The effect of doxorubicin or cyclophosphamide treatment on auditory brainstem response in mice.

Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. Several underlying mechanisms have been proposed; however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. There is evidence that oligodendrocytes and white matter tracts within the CNS may be particularly vulnerable to chemotherapy-related damage and dysfunction. Auditory brainstem responses (ABRs) have been used to detect and measure functional integrity of myelin in a variety of animal models of autoimmune disorders and demyelinating diseases. Limited evidence suggests that increases in interpeak latencies, associated with disrupted impulse conduction, can be detected in ABRs following 5-fluorouracil administration in mice. It is unknown if similar functional disruptions can be detected following treatment with other chemotherapeutic compounds and the extent to which alterations in ABR signals represent robust and long-lasting impairments associated with chemotherapy-related cognitive impairment. Thus, C57BL/6 J mice were treated every 3rd day for a total of 3 injections with low or high dose cyclophosphamide, or doxorubicin. ABRs of mice were assessed on days 1, 7, 14, 56 and 6 months following completion of chemotherapy administration. There were timing and amplitude differences in the ABRs of the doxorubicin and the high dose cyclophosphamide groups relative to the control animals. However, despite significant toxic effects as assessed by weight loss, the changes in the ABR were transient.

Decoding stimulus duration from neural responses in the auditory midbrain.

Neurons with responses selective for the duration of an auditory stimulus are called duration-tuned neurons (DTNs). Temporal specificity in their spiking suggests that one function of DTNs is to encode stimulus duration; however, the efficacy of duration encoding by DTNs has yet to be investigated. Herein, we characterize the information content of individual cells and a population of DTNs from the mammalian inferior colliculus (IC) by measuring the stimulus-specific information (SSI) and estimated Fisher information (FI) of spike count responses. We found that SSI was typically greatest for those stimulus durations that evoked maximum spike counts, defined as best duration (BD) stimuli, and that FI was maximal for stimulus durations off BD where sensitivity to a change in duration was greatest. Using population data, we demonstrate that a maximum likelihood estimator (MLE) can accurately decode stimulus duration from evoked spike counts. We also simulated a two-alternative forced choice task by having MLE models decide whether two durations were the same or different. With this task we measured the just-noticeable difference threshold for stimulus duration and calculated the corresponding Weber fractions across the stimulus domain. Altogether, these results demonstrate that the spiking responses of DTNs from the mammalian IC contain sufficient information for the CNS to encode, decode, and discriminate behaviorally relevant auditory signal durations.

Organization and trade-off of spectro-temporal tuning properties of duration-tuned neurons in the mammalian inferior colliculus.

Neurons throughout the mammalian central auditory pathway respond selectively to stimulus frequency and amplitude, and some are also selective for stimulus duration. First found in the auditory midbrain or inferior colliculus (IC), these duration-tuned neurons (DTNs) provide a potential neural mechanism for encoding temporal features of sound. In this study, we investigated how having an additional neural response filter, one selective to the duration of an auditory stimulus, influences frequency tuning and neural organization by recording single-unit responses and measuring the dorsal-ventral position and spectral-temporal tuning properties of auditory DTNs from the IC of the awake big brown bat (Eptesicus fuscus). Like other IC neurons, DTNs were tonotopically organized and had either V-shaped, U-shaped, or O-shaped frequency tuning curves (excitatory frequency response areas). We hypothesized there would be an interaction between frequency and duration tuning in DTNs, as electrical engineering theory for resonant filters dictates a trade-off in spectral-temporal resolution: sharp tuning in the frequency domain results in poorer resolution in the time domain and vice versa. While the IC is a more complex signal analyzer than an electrical filter, a similar operational trade-off could exist in the responses of DTNs. Our data revealed two patterns of spectro-temporal sensitivity and spatial organization within the IC: DTNs with sharp frequency tuning and broad duration tuning were located in the dorsal IC, whereas cells with wide spectral tuning and narrow temporal tuning were found in the ventral IC.

Preserved learning and memory in mice following chemotherapy: 5-Fluorouracil and doxorubicin single agent treatment, doxorubicin-cyclophosphamide combination treatment.

Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. A number of underlying mechanisms have been proposed, however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. As part of a multifaceted approach, animal models of chemotherapy induced cognitive impairment are being developed. Thus far, the majority of animal studies have utilized rats, however, mice may prove particularly beneficial in studying genetic risk factors for developing chemotherapy induced cognitive impairment. Thus, C57BL/6J mice were treated once a week for three weeks with saline, doxorubicin and cyclophosphamide (D&C), doxorubicin (Dox), or 5-fluorouracil (5-FU). Recent and remote contextual fear conditioning and novel object recognition (NOR) was assessed. Despite significant toxic effects as assessed by weight loss, the chemotherapy treated mice performed as well as control mice on all task. As are some humans, C57BL/6J mice may be resistant to at least some aspects of chemotherapy induced cognitive decline.

Recent and remote spatial memory in mice treated with cytosine arabinoside.

Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. A number of underlying mechanisms have been proposed, however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. As part of a multifaceted approach, animal models of chemotherapy-induced cognitive impairment are being developed. Thus far, the majority of animal studies have utilized a rat model, however, mice may prove particularly beneficial in studying genetic risk factors for developing chemotherapy-induced cognitive impairment. Various chemotherapy agents, including cytosine arabinoside (Ara-C), have been found to impair remote spatial memory in rats in the Morris water maze. The present study evaluated the effects of Ara-C on remote (30 d) spatial memory in mice. In addition, the possibility that time relative to chemotherapy treatment may modulate the effect of chemotherapy on spatial learning and/or recent (1 d) memory was explored. Male C57BL/6J mice received either Ara-C (275 mg/kg i.p. daily for 5 days) or saline. Spatial learning and memory was assessed using the Morris water maze. Half the mice performed a remote (30 d) memory version of the task and the other half performed a recent (1 d) memory version of the task. The experiment was designed such that the probe trial for the recent memory version occurred on the same day relative to chemotherapy treatment as the remote memory version. Despite significant toxic effects as assessed by weight loss, Ara-C treated mice performed as well as control mice during acquisition, recent memory, and remote memory portions of the task. As are some humans, C57BL/6J mice may be resistant to at least some aspects of chemotherapy induced cognitive decline.

Functional groups in the avian auditory system.

Auditory perception depends on the coding and organization of the information-bearing acoustic features of sounds by auditory neurons. We report here that auditory neurons can be classified into functional groups, each of which plays a specific role in extracting distinct complex sound features. We recorded the electrophysiological responses of single auditory neurons in the songbird midbrain and forebrain to conspecific song, measured their tuning by calculating spectrotemporal receptive fields (STRFs), and classified them using multiple cluster analysis methods. Based on STRF shape, cells clustered into functional groups that divided the space of acoustical features into regions that represent cues for the fundamental acoustic percepts of pitch, timbre, and rhythm. Four major groups were found in the midbrain, and five major groups were found in the forebrain. Comparing STRFs in midbrain and forebrain neurons suggested that both inheritance and emergence of tuning properties occur as information ascends the auditory processing stream.

What's that sound? Auditory area CLM encodes stimulus surprise, not intensity or intensity changes.

High-level sensory neurons encoding natural stimuli are not well described by linear models operating on the time-varying stimulus intensity. Here we show that firing rates of neurons in a secondary sensory forebrain area can be better modeled by linear functions of how surprising the stimulus is. We modeled auditory neurons in the caudal lateral mesopallium (CLM) of adult male zebra finches under urethane anesthesia with linear filters convolved not with stimulus intensity, but with stimulus surprise. Surprise was quantified as the logarithm of the probability of the stimulus given the local recent stimulus history and expectations based on conspecific song. Using our surprise method, the predictions of neural responses to conspecific song improved by 67% relative to those obtained using stimulus intensity. Similar prediction improvements cannot be replicated by assuming CLM performs derivative detection. The explanatory power of surprise increased from the midbrain through the primary forebrain and to CLM. When the stimulus presented was a random synthetic ripple noise, CLM neurons (but not neurons in lower auditory areas) were best described as if they were expecting conspecific song, finding the inconsistencies between birdsong and noise surprising. In summary, spikes in CLM neurons indicate stimulus surprise more than they indicate stimulus intensity features. The concept of stimulus surprise may be useful for modeling neural responses in other higher-order sensory areas whose functions have been poorly understood.

Sound representation methods for spectro-temporal receptive field estimation.

The spectro-temporal receptive field (STRF) of an auditory neuron describes the linear relationship between the sound stimulus in a time-frequency representation and the neural response. Time-frequency representations of a sound in turn require a nonlinear operation on the sound pressure waveform and many different forms for this non-linear transformation are possible. Here, we systematically investigated the effects of four factors in the non-linear step in the STRF model: the choice of logarithmic or linear filter frequency spacing, the time-frequency scale, stimulus amplitude compression and adaptive gain control. We quantified the goodness of fit of these different STRF models on data obtained from auditory neurons in the songbird midbrain and forebrain. We found that adaptive gain control and the correct stimulus amplitude compression scheme are paramount to correctly modelling neurons. The time-frequency scale and frequency spacing also affected the goodness of fit of the model but to a lesser extent and the optimal values were stimulus dependent.

Tuning for spectro-temporal modulations as a mechanism for auditory discrimination of natural sounds.

Vocal communicators discriminate conspecific vocalizations from other sounds and recognize the vocalizations of individuals. To identify neural mechanisms for the discrimination of such natural sounds, we compared the linear spectro-temporal tuning properties of auditory midbrain and forebrain neurons in zebra finches with the statistics of natural sounds, including song. Here, we demonstrate that ensembles of auditory neurons are tuned to auditory features that enhance the acoustic differences between classes of natural sounds, and among the songs of individual birds. Tuning specifically avoids the spectro-temporal modulations that are redundant across natural sounds and therefore provide little information; rather, it overlaps with the temporal modulations that differ most across sounds. By comparing the real tuning and a less selective model of spectro-temporal tuning, we found that the real modulation tuning increases the neural discrimination of different sounds. Additionally, auditory neurons discriminate among zebra finch song segments better than among synthetic sound segments.

Duration selectivity of neurons in the inferior colliculus of the big brown bat: tolerance to changes in sound level.

At and above the level of the inferior colliculus (IC), some neurons respond maximally to a limited range of sound durations, with little or no excitatory response to durations outside of this range. Such neurons have been termed "duration tuned" or "duration selective." In this study we examined the effects of varying signal amplitude on best duration, width of tuning, and first spike latency of duration tuned neurons in the IC of the big brown bat, Eptesicus fuscus. Response areas as a function of stimulus duration and intensity took a variety of forms, including open (V-shaped), narrow and level tolerant (U-shaped), or closed (O-shaped). The majority (82%) of duration tuned neurons had narrow U-shaped or O-shaped duration response areas. Those with narrow U-shaped response areas retained their duration tuning across a broad dynamic range, < or = 50 dB above threshold, whereas those with O-shaped response areas were narrowly tuned to both stimulus duration and amplitude. For about one-half (55%) of the neurons with either a U- or O-shaped response areas, best duration (BD) changed by <1 ms across the range of suprathreshold amplitudes tested. Changes in BD most often took the form of a shift to slightly shorter durations as stimulus level increased. For the majority (65%) of U- and O-shaped neurons, 50% width of duration tuning changed by <2 ms with increasing amplitude. Latency of response at BD remained stable across changes in sound level, suggesting that the relative strengths of excitatory and inhibitory inputs to duration tuned neurons remain in balance over a wide dynamic range of sound pressure levels.

Modulation power and phase spectrum of natural sounds enhance neural encoding performed by single auditory neurons.

We examined the neural encoding of synthetic and natural sounds by single neurons in the auditory system of male zebra finches by estimating the mutual information in the time-varying mean firing rate of the neuronal response. Using a novel parametric method for estimating mutual information with limited data, we tested the hypothesis that song and song-like synthetic sounds would be preferentially encoded relative to other complex, but non-song-like synthetic sounds. To test this hypothesis, we designed two synthetic stimuli: synthetic songs that matched the power of spectral-temporal modulations but lacked the modulation phase structure of zebra finch song and noise with uniform band-limited spectral-temporal modulations. By defining neural selectivity as relative mutual information, we found that the auditory system of songbirds showed selectivity for song-like sounds. This selectivity increased in a hierarchical manner along ascending processing stages in the auditory system. Midbrain neurons responded with highest information rates and efficiency to synthetic songs and thus were selective for the spectral-temporal modulations of song. Primary forebrain neurons showed increased information to zebra finch song and synthetic song equally over noise stimuli. Secondary forebrain neurons responded with the highest information to zebra finch song relative to other stimuli and thus were selective for its specific modulation phase relationships. We also assessed the relative contribution of three response properties to this selectivity: (1) spiking reliability, (2) rate distribution entropy, and (3) bandwidth. We found that rate distribution and bandwidth but not reliability were responsible for the higher average information rates found for song-like sounds.

Methods for the analysis of auditory processing in the brain.

Understanding song perception and singing behavior in birds requires the study of auditory processing of complex sounds throughout the avian brain. We can divide the basics of auditory perception into two general processes: (1) encoding, the process whereby sound is transformed into neural activity and (2) decoding, the process whereby patterns of neural activity take on perceptual meaning and therefore guide behavioral responses to sounds. In birdsong research, most studies have focused on the decoding process: What are the responses of the specialized auditory neurons in the song control system? and What do they mean for the bird? Recently, new techniques addressing both encoding and decoding have been developed for use in songbirds. Here, we first describe some powerful methods for analyzing what acoustical aspects of complex sounds like songs are encoded by auditory processing neurons in songbird brain. These methods include the estimation and analysis of spectro-temporal receptive fields (STRFs) for auditory neurons. Then we discuss the decoding methods that have been used to understand how songbird neurons may discriminate among different songs and other sounds based on mean spike-count rates.

Song selectivity in the song system and in the auditory forebrain.

The sensorimotor neurons found in the song-system nuclei are responsive to the sounds of the bird's own song. This selectivity emerges during vocal learning and appears to follow the development of the bird's song vocalization in two ways: at each stage, the neurons are most selective for the bird's current vocalizations and this selectivity increases as the bird learns to produce a stable adult song. Also, because of their location in the sensori-vocal pathway and because their physiological properties are correlated with the motor program, it is postulated that these neurons play a crucial role in interpreting the auditory feedback during song to preserve a desirable vocal output. The neurons found in presynaptic auditory areas lack this selectivity for the bird's own song. Auditory neurons in the secondary auditory areas caudal nidopallium and caudal mesopallium show specific responses to familiar songs or behaviorally relevant songs. These auditory areas might therefore be involved in perceptual tasks. Neurons in the primary forebrain auditory area are selective for the spectrotemporal modulations that are common in song, yielding an efficient neural representation of those sounds. Neurons that are particularly selective for the tutor song at the end of the sensory period have not yet been described in any areas. Although these three levels of selectivity found in the primary auditory forebrain areas, the secondary auditory forebrain areas, and the song system suggest a form of hierarchical sensory processing, the functional connectivity between these areas and the mechanisms generating the specific selectivity for songs that are behaviorally relevant or crucial in song learning and production have yet to be revealed.

Expression of the Kv1.1 ion channel subunit in the auditory brainstem of the big brown bat, Eptesicus fuscus.

Voltage-gated potassium channels play an important role in shaping membrane properties that underlie neurons' discharge patterns and the ways in which they transform their input. In the auditory system, low threshold potassium currents such as those created by Kv1.1 subunits contribute to precise phaselocking and to transient onset responses that provide time markers for temporal features of sounds. The purpose of the present study was to compare information about the distribution of neurons expressing the KV 1.1 in the brainstem auditory nuclei with the distribution of neurons with known functional properties in the auditory system of the big brown bat, Eptesicus fuscus. We used immunocytochemistry and light microscopy to look at the distribution of Kv1.1 subunits in the brainstem auditory nuclei. There was prominent expression in cell types known to contain high levels of Kv1.1 in other species and known to respond to auditory signals with high temporal precision. These included octopus cells and spherical bushy cells of the cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body. In addition, we found high levels of Kv1.1 in neurons of the columnar subdivision of the ventral nucleus of the lateral lemniscus and in ventral periolivary cell groups. Neurons with high levels of Kv1.1 were differentially distributed in the intermediate nucleus of the lateral lemniscus and in the inferior colliculus, suggesting that these structures contain functionally distinct cell populations, some of which may be involved in high-precision temporal processing.

Temporal masking reveals properties of sound-evoked inhibition in duration-tuned neurons of the inferior colliculus.

The inferior colliculus (IC) is the first place in the central auditory pathway where duration-selective neurons are found. Previous neuropharmacological and electrophysiological studies have shown that they are created there and have led to a conceptual model in which excitatory and inhibitory inputs are offset in time so that the cell fires only when sound duration is such that onset- and offset-evoked excitation coincide; the response is suppressed by inhibition at other durations. We tested predictions from the model using paired tone stimulation and extracellular recording in the IC of the big brown bat, Eptesicus fuscus. Responses to a best duration (BD) tone were used as a probe to examine the strength and time course of inhibition activated by a nonexcitatory (NE) tone of the same frequency but differing in duration. As the relative time between the BD and NE tones was varied, the activity evoked by the BD tone was affected in ways comparable with backward, simultaneous, and forward masking. Responses to the BD tone were completely suppressed at short interstimulus intervals when the BD tone preceded the NE tone. Suppression was also seen when the stimuli temporally overlapped and summed and at intervals when the BD tone followed the NE tone. The results show that duration-selective neurons receive an onset-evoked, inhibitory input that precedes their excitatory input. The period of leading inhibition was correlated with BD and first spike latency. The results suggest how inhibition in the CNS could explain temporal masking phenomena, including backward masking.

Dynamic shifts of pigeon local/global attention.

It has previously been shown that pigeons can shift attention between parts and wholes of complex stimuli composed of larger, "global" characters constructed from smaller, "local" characters. The base-rate procedure used biased target level within any condition at either the local or global level; targets were more likely at one level than at the other. Biasing of target level in this manner demonstrated shifts of local/global attention over a time span consisting of several days with a fixed base rate. Experiment 1 examined the possibility that pigeons can shift attention between local and global levels of perceptual analysis in seconds rather than days. The experiment used priming cues the color of which predicted on a trial-by-trial basis targets at different perceptual levels. The results confirmed that pigeons, like humans, can display highly dynamic stimulus-driven shifts of local/global attention. Experiment 2 changed spatial relations between features of priming cues and features of targets within a task otherwise similar to that used in experiment 1. It was predicted that this change in cues might affect asymmetry but not the occurrence of a priming effect. A priming effect was again obtained, thereby providing generality to the claim that pigeons can learn that trial-by-trial primes predict targets at different levels of perceptual analysis. Pigeons can display perceptual, stimulus-driven priming of a highly dynamic nature.

Categorizing a moving target in terms of its speed, direction, or both.

Pigeons categorized a moving target in terms of its speed and direction in an adaptation of the randomization procedure used to study human categorization behavior (Ashby & Maddox, 1998). The target moved according to vectors that were sampled with equal probabilities from two slightly overlapping bivariate normal distributions with the dimensions of speed and direction. On the average, pigeons categorized optimally in that they attended to either speed or direction alone, or divided attention between them, as was required by different reinforcement contingencies. Decision bounds were estimated for individual pigeons for each attentional task. Average slopes and y intercepts of these individually estimated decision bounds closely approximated the corresponding values for optimal decision bounds. There is therefore at least one task in which pigeons, on the average, display flexibility and quantitative precision in allocating attention to speed and direction when they categorize moving targets.