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Functional Microarchitecture of the Mouse Dorsal Inferior Colliculus Revealed through In Vivo Two-Photon Calcium Imaging.
UNLABELLED: The inferior colliculus (IC) is an obligatory relay for ascending auditory inputs from the brainstem and receives descending input from the auditory cortex. The IC comprises a central nucleus (CNIC), surrounded by several shell regions, but the internal organization of this midbrain nucleus remains incompletely understood. We used two-photon calcium imaging to study the functional microarchitecture of both neurons in the mouse dorsal IC and corticocollicular axons that terminate there. In contrast to previous electrophysiological studies, our approach revealed a clear functional distinction between the CNIC and the dorsal cortex of the IC (DCIC), suggesting that the mouse midbrain is more similar to that of other mammals than previously thought. We found that the DCIC comprises a thin sheet of neurons, sometimes extending barely 100 μm below the pial surface. The sound frequency representation in the DCIC approximated the mouse's full hearing range, whereas dorsal CNIC neurons almost exclusively preferred low frequencies. The response properties of neurons in these two regions were otherwise surprisingly similar, and the frequency tuning of DCIC neurons was only slightly broader than that of CNIC neurons. In several animals, frequency gradients were observed in the DCIC, and a comparable tonotopic arrangement was observed across the boutons of the corticocollicular axons, which form a dense mesh beneath the dorsal surface of the IC. Nevertheless, acoustically responsive corticocollicular boutons were sparse, produced unreliable responses, and were more broadly tuned than DCIC neurons, suggesting that they have a largely modulatory rather than driving influence on auditory midbrain neurons. SIGNIFICANCE STATEMENT: Due to its genetic tractability, the mouse is fast becoming the most popular animal model for sensory neuroscience. Nevertheless, many aspects of its neural architecture are still poorly understood. Here, we image the dorsal auditory midbrain and its inputs from the cortex, revealing a hitherto hidden level of organization and paving the way for the direct observation of corticocollicular interactions. We show that a precise functional organization exists in the mouse auditory midbrain, which has been missed by previous, more macroscopic approaches. The fine-scale distribution of sound-frequency tuning suggests that the mouse midbrain is more similar to that of other mammals than previously thought and contrasts with the more heterogeneous organization reported in imaging studies of auditory cortex.
Complementary adaptive processes contribute to the developmental plasticity of spatial hearing
Spatial hearing evolved independently in mammals and birds and is thought to adapt to altered developmental input in different ways. We found, however, that ferrets possess multiple forms of plasticity that are expressed according to which spatial cues are available, suggesting that the basis for adaptation may be similar across species. Our results also provide insight into the way sound source location is represented by populations of cortical neurons.
The memory function of noradrenergic activity in non-REM sleep.
There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense firing during non-REM sleep, without any signs of awakening. This transient locus coeruleus activation during sleep seems to occur in response to preceding learning-related episodes. In the present study, we manipulate noradrenergic activity during sleep in humans with either the α2-autoreceptor agonist clonidine or the noradrenaline reuptake inhibitor reboxetine. We show that reducing noradrenergic activity during sleep, but not during wakefulness, impairs subsequent memory performance in an odor recognition task. Increasing noradrenergic availability during sleep, in contrast, enhances memory retention. We conclude that noradrenergic activity during non-REM sleep interacts with other sleep-related mechanisms to functionally contribute to off-line memory consolidation.
Neural correlates of disparity-defined shape discrimination in the human brain.
Binocular disparity, the slight differences between the images registered by our two eyes, provides an important cue when estimating the three-dimensional (3D) structure of the complex environment we inhabit. Sensitivity to binocular disparity is evident at multiple levels of the visual hierarchy in the primate brain, from early visual cortex to parietal and temporal areas. However, the relationship between activity in these areas and key perceptual functions that exploit disparity information for 3D shape perception remains an important open question. Here we investigate the link between human cortical activity and the perception of disparity-defined shape, measuring fMRI responses concurrently with psychophysical shape judgments. We parametrically degraded the coherence of shapes by shuffling the spatial position of dots whose disparity defined the 3D structure and investigated the effect of this stimulus manipulation on both cortical activity and shape discrimination. We report significant relationships between shape coherence and fMRI response in both dorsal (V3, hMT+/V5) and ventral (LOC) visual areas that correspond to the observers' discrimination performance. In contrast to previous suggestions of a dichotomy of disparity-related processes in the ventral and dorsal streams, these findings are consistent with proposed interactions between these pathways that may mediate a continuum of processes important in perceiving 3D shape from coarse contour segmentation to fine curvature estimation.
Prepulse-elicited startle in prepulse inhibition.
BACKGROUND: Prepulse inhibition (PPI) has become a major experimental paradigm in the study of psychiatric disorders. In this study, a potential confound in measurement and interpretation of PPI, namely startle reactions to so-called "nonstartling" prepulses, was examined. METHODS: Prepulses of 80, 85, and 90 dB(A) were presented on their own or followed by a pulse of 115 dB(A) (lead interval: 120 msec). RESULTS: Even at only 80 dB(A), prepulses presented alone elicited a response in about 50% of trials; and, except in the first stage of the experiment, responses became more frequent as prepulse intensity increased. Importantly, PPI at 80 and 85 dB(A) was negatively correlated with response probability to prepulses presented alone. CONCLUSIONS: Prepulses reliably activate the very startle system that they are thought to inhibit, and a high level of responsiveness to prepulses is associated with relatively lower levels of PPI. These findings might hold important implications for clinical and psychopharmacologic studies of PPI, and we suggest that the extent and influence of prepulse-elicited startles should be routinely examined.
Thalamic nuclei convey diverse contextual information to layer 1 of visual cortex.
Sensory perception depends on the context in which a stimulus occurs. Prevailing models emphasize cortical feedback as the source of contextual modulation. However, higher order thalamic nuclei, such as the pulvinar, interconnect with many cortical and subcortical areas, suggesting a role for the thalamus in providing sensory and behavioral context. Yet the nature of the signals conveyed to cortex by higher order thalamus remains poorly understood. Here we use axonal calcium imaging to measure information provided to visual cortex by the pulvinar equivalent in mice, the lateral posterior nucleus (LP), as well as the dorsolateral geniculate nucleus (dLGN). We found that dLGN conveys retinotopically precise visual signals, while LP provides distributed information from the visual scene. Both LP and dLGN projections carry locomotion signals. However, while dLGN inputs often respond to positive combinations of running and visual flow speed, LP signals discrepancies between self-generated and external visual motion. This higher order thalamic nucleus therefore conveys diverse contextual signals that inform visual cortex about visual scene changes not predicted by the animal's own actions.
Behavioral training promotes multiple adaptive processes following acute hearing loss.
The brain possesses a remarkable capacity to compensate for changes in inputs resulting from a range of sensory impairments. Developmental studies of sound localization have shown that adaptation to asymmetric hearing loss can be achieved either by reinterpreting altered spatial cues or by relying more on those cues that remain intact. Adaptation to monaural deprivation in adulthood is also possible, but appears to lack such flexibility. Here we show, however, that appropriate behavioral training enables monaurally-deprived adult humans to exploit both of these adaptive processes. Moreover, cortical recordings in ferrets reared with asymmetric hearing loss suggest that these forms of plasticity have distinct neural substrates. An ability to adapt to asymmetric hearing loss using multiple adaptive processes is therefore shared by different species and may persist throughout the lifespan. This highlights the fundamental flexibility of neural systems, and may also point toward novel therapeutic strategies for treating sensory disorders.
Midbrain encodes sound detection behavior without auditory cortex.
Hearing involves analyzing the physical attributes of sounds and integrating the results of this analysis with other sensory, cognitive, and motor variables in order to guide adaptive behavior. The auditory cortex is considered crucial for the integration of acoustic and contextual information and is thought to share the resulting representations with subcortical auditory structures via its vast descending projections. By imaging cellular activity in the corticorecipient shell of the inferior colliculus of mice engaged in a sound detection task, we show that the majority of neurons encode information beyond the physical attributes of the stimulus and that the animals' behavior can be decoded from the activity of those neurons with a high degree of accuracy. Surprisingly, this was also the case in mice in which auditory cortical input to the midbrain had been removed by bilateral cortical lesions. This illustrates that subcortical auditory structures have access to a wealth of non-acoustic information and can, independently of the auditory cortex, carry much richer neural representations than previously thought.
Decoding mouse behavior to explain single-trial decisions and their relationship with neural activity
AbstractModels of behavior typically focus on sparse measurements of motor output over long timescales, limiting their ability to explain momentary decisions or neural activity. We developed data-driven models relating experimental variables to videos of behavior. Applied to mouse operant behavior, they revealed behavioral encoding of cognitive variables. Model-based decoding of videos yielded an accurate account of single-trial behavior in terms of the relationship between cognition, motor output and cortical activity.
Context-specific reweighting of auditory spatial cues following altered experience during development.
BACKGROUND: Neural systems must weight and integrate different sensory cues in order to make decisions. However, environmental conditions often change over time, altering the reliability of different cues and therefore the optimal way for combining them. To explore how cue integration develops in dynamic environments, we examined the effects on auditory spatial processing of rearing ferrets with localization cues that were modified via a unilateral earplug, interspersed with brief periods of normal hearing. RESULTS: In contrast with control animals, which rely primarily on timing and intensity differences between their two ears to localize sound sources, the juvenile-plugged ferrets developed the ability to localize sounds accurately by relying more on the unchanged spectral localization cues provided by the single normal ear. This adaptive process was paralleled by changes in neuronal responses in the primary auditory cortex, which became relatively more sensitive to these monaural spatial cues. Our behavioral and physiological data demonstrated, however, that the reweighting of different spatial cues disappeared as soon as normal hearing was experienced, showing for the first time that this type of plasticity can be context specific. CONCLUSIONS: These results show that developmental changes can be selectively expressed in response to specific acoustic conditions. In this way, the auditory system can develop and simultaneously maintain two distinct models of auditory space and switch between these models depending on the prevailing sensory context. This ability is likely to be critical for maintaining accurate perception in dynamic environments and may point toward novel therapeutic strategies for individuals who experience sensory deficits during development.
Complementary adaptive processes contribute to the developmental plasticity of spatial hearing.
Spatial hearing evolved independently in mammals and birds and is thought to adapt to altered developmental input in different ways. We found, however, that ferrets possess multiple forms of plasticity that are expressed according to which spatial cues are available, suggesting that the basis for adaptation may be similar across species. Our results also provide insight into the way sound source location is represented by populations of cortical neurons.
Subcortical circuits mediate communication between primary sensory cortical areas in mice.
Integration of information across the senses is critical for perception and is a common property of neurons in the cerebral cortex, where it is thought to arise primarily from corticocortical connections. Much less is known about the role of subcortical circuits in shaping the multisensory properties of cortical neurons. We show that stimulation of the whiskers causes widespread suppression of sound-evoked activity in mouse primary auditory cortex (A1). This suppression depends on the primary somatosensory cortex (S1), and is implemented through a descending circuit that links S1, via the auditory midbrain, with thalamic neurons that project to A1. Furthermore, a direct pathway from S1 has a facilitatory effect on auditory responses in higher-order thalamic nuclei that project to other brain areas. Crossmodal corticofugal projections to the auditory midbrain and thalamus therefore play a pivotal role in integrating multisensory signals and in enabling communication between different sensory cortical areas.
Neural processing in the primary auditory cortex following cholinergic lesions of the basal forebrain in ferrets.
Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.
Complexity of frequency receptive fields predicts tonotopic variability across species
Primary cortical areas contain maps of sensory features, including sound frequency in primary auditory cortex (A1). Two-photon calcium imaging in mice has confirmed the presence of these global tonotopic maps, while uncovering an unexpected local variability in the stimulus preferences of individual neurons in A1 and other primary regions. Here we show that local heterogeneity of frequency preferences is not unique to rodents. Using two-photon calcium imaging in layers 2/3, we found that local variance in frequency preferences is equivalent in ferrets and mice. Neurons with multipeaked frequency tuning are less spatially organized than those tuned to a single frequency in both species. Furthermore, we show that microelectrode recordings may describe a smoother tonotopic arrangement due to a sampling bias towards neurons with simple frequency tuning. These results help explain previous inconsistencies in cortical topography across species and recording techniques.
Thalamic input to auditory cortex is locally heterogeneous but globally tonotopic.
Topographic representation of the receptor surface is a fundamental feature of sensory cortical organization. This is imparted by the thalamus, which relays information from the periphery to the cortex. To better understand the rules governing thalamocortical connectivity and the origin of cortical maps, we used in vivo two-photon calcium imaging to characterize the properties of thalamic axons innervating different layers of mouse auditory cortex. Although tonotopically organized at a global level, we found that the frequency selectivity of individual thalamocortical axons is surprisingly heterogeneous, even in layers 3b/4 of the primary cortical areas, where the thalamic input is dominated by the lemniscal projection. We also show that thalamocortical input to layer 1 includes collaterals from axons innervating layers 3b/4 and is largely in register with the main input targeting those layers. Such locally varied thalamocortical projections may be useful in enabling rapid contextual modulation of cortical frequency representations.
Local and Global Spatial Organization of Interaural Level Difference and Frequency Preferences in Auditory Cortex.
Despite decades of microelectrode recordings, fundamental questions remain about how auditory cortex represents sound-source location. Here, we used in vivo 2-photon calcium imaging to measure the sensitivity of layer II/III neurons in mouse primary auditory cortex (A1) to interaural level differences (ILDs), the principal spatial cue in this species. Although most ILD-sensitive neurons preferred ILDs favoring the contralateral ear, neurons with either midline or ipsilateral preferences were also present. An opponent-channel decoder accurately classified ILDs using the difference in responses between populations of neurons that preferred contralateral-ear-greater and ipsilateral-ear-greater stimuli. We also examined the spatial organization of binaural tuning properties across the imaged neurons with unprecedented resolution. Neurons driven exclusively by contralateral ear stimuli or by binaural stimulation occasionally formed local clusters, but their binaural categories and ILD preferences were not spatially organized on a more global scale. In contrast, the sound frequency preferences of most neurons within local cortical regions fell within a restricted frequency range, and a tonotopic gradient was observed across the cortical surface of individual mice. These results indicate that the representation of ILDs in mouse A1 is comparable to that of most other mammalian species, and appears to lack systematic or consistent spatial order.
Neural circuits underlying adaptation and learning in the perception of auditory space.
Sound localization mechanisms are particularly plastic during development, when the monaural and binaural acoustic cues that form the basis for spatial hearing change in value as the body grows. Recent studies have shown that the mature brain retains a surprising capacity to relearn to localize sound in the presence of substantially altered auditory spatial cues. In addition to the long-lasting changes that result from learning, behavioral and electrophysiological studies have demonstrated that auditory spatial processing can undergo rapid adjustments in response to changes in the statistics of recent stimulation, which help to maintain sensitivity over the range where most stimulus values occur. Through a combination of recording studies and methods for selectively manipulating the activity of specific neuronal populations, progress is now being made in identifying the cortical and subcortical circuits in the brain that are responsible for the dynamic coding of auditory spatial information.
Binaural sensitivity changes between cortical on and off responses.
Neurons exhibiting on and off responses with different frequency tuning have previously been described in the primary auditory cortex (A1) of anesthetized and awake animals, but it is unknown whether other tuning properties, including sensitivity to binaural localization cues, also differ between on and off responses. We measured the sensitivity of A1 neurons in anesthetized ferrets to 1) interaural level differences (ILDs), using unmodulated broadband noise with varying ILDs and average binaural levels, and 2) interaural time delays (ITDs), using sinusoidally amplitude-modulated broadband noise with varying envelope ITDs. We also assessed fine-structure ITD sensitivity and frequency tuning, using pure-tone stimuli. Neurons most commonly responded to stimulus onset only, but purely off responses and on-off responses were also recorded. Of the units exhibiting significant binaural sensitivity nearly one-quarter showed binaural sensitivity in both on and off responses, but in almost all (∼97%) of these units the binaural tuning of the on responses differed significantly from that seen in the off responses. Moreover, averaged, normalized ILD and ITD tuning curves calculated from all units showing significant sensitivity to binaural cues indicated that on and off responses displayed different sensitivity patterns across the population. A principal component analysis of ITD response functions suggested a continuous cortical distribution of binaural sensitivity, rather than discrete response classes. Rather than reflecting a release from inhibition without any functional significance, we propose that binaural off responses may be important to cortical encoding of sound-source location.
Adaptation to stimulus statistics in the perception and neural representation of auditory space.
Sensory systems are known to adapt their coding strategies to the statistics of their environment, but little is still known about the perceptual implications of such adjustments. We investigated how auditory spatial processing adapts to stimulus statistics by presenting human listeners and anesthetized ferrets with noise sequences in which interaural level differences (ILD) rapidly fluctuated according to a Gaussian distribution. The mean of the distribution biased the perceived laterality of a subsequent stimulus, whereas the distribution's variance changed the listeners' spatial sensitivity. The responses of neurons in the inferior colliculus changed in line with these perceptual phenomena. Their ILD preference adjusted to match the stimulus distribution mean, resulting in large shifts in rate-ILD functions, while their gain adapted to the stimulus variance, producing pronounced changes in neural sensitivity. Our findings suggest that processing of auditory space is geared toward emphasizing relative spatial differences rather than the accurate representation of absolute position.
Stimulus-timing-dependent plasticity of cortical frequency representation.
Adult cortical circuits possess considerable plasticity, which can be induced by modifying their inputs. One mechanism proposed to underlie changes in neuronal responses is spike-timing-dependent plasticity (STDP), an up- or downregulation of synaptic efficacy contingent upon the order and timing of presynaptic and postsynaptic activity. The repetitive and asynchronous pairing of a sensory stimulus with either another sensory stimulus or current injection can alter the response properties of visual and somatosensory neurons in a manner consistent with STDP. To examine whether such plasticity also exists in the auditory system, we recorded from neurons in the primary auditory cortex of anesthetized and awake adult ferrets. The repetitive pairing of pure tones of different frequencies induced shifts in neuronal frequency selectivity, which exhibited a temporal specificity akin to STDP. Only pairs with stimulus onset asynchronies of 8 or 12 ms were effective and the direction of the shifts depended upon the order in which the tones within a pair were presented. Six hundred stimulus pairs (lasting approximately 70 s) were enough to produce a significant shift in frequency tuning and the changes persisted for several minutes. The magnitude of the observed shifts was largest when the frequency separation of the conditioning stimuli was < approximately 1 octave. Moreover, significant shifts were found only in the upper cortical layers. Our findings highlight the importance of millisecond-scale timing of sensory input in shaping neural function and strongly suggest STDP as a relevant mechanism for plasticity in the mature auditory system.