Behavioral Neuroscience publications

Hypothesis: Impairments of the medial olivocochlear system (MOCS) increase the risk of environmentally induced auditory neuropathy spectrum disorder (ANSD). Background: ANSD is a problem in the neural transmission of auditory information that accounts for 10% to 15% of the cases of pediatric hearing loss. The underlying mechanisms of the disorder remain poorly understood, but noise exposure is an important risk factor. The goal of this study was to identify environmental conditions and genetic predispositions that lead to ANSD. Our approach was based on the assumption that noise induces ANSD by impeding the functional maturation of the brain's sound coding pathways. Because the MOCS adjusts the sensitivity of the inner ear to noise, impairments of this feedback are predicted to increase the disruptive effects of environmental exposures. Methods: An animal model of ANSD was created by rearing mice in noise. MOCS protection was assessed by comparing the incidence of noise-induced ANSD among knockout mice lacking feedback and wild-type (WT) controls. The mice were screened for ANSD with distortion product otoacoustic emissions, auditory brainstem responses, and behavioral measures of gap detection. Single-unit recording procedures were used to link these deficits to impaired synaptic transmission in the ventral cochlear nucleus. Results: ANSD manifested in noise-reared mice as intact distortion product otoacoustic emissions, abnormal auditory brainstem responses, and impaired gap detection. The phenotype was not observed among quiet-reared WT mice but was occasionally noted among noise-reared WT mice. The incidence of ANSD significantly increased among knockout mice, especially when they were reared in noise. Conclusion: Noise promotes ANSD by altering the functional maturation of the brain's temporal pathways. Noise-induced impairments are reduced by the sound-attenuating effects of the MOCS. Noise levels do not need to be unnaturally loud to constitute significant risk in MOCS-compromised individuals.

As opposed to visual imaging, biosonar imaging of spatial object properties represents a challenge for the auditory system because its sensory epithelium is not arranged along space axes. For echolocating bats, object width is encoded by the amplitude of its echo (echo intensity) but also by the naturally covarying spread of angles of incidence from which the echoes impinge on the bat's ears (sonar aperture). It is unclear whether bats use the echo intensity and/or the sonar aperture to estimate an object's width. We addressed this question in a combined psychophysical and electrophysiological approach. In three virtual-object playback experiments, bats of the species Phyllostomus discolor had to discriminate simple reflections of their own echolocation calls differing in echo intensity, sonar aperture, or both. Discrimination performance for objects with physically correct covariation of sonar aperture and echo intensity (“object width”) did not differ from discrimination performances when only the sonar aperture was varied. Thus, the bats were able to detect changes in object width in the absence of intensity cues. The psychophysical results are reflected in the responses of a population of units in the auditory midbrain and cortex that responded strongest to echoes from objects with a specific sonar aperture, regardless of variations in echo intensity. Neurometric functions obtained from cortical units encoding the sonar aperture are sufficient to explain the behavioral performance of the bats. These current data show that the sonar aperture is a behaviorally relevant and reliably encoded cue for object size in bat sonar.

Acoustic information is conveyed to the brain by the spike patterns in auditory-nerve fibers (ANFs). In mammals, each ANF is excited via a single ribbon synapse in a single inner hair cell (IHC), and the spike patterns therefore also provide valuable information about those intriguing synapses. Here we reexamine and model a key property of ANFs, the dependence of their spike rates on the sound pressure level of acoustic stimuli (rate–level functions). We build upon the seminal model of Sachs and Abbas (1974), which provides good fits to experimental data but has limited utility for defining physiological mechanisms. We present an improved, physiologically plausible model according to which the spike rate follows a Hill equation and spontaneous activity and its experimentally observed tight correlation with ANF sensitivity are emergent properties. We apply it to 156 cat ANF rate–level functions using frequencies where the mechanics are linear and find that a single Hill coefficient of 3 can account for the population of functions. We also demonstrate a tight correspondence between ANF rate–level functions and the Ca 2+ dependence of exocytosis from IHCs, and derive estimates of the effective intracellular Ca 2+ concentrations at the individual active zones of IHCs. We argue that the Hill coefficient might reflect the intrinsic, biochemical Ca 2+ cooperativity of the Ca 2+ sensor involved in exocytosis from the IHC. The model also links ANF properties with properties of psychophysical absolute thresholds.

We can recognize the melody of a familiar song when it is played on different musical instruments. Similarly, an animal must be able to recognize a warning call whether the caller has a high-pitched female or a lower-pitched male voice, and whether they are sitting in a tree to the left or right. This type of perceptual invariance to “nuisance” parameters comes easily to listeners, but it is unknown whether or how such robust representations of sounds are formed at the level of sensory cortex. In this study, we investigate whether neurons in both core and belt areas of ferret auditory cortex can robustly represent the pitch, formant frequencies, or azimuthal location of artificial vowel sounds while the other two attributes vary. We found that the spike rates of the majority of cortical neurons that are driven by artificial vowels carry robust representations of these features, but the most informative temporal response windows differ from neuron to neuron and across five auditory cortical fields. Furthermore, individual neurons can represent multiple features of sounds unambiguously by independently modulating their spike rates within distinct time windows. Such multiplexing may be critical to identifying sounds that vary along more than one perceptual dimension. Finally, we observed that formant information is encoded in cortex earlier than pitch information, and we show that this time course matches ferrets' behavioral reaction time differences on a change detection task.

Animal experiments suggest that chronic tinnitus ("ringing in the ears") may result from processes that overcompensate for lost afferent input. Abnormally elevated spontaneous neural activity has been found in the dorsal cochlear nucleus (DCN) of animals with psychophysical evidence of tinnitus. However, it has also been reported that DCN ablation fails to reduce established tinnitus. Since other auditory areas have been implicated in tinnitus, the role of the DCN is unresolved. The apparently conflicting electrophysiological and lesion data can be reconciled if the DCN serves as a necessary trigger zone rather than a chronic generator of tinnitus. The present experiment used lesion procedures identical to those that failed to decrease pre-existing tinnitus. The exception was that lesions were done prior to tinnitus induction. Young adult rats were trained and tested using a psychophysical procedure shown to detect tinnitus. Tinnitus was induced by a single unilateral high-level noise exposure. Consistent with the trigger hypothesis, bilateral dorsal DCN lesions made before high-level noise exposure prevented the development of tinnitus. A protective effect stemming from disruption of the afferent pathway could not explain the outcome because unilateral lesions ipsilateral to the noise exposure did not prevent tinnitus and unilateral lesions contralateral to the noise exposure actually exacerbated the tinnitus. The DCN trigger mechanism may involve plastic circuits that, through loss of inhibition, or upregulation of excitation, increase spontaneous neural output to rostral areas such as the inferior colliculus. The increased drive could produce persistent pathological changes in the rostral areas, such as high-frequency bursting and decreased interspike variance, that comprise the chronic tinnitus signal.

Aberrant, lesion-induced neuroplastic changes in the auditory pathway are believed to give rise to the phantom sound of tinnitus. Noise-induced cochlear damage can induce extensive fiber growth and synaptogenesis in the cochlear nucleus, but it is currently unclear if these changes are linked to tinnitus. To address this issue, we unilaterally exposed nine rats to narrow-band noise centered at 12 kHz at 126 dB sound pressure level (SPL) for 2 h and sacrificed them 10 weeks later for evaluation of synaptic plasticity (growth-associated protein 43 [GAP-43] expression) in the cochlear nucleus. Noise-exposed rats along with three age-matched controls were screened for tinnitus-like behavior with gap prepulse inhibition of the acoustic startle (GPIAS) before, 1-10 days after, and 8-10 weeks after the noise exposure. All nine noise-exposed rats showed similar patterns of severe hair cell loss at high- and mid-frequency regions in the exposed ear. Eight of the nine showed strong up-regulation of GAP-43 in auditory nerve fibers and pronounced shrinkage of the ventral cochlear nucleus (VCN) on the noise-exposed side, and strong up-regulation of GAP-43 in the medial ventral VCN, but not in the lateral VCN or the dorsal cochlear nucleus. GAP-43 up-regulation in VCN was significantly greater in Noise-No-Tinnitus rats than in Noise-Tinnitus rats. One Noise-No-Tinnitus rat showed no up-regulation of GAP-43 in auditory nerve fibers and only little VCN shrinkage, suggesting that auditory nerve degeneration plays a role in tinnitus generation. Our results suggest that noise-induced tinnitus is suppressed by strong up-regulation of GAP-43 in the medial VCN. GAP-43 up-regulation most likely originates from medial olivocochlear neurons. Their increased excitatory input on inhibitory neurons in VCN may possibly reduce central hyperactivity and tinnitus.

Intracortical microstimulation (ICMS), which has shown promise in the visual, auditory and somatosensory systems as a platform for sensory prostheses, typically relies on charged balanced, symmetric, biphasic stimulation. However, neural stimulation models as well as experiments conducted in cochlear implant users have suggested that charge balanced asymmetric pulses could generate lower detection thresholds for stimulation in terms of charge per phase. For this study, rats were chronically implanted with microelectrode arrays unilaterally in their right auditory cortex and then trained to detect ICMS delivered through a single electrode site in order to determine their behavioral threshold. This model was used in two experiments. The first experiment addressed the effect of lead phase direction, asymmetry, and phase duration on detection threshold. The second experiment fixed the cathode phase duration at 123 μs and varied only the phase asymmetry and lead phase direction. Taken together, the results of these experiments suggest that, for ICMS, the primary determinant of threshold level is cathode phase duration, and that asymmetry provides no significant advantage when compared to symmetric, cathode leading pulses. However, symmetric anode leading pulses of less than or equal to 205 μs per phase consistently showed higher thresholds when compared to all other pulses of equal cathode phase duration.

Performance evaluation is a critical feature of motor learning. In the vocal system, it requires the integration of auditory feedback signals with vocal motor commands. The network activity that supports such integration is unknown, but it has been proposed that vocal performance evaluation occurs offline. Recording from NIf, a sensorimotor structure in the avian song system, we show that short bouts of singing in adult male zebra finches ( Taeniopygia guttata ) induce persistent increases in firing activity and coherent oscillations in the fast gamma range (90–150 Hz). Single units are strongly phase locked to these oscillations, which can last up to 30 s, often outlasting vocal activity by an order of magnitude. In other systems, oscillations often are triggered by events or behavioral tasks but rarely outlast the event that triggered them by more than 1 s. The present observations are the longest reported gamma oscillations triggered by an isolated behavioral event. In mammals, gamma oscillations have been associated with memory consolidation and are hypothesized to facilitate communication between brain regions. We suggest that the timing and persistent nature of NIf's fast gamma oscillations make them well suited to facilitate the integration of auditory and vocal motor traces associated with vocal performance evaluation.

Gamma-band oscillations are a ubiquitous phenomenon in the nervous system and have been implicated in multiple aspects of cognition. In particular, the strength of gamma oscillations at the time a stimulus is encoded predicts its subsequent retrieval, suggesting that gamma may reflect enhanced mnemonic processing. Likewise, activity in the gamma-band can modulate plasticity in vitro . However, it is unclear whether experience-dependent plasticity in vivo is also related to gamma-band activation. The aim of the present study was to determine whether gamma activation in primary auditory cortex modulates both the associative memory for an auditory stimulus during classical conditioning and its accompanying specific receptive field plasticity. Rats received multiple daily sessions of single tone/shock trace and two-tone discrimination conditioning, during which local field potentials and multiunit discharges were recorded from chronically implanted electrodes. We found that the strength of tone-induced gamma predicted the acquisition of associative memory 24 h later and ceased to predict subsequent performance once asymptote was reached. Gamma activation also predicted receptive field plasticity that specifically enhanced representation of the signal tone. This concordance provides a long-sought link between gamma oscillations, cortical plasticity, and the formation of new memories.

The plastic changes in the auditory cortex induced by a fear conditioning, through pairing a sound (CS) with an electric foot-shock (US), were investigated using an optical recording method with voltage sensitive dye, RH795. In order to investigate the effects of association learning, optical signals in the auditory cortex in response to CS (12 kHz pure tone) and non-CS (4, 8, 16 kHz pure tone) were recorded before and after normal and sham conditioning. As a result, the response area to CS enlarged only in the conditioning group after the conditioning. Additionally, the rise time constant of the auditory response to CS significantly decreased and the relative peak value and the decay time constant of the auditory response to CS significantly increased after the conditioning. This study introduces an optical approach to the investigation of fear conditioning, representational plasticity, and the cholinergic system. The findings are synthesized in a model of the synaptic mechanisms that underlie cortical plasticity.

Although high doses of sodium salicylate impair cochlear function, it paradoxically enhances sound-evoked activity in the auditory cortex (AC) and augments acoustic startle reflex responses, neural and behavioral metrics associated with hyperexcitability and hyperacusis. To explore the neural mechanisms underlying salicylate (SS)-induced hyperexcitability and "increased central gain," we examined the effects of GABA receptor agonists and antagonists on SS-induced hyperexcitability in the AC and startle reflex responses. Consistent with our previous findings, local or systemic application of SS significantly increased the amplitude of sound-evoked AC neural activity, but generally reduced spontaneous activity in the AC. Systemic injection of SS also significantly increased the acoustic startle reflex. S-baclofen or R-baclofen, GABA-B agonists, which suppressed sound-evoked AC neural firing rate and local field potentials, also suppressed the SS-induced enhancement of the AC field potential and the acoustic startle reflex. Local application of vigabatrin, which enhances GABA concentration in the brain, suppressed the SS-induced enhancement of AC firing rate. Systemic injection of vigabatrin also reduced the SS-induced enhancement of acoustic startle reflex. Collectively, these results suggest that the sound-evoked behavioral and neural hyperactivity induced by SS may arise from a SS-induced suppression of GABAergic inhibition in the AC.

In the development of sensory prosthetic devices based on intracortical microstimulation (ICMS) an important objective is to optimize the stimulus waveform. However, because of the large design space such optimization is an imposing challenge. This study highlights the ability of individual rats, trained using a conditioned avoidance paradigm and performing an adaptive task, to generate highly consistent and significant data. Three experiments on the effects of phase delay, stimulus pulse rate, and waveform asymmetry were completed and revealed detailed and significant results. These results, consisting of 244 individual thresholds, were generated by one rat in 19 days.

Hypoxia ischemia (HI; reduced blood oxygenation and/or flow to the brain) represents one of the most common injuries for both term and preterm/very low birth weight (VLBW) infants. These children experience elevated incidence of cognitive and/or sensory processing disabilities, including language based learning disabilities. Clinical data also indicate more substantial long‐term deficits for HI injured male babies as compared to HI injured females. Previously, we reported significant deficits in rapid auditory processing and spatial learning in male rats with postnatal day 1 (P1), P7, or P10 HI injury. We also showed sex differences in HI injured animals, with more severe deficits in males as compared to females. Given these findings, combined with extant clinical data, the current study sought to assess a putative role for perinatal testosterone in modulating behavioral outcome following early hypoxic‐ischemic injury in rats. Male, female, and testosterone‐propionate (TP) treated females were subjected to P7 HI or sham surgery, and subsequently (P30+) underwent a battery of auditory testing and water maze assessment. Results confirm previous reports of sex differences following HI, and add new findings of significantly worse performance in TP‐treated HI females compared to vehicle treated HI females. Post mortem anatomic analyses showed consistent effects, with significant brain weight decreases seen in HI male and TP‐treated HI females but not female HI or sham groups. Further neuromorphometric analysis of brain structures showed that HI male animals exhibited increased pathology relative to HI females as reflected in ventricular enlargement. Findings suggest that neonatal testosterone may act to enhance the deleterious consequences of early HI brain injury, as measured by both neuropathology and behavior.

Aged humans show severe difficulties in temporal auditory processing tasks (e.g., speech recognition in noise, low-frequency sound localization, gap detection). A degradation of auditory function with age is also evident in experimental animals. To investigate age-related changes in temporal processing, we compared extracellular responses to temporally variable pulse trains and human speech in the inferior colliculus of young adult (3 month) and aged (3 years) Mongolian gerbils. We observed a significant decrease of selectivity to the pulse trains in neuronal responses from aged animals. This decrease in selectivity led, on the population level, to an increase in signal correlations and therefore a decrease in heterogeneity of temporal receptive fields and a decreased efficiency in encoding of speech signals. A decrease in selectivity to temporal modulations is consistent with a downregulation of the inhibitory transmitter system in aged animals. These alterations in temporal processing could underlie declines in the aging auditory system, which are unrelated to peripheral hearing loss. These declines cannot be compensated by traditional hearing aids (that rely on amplification of sound) but may rather require pharmacological treatment.

The common marmoset is a small, arboreal, New World primate that has emerged as a promising non-human model system in auditory neuroscience. A complete understanding of the neuroethology of auditory processing in marmosets will include behavioral work examining how sounds are perceived by these animals. However, there have been few studies of the marmoset's hearing and perceptual abilities and the audiogram of this species has not been measured using modern psychophysical methods. The present experiment pairs psychophysics with an operant conditioning technique to examine perception of pure tone stimuli by marmosets using an active behavioral paradigm. Subjects were trained to lick at a feeding tube when they detected a sound. Correct responses provided access to a food reward. Pure tones of varying intensities were presented to subjects using the method of constant stimuli. Behavioral thresholds were calculated for each animal based on hit rate--threshold was defined by the tone intensity that the animal correctly identified 50% of the time. Results show that marmoset hearing is comparable to that of other New World monkeys, with a hearing range extending from about 125 Hz up to 36 kHz and a sensitivity peak around 7 kHz.

The acoustic basis of auditory spatial acuity was investigated in CBA/129 mice by relating patterns of behavioral errors to directional features of the head-related transfer function (HRTF). Behavioral performance was assessed by training the mice to lick a water spout during sound presentations from a "safe" location and to suppress the response during presentations from "warning" locations. Minimum audible angles (MAAs) were determined by delivering the safe and warning sounds from different locations in the inter-aural horizontal and median vertical planes. HRTFs were measured at the same locations by implanting a miniature microphone and recording the gain of sound energy near the ear drum relative to free field. Mice produced an average MAA of 31° when sound sources were located in the horizontal plane. Acoustic measures indicated that binaural inter-aural level differences (ILDs) and monaural spectral features of the HRTF change systematically with horizontal location and therefore may have contributed to the accuracy of behavioral performance. Subsequent manipulations of the auditory stimuli and the directional properties of the ear produced errors that suggest the mice primarily relied on ILD cues when discriminating changes in azimuth. The MAA increased beyond 80° when the importance of ILD cues was minimized by testing in the median vertical plane. Although acoustic measures demonstrated a less robust effect of vertical location on spectral features of the HRTF, this poor performance provides further evidence for the insensitivity to spectral cues that was noted during behavioral testing in the horizontal plane.

With increasing efforts to develop and utilize mouse models of a variety of neuro-developmental diseases, there is an urgent need for sensitive neuroimaging methods that enable in vivo analysis of subtle alterations in brain anatomy and function in mice. Previous studies have shown that the brains of Fibroblast Growth Factor 17 null mutants (Fgf17(-/-)) have anatomical abnormalities in the inferior colliculus (IC)-the auditory midbrain-and minor foliation defects in the cerebellum. In addition, changes in the expression domains of several cortical patterning genes were detected, without overt changes in forebrain morphology. Recently, it has also been reported that Fgf17(-/-) mutants have abnormal vocalization and social behaviors, phenotypes that could reflect molecular changes in the cortex and/or altered auditory processing / perception in these mice. We used manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) to analyze the anatomical phenotype of Fgf17(-/-) mutants in more detail than achieved previously, detecting changes in IC, cerebellum, olfactory bulb, hypothalamus and frontal cortex. We also used MEMRI to characterize sound-evoked activity patterns, demonstrating a significant reduction of the active IC volume in Fgf17(-/-) mice. Furthermore, tone-specific (16- and 40-kHz) activity patterns in the IC of Fgf17(-/-) mice were observed to be largely overlapping, in contrast to the normal pattern, separated along the dorsal-ventral axis. These results demonstrate that Fgf17 plays important roles in both the anatomical and functional development of the auditory midbrain, and show the utility of MEMRI for in vivo analyses of mutant mice with subtle brain defects.

Auditory cortex (AC) lesions impair complex sound discrimination. However, a recent study demonstrated spared performance on an acoustic startle response test of speech discrimination following AC lesions (Floody et al., 2010). The current study reports the effects of AC lesions on two operant speech discrimination tasks. AC lesions caused a modest and quickly recovered impairment in the ability of rats to discriminate consonant-vowel-consonant speech sounds. This result seems to suggest that AC does not play a role in speech discrimination. However, the speech sounds used in both studies differed in many acoustic dimensions and an adaptive change in discrimination strategy could allow the rats to use an acoustic difference that does not require an intact AC to discriminate. Based on our earlier observation that the first 40 ms of the spatiotemporal activity patterns elicited by speech sounds best correlate with behavioral discriminations of these sounds (Engineer et al., 2008), we predicted that eliminating additional cues by truncating speech sounds to the first 40 ms would render the stimuli indistinguishable to a rat with AC lesions. Although the initial discrimination of truncated sounds took longer to learn, the final performance paralleled rats using full-length consonant-vowel-consonant sounds. After 20 days of testing, half of the rats using speech onsets received bilateral AC lesions. Lesions severely impaired speech onset discrimination for at least one-month post lesion. These results support the hypothesis that auditory cortex is required to accurately discriminate the subtle differences between similar consonant and vowel sounds.

Zebra finches produce a learned song that is rich in harmonic structure and highly stereotyped. More is generally known about how birds learn and produce this song than how they perceive it. Here, zebra finches were trained with operant techniques to discriminate changes in natural and synthetic song motifs. Results show that zebra finches are quite insensitive to changes to the overall envelope of the motif since they were unable to discriminate more than a doubling in inter-syllable interval durations. By contrast, they were quite sensitive to changes in individual syllables. A series of tests with synthetic song syllables, including some made of frozen noise and Schroeder harmonic complexes, showed that birds used a suite of acoustic cues in normal listening but they could also distinguish among syllables simply on the basis of the temporal fine structure in the waveform. Thus, while syllable perception is maintained by multiple redundant cues, temporal fine structure features alone are sufficient for syllable discrimination and may be more important for communication than previously thought.

Sensory experience during development can modify the CNS and alter adult perceptual skills. While this principle draws support from deprivation or chronic stimulus exposure studies, the effect of training is addressed only in adults. Here, we asked whether a brief period of training during development can exert a unique impact on adult perceptual skills. Juvenile gerbils were trained to detect amplitude modulation (AM), a stimulus feature elemental to animal communication sounds. When the performance of these juvenile-trained animals was subsequently assessed in adulthood, it was superior to a control group that received an identical regimen of training as adults. The juvenile-trained animals displayed significantly better AM detection thresholds. This was not observed in an adult group that received only exposure to AM stimuli as juveniles. To determine whether enhanced adult performance was due solely to learning the conditioned avoidance procedure, juveniles were trained on frequency modulation (FM) detection, and subsequently assessed on AM detection as adults. These animals displayed significantly poorer AM detection thresholds than all other groups. Thus, training on a specific auditory task (AM detection) during development provided a benefit to performance on that task in adulthood, whereas an identical training regimen in adulthood did not bring about this enhancement. In contrast, there was a cost, in adulthood, following developmental training on a different task (FM detection). Together, the results demonstrate a period of heightened sensitivity in the developing CNS such that behavioral training in juveniles has a unique impact on adult behavioral capabilities.