Editorial: Neuromodulatory Function in Auditory Processing (original) (raw)
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The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex
2014
Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus-specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4-SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers.
Multiple origins of cholinergic innervation of the cochlear nucleus
Neuroscience, 2011
Acetylcholine affects a variety of cell types in the cochlear nucleus (CN) and is likely to play a role in numerous functions. Previous work in rats suggested that the acetylcholine arises from cells in the superior olivary complex, including cells that have axonal branches that innervate both the CN and the cochlea (i.e., olivocochlear cells) as well as cells that innervate only the CN. We combined retrograde tracing with immunohistochemistry for choline acetyltransferase to identify the source of ACh in the CN of guinea pigs. The results confirm a projection from cholinergic cells in the superior olivary complex to the CN. In addition, we identified a substantial number of cholinergic cells in the pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT) that project to the CN. On average, the PPT and LDT together contained about 26% of the cholinergic cells that project to CN, whereas the superior olivary complex contained about 74%. A small number of additional cholinergic cells were located in other areas, including the parabrachial nuclei.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016
The neuromodulator acetylcholine (ACh) is crucial for several cognitive functions, such as perception, attention, and learning and memory. Whereas, in most cases, the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) neurons projecting from layer 5B (L5B) to the inferior colliculus, corticocollicular neurons, are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Because AC L5B contains another class of neurons that project to the contralateral cortex, corticocallosal neurons, to identify the cell-specific mechanisms that enable corticocollicular neurons to participate in sound localization relearning, we investigated the effects of ACh release on both L5B corticocallosal and corticocollicular neur...
Hearing Research, 2011
Acetylcholine (ACh) is a neuromodulator that is likely to play a role in plasticity as well as other phenomena at many sites in the auditory system. The auditory cortex receives cholinergic innervation from the basal forebrain, whereas the cochlea receives cholinergic innervation from the superior olivary complex. Much of the remainder of the auditory pathways receives innervation from the pedunculopontine and laterodorsal tegmental nuclei, two nuclei referred to collectively as the pontomesencephalic tegmentum (PMT). The PMT provides the major source of ACh to the auditory thalamus and the midbrain, and is a substantial source (in addition to the superior olivary complex) of ACh in the cochlear nucleus. Individual cholinergic cells in the PMT often have axon branches that innervate multiple auditory nuclei, including nuclei on both sides of the brain as well as nuclei at multiple levels of the auditory system. The auditory cortex has direct axonal projections to the PMT cells, including cholinergic cells that project to the inferior colliculus or cochlear nucleus. The divergent projections of PMT cholinergic cells suggest widespread effects on the auditory pathways. These effects are likely to include plasticity as well as novelty detection, sensory gating, reward behavior, arousal and attention. Descending projections from the forebrain, including the auditory cortex, are likely to provide a high level of cognitive input to these cholinergic effects. Dysfunction associated with the cholinergic system may play a role in disorders such as tinnitus and schizophrenia.
Journal of Neuroscience, 2013
The nucleus basalis (NB) in the basal forebrain provides most of the cholinergic input to the neocortex and has been implicated in a variety of cognitive functions related to the processing of sensory stimuli. However, the role that cortical acetylcholine release plays in perception remains unclear. Here we show that selective loss of cholinergic NB neurons that project to the cortex reduces the accuracy with which ferrets localize brief sounds and prevents them from adaptively reweighting auditory localization cues in response to chronic occlusion of one ear. Cholinergic input to the cortex was disrupted by making bilateral injections of the immunotoxin ME20.4-SAP into the NB. This produced a substantial loss of both p75 neurotrophin receptor (p75 NTR )-positive and choline acetyltransferase-positive cells in this region and of acetylcholinesterase-positive fibers throughout the auditory cortex. These animals were significantly impaired in their ability to localize short broadband sounds (40 -500 ms in duration) in the horizontal plane, with larger cholinergic cell lesions producing greater performance impairments. Although they localized longer sounds with normal accuracy, their response times were significantly longer than controls. Ferrets with cholinergic forebrain lesions were also less able to relearn to localize sound after plugging one ear. In contrast to controls, they exhibited little recovery of localization performance after behavioral training. Together, these results show that cortical cholinergic inputs contribute to the perception of sound source location under normal hearing conditions and play a critical role in allowing the auditory system to adapt to changes in the spatial cues available.
Cholinergic basal forebrain (CBF) signaling exhibits multiple timescales of activity with classic, slow signals related to brain and behavioral states and faster, phasic signals reflecting behavioral events, including movement and reinforcement. Recent evidence suggests that the CBF may also exhibit fast, sensory-evoked responses. It remains unknown, however, whether such sensory signals target the sensory cortex and how they relate to local functional topography. Moreover, the extent to which fast and slow CBF activity interact has been largely unexplored. Here, we used simultaneous two-channel, two-photon imaging of CBF axons and auditory cortical (AC) neurons to reveal that CBF axons project a robust, non-habituating, and stimulus-specific sensory signal to the AC. Individual axon segments exhibited heterogeneous but stable tuning to auditory stimuli allowing stimulus identity to be decoded from the population. However, CBF axons displayed no tonotopy and their frequency tuning w...
Frontiers in systems neuroscience, 2014
Descending projections from the auditory cortex (AC) terminate in subcortical auditory centers from the medial geniculate nucleus (MG) to the cochlear nucleus, allowing the AC to modulate the processing of acoustic information at many levels of the auditory system. The nucleus of the brachium of the inferior colliculus (NBIC) is a large midbrain auditory nucleus that is a target of these descending cortical projections. The NBIC is a source of several auditory projections, including an ascending projection to the MG. This ascending projection appears to originate from both excitatory and inhibitory NBIC cells, but whether the cortical projections contact either of these cell groups is unknown. In this study, we first combined retrograde tracing and immunochemistry for glutamic acid decarboxylase (GAD, a marker of GABAergic cells) to identify GABAergic and non-GABAergic NBIC projections to the MG. Our first result is that GAD-immunopositive cells constitute ~17% of the NBIC to MG pro...
Dissecting the circuitry of the auditory system
Trends in Neurosciences, 2003
The brainstem auditory system is a complex system composed of numerous parallel and serial pathways that converge on a common destination in the inferior colliculus (IC). The exact nature of the response transformations that occur in the IC have, however, been elusive -even though the IC has been the subject of numerous studies for more than 30 years. Recent studies have addressed this issue by recording from IC neurons before and during micro-iontophoresis of drugs that selectively block GABA A or glycine receptors (the dominant inhibitory receptors in the IC) or by reversibly inactivating a lower nucleus that provides inhibitory innervation to the IC. These studies have revealed some of the ways that signals, relayed via many different parallel routes, interact in the IC, and suggest some functional advantages that these interactions might have.
Descending projections from the inferior colliculus to the dorsal cochlear nucleus are excitatory
Journal of comparative neurology, 2017
Ascending projections of the dorsal cochlear nucleus (DCN) target primarily the contralateral inferior colliculus (IC). In turn, the IC sends bilateral descending projections back to the DCN. We sought to determine the nature of these descending axons in order to infer circuit mechanisms of signal processing at one of the earliest stages of the central auditory pathway. An anterograde tracer was injected in the IC of CBA/Ca mice to reveal terminal characteristics of the descending axons. Retrograde tracer deposits were made in the DCN of CBA/Ca and transgenic GAD67-EGFP mice to investigate the cells giving rise to these projections. A multiunit best frequency was determined for each injection site. Brains were processed by using standard histologic methods for visualization and examined by fluorescent, brightfield, and electron microscopy. Descending projections from the IC were inferred to be excitatory because the cell bodies of retrogradely labeled neurons did not colabel with EGFP expression in neurons of GAD67-EGFP mice. Furthermore, additional experiments yielded no glycinergic or cholinergic positive cells in the IC, and descending projections to the DCN were colabeled with antibodies against VGluT2, a glutamate transporter. Anterogradely labeled endings in the DCN formed asymmetric postsynaptic densities, a feature of excitatory neurotransmission. These descending projections to the DCN from the IC were topographic and suggest a feedback pathway that could underlie a frequency-specific enhancement of some acoustic signals and suppression of others. The involvement of this IC-DCN circuit is especially noteworthy when considering the gating of ascending signal streams for auditory processing. J. Comp. Neurol. 525:773-793, 2017. © 2016 Wiley Periodicals, Inc.
Efferent inhibition of cochlear hair cells is mediated by alpha9alpha10 nicotinic cholinergic receptors (nAChRs) functionally coupled to calcium-activated, small conductance (SK2) potassium channels. Before the onset of hearing, efferent fibers transiently make functional cholinergic synapses with inner hair cells (IHCs). The retraction of these fibers after the onset of hearing correlates with the cessation of transcription of the Chrna10 (but not the Chrna9) gene in IHCs. To further analyze this developmental change, we generated a transgenic mice whose IHCs constitutively express alpha10 into adulthood by expressing the alpha10 cDNA under the control of the Pou4f3 gene promoter. In situ hybridization showed that the alpha10 mRNA is expressed in IHCs of 8-week-old transgenic mice, but not in wild-type mice. Moreover, this mRNA is translated into a functional protein, since IHCs from P8-P10 alpha10 transgenic mice backcrossed to a Chrna10(-/-) background (whose IHCs have no cholinergic function) displayed normal synaptic and acetylcholine (ACh)-evoked currents in patch-clamp recordings. Thus, the alpha10 transgene restored nAChR function. However, in the alpha10 transgenic mice, no synaptic or ACh-evoked currents were observed in P16-18 IHCs, indicating developmental down-regulation of functional nAChRs after the onset of hearing, as normally observed in wild-type mice. The lack of functional ACh currents correlated with the lack of SK2 currents. These results indicate that multiple features of the efferent postsynaptic complex to IHCs, in addition to the nAChR subunits, are down-regulated in synchrony after the onset of hearing, leading to lack of responses to ACh.