC) and Dorsal Cochlear Nucleus (DCN). Compared to sham-exposed controls, noise-exposed animals had significantly (p<0.05): lower levels of GABA(A)α1 in the contralateral AC at day-16 and day-32, lower levels of GAD-67 in the ipsilateral DCN at day-4, lower levels of Calb1 in the ipsilateral DCN at day-0, lower levels of GABA(A)α1 in the ipsilateral AC at day-4 and day-32. GAP-43 was reduced in the ipsilateral AC for the duration of the experiment. These complex fluctuations in protein expression suggests that for at least a month following acoustic trauma the auditory system is adapting to a new pattern of sensory input.

Behavioral adaption to a changing environment is critical for an animal's survival. How well the brain can modify its functional properties based on experience essentially defines the limits of behavioral adaptation. In adult animals the extent to which experience shapes brain function has not been fully explored. Moreover, the perceptual consequences of experience-induced changes in the brains of adults remain unknown. Here we show that the tonotopic map in the primary auditory cortex of adult rats living with low-level ambient noise underwent a dramatic reorganization. Behaviorally, chronic noise-exposure impaired fine, but not coarse pitch discrimination. When tested in a noisy environment, the noise-exposed rats performed as well as in a quiet environment whereas the control rats performed poorly. This suggests that noise-exposed animals had adapted to living in a noisy environment. Behavioral pattern analyses revealed that stress or distraction engendered by the noisy background could not account for the poor performance of the control rats in a noisy environment. A reorganized auditory map may therefore have served as the neural substrate for the consistent performance of the noise-exposed rats in a noisy environment.

The inferior colliculus (IC) receives ascending excitatory and inhibitory inputs from multiple sources, but how these auditory inputs converge to generate IC spike patterns is poorly understood. Simulating patterns of in vivo spike train data from cellular and synaptic models creates a powerful framework to identify factors that contribute to changes in IC responses, such as those resulting in age-related loss of temporal processing. A conductance-based single neuron IC model was constructed, and its responses were compared to those observed during in vivo IC recordings in rats. IC spike patterns were evoked using amplitude-modulated tone or noise carriers at 20-40 dB above threshold and were classified as low-pass, band-pass, band-reject, all-pass, or complex based on their rate modulation transfer function tuning shape. Their temporal modulation transfer functions were also measured. These spike patterns provided experimental measures of rate, vector strength, and firing pattern for comparison with model outputs. Patterns of excitatory and inhibitory synaptic convergence to IC neurons were based on anatomical studies and generalized input tuning for modulation frequency. Responses of modeled ascending inputs were derived from experimental data from previous studies. Adapting and sustained IC intrinsic models were created, with adaptation created via calcium-activated potassium currents. Short-term synaptic plasticity was incorporated into the model in the form of synaptic depression, which was shown to have a substantial effect on the magnitude and time course of the IC response. The most commonly observed IC response sub-types were recreated and enabled dissociation of inherited response properties from those that were generated in IC. Furthermore, the model was used to make predictions about the consequences of reduction in inhibition for age-related loss of temporal processing due to a reduction in GABA seen anatomically with age.

The visual information we receive during natural vision changes rapidly and continuously. The visual system must adapt to the spatiotemporal contents of the environment in order to efficiently process the dynamic signals. However, neuronal responses to luminance contrast are usually measured using drifting or stationary gratings presented for a prolonged duration. Since motion in our visual field is continuous, the signals received by the visual system contain an abundance of transient components in the contrast domain. Here using a modified reverse correlation method, we studied the properties of responses of neurons in the cat primary visual cortex to different contrasts of grating stimuli presented statically and transiently for 40 ms, and showed that neurons can effectively discriminate the rapidly changing contrasts. The change in the contrast response function (CRF) over time mainly consisted of an increment in contrast gain (CRF shifts to left) in the developing phase of temporal responses and a decrement in response gain (CRF shifts downward) in the decay phase. When the distribution range of stimulus contrasts was increased, neurons demonstrated decrement in contrast gain and response gain. Our results suggest that contrast gain control (contrast adaptation) and response gain control mechanisms are well established during the first tens of milliseconds after stimulus onset and may cooperatively mediate the rapid dynamic responses of visual cortical neurons to the continuously changing contrast. This fast contrast adaptation may play a role in detecting contrast contours in the context of visual scenes that are varying rapidly.