Tone Conditions Research Articles

Suppression of the µ Rhythm during Speech and Non-Speech Discrimination Revealed by Independent Component Analysis: Implications for Sensorimotor Integration in Speech Processing

BackgroundConstructivist theories propose that articulatory hypotheses about incoming phonetic targets may function to enhance perception by limiting the possibilities for sensory analysis. To provide evidence for this proposal, it is necessary to map ongoing, high-temporal resolution changes in sensorimotor activity (i.e., the sensorimotor μ rhythm) to accurate speech and non-speech discrimination performance (i.e., correct trials.)MethodsSixteen participants (15 female and 1 male) were asked to passively listen to or actively identify speech and tone-sweeps in a two-force choice discrimination task while the electroencephalograph (EEG) was recorded from 32 channels. The stimuli were presented at signal-to-noise ratios (SNRs) in which discrimination accuracy was high (i.e., 80–100%) and low SNRs producing discrimination performance at chance. EEG data were decomposed using independent component analysis and clustered across participants using principle component methods in EEGLAB.ResultsICA revealed left and right sensorimotor µ components for 14/16 and 13/16 participants respectively that were identified on the basis of scalp topography, spectral peaks, and localization to the precentral and postcentral gyri. Time-frequency analysis of left and right lateralized µ component clusters revealed significant (pFDR<.05) suppression in the traditional beta frequency range (13–30 Hz) prior to, during, and following syllable discrimination trials. No significant differences from baseline were found for passive tasks. Tone conditions produced right µ beta suppression following stimulus onset only. For the left µ, significant differences in the magnitude of beta suppression were found for correct speech discrimination trials relative to chance trials following stimulus offset.ConclusionsFindings are consistent with constructivist, internal model theories proposing that early forward motor models generate predictions about likely phonemic units that are then synthesized with incoming sensory cues during active as opposed to passive processing. Future directions and possible translational value for clinical populations in which sensorimotor integration may play a functional role are discussed.

Bidirectional effects of aversive learning on perceptual acuity are mediated by the sensory cortex

Although emotional learning affects sensory acuity, little is known about how these changes are facilitated in the brain. We found that auditory fear conditioning in mice elicited either an increase or a decrease in frequency discrimination acuity depending on how specific the learned response was to the conditioned tone. Using reversible pharmacological inactivation, we found that the auditory cortex mediated learning-evoked changes in acuity in both directions.

Age differences in fear retention and extinction in male Sprague-Dawley rats: Effects of ethanol challenge during conditioning

Pavlovian fear conditioning is an ideal model to investigate how learning and memory are influenced by alcohol use during adolescence because the neural mechanisms involved have been studied extensively. In Exp 1, adolescent and adult male Sprague-Dawley rats were non-injected or injected with saline, 1 or 1.5g/kg ethanol intraperitoneally 10min prior to tone or context conditioning. Twenty-four hours later, animals were tested for tone or context retention and extinction, with examination of extinction retention conducted 24h thereafter. In Exp 2, a context extinction session was inserted between the tone conditioning and the tone fear retention/extinction days to reduce pre-CS baseline freezing levels at test. Basal levels of acquisition, fear retention, extinction, and extinction retention after tone conditioning were similar between adolescent and adult rats. In contrast adolescents showed faster context extinction than adults, while again not differing from adults during context acquisition, retention or extinction retention. In terms of ethanol effects, adolescents were less sensitive to ethanol-induced context retention deficits than adults. No age differences emerged in terms of tone fear retention, with ethanol disrupting tone fear retention at both ages in Exp 1, but at neither age in Exp 2, a difference seemingly due to group differences in pre-CS freezing during tone testing in Exp 1, but not Exp 2. These results suggest that age differences in the acute effects of ethanol on cognitive function are task-specific, and provide further evidence for age differences cognitive functioning in a task thought to be hippocampally related.

A role for anterior thalamic nuclei in contextual fear memory

Understanding the neural processes that govern the attribution of a predictive value to environmental stimuli is a major issue in behavioural neuroscience. The main strategy to explore this question has been the use of Pavlovian fear conditioning paradigms. While a majority of studies have focussed on the specific role of the hippocampus and amygdala in contextual versus cued fear, very few studies examined the potential role of subcortical limbic areas. Among those, the anterior thalamic nuclei (ATN) connect to both the hippocampus and the amygdala and also to the cingulate region which is known to support fear-related activity. Here, we show that rats sustaining ATN lesions exhibit a specific impairment following context but not tone conditioning. ATN lesions slowed down acquisition without preventing normal freezing behaviour when rats were reexposed to the conditioning context 24h later. However, ATN rats exhibited poor retrieval of contextual but not cued fear when assessed 3weeks after conditioning. In addition, extinction was faster in ATN rats and spontaneous recovery of contextual fear was impaired by the lesions. These deficits indicate that contextual fear memories established in the absence of the ATN are not robust. Collectively, these findings support an involvement of the ATN in the circuits underlying contextual fear memory.

Cyclooxygenase-1 and Prostacyclin Production by Endothelial Cells in the Presence of Mild Oxidative Stress

This study aimed at evaluating the relative contribution of endothelial cyclooxygenase-1 and -2 (COX-1 and COX-2) to prostacyclin (PGI2) production in the presence of mild oxidative stress resulting from autooxidation of polyphenols such as (-)-epigallocatechin 3-gallate (EGCG), using both endothelial cells in culture and isolated blood vessels. EGCG treatment resulted in an increase in hydrogen peroxide formation in human umbilical vein endothelial cells. In the presence of exogenous arachidonic acid and EGCG, PGI2 production was preferentially inhibited by a selective COX-1 inhibitor. This effect of selective inhibition was also substantially reversed by catalase. In addition, EGCG caused vasorelaxation of rat aortic ring only partially abolished by a nitric oxide synthase inhibitor. Concomitant treatment with a selective COX-1 inhibitor completely prevented the vasorelaxation as well as the increase in PGI2 accumulation in the perfusate observed in EGCG-treated aortic rings, while a selective COX-2 inhibitor was completely uneffective. Our data strongly support the notions that H2O2 generation affects endothelial PGI2 production, making COX-1, and not COX-2, the main source of endothelial PGI2 under altered oxidative tone conditions. These results might be relevant to the reappraisal of the impact of COX inhibitors on vascular PGI2 production in patients undergoing significant oxidative stress.

Pain-Specific Modulation of Hippocampal Activity and Functional Connectivity during Visual Encoding

Acute and chronic pain automatically attract attention and thus interfere with cognitive functioning. Impaired memory is a prominent complaint of patients with chronic pain that substantially contributes to pain-related disability. In this fMRI study, we investigated the specific influence of pain on neural processes of memory encoding in healthy human volunteers using a visual task. To investigate the specificity of the interruptive effect of pain on the encoding of visual objects, objects were presented (1) alone, (2) with painful heat stimuli, or (3) with auditory stimuli that were matched for unpleasantness to the heat stimuli. The interruptive effect of concomitant aversive stimulation on behavioral measures and neural processing was assessed in a categorization task during encoding and in a subsequent recognition task. Pain interfered with object processing and encoding of visual stimuli. On the behavioral level, this resulted in slower reaction times during the categorization task for pain compared with auditory stimuli and in a lower recognition rate in the pain condition but not in the tone condition. Pain catastrophizing amplified this interruptive effect of pain. On the neural level, this pain-related disruption of encoding was associated with reduced activity in the right anterior hippocampus during encoding. Moreover, the hippocampus exhibited reduced functional connectivity with extrastriate regions during painful stimulation relative to auditory stimulation. In summary, our results show a pain-related disruption of visual encoding over and above the unpleasantness of a stimulus, suggesting a pain-specific interruptive mechanism that interferes with an early stage of memory formation.

Extracellular ATP signaling in equine digital blood vessels

The functional distribution of ATP-activated P2 receptors is well characterized for many blood vessels, but not in the equine digital vasculature, which is a superficial vascular bed that displays thermoregulatory functions and has been implicated in ischemia-reperfusion injuries of the hoof. Isolated equine digital arteries (EDA) and veins (EDV) were submitted to isometric tension studies, whereby electric field stimulation (EFS) and concentration–response curves to exogenously applied agonists were constructed under low tone conditions. Additionally, immunofluorescent localization of P2X and P2Y receptor subtypes was performed. EFS-induced constriction was abolished by tetrodotoxin (1μM, n=4). Endothelium denudation did not modify the EFS-induced constriction (n=3). The EFS-induced constriction in EDA was inhibited by phentolamine (67.7±1.8%, n=6; 10μM), and by the non-selective P2 receptor antagonist suramin (46.2±1.3%, n=6; 10μM). EFS-induced constriction in EDV was reduced by suramin (48.2±2.4%, n=6; 10μM), the P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (58.3±4.5%, n=6; 10μM), and phentolamine (23.2±2.5%, n=6; 10μM). Exogenous methoxamine and ATP mimicked EFS-induced constriction in EDA and EDV. Immunostaining for P2X1, P2X2 and P2X3, and, for P2X1 and P2X7 receptor subunits were observed in EDA and EDV smooth muscle and adventitia, respectively. ATP and noradrenaline are co-transmitters in sympathetic nerves supplying the equine digital vasculature, noradrenaline being the dominant agonist in EDA, and ATP in EDV. In conclusion, P2X receptors mediate vasoconstriction in EDA and EDV, although different P2X subunits are involved in these vessels. The physiological significance of this finding in relation to thermoregulatory functions and equine laminitis is discussed.

The Vocal Generosity Effect: How Bad Can Your Singing Be?

prior work indicates that listeners may be more likely to call a note in-tune when it is sung than when it is in another timbre. The current study seeks to confirm whether this vocal generosity effect generalizes to melodies. Musicians and nonmusicians listened to pairs of single tones and scale-based melodies performed with the voice or the violin. The final note was varied in how well it was tuned to the prior context, and for each example, listeners judged whether the final note was intune or not. A strong vocal generosity effect was found for musicians and nonmusicians in both melodic and single tone conditions – a higher degree of mistuning was necessary for listeners to decide that sung tones were out-of-tune compared with violin notes. These results confirm the role of timbre in tuning judgments, and help explain why singers are typically less well-tuned than instrumentalists in performance.

Gating of Fear in Prelimbic Cortex by Hippocampal and Amygdala Inputs

The prefrontal cortex (PFC) regulates emotional responses, but it is unclear how PFC integrates diverse inputs to select the appropriate response. We therefore evaluated the contribution of basolateral amygdala (BLA) and ventral hippocampus (vHPC) inputs to fear signaling in the prelimbic (PL) cortex, a PFC region critical for the expression of conditioned fear. In conditioned rats trained to press for food, BLA inactivation decreased the activity of projection cells in PL, and reduced PL conditioned tone responses. In contrast, vHPC inactivation decreased activity of interneurons in PL and increased PL conditioned tone responses. Consistent with hippocampal gating of fear after extinction, vHPC inactivation increased fear and PL pyramidal activity in extinguished, but not in conditioned, rats. These results suggest a prefrontal circuit whereby hippocampus gates amygdala-based fear. Thus, deficient hippocampal inhibition of PFC may underlie emotional disorders, especially in light of reduced hippocampal volume observed in depression and PTSD.

Brain region-specific activity patterns after recent or remote memory retrieval of auditory conditioned fear

Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or retrieval. To investigate this possibility, we systematically imaged the brain activity patterns in the lateral amygdala, MGm/PIN, and AuV/TeA using activity-dependent induction of immediate early gene zif268 after recent and remote memory retrieval of auditory conditioned fear. Consistent with the critical role of the amygdala in fear memory, the zif268 activity in the lateral amygdala was significantly increased after both recent and remote memory retrieval. Interesting, however, the density of zif268 (+) neurons in both MGm/PIN and AuV/TeA, particularly in layers IV and VI, was increased only after remote but not recent fear memory retrieval compared to control groups. Further analysis of zif268 signals in AuV/TeA revealed that conditioned tone induced stronger zif268 induction compared to familiar tone in each individual zif268 (+) neuron after recent memory retrieval. Taken together, our results support that the lateral amygdala is a key brain site for permanent fear memory storage and suggest that MGm/PIN and AuV/TeA might play a role for remote memory storage or retrieval of auditory conditioned fear, or, alternatively, that these auditory brain regions might have a different way of processing for familiar or conditioned tone information at recent and remote time phases.

Stream Segregation in the Perception of Sinusoidally Amplitude-Modulated Tones

Amplitude modulation can serve as a cue for segregating streams of sounds from different sources. Here we evaluate stream segregation in humans using ABA- sequences of sinusoidally amplitude modulated (SAM) tones. A and B represent SAM tones with the same carrier frequency (1000, 4000 Hz) and modulation depth (30, 100%). The modulation frequency of the A signals (fmodA) was 30, 100 or 300 Hz, respectively. The modulation frequency of the B signals was up to four octaves higher (Δfmod). Three different ABA- tone patterns varying in tone duration and stimulus onset asynchrony were presented to evaluate the effect of forward suppression. Subjects indicated their 1- or 2-stream percept on a touch screen at the end of each ABA- sequence (presentation time 5 or 15 s). Tone pattern, fmodA, Δfmod, carrier frequency, modulation depth and presentation time significantly affected the percentage of a 2-stream percept. The human psychophysical results are compared to responses of avian forebrain neurons evoked by different ABA- SAM tone conditions [1] that were broadly overlapping those of the present study. The neurons also showed significant effects of tone pattern and Δfmod that were comparable to effects observed in the present psychophysical study. Depending on the carrier frequency, modulation frequency, modulation depth and the width of the auditory filters, SAM tones may provide mainly temporal cues (sidebands fall within the range of the filter), spectral cues (sidebands fall outside the range of the filter) or possibly both. A computational model based on excitation pattern differences was used to predict the 50% threshold of 2-stream responses. In conditions for which the model predicts a considerably larger 50% threshold of 2-stream responses (i.e., larger Δfmod at threshold) than was observed, it is unlikely that spectral cues can provide an explanation of stream segregation by SAM.

Low-Frequency Stimulation Depresses the Primate Anterior-Cingulate-Cortex and Prevents Spontaneous Recovery of Aversive Memories

Functional abnormalities in the dorsal-anterior-cingulate-cortex (dACC) underlie anxiety disorders and specifically post-traumatic stress disorder (PTSD). Promising and common behavioral approaches have limited effectiveness and many subjects exhibit spontaneous recovery of fear, as also evident in animal models following extinction training. Here, we use low-frequency stimulation (LFS), a protocol shown to induce long-term depression, with the aim of affecting synaptic plasticity induced by fear acquisition and extinction. We use aversive conditioning of either tone or visual stimuli paired with an aversive air-puff to the eye in a trace-conditioning paradigm. We find that LFS in the nonhuman primate (Macaca fascicularis) dACC, when combined with extinction training, was successful in preventing spontaneous recovery of the memory 24-72 h following extinction. We simultaneously record single-units and local-field-potentials across the dACC, and show that LFS gradually depressed evoked responses. Moreover, this decrease in neural excitability predicted the successful reduction of overnight spontaneous recovery on a day-by-day basis. Finally, we show that this effect occurs when using either visual or auditory modality as the conditioned stimulus, and that the reduction was specific to the conditioned modality. Our results suggest that the primate dACC is actively involved in maintaining the original aversive memory, and propose that a combination of LFS with behavioral therapy might significantly improve treatment in severe cases.

An experimental study of VEGF induced changes in vasoactivity in pig retinal arterioles and the influence of an anti-VEGF agent

BackgroundVascular endothelial growth factor (VEGF) plays an important role in ocular physiology. Anti-VEGF agents are now used for treatment of common retinal diseases. This study characterises the vasoactive properties of VEGF in isolated perfused pig retinal arterioles under normal tone or endothelin-1 (ET-1) pre-contracted conditions and determines the influence of an anti VEGF agent on VEGF induced vasoactivity.MethodsAn isolated perfused retinal arteriole preparation was used. The outer diameter of retinal vessels was monitored at 2 second intervals in response to VEGF and the anti VEGF agent, bevacizumab. The effect of intraluminal delivery of VEGF was determined over a wide concentration range (10-16 to 10-7 M) both with and without pre-contraction with ET-1 (3 x 10-9 M). Bevacizumab (0.35 mg mL-1) was applied extraluminally to determine the influence of bevacizumab on VEGF induced vasoactive changes on ET-1 pre-contracted vessels.ResultsIn retinal arterioles with normal tone, VEGF induced a concentration dependent contraction at low concentrations, reaching 93.5% at 10-11 M and then contraction was reduced at higher concentrations, recovering to 98.1% at 10-7 M. VEGF produced a potent concentration dependent vasodilatation in arterioles pre-contracted with ET-1. VEGF induced vasodilatation in arterioles pre-contracted with ET-1 was significantly inhibited by bevacizumab.ConclusionsVEGF induced vasoactive changes in pig retinal arterioles are dependent on concentration and vascular tone. Bevacizumab inhibits VEGF-induced vasodilatation in pre-contracted arterioles.

Comparative Analysis of the Response of Microcirculation Parameters and Blood Pressure to Geomagnetic Activity in Healthy People

We analyze the results of daily laser Doppler flowmetry monitoring of blood microcirculation parameters in 9 healthy volunteers performed in 2006-2009. Dependence of microcirculation and BP parameters on geomagnetic activity was analyzed separately in each volunteer (the influence of ambient temperature was previously excluded). Significantly increased parameters of microcirculation in response to higher geomagnetic activity were found in 4 volunteers (44%) and elevated BP in 1 volunteer; in other cases, no reaction was detected. It was shown that individual sensitivity to geomagnetic activity is proportional to its mean level during the period of measurement. Since blood perfusion volume in tissues directly depends on peripheral vascular resistance, we can conclude that under conditions of high geomagnetic activity microvascular tone varies to a greater extent than the tone of major vessels.

Estradiol protects against hippocampal damage and impairments in fear conditioning resulting from transient global ischemia in mice

Estradiol protects against hippocampal damage and some learning impairments resulting from transient global ischemia in rats. Here, we seek to validate a mouse model of transient global ischemia and evaluate the effects of estradiol on ischemia-induced hippocampal damage and behavioral impairments. Female C57Bl6/J mice were ovariectomized and implanted with estradiol- or oil-secreting capsules. One week later, mice experienced 15-min of 2-vessel occlusion (2-VO) or sham surgical procedures. Five days later, mice were exposed to a fear conditioning protocol in which a specific context and novel tone were paired with mild footshock. Twenty-four hours following conditioning, contextual fear was assessed by measuring freezing behavior in the conditioned context (in the absence of the tone). This was followed by assessment of cue fear by measuring freezing behavior to the conditioned tone presented in a new context. When tested in the conditioned context, oil-treated mice that experienced 2-VO exhibited a significant reduction in freezing behavior whereas estradiol-treated mice that experienced 2-VO showed no disruption in freezing behavior. Freezing behavior when presented with the conditioned tone was unaffected by either surgery or hormone treatment. These findings suggest that global ischemia causes impairments in performance on the hippocampally-dependent contextual fear task but not conditioned cue-based fear. Furthermore, estradiol prevented the ischemia-induced impairment in contextual fear conditioning. Fluoro-Jade (FJ) staining revealed neuronal degeneration throughout the dorsal hippocampus of mice that experienced 2-VO. Estradiol treatment reduced the number of FJ+ cells in CA1 and CA2, but not in CA3 or in the dentate gyrus. Together, these findings suggest that 15min of global ischemia causes extensive hippocampal neurodegeneration and disrupts contextual fear conditioning processes in mice and that estradiol protects against these adverse effects.

Timing of Tone Presentation Does Alter Training Performance but Not Retention Performance of a Point-To-Point Sequence Task

Objective: To investigate whether the timing of presentation of tones while practicing a serial reaction time task affects retention. Design: Thirty-eight young adults practiced 4 different 12-sequence aiming tasks. There was one control condition without a tone and three experimental conditions in which a tone was presented; i.e., a tone could appear before the next target onset, at the next target onset, or after the next target onset. Sequence learning for each condition was assessed with a retention block in which no tones were presented. Performance changes as compared to the control condition were analyzed to assess if acquisition and/or learning was affected by the presentation of the tones. Results: Tone condition affected mainly reaction time. It was shown that if a tone was presented 150 ms before displaying the next target in the sequence the reaction time of the aiming movement decreased significantly. Furthermore, it was shown that tone onset 150 ms before target presentation and tone onset at target presentation resulted in a benefit during acquisition after block 5 and 6 respectively. However, the benefit disappeared during retention, because none of the tone conditions showed differential performance as compared to the control condition. Conclusions: Timing of tones affects the acquisition of serial reaction time tasks, but it does not alter learning. It is suggested that this pattern of findings supports the notion that tones result in a non-specific activation of the motor system, which affect immediate performance but not learning.

Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis

IntroductionThe current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Aβ) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially the hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Aβ plaque burden.MethodsMice were tested at three, six, and 12 months of age, which corresponds to early, mild, and severe Aβ plaque deposition, following a cross-sectional experimental design. We used a delay version of the fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of the training chamber. The Aβ plaque burden was evaluated at each age after the completion of the behavioral tests.ResultsCRDN8 mice showed context fear memory comparable to control mice at three and six months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Aβ plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age.ConclusionsOur data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlates well with an overall increase in Aβ burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.

Mapping Functional Brain Activation Using [14C]-Iodoantipyrine in Male Serotonin Transporter Knockout Mice

BackgroundSerotonin transporter knockout mice have been a powerful tool in understanding the role played by the serotonin transporter in modulating physiological function and behavior. However, little work has examined brain function in this mouse model. We tested the hypothesis that male knockout mice show exaggerated limbic activation during exposure to an emotional stressor, similar to human subjects with genetically reduced transcription of the serotonin transporter.Methodology/Principal FindingsFunctional brain mapping using [14C]-iodoantipyrine was performed during recall of a fear conditioned tone. Regional cerebral blood flow was analyzed by statistical parametric mapping from autoradiographs of the three-dimensionally reconstructed brains. During recall, knockout mice compared to wild-type mice showed increased freezing, increased regional cerebral blood flow of the amygdala, insula, and barrel field somatosensory cortex, decreased regional cerebral blood flow of the ventral hippocampus, and conditioning-dependent alterations in regional cerebral blood flow in the medial prefrontal cortex (prelimbic, infralimbic, and cingulate). Anxiety tests relying on sensorimotor exploration showed a small (open field) or paradoxical effect (marble burying) of loss of the serotonin transporter on anxiety behavior, which may reflect known abnormalities in the knockout animal's sensory system. Experiments evaluating whisker function showed that knockout mice displayed impaired whisker sensation in the spontaneous gap crossing task and appetitive gap cross training.ConclusionsThis study is the first to demonstrate altered functional activation in the serotonin transporter knockout mice of critical nodes of the fear conditioning circuit. Alterations in whisker sensation and functional activation of barrel field somatosensory cortex extend earlier reports of barrel field abnormalities, which may confound behavioral measures relying on sensorimotor exploration.

The quantification of kanamycin ototoxicity in the rat using conditioned tone discrimination.

Twelve male Lister hooded rats were conditioned to discriminate an 8 kHz tone (56.5 +/- 0.5 dB re 0.0002 dyne cm-2) and were subsequently injected subcutaneously with kanamycin (400 mg kg-1 day-1) for 28 days; during this time and for five weeks after dosage was stopped, the nature and extent of the resultant hearing deficits were studied. The animals' Preyer reflex thresholds were determined at intervals during the study. Only one rat was unaffected by the kanamycin dosage. The onset of hearing impairment (reduced discrimination performance), which was gradual in some rats and sudden in others, generally occurred during the fourth week of kanamycin dosage although the earliest onset was towards the end of the second week. In most animals the hearing impairment progressed after kanamycin was stopped and in one rat there was a latency between the end of drug dosage and onset of hearing impairment. Hearing impairment was irreversible in five rats. One rat, whose impairment was slight, recovered normal hearing. Some rats showed a reduced discrimination performance at a time when their Preyer reflex threshold showed no elevation suggesting that kanamycin, at least initially, caused a threshold elevation rather than reduced sensitivity to intense sounds.

Convergent Processing of Both Positive and Negative Motivational Signals by the VTA Dopamine Neuronal Populations

Dopamine neurons in the ventral tegmental area (VTA) have been traditionally studied for their roles in reward-related motivation or drug addiction. Here we study how the VTA dopamine neuron population may process fearful and negative experiences as well as reward information in freely behaving mice. Using multi-tetrode recording, we find that up to 89% of the putative dopamine neurons in the VTA exhibit significant activation in response to the conditioned tone that predict food reward, while the same dopamine neuron population also respond to the fearful experiences such as free fall and shake events. The majority of these VTA putative dopamine neurons exhibit suppression and offset-rebound excitation, whereas ∼25% of the recorded putative dopamine neurons show excitation by the fearful events. Importantly, VTA putative dopamine neurons exhibit parametric encoding properties: their firing change durations are proportional to the fearful event durations. In addition, we demonstrate that the contextual information is crucial for these neurons to respectively elicit positive or negative motivational responses by the same conditioned tone. Taken together, our findings suggest that VTA dopamine neurons may employ the convergent encoding strategy for processing both positive and negative experiences, intimately integrating with cues and environmental context.