Behavioral Neuroscience publications

How the brain maintains an accurate and stable representation of visual target locations despite the occurrence of saccadic gaze shifts is a classical problem in oculomotor research. Here we test and dissociate the predictions of different conceptual models for head-unrestrained gaze-localization behavior of macaque monkeys. We adopted the double-step paradigm with rapid eye-head gaze shifts to measure localization accuracy in response to flashed visual stimuli in darkness. We presented the second target flash either before (static), or during (dynamic) the first gaze displacement. In the dynamic case the brief visual flash induced a small retinal streak of up to about 20 deg at an unpredictable moment and retinal location during the eye-head gaze shift, which provides serious challenges for the gaze-control system. However, for both stimulus conditions, monkeys localized the flashed targets with accurate gaze shifts, which rules out several models of visuomotor control. First, these findings exclude the possibility that gaze-shift programming relies on retinal inputs only. Instead, they support the notion that accurate eye-head motor feedback updates the gaze-saccade coordinates. Second, in dynamic trials the visuomotor system cannot rely on the coordinates of the planned first eye-head saccade either, which rules out remapping on the basis of a predictive corollary gaze-displacement signal. Finally, because gaze-related head movements were also goal-directed, requiring continuous access to eye-in-head position, we propose that our results best support a dynamic feedback scheme for spatial updating in which visuomotor control incorporates accurate signals about instantaneous eye- and head positions rather than relative eye- and head displacements.

Key points The cerebral cortex plays a critical role in perception and in learning‐induced plasticity. We show that reversibly silencing any of the main regions of auditory cortex impairs the ability of adult ferrets to localize sound, with the largest deficit seen after deactivating the primary fields. Although these animals had no trouble localizing longer sound bursts, their performance dropped considerably when auditory spatial cues were altered by occluding one ear with an earplug. In contrast to control ferrets, which recovered their localization abilities with intensive training, adaptation to an earplug was impaired following cortical inactivation, with the greatest disruption in plasticity observed after silencing higher‐level cortical areas. These findings imply regional differences in the processing of spatial information across the auditory cortex. Abstract The contribution of auditory cortex to spatial information processing was explored behaviourally in adult ferrets by reversibly deactivating different cortical areas by subdural placement of a polymer that released the GABA A agonist muscimol over a period of weeks. The spatial extent and time course of cortical inactivation were determined electrophysiologically. Muscimol‐Elvax was placed bilaterally over the anterior (AEG), middle (MEG) or posterior ectosylvian gyrus (PEG), so that different regions of the auditory cortex could be deactivated in different cases. Sound localization accuracy in the horizontal plane was assessed by measuring both the initial head orienting and approach‐to‐target responses made by the animals. Head orienting behaviour was unaffected by silencing any region of the auditory cortex, whereas the accuracy of approach‐to‐target responses to brief sounds (40 ms noise bursts) was reduced by muscimol‐Elvax but not by drug‐free implants. Modest but significant localization impairments were observed after deactivating the MEG, AEG or PEG, although the largest deficits were produced in animals in which the MEG, where the primary auditory fields are located, was silenced. We also examined experience‐induced spatial plasticity by reversibly plugging one ear. In control animals, localization accuracy for both approach‐to‐target and head orienting responses was initially impaired by monaural occlusion, but recovered with training over the next few days. Deactivating any part of the auditory cortex resulted in less complete recovery than in controls, with the largest deficits observed after silencing the higher‐level cortical areas in the AEG and PEG. Although suggesting that each region of auditory cortex contributes to spatial learning, differences in the localization deficits and degree of adaptation between groups imply a regional specialization in the processing of spatial information across the auditory cortex.

Damage to the auditory system following high-level sound exposure reduces afferent input. Homeostatic mechanisms appear to compensate for the loss. Overcompensation may produce the sensation of sound without an objective physical correlate, i.e., tinnitus. Several potential compensatory neural processes have been identified, such as increased spontaneous activity. The cellular mechanisms enabling such compensatory processes may involve down-regulation of inhibitory neurotransmission mediated by γ-amino butyric acid (GABA), and/or up-regulation of excitatory neurotransmission, mediated by glutamic acid (Glu). Because central processing systems are integrated and well-regulated, compensatory changes in one system may produce reactive changes in others. Some or all may be relevant to tinnitus. To examine the roles of GABA and Glu in tinnitus, high resolution point-resolved proton magnetic resonance spectroscopy ((1)H-MRS) was used to quantify their levels in the dorsal cochlear nucleus (DCN), inferior colliculus (IC), medial geniculate body (MGB), and primary auditory cortex (A1) of rats. Chronic tinnitus was produced by a single high-level unilateral exposure to noise, and was measured using a psychophysical procedure sensitive to tinnitus. Decreased GABA levels were evident only in the MGB, with the greatest decrease, relative to unexposed controls, obtained in the contralateral MGB. Small GABA increases may have been present bilaterally in A1 and in the contralateral DCN. Although Glu levels showed considerable variation, Glu was moderately and bilaterally elevated both in the DCN and in A1. In the MGB Glu was increased ipsilaterally but decreased contralaterally. These bidirectional and region-specific alterations in GABA and Glu may reflect large-scale changes in inhibitory and excitatory equilibrium accompanying chronic tinnitus. The present results also suggest that targeting both neurotransmitter systems may be optimal in developing more effective therapeutics.

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.

Many fishes rely on their auditory skills to interpret crucial information about predators and prey, and to communicate intraspecifically. Few studies, however, have examined how complex natural sounds are perceived in fishes. We investigated the representation of conspecific mating and agonistic calls in the auditory system of the Lusitanian toadfish Halobatrachus didactylus , and analysed auditory responses to heterospecific signals from ecologically relevant species: a sympatric vocal fish (meagre Argyrosomus regius ) and a potential predator (dolphin Tursiops truncatus ). Using auditory evoked potential (AEP) recordings, we showed that both sexes can resolve fine features of conspecific calls. The toadfish auditory system was most sensitive to frequencies well represented in the conspecific vocalizations (namely the mating boatwhistle), and revealed a fine representation of duration and pulsed structure of agonistic and mating calls. Stimuli and corresponding AEP amplitudes were highly correlated, indicating an accurate encoding of amplitude modulation. Moreover, Lusitanian toadfish were able to detect T. truncatus foraging sounds and A. regius calls, although at higher amplitudes. We provide strong evidence that the auditory system of a vocal fish, lacking accessory hearing structures, is capable of resolving fine features of complex vocalizations that are probably important for intraspecific communication and other relevant stimuli from the auditory scene.

A growing number of studies of auditory processing are being carried out in awake, behaving animals, creating a need for precisely controlled sound delivery without restricting head movements. We have designed a system for closed-field stimulus presentation in freely moving ferrets, which comprises lightweight, adjustable headphones that can be consistently positioned over the ears via a small, skull-mounted implant. The invasiveness of the implant was minimized by simplifying its construction and using dental adhesive only for attaching it to the skull, thereby reducing the surgery required and avoiding the use of screws or other anchoring devices. Attaching the headphones to a chronic implant also reduced the amount of contact they had with the head and ears, increasing the willingness of the animals to wear them. We validated sound stimulation via the headphones in ferrets trained previously in a free-field task to localize stimuli presented from one of two loudspeakers. Noise bursts were delivered binaurally over the headphones and interaural level differences (ILDs) were introduced to allow the sound to be lateralized. Animals rapidly transferred from the free-field task to indicate the perceived location of the stimulus presented over headphones. They showed near perfect lateralization with a 5 dB ILD, matching the scores achieved in the free-field task. As expected, the ferrets' performance declined when the ILD was reduced in value. This closed-field system can easily be adapted for use in other species, and provides a reliable means of presenting closed-field stimuli whilst monitoring behavioral responses in freely moving animals.

This thesis is divided into six chapters (following Introduction). Each chapter was intended to be self-contained, so they do not have to be read in the order they are presented. Second chapter (Sec. 2) contains a detailed description of experimental techniques: surgery, recording, and training techniques we used in awake head-fixed rats. We have also included a detailed description of all sets of stimuli we used to probe neurons, analytical methods used to analyze data, and description of computational models used in other parts of the thesis.Third chapter (Sec. 3) focuses on description of single-neuron responses in primary auditory cortex of awake head-fixed rats. The primary emphasis of this part is on the sparse representation of various auditory stimuli we used to probe neurons, and the heterogeneity of responses of single neurons. To characterize population responses to sound in the auditory cortex we asked the question "What is the typical response to acoustic stimuli?" instead of what is usually asked "What is the stimulus that evokes a response?" We found that the population response was sparse, with many unresponsive neurons. In addition, the responsive neurons showed a great variety of responses. This heterogeneity of neuronal responses ("response zoo," courtesy of Anthony M. Zádor) was, however, surprisingly well characterized by lognormal distribution of firing rates. The observation that firing rates in awake auditory cortex were lognormally distributed was even more interesting given the observation of lognormal distribution of synaptic weights in the cerebral cortex.The fourth chapter (Sec. 4) focuses on mechanisms which could give rise to lognormal distribution of firing rates, as well as synaptic weights. We proposed specific types of correlations among synaptic connections, and formulated a multiplicative learning rule which led to the observed distributions. We were also able to characterize intracellular activity of neurons in awake auditory cortex. The fifth chapter (Sec. 5) contains analysis of so-called up and down states in awake auditory cortex. We show that up and down states—the "signature" subthreshold dynamics so often described in various cortical areas of anesthetized animals—were rare in the primary auditory cortex of awake rats, instead, subthreshold dynamics was consisted of brief, infrequent fluctuations of membrane potential.The experiments described and analyzed in chapters 2—-4 were conducted in naïve awake rats. As behavior or attention can influence neuronal activity even in primary sensory areas, we developed a setup for head-fixed behavior. In the sixth chapter (Sec. 6) we describe the sound discrimination task we have used to study behavior in head-fixed rats. We present a comparison of basic behavioral parameters between restrained and unrestrained rats, as well as evidence of nonauditory modulations of single neuron activity in auditory cortex.

Background: Mucopolysaccharidosis (MPS) IIIB (Sanfilippo Syndrome type B) is caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop disturbances of sleep, activity levels, coordination, vision, hearing, and mental functioning culminating in early death. The murine model of MPS IIIB demonstrates lysosomal distention in multiple tissues, a shortened life span, and behavioral changes. Principal findings: To more thoroughly assess MPS IIIB in mice, alterations in circadian rhythm, activity level, motor function, vision, and hearing were tested. The suprachiasmatic nucleus (SCN) developed pathologic changes and locomotor analysis showed that MPS IIIB mice start their daily activity later and have a lower proportion of activity during the night than wild-type controls. Rotarod assessment of motor function revealed a progressive inability to coordinate movement in a rocking paradigm. Purkinje cell counts were significantly reduced in the MPS IIIB animals compared to age matched controls. By electroretinography (ERG), MPS IIIB mice had a progressive decrease in the amplitude of the dark-adapted b-wave response. Corresponding pathology revealed shortening of the outer segments, thinning of the outer nuclear layer, and inclusions in the retinal pigmented epithelium. Auditory-evoked brainstem responses (ABR) demonstrated progressive hearing deficits consistent with the observed loss of hair cells in the inner ear and histologic abnormalities in the middle ear. Conclusions/significance: The mouse model of MPS IIIB has several quantifiable phenotypic alterations and is similar to the human disease. These physiologic and histologic changes provide insights into the progression of this disease and will serve as important parameters when evaluating various therapies.

Plasticity studies suggest that behavioral relevance can change the cortical processing of trained or conditioned sensory stimuli. However, whether this occurs in the context of natural communication, where stimulus significance is acquired through social interaction, has not been well investigated, perhaps because neural responses to species-specific vocalizations can be difficult to interpret within a systematic framework. The ultrasonic communication system between isolated mouse pups and adult females that either do or do not recognize the calls' significance provides an opportunity to explore this issue. We applied an information-based analysis to multi- and single unit data collected from anesthetized mothers and pup-naïve females to quantify how the communicative significance of pup calls affects their encoding in the auditory cortex. The timing and magnitude of information that cortical responses convey (at a 2-ms resolution) for pup call detection and discrimination was significantly improved in mothers compared to naïve females, most likely because of changes in call frequency encoding. This was not the case for a non-natural sound ensemble outside the mouse vocalization repertoire. The results demonstrate that a sensory cortical change in the timing code for communication sounds is correlated with the vocalizations' behavioral relevance, potentially enhancing functional processing by improving its signal to noise ratio.