Histaminergic modulation of nonspecific plasticity of the auditory system and differential gating.

In the auditory system of the big brown bat (Eptesicus fuscus), paired conditioned tonal (CS) and unconditioned leg stimuli (US) for auditory fear conditioning elicit tone-specific plasticity represented by best-frequency (BF) shifts that are augmented by acetylcholine, whereas unpaired CS and US for pseudoconditioning elicit a small BF shift and prominent nonspecific plasticity at the same time. The latter represents the nonspecific augmentations of auditory responses accompanied by the broadening of frequency tuning and decrease in threshold. It is unknown which neuromodulators are important in evoking the nonspecific plasticity. We found that histamine (HA) and an HA3 receptor (HA3R) agonist (α-methyl-HA) decreased, but an HA3R antagonist (thioperamide) increased, cortical auditory responses; that the HA3R agonist applied to the primary auditory cortex before pseudoconditioning abolished the nonspecific augmentation in the cortex without affecting the small cortical BF shift; and that antagonists of acetylcholine, norepinephrine, dopamine, and serotonin receptors did not abolish the nonspecific augmentation elicited by pseudoconditioning. The histaminergic system plays an important role in eliciting the arousal and defensive behavior, possibly through nonspecific augmentation. Thus HA modulates the nonspecific augmentation, whereas acetylcholine amplifies the BF shifts. These two neuromodulators may mediate differential gating of cortical plasticity.

Modulation of thalamic auditory neurons by the primary auditory cortex.

The central auditory system consists of the lemniscal and nonlemniscal pathways or systems, which are anatomically and physiologically different from each other. In the thalamus, the ventral division of the medial geniculate body (MGBv) belongs to the lemniscal system, whereas its medial (MGBm) and dorsal (MGBd) divisions belong to the nonlemniscal system. Lemniscal neurons are sharply frequency-tuned and provide highly frequency-specific information to the primary auditory cortex (AI), whereas nonlemniscal neurons are generally broadly frequency-tuned and project widely to cortical auditory areas including AI. These two systems are presumably different not only in auditory signal processing, but also in eliciting cortical plastic changes. Electric stimulation of narrowly frequency-tuned MGBv neurons evokes the shift of the frequency-tuning curves of AI neurons toward the tuning curves of the stimulated MGBv neurons (tone-specific plasticity). In contrast, electric stimulation of broadly frequency-tuned MGBm neurons augments the auditory responses of AI neurons and broadens their frequency-tuning curves (nonspecific plasticity). In our current studies, we found that electric stimulation of AI evoked tone-specific plastic changes of the MGBv neurons, whereas it degraded the frequency tuning of MGBm neurons by inhibiting their auditory responses. AI apparently modulates the lemniscal and nonlemniscal thalamic neurons in quite different ways. High MGBm activity presumably makes AI neurons less favorable for fine auditory signal processing, whereas high MGBv activity makes AI neurons more suitable for fine processing of specific auditory signals and reduces MGBm activity.

Modulation of auditory processing by cortico-cortical feed-forward and feedback projections.

The auditory center in the cerebrum, the auditory cortex, consists of multiple interconnected areas. The functional role of these interconnections is poorly understood. The auditory cortex of the mustached bat consists of at least nine areas, including the frequency modulation-frequency modulation (FF) and dorsal fringe (DF) areas. The FF and DF areas consist of neurons tuned to specific echo delays carrying target-distance information. The DF area is hierarchically at a higher level than the FF area. Here, we show that the feedback projection from the DF area to the FF area shifts the delay-tuning of FF neurons toward that of the stimulated DF neurons. In contrast, the feed-forward projection from the FF area to the DF area shifts the delay-tuning of DF neurons away from that of the stimulated FF neurons. The lateral projection within the DF area shifts the delay-tuning of DF neurons toward that of the stimulated DF neurons. In contrast, the lateral projection within the FF area shifts the delay-tuning of FF neurons away from that of the stimulated FF neurons. The delay-tuning shift evoked by the DF stimulation was 2.5 times larger than that evoked by the FF stimulation. Our data indicate that the FF-DF feed-forward and FF-FF lateral projections shape the highly selective neural representation of the tuning of the excited DF neurons, whereas the DF-FF feedback and DF-DF lateral projections enhance the representation of the selected tuning, perhaps, for focal processing of information carried by the excited FF neurons.

Specific and nonspecific plasticity of the primary auditory cortex elicited by thalamic auditory neurons.

The ventral and medial divisions of the medial geniculate body (MGBv and MGBm) respectively are the lemniscal and nonlemniscal thalamic auditory nuclei. Lemniscal neurons are narrowly frequency tuned and provide highly specific frequency information to the primary auditory cortex (AI), whereas nonlemniscal neurons are broadly frequency tuned and project widely to auditory cortical areas including AI. The MGBv and MGBm are presumably different not only in auditory signal processing, but also in eliciting cortical plastic changes. We electrically stimulated MGBv or MGBm neurons and found the following: (1) electric stimulation of narrowly frequency-tuned MGBv neurons evoked the shift of the frequency-tuning curves of AI neurons toward the tuning curves of the stimulated MGBv neurons. This shift was the same as that in the central nucleus of the inferior colliculus and AI elicited by focal electric stimulation of AI or auditory fear conditioning. The widths of the tuning curves of the AI neurons stayed the same or slightly increased. (2) Electric stimulation of broad frequency-tuned MGBm neurons augmented the auditory responses of AI neurons and broadened their frequency-tuning curves which did not shift. These cortical changes evoked by MGBv or MGBm neurons slowly disappeared over 45-60 min after the onset of the electric stimulation. Our findings indicate that lemniscal and nonlemniscal nuclei are indeed different in eliciting cortical plastic changes: the MGBv evokes tone-specific plasticity in AI for adjusting auditory signal processing in the frequency domain, whereas the MGBm evokes nonspecific plasticity in AI for increasing the sensitivity of cortical neurons.

Corticocortical interactions between and within three cortical auditory areas specialized for time-domain signal processing.

In auditory cortex of the mustached bat, the FF (F means frequency modulation), dorsal fringe (DF), and ventral fringe (VF) areas consist of "combination-sensitive" neurons tuned to the pair of an emitted biosonar pulse and its echo with a specific delay (best delay: BD). The DF and VF areas are hierarchically at a higher level than the FF area. Focal electric stimulation of the FF area evokes "centrifugal" BD shifts of DF neurons, i.e., shifts away from the BD of the stimulated FF neurons, whereas stimulation of the DF neurons evokes "centripetal" BD shifts of FF neurons, i.e., shifts toward the BD of the stimulated DF neurons. In our current studies, we found that the feedforward projection from FF neurons evokes centrifugal BD shifts of VF neurons, that the feedback projection from VF neurons evokes centripetal BD shifts of FF neurons, that the contralateral projection from DF neurons evokes centripetal BD shifts of DF neurons, and that the centripetal BD shifts evoked by the DF and VF neurons are 2.5 times larger than the centrifugal BD shifts evoked by the FF neurons. The centrifugal BD shifts shape the selective neural representation of a specific target distance, whereas the centripetal BD shifts expand the representation of the selected specific target distance to focus on the processing of the target information at a specific distance. The centrifugal and centripetal BD shifts evoked by the feedforward and feedback projections promote finer analysis of a target at shorter distances.

Plasticity of the adult auditory system based on corticocortical and corticofugal modulations.

Suga, N. Plasticity of the adult auditory system based on corticocortical and corticofugal modulations. NEUROSCI. BIOBEHAV. REV. XXX-XXX, 2020. Corticocortical and corticofugal modulations mediated by neurons in the lemniscal pathway are based on positive feedback associated with lateral inhibition and play an essential role not only in auditory signal processing, but also sound-specific plastic changes (e.g., frequency-tuning shifts) for the reorganization of the adult auditory system based on auditory experiences. The modulations evoke the facilitation of auditory responses of "tuning-matched" neurons and the tuning shifts of "tuning-unmatched" neurons in the auditory cortex and subcortical auditory nuclei. Here, "tuning-matched" means that the tuning properties of a recorded neuron are the same as those of an electrically stimulated cortical neuron or the frequency of tone burst stimuli. Tuning shifts, corticocortical and corticofugal modulations, evoked by focal cortical electric stimulation or tone burst stimulation are augmented by electric stimulation of the somatosensory cortex, acetylcholine application to the auditory cortex and associative learning such as auditory fear conditioning. Tuning shifts occur not only in the frequency domain, but also in the time, amplitude and spatial domains.

Inhibitory mechanisms shaping delay-tuned combination-sensitivity in the auditory cortex and thalamus of the mustached bat.

Delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. The subcollicular nuclei produce latency-constant phasic on-responding neurons, and the inferior colliculus produces delay-tuned combination-sensitive neurons, designated "FM-FM" neurons. The combination-sensitivity is a facilitated response to the coincidence of the excitatory rebound following glycinergic inhibition to the pulse (1st harmonic) and the short-latency response to the echo (2nd-4th harmonics). The facilitative response of thalamic FM-FM neurons is mediated by glutamate receptors (NMDA and non-NMDA receptors). Different from collicular FM-FM neurons, thalamic ones respond more selectively to pulse-echo pairs than individual signal elements. A number of differences in response properties between collicular and thalamic or cortical FM-FM neurons have been reported. However, differences between thalamic and cortical FM-FM neurons have remained to be studied. Here, we report that GABAergic inhibition controls the duration of burst of spikes of facilitative responses of thalamic FM-FM neurons and sharpens the delay tuning of cortical ones. That is, intra-cortical inhibition sharpens the delay tuning of cortical FM-FM neurons that is potentially broad because of divergent/convergent thalamo-cortical projections. Compared with thalamic neurons, cortical ones tend to show sharper delay tuning, longer response duration, and larger facilitation index. However, those differences are statistically insignificant.

Plasticity and corticofugal modulation for hearing in adult animals.

The descending (corticofugal) auditory system adjusts and improves auditory signal processing in the subcortical auditory nuclei. The auditory cortex and corticofugal system evoke small, short-term changes of the subcortical auditory nuclei in response to a sound repetitively delivered to an animal. These changes are specific to the parameters characterizing the sound. When the sound becomes significant to the animal through conditioning (associative learning), the changes are augmented and the cortical changes become long-term. There are two types of reorganizations: expanded reorganization resulting from centripetal shifts in tuning curves of neurons toward the values of the parameters characterizing a sound and compressed reorganization resulting from centrifugal shifts in tuning curves of neurons away from these values. The two types of reorganizations are based on a single mechanism consisting of two components: facilitation and inhibition.

Serotonergic modulation of plasticity of the auditory cortex elicited by fear conditioning.

In the awake big brown bat, 30 min auditory fear conditioning elicits conditioned heart rate decrease and long-term best frequency (BF) shifts of cortical auditory neurons toward the frequency of the conditioned tone; 15 min conditioning elicits subthreshold cortical BF shifts that can be augmented by acetylcholine. The fear conditioning causes stress and an increase in the cortical serotonin (5-HT) level. Serotonergic neurons in the raphe nuclei associated with stress and fear project to the cerebral cortex and cholinergic basal forebrain. Recently, it has been shown that 5-HT(2A) receptors are mostly expressed on pyramidal neurons and their activation improves learning and memory. We applied 5-HT, an agonist (alpha-methyl-5-HT), or an antagonist (ritanserin) of 5-HT(2A) receptors to the primary auditory cortex and discovered the following drug effects: (1) 5-HT had no effect on the conditioned heart rate change, although it reduced the auditory responses; (2) 4 mm 5-HT augmented the subthreshold BF shifts, whereas 20 mm 5-HT did not; (3) 20 mm 5-HT reduced the long-term BF shifts and changed them into short-term; (4) alpha-methyl-5-HT increased the auditory responses and augmented the subthreshold BF shifts as well as the long-term BF shifts; (5) in contrast, ritanserin reduced the auditory responses and reversed the direction of the BF shifts. Our data indicate that the BF shift can be modulated by serotonergic neurons that augment or reduce the BF shift or even reverse the direction of the BF shift. Therefore, not only the cholinergic system, but also the serotonergic system, plays an important role in cortical plasticity according to behavioral demands.

Bilateral cortical interaction: modulation of delay-tuned neurons in the contralateral auditory cortex.

Transcallosal excitation and inhibition have been theorized based on the effect of callosotomy on intractable epilepsy and dichotic listening research, respectively. We studied bilateral interaction of cortical auditory neurons and found that this interaction consisted of focused facilitation and widespread lateral inhibition. The frequency modulated (FM)-FM area of the auditory cortex of the mustached bat is composed of delay-tuned neurons tuned to the combination of the emitted biosonar pulse and its echo with a specific echo delay [best delay (BD)] and consists of three subdivisions in terms of the combination sensitivity of neurons. We found that focal electric stimulation of one of these three subdivisions evoked BD shifts of delay-tuned neurons in all three subdivisions of the contralateral FM-FM area, presumably via the corpus callosum. The effect of electric stimulation of the delay-tuned neurons on the contralateral delay-tuned neurons was different depending on whether the BD of a recorded neuron was matched or unmatched in BD with that of the stimulated neurons. BD-matched neurons did not change their BDs and increased the responses at their BDs, whereas BD-unmatched neurons shifted their BDs away from the BD of the stimulated neurons and reduced their responses. The ipsilateral and contralateral BD shifts evoked by the electric stimulation were identical to each other. The contralateral modulation, in addition to the ipsilateral modulation, increases the contrast in the neural representation of the echo delay to which the stimulated neurons are tuned.

Modulation of cochlear hair cells by the auditory cortex in the mustached bat.

The corticofugal (descending) auditory system forms multiple feedback loops, and adjusts and improves auditory signal processing in the subcortical auditory nuclei. However, the mechanism by which the corticofugal system modulates cochlear hair cells has been unexplored. We found that electric stimulation of cortical neurons via the corticofugal system modulates cochlear hair cells in a highly specific way according to the relationship in terms of best frequency between cortical neurons and hair cells. Such frequency-specific effects can be explained by selective corticofugal modulation of individual olivocochlear efferent fibers.

Specialization of the auditory system for the processing of bio-sonar information in the frequency domain: Mustached bats.

For echolocation, mustached bats emit velocity-sensitive orientation sounds (pulses) containing a constant-frequency component consisting of four harmonics (CF1-4). They show unique behavior called Doppler-shift compensation for Doppler-shifted echoes and hunting behavior for frequency and amplitude modulated echoes from fluttering insects. Their peripheral auditory system is highly specialized for fine frequency analysis of CF2 (∼61.0 kHz) and detecting echo CF2 from fluttering insects. In their central auditory system, lateral inhibition occurring at multiple levels sharpens V-shaped frequency-tuning curves at the periphery and creates sharp spindle-shaped tuning curves and amplitude tuning. The large CF2-tuned area of the auditory cortex systematically represents the frequency and amplitude of CF2 in a frequency-versus-amplitude map. "CF/CF" neurons are tuned to a specific combination of pulse CF1 and Doppler-shifted echo CF2 or 3. They are tuned to specific velocities. CF/CF neurons cluster in the CC ("C" stands for CF) and DIF (dorsal intrafossa) areas of the auditory cortex. The CC area has the velocity map for Doppler imaging. The DIF area is particularly for Dopper imaging of other bats approaching in cruising flight. To optimize the processing of behaviorally relevant sounds, cortico-cortical interactions and corticofugal feedback modulate the frequency tuning of cortical and sub-cortical auditory neurons and cochlear hair cells through a neural net consisting of positive feedback associated with lateral inhibition.

Acuity in ranging based on delay-tuned combination-sensitive neurons in the auditory cortex of mustached bats.

A 1.0-ms echo delay from an emitted bio-sonar pulse at 25 °C corresponds to a 17.3-cm target distance. In the auditory cortex of the mustached bat, Pteronotus parnellii, neurons tuned to a specific delay (best delay) of an echo from an emitted pulse are clustered in the FF, dorsal fringe and ventral fringe areas. ("FF" stands for the frequency-modulated components of a pulse and its echo.) Those delay-tuned neurons are systematically arranged in the FF area according to their best delays and form a 18-ms-long delay axis. Using the neurophysiological data, the theoretical acuity at a 75% correct level was computed as just-noticeable changes in (a) the location of maximally responding delay-tuned neurons, (b) the location of the center of all responses in the FF area, and (c) the weighted sum of responses of all delay-tuned neurons. The acuity is range-dependent: the shorter the target range, the higher the acuity is. The just-noticeable changes in target range are 7.57-46.2, 0.50-2.32 and 0.22-2.53 mm at the target ranges of up to 140 cm for (a), (b) and (c), respectively. When the dorsal and ventral fringe areas are included in the computation, the just-noticeable changes become smaller than those in the FF area alone. Those acuities computed are comparable to certain behavioral acuities.

Differences in velocity-information processing between two areas in the auditory cortex of mustached bats.

The bio-sonar pulse of the mustached bat, Pteronotus parnellii parnellii, consists of four harmonics of constant frequency (CF1-4) and frequency-modulated (FM1-4) components. The CF and FM components carry velocity and distance information, respectively. In the auditory cortex of mustached bats, the CC ("C" stands for constant frequency) and DIF (dorsal intrafossa) areas consist of CF/CF neurons tuned to a combination of pulse CF1 and echo CFn (n = 2 or 3). They show facilitative responses to pulse-echo stimuli with specific frequency differences, corresponding to Doppler shifts. Their facilitative responses are sharply tuned to a specific relative target velocity (best velocity). Compared with CC neurons, DIF neurons are tuned to higher velocities and to larger CF1 amplitudes, and adapt faster to repetitive pulse-echo stimuli. The great majority of CC neurons are suited for the processing of velocity information during cruising and target-directed flight, whereas the majority of DIF neurons are suited for the processing of velocity information when the bat is emitting loud pulses at low repetition rates during cruising flight. CC and DIF neurons are broadly tuned to 0-2-ms echo delays and not suited for ranging.

Synaptic mechanisms shaping delay-tuned combination-sensitivity in the auditory thalamus of mustached bats.

For the processing of target-distance information, delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. They are initially produced in the inferior colliculus by facilitative responses based on the coincidence of the rebound response following glycinergic inhibition to the first harmonic of the pulse and a short-latency response to the 2nd-4th harmonics of its echo. Here, we report that further facilitative responses to pulse-echo pairs of thalamic delay-tuned neurons are mediated by glutamate receptors (NMDA and non-NMDA receptors), and that GABAergic inhibition shortens the duration of facilitative responses mediated by NMDA-receptors, without changing the delay tuning of thalamic delay-tuned neurons. Different from collicular delay-tuned neurons, thalamic ones respond much more to pulse-echo pairs than individual signal elements. The neural mechanisms involved in shaping thalamic delay-tuning support a model of hierarchical signal processing in the auditory system.

Neural processing of auditory signals in the time domain: delay-tuned coincidence detectors in the mustached bat.

The central auditory system produces combination-sensitive neurons tuned to a specific combination of multiple signal elements. Some of these neurons act as coincidence detectors with delay lines for the extraction of spectro-temporal information from sounds. "Delay-tuned" neurons of mustached bats are tuned to a combination of up to four signal elements with a specific delay between them and form a delay map. They are produced in the inferior colliculus by the coincidence of the rebound response following glycinergic inhibition to the first harmonic of a biosonar pulse with the short-latency response to the 2nd-4th harmonics of its echo. Compared with collicular delay-tuned neurons, thalamic and cortical ones respond more to pulse-echo pairs than individual sounds. Cortical delay-tuned neurons are clustered in the three separate areas. They interact with each other through a circuit mediating positive feedback and lateral inhibition for adjustment and improvement of the delay tuning of cortical and subcortical neurons. The current article reviews the mechanisms for delay tuning and the response properties of collicular, thalamic and cortical delay-tuned neurons in relation to hierarchical signal processing.

Tuning shifts of the auditory system by corticocortical and corticofugal projections and conditioning.

The central auditory system consists of the lemniscal and nonlemniscal systems. The thalamic lemniscal and nonlemniscal auditory nuclei are different from each other in response properties and neural connectivities. The cortical auditory areas receiving the projections from these thalamic nuclei interact with each other through corticocortical projections and project down to the subcortical auditory nuclei. This corticofugal (descending) system forms multiple feedback loops with the ascending system. The corticocortical and corticofugal projections modulate auditory signal processing and play an essential role in the plasticity of the auditory system. Focal electric stimulation - comparable to repetitive tonal stimulation - of the lemniscal system evokes three major types of changes in the physiological properties, such as the tuning to specific values of acoustic parameters of cortical and subcortical auditory neurons through different combinations of facilitation and inhibition. For such changes, a neuromodulator, acetylcholine, plays an essential role. Electric stimulation of the nonlemniscal system evokes changes in the lemniscal system that is different from those evoked by the lemniscal stimulation. Auditory signals ascending from the lemniscal and nonlemniscal thalamic nuclei to the cortical auditory areas appear to be selected or adjusted by a "differential" gating mechanism. Conditioning for associative learning and pseudo-conditioning for nonassociative learning respectively elicit tone-specific and nonspecific plastic changes. The lemniscal, corticofugal and cholinergic systems are involved in eliciting the former, but not the latter. The current article reviews the recent progress in the research of corticocortical and corticofugal modulations of the auditory system and its plasticity elicited by conditioning and pseudo-conditioning.

Tone-specific and nonspecific plasticity of inferior colliculus elicited by pseudo-conditioning: role of acetylcholine and auditory and somatosensory cortices.

Experience-dependent plasticity in the central sensory systems depends on activation of both the sensory and neuromodulatory systems. Sensitization or nonspecific augmentation of central auditory neurons elicited by pseudo-conditioning with unpaired conditioning tonal (CS) and unconditioned electric leg (US) stimuli is quite different from tone-specific plasticity, called best frequency (BF) shifts, of the neurons elicited by auditory fear conditioning with paired CS and US. Therefore the neural circuits eliciting the nonspecific augmentation must be different from that eliciting the BF shifts. We first examined plastic changes in the response properties of collicular neurons of the big brown bat elicited by pseudo-conditioning and found that it elicited prominent nonspecific augmentation-an auditory response increase, a frequency-tuning broadening, and a threshold decreas-and that, in addition, it elicited a small short-lasting BF shift only when the CS frequency was 5 kHz lower than the BF of a recorded neuron. We examined the role of acetylcholine and the auditory and somatosensory cortices in these collicular changes. The development of the nonspecific augmentation was affected little by a muscarinic acetylcholine receptor antagonist applied to the inferior colliculus and by a GABA(A) receptor agonist applied to the auditory or somatosensory cortex. However, these drugs abolished the small short-lasting BF shift as they abolished the large long-lasting cortical and short-lasting collicular BF shifts elicited by the conditioning. These results indicate that, different from the BF shift, the nonspecific augmentation of the inferior colliculus depends on neither the cholinergic neuromodulator nor the auditory and somatosensory cortices.

Role of corticofugal feedback in hearing.

The auditory system consists of the ascending and descending (corticofugal) systems. The corticofugal system forms multiple feedback loops. Repetitive acoustic or auditory cortical electric stimulation activates the cortical neural net and the corticofugal system and evokes cortical plastic changes as well as subcortical plastic changes. These changes are short-term and are specific to the properties of the acoustic stimulus or electrically stimulated cortical neurons. These plastic changes are modulated by the neuromodulatory system. When the acoustic stimulus becomes behaviorally relevant to the animal through auditory fear conditioning or when the cortical electric stimulation is paired with an electric stimulation of the cholinergic basal forebrain, the cortical plastic changes become larger and long-term, whereas the subcortical changes stay short-term, although they also become larger. Acetylcholine plays an essential role in augmenting the plastic changes and in producing long-term cortical changes. The corticofugal system has multiple functions. One of the most important functions is the improvement and adjustment (reorganization) of subcortical auditory signal processing for cortical signal processing.