No abstract

Peripheral auditory neurons are tuned to single frequencies of sound. In the central auditory system, excitatory (or facilitatory) and inhibitory neural interactions take place at multiple levels and produce neurons with sharp level-tolerant frequency-tuning curves, neurons tuned to parameters other than frequency, cochleotopic (frequency) maps, which are different from the peripheral cochleotopic map, and computational maps. The mechanisms to create the response properties of these neurons have been considered to be solely caused by divergent and convergent projections of neurons in the ascending auditory system. The recent research on the corticofugal (descending) auditory system, however, indicates that the corticofugal system adjusts and improves auditory signal processing by modulating neural responses and maps. The corticofugal function consists of at least the following subfunctions. auditory system ͉ descending system ͉ learning and memory ͉ plasticity ͉ tonotopic map T he central auditory system creates many physiologically distinct types of neurons for auditory signal processing. Their response properties have been interpreted to be produced by divergent and convergent interactions between neurons in the ascending auditory system. Until recently, the contribution of the descending (corticofugal) system to the shaping (or even creation) of their response properties has hardly been considered. Recent findings indicate that the corticofugal system plays important roles in shaping or even creating the response properties of central auditory neurons and in reorganizing cochleotopic (frequency) and computational (e.g., echo-delay) maps. Therefore, the understanding of the neural mechanisms for auditory signal processing is incomplete without the exploration of the functional roles of the corticofugal system. In this article, we first enumerate several types of neurons and computational maps created in the bat's central auditory system and then describe the anatomy and physiology of the corticofugal system. Neurons Tuned to Acoustic Parameters Characterizing Biosonar Signals and Cochleotopic and Computational MapsAll peripheral neurons are tuned to single frequencies (best frequencies, BFs). In the central auditory system, excitatory, inhibitory, and facilitatory neural interactions take place at multiple levels and produce neurons with sharp level-tolerant (the width of a frequency tuning curve is narrow regardless of sound levels) frequency tuning curves (1) and also neurons tuned to specific values of parameters other than frequency. Some of these neurons apparently are related to the processing of biosonar signals. They are latency-constant, phasic on-responding neurons (2, 3); paradoxical latency-shift neurons (4); durationtuned neurons (5) amplitude coordinates for the fine spatio-temporal representation of periodic frequency and amplitude modulations of echoes from flying insects (9). In the superior colliculus of the big brown bat, there is a space map, and some neurons are tuned to a sound source at ...

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.

Recent findings indicate that the corticofugal system would play an important role in cortical plasticity as well as collicular plasticity. To understand the role of the corticofugal system in plasticity, therefore, we studied the amount and the time course of plasticity in the inferior colliculus (IC) and auditory cortex (AC) evoked by focal electrical stimulation of the AC and also the effect of electrical stimulation of the somatosensory cortex on the plasticity evoked by the stimulation of the AC. In adult big brown bats (Eptesicus fuscus), we made the following major findings. 1) Electric stimulation of the AC evokes best frequency (BF) shifts, i.e., shifts in frequency-response curves of collicular and cortical neurons. These BF shifts start to occur within 2 min, reach a maximum (or plateau) at 30 min, and then recover approximately 180 min after a 30-min-long stimulus session. When the stimulus session is lengthened from 30 to 90 min, the plateau lasts approximately 60 min, but BF shifts recover approximately 180 min after the session. 2) The electric stimulation of the somatosensory cortex delivered immediately after that of the AC, as in fear conditioning, evokes a dramatic lengthening of the recovery period of the cortical BF shifts but not that of the collicular BF shift. The electric stimulation of the somatosensory cortex delivered before that of the AC, as in backward conditioning, has no effect on the collicular and cortical BF shifts. 3) Electric stimulation of the AC evokes BF shifts not only in the ipsilateral IC and AC but also in the contralateral IC and AC. BF shifts are smaller in amount and shorter in recovery time for contralateral collicular and cortical neurons than for ipsilateral ones. Our findings support the hypothesis that the AC and the corticofugal system have an intrinsic mechanism for reorganization of the IC and AC, that the reorganization is highly specific to a value of an acoustic parameter (frequency), and that the reorganization is augmented by excitation of nonauditory sensory cortex that makes the acoustic stimulus behaviorally relevant to the animal through associative learning.

Temporal filtering is a fundamental operation of nervous systems. In peripheral sensory systems, the temporal pattern of spiking activity can encode various stimulus qualities, and temporal filtering allows postsynaptic neurons to detect behaviorally-relevant stimulus features from these spike trains. Intrinsic excitability, short-term synaptic plasticity, and voltage-dependent dendritic conductances have all been identified as mechanisms that can establish temporal filtering behavior in single neurons. Here we show that synaptic integration of temporally-summating excitation and inhibition can establish diverse temporal filters of presynaptic input. Mormyrid electric fish communicate by varying the intervals between electric organ discharges. The timing of each discharge is coded by peripheral receptors into precisely-timed spikes. Within the midbrain posterior exterolateral nucleus, temporal filtering by individual neurons results in selective responses to a particular range of presynaptic interspike intervals. These neurons are diverse in their temporal filtering properties, reflecting the wide range of intervals that must be detected during natural communication behavior. By manipulating presynaptic spike timing with high temporal resolution, we demonstrate that tuning to behaviorally-relevant patterns of presynaptic input is similar in vivo and in vitro. We reveal that GABAergic inhibition plays a critical role in establishing different temporal filtering properties. Further, our results demonstrate that temporal summation of excitation and inhibition establishes selective responses to high and low rates of synaptic input, respectively. Simple models of synaptic integration reveal that variation in these two competing influences provides a basic mechanism for generating diverse temporal filters of synaptic input.

Auditory conditioning (associative learning) or focal electric stimulation of the primary auditory cortex (AC) evokes reorganization (plasticity) of the cochleotopic (frequency) map of the inferior colliculus (IC) as well as that of the AC. The reorganization results from shifts in the best frequencies (BFs) and frequency-tuning curves of single neurons. Since the importance of the cholinergic basal forebrain for cortical plasticity and the importance of the somatosensory cortex and the corticofugal auditory system for collicular and cortical plasticity have been demonstrated, Gao and Suga proposed a hypothesis that states that the AC and corticofugal system play an important role in evoking auditory collicular and cortical plasticity and that auditory and somatosensory signals from the cerebral cortex to the basal forebrain play an important role in augmenting collicular and cortical plasticity. To test their hypothesis, we studied whether the amount and the duration of plasticity of both collicular and cortical neurons evoked by electric stimulation of the AC or by acoustic stimulation were increased by electric stimulation of the basal forebrain and/or the somatosensory cortex. In adult big brown bats (Eptesicus fuscus), we made the following major findings. 1) Collicular and cortical plasticity evoked by electric stimulation of the AC is augmented by electric stimulation of the basal forebrain. The amount of augmentation is larger for cortical plasticity than for collicular plasticity. 2) Collicular and cortical plasticity evoked by AC stimulation is augmented by somatosensory cortical stimulation mimicking fear conditioning. The amount of augmentation is larger for cortical plasticity than for collicular plasticity. 3) Collicular and cortical plasticity evoked by both AC and basal forebrain stimulations is further augmented by somatosensory cortical stimulation. 4) A lesion of the basal forebrain tends to reduce collicular and cortical plasticity evoked by AC stimulation. The reduction is small and statistically insignificant for collicular plasticity but significant for cortical plasticity. 5) The lesion of the basal forebrain eliminates the augmentation of collicular and cortical plasticity that otherwise would be evoked by somatosensory cortical stimulation. 6) Collicular and cortical plasticity evoked by repetitive acoustic stimuli is augmented by basal forebrain and/or somatosensory cortical stimulation. However, the lesion of the basal forebrain eliminates the augmentation of collicular and cortical plasticity that otherwise would be evoked by somatosensory cortical stimulation. These findings support the hypothesis proposed by Gao and Suga.

p62 is a multidomain protein that contains different kinds of protein-protein interaction domains, including an N-terminal PB1 domain, a ZZ-type zinc finger domain, a nuclear localization signal (NLS), an export motif (NES), the LC3-interacting region (LIR), the KEAP1-interacting region (KIR), and a C-terminal Ub-associated domain (UBA). p62 is involved in the degradation of protein aggregates and cytoplasmic bodies via selective autophagy through its PB1, LIR, and UBA domains to maintain homeostasis in the cell. Moreover, NES, NLS, KIR, and ZZ domains have been found to be linked to ubiquitinated protein degradation by autophagy. Therefore, understanding the functional domains of p62 is important. In this review, we attempt to expound the mechanism of connection between p62 and selective autophagy to illustrate how the domains of p62 regulate selective autophagy, and to provide a new direction and perspective on selective autophagy research.

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1 cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.