Cholinergic projections from the pedunculopontine tegmental nucleus contact excitatory and inhibitory neurons in the inferior colliculus
rat; acetylcholine; auditory; brain-stem; plasticity; cells; modulation; neuromodulation; pathways; midbrain; hearing; arousal; acetylcholine-receptors; auditory input; choline acetyltransferase; gabaergic neurons; viral tracing; volume transmission; viral tracing
The inferior colliculus processes nearly all ascending auditory information. Most collicular cells respond to sound, and for a majority of these cells, the responses can be modulated by acetylcholine (ACh). The cholinergic effects are varied and, for the most part, the underlying mechanisms are unknown. The major source of cholinergic input to the inferior colliculus is the pedunculopontine tegmental nucleus (PPT), part of the pontomesencephalic tegmentum known for projections to the thalamus and roles in arousal and the sleep-wake cycle. Characterization of PPT inputs to the inferior colliculus has been complicated by the mixed neurotransmitter population within the PPT. Using selective viral-tract tracing techniques in a ChAT-Cre Long Evans rat, the present study characterizes the distribution and targets of cholinergic projections from PPT to the inferior colliculus. Following the deposit of viral vector in one PPT, cholinergic axons studded with boutons were present bilaterally in the inferior colliculus, with the greater density of axons and boutons ipsilateral to the injection site. On both sides, cholinergic axons were present throughout the inferior colliculus, distributing boutons to the central nucleus, lateral cortex, and dorsal cortex. In each inferior colliculus (IC) subdivision, the cholinergic PPT axons appear to contact both GABAergic and glutamatergic neurons. These findings suggest cholinergic projections from the PPT have a widespread influence over the IC, likely affecting many aspects of midbrain auditory processing. Moreover, the effects are likely to be mediated by direct cholinergic actions on both excitatory and inhibitory circuits in the inferior colliculus.
Noftz WA; Beebe NL; Mellott JG; Schofield BR
Frontiers in Neural Circuits
2020
2020-07-16
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3389/fncir.2020.00043" target="_blank" rel="noreferrer noopener">10.3389/fncir.2020.00043</a>
Endogenous Cholinergic Signaling Modulates Sound-evoked Responses of Medial Nucleus of Trapezoid Body.
The medial nucleus of trapezoid body (MNTB) is a major source of inhibition in auditory brainstem circuitry. The MNTB projects well-timed inhibitory output to principal sound-localization nuclei in the superior olive (SOC) as well as other computationally important centers. Acoustic information is conveyed to MNTB neurons through a single calyx of Held excitatory synapse arising from the cochlear nucleus. The encoding efficacy of this large synapse depends on its activity rate, which is primarily determined by sound intensity and stimulus frequency. However, MNTB activity rate is additionally influenced by inhibition and possibly neuromodulatory inputs, albeit their functional role is unclear. Happe and Morley (2004) discovered prominent expression of α7-nicotinic acetylcholine receptors (nAChRs) in rat SOC, suggesting possible engagement of acetylcholine (ACh)-mediated modulation of neural activity in the MNTB. However, the existence and nature of this putative modulation has never been physiologically demonstrated. We probed nicotinic cholinergic influences on acoustic responses of MNTB neurons from adult gerbils (Meriones unguiculatus) of either sex. We recorded tone evoked MNTB single neuron activity in vivo using extracellular single-unit recording. Piggyback multi-barrel electrodes enabled pharmacological manipulation of nAChRs by reversibly applying antagonists to two receptor types, α7 and α4β2. We observed that tone-evoked responses are dependent on ACh modulation by both nAChR subtypes. Spontaneous activity was not affected by antagonist application. Functionally, we demonstrate that ACh contributes to sustaining high discharge rates and enhances signal encoding efficacy. Additionally, we report anatomical evidence revealing novel cholinergic projections to MNTB arising from pontine and superior olivary nuclei.SIGNIFICANCE STATEMENTThis study is the first to physiologically probe how acetylcholine, a pervasive neuromodulator in the brain, influences the encoding of acoustic information by the MNTB, the most prominent source of inhibition in brainstem sound-localization circuitry. We demonstrate that this cholinergic input enhances neural discrimination of tones from noise stimuli, which may contribute to processing important acoustic signals such as speech. Additionally, we describe novel anatomical projections providing cholinergic input to the MNTB. Together, these findings shed new light on the contribution of neuromodulation to fundamental computational processes in auditory brainstem circuitry and to a more holistic understanding of modulatory influences in sensory processing.
Zhang C; Beebe NL; Schofield BR; Pecka M; Burger RM
The Journal Of Neuroscience
2020
2020-11-30
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journalArticle
<a href="http://doi.org/10.1523/JNEUROSCI.1633-20.2020" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.1633-20.2020</a>
Group II metabotropic glutamate receptors modulate sound evoked and spontaneous activity in the mouse inferior colliculus.
auditory; GABAergic; LY354740; mGluR2/3; neuromodulation; non-GABAergic
Little is known about the functions of group II metabotropic glutamate receptors (mGluRs2/3) in the inferior colliculus (IC)-a midbrain structure that is a major integration region of the central auditory system. We investigated how these receptors modulate sound-evoked and spontaneous firing in the mouse IC in vivo We first performed immunostaining and tested hearing thresholds to validate VGAT-ChR2 transgenic mice on a mixed CBA/CaJ x C57BL/6J genetic background. Transgenic animals allowed for optogenetic cell type identification. Extracellular single neuron recordings were obtained before and after pharmacological mGluR2/3 activation. We observed increased sound-evoked firing-as assessed by the rate-level functions-in a subset of both GABAergic and non-GABAergic IC neurons following mGluR2/3 pharmacological activation. These neurons also displayed elevated spontaneous excitability and were distributed throughout the IC area tested, suggesting a widespread mGluR2/3 distribution in the mouse IC.Significance Glutamate is the primary excitatory neurotransmitter in the brain. It binds to both ionotropic and metabotropic glutamate receptors. Fast ionotropic receptors generate rapid synaptic transmission, whereas slower metabotropic glutamate receptors (mGluRs) modulate this synaptic transmission. Here, we discovered that activation of group II mGluRs enhances sound-evoked and spontaneous neuronal firing in the inferior colliculus-the hub of the central auditory system. We used transgenic mice which allowed for identification of excitatory and inhibitory neurons and found that both these cell types are modulated by group II mGluRs. Our results provide better understanding of mGluR modulatory roles, which is crucial in opening avenues for using mGluR-targeting drugs to treat hearing disorders.
Kristaponyte I; Beebe NL; Young JW; Shanbhag SJ; Schofield BR; Galazyuk AV
eNeuro
2020
2020-12-14
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1523/ENEURO.0328-20.2020" target="_blank" rel="noreferrer noopener">10.1523/ENEURO.0328-20.2020</a>
Cholinergic boutons are closely associated with excitatory cells and four subtypes of inhibitory cells in the inferior colliculus.
Acetylcholine; Mouse; Perineuronal net; VGLUT2
Acetylcholine (ACh) is a neuromodulator that has been implicated in multiple roles across the brain, including the central auditory system, where it sets neuronal excitability and gain and affects plasticity. In the cerebral cortex, subtypes of GABAergic interneurons are modulated by ACh in a subtype-specific manner. Subtypes of GABAergic neurons have also begun to be described in the inferior colliculus (IC), a midbrain hub of the auditory system. Here, we used male and female mice (Mus musculus) that express fluorescent protein in cholinergic cells, axons, and boutons to look at the association between ACh and four subtypes of GABAergic IC cells that differ in their associations with extracellular markers, their soma sizes, and their distribution within the IC. We found that most IC cells, including excitatory and inhibitory cells, have cholinergic boutons closely associated with their somas and proximal dendrites. We also found that similar proportions of each of four subtypes of GABAergic cells are closely associated with cholinergic boutons. Whether the different types of GABAergic cells in the IC are differentially regulated remains unclear, as the response of cells to ACh is dependent on which types of ACh receptors are present. Additionally, this study confirms the presence of these four subtypes of GABAergic cells in the mouse IC, as they had previously been identified only in guinea pigs. These results suggest that cholinergic projections to the IC modulate auditory processing via direct effects on a multitude of inhibitory circuits.
Beebe NL; Schofield BR
Journal Of Chemical Neuroanatomy
2021
2021-06-26
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<a href="http://doi.org/10.1016/j.jchemneu.2021.101998" target="_blank" rel="noreferrer noopener">10.1016/j.jchemneu.2021.101998</a>
Multiple Sources of Cholinergic Input to the Superior Olivary Complex.
acetylcholine; arousal; collateral; gerbil; hearing; modulation; plasticity; pontomesencephalic tegmentum
The superior olivary complex (SOC) is a major computation center in the brainstem auditory system. Despite previous reports of high expression levels of cholinergic receptors in the SOC, few studies have addressed the functional role of acetylcholine in the region. The source of the cholinergic innervation is unknown for all but one of the nuclei of the SOC, limiting our understanding of cholinergic modulation. The medial nucleus of the trapezoid body, a key inhibitory link in monaural and binaural circuits, receives cholinergic input from other SOC nuclei and also from the pontomesencephalic tegmentum. Here, we investigate whether these same regions are sources of cholinergic input to other SOC nuclei. We also investigate whether individual cholinergic cells can send collateral projections bilaterally (i.e., into both SOCs), as has been shown at other levels of the subcortical auditory system. We injected retrograde tract tracers into the SOC in gerbils, then identified retrogradely-labeled cells that were also immunolabeled for choline acetyltransferase, a marker for cholinergic cells. We found that both the SOC and the pontomesencephalic tegmentum (PMT) send cholinergic projections into the SOC, and these projections appear to innervate all major SOC nuclei. We also observed a small cholinergic projection into the SOC from the lateral paragigantocellular nucleus of the reticular formation. These various sources likely serve different functions; e.g., the PMT has been associated with things such as arousal and sensory gating whereas the SOC may provide feedback more closely tuned to specific auditory stimuli. Further, individual cholinergic neurons in each of these regions can send branching projections into both SOCs. Such projections present an opportunity for cholinergic modulation to be coordinated across the auditory brainstem. (Copyright © 2021 Beebe, Zhang, Burger and Schofield.)
Beebe NL; Zhang C; Burger RM; Schofield BR
Frontiers in Neural Circuits
2021
2021-07-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3389/fncir.2021.715369" target="_blank" rel="noreferrer noopener">10.3389/fncir.2021.715369</a>