Inhibition plays an important role in shaping responses to stimuli throughout the CNS, including in the inferior colliculus (IC), a major hub in both ascending and descending auditory pathways. Subdividing GABAergic cells has furthered the understanding of inhibition in many brain areas, most notably in the cerebral cortex. Here, we seek the same understanding of subcortical inhibitory cell types by combining staining for two types of extracellular markers-perineuronal nets (PNs) and perisomatic rings of terminals expressing vesicular glutamate transporter 2 (VGLUT2) -to subdivide IC GABAergic cells in adult guinea pigs. We found four distinct groups of GABAergic cells in the IC: (1) those with both a PN and a VGLUT2 ring; (2) those with only a PN; (3) those with only a VGLUT2 ring; and (4) those with neither marker. In addition, these four GABAergic subtypes differ in their soma size and distribution among IC subdivisions. Functionally, the presence or absence of VGLUT2 rings indicates differences in inputs, whereas the presence or absence of PNs indicates different potential for plasticity and temporal processing. We conclude that these markers distinguish four GABAergic subtypes that almost certainly serve different roles in the processing of auditory stimuli within the IC.
Located in the midbrain, the inferior colliculus (IC) is the hub of the central auditory system. Although the IC plays important roles in speech processing, sound localization, and other auditory computations, the organization of the IC microcircuitry remains largely unknown. Using a multifaceted approach in mice, we have identified vasoactive intestinal peptide (VIP) neurons as a novel class of IC principal neurons. VIP neurons are glutamatergic stellate cells with sustained firing patterns. Their extensive axons project to long-range targets including the auditory thalamus, auditory brainstem, superior colliculus, and periaqueductal gray. Using optogenetic circuit mapping, we found that VIP neurons integrate input from the contralateral IC and the dorsal cochlear nucleus. The dorsal cochlear nucleus also drove feedforward inhibition to VIP neurons, indicating that inhibitory circuits within the IC shape the temporal integration of ascending inputs. Thus, VIP neurons are well-positioned to influence auditory computations in a number of brain regions.
Located in the midbrain, the inferior colliculus (IC) integrates information from numerous auditory nuclei and is an important hub for sound processing. Despite its importance, little is known about the molecular identity and functional roles of defined neuron types in the IC. Using a multifaceted approach in mice of both sexes, we found that neuropeptide Y (NPY) expression identifies a major class of inhibitory neurons, accounting for approximately one-third of GABAergic neurons in the IC. Retrograde tracing showed that NPY neurons are principal neurons that can project to the medial geniculate nucleus. In brain slice recordings, many NPY neurons fired spontaneously, suggesting that NPY neurons may drive tonic inhibition onto postsynaptic targets. Morphologic reconstructions showed that NPY neurons are stellate cells, and the dendrites of NPY neurons in the tonotopically organized central nucleus of the IC cross isofrequency laminae. Immunostaining confirmed that NPY neurons express NPY, and we therefore hypothesized that NPY signaling regulates activity in the IC. In crosses between Npy1r cre and Ai14 Cre-reporter mice, we found that NPY Y 1 receptor (Y 1 R)-expressing neurons are glutamatergic and were broadly distributed throughout the rostrocaudal extent of the IC. In whole-cell recordings, application of a high-affinity Y 1 R agonist led to hyperpolarization in most Y 1 R-expressing IC neurons. Thus, NPY neurons represent a novel class of inhibitory principal neurons that are well poised to use GABAergic and NPY signaling to regulate the excitability of circuits in the IC and auditory thalamus.
10Located in the midbrain, the inferior colliculus (IC) is the hub of the central auditory system. Although 11 the IC plays important roles in speech processing, sound localization, and other auditory computations, 12 the organization of the IC microcircuitry remains largely unknown. Using a multifaceted approach in 13 mice, we have identified vasoactive intestinal peptide (VIP) neurons as a novel class of IC principal 14 neurons. VIP neurons are glutamatergic stellate cells with sustained firing patterns. Their extensive 15 axons project to long-range targets including the auditory thalamus, auditory brainstem, superior 16 colliculus, and periaqueductal gray. Using optogenetic circuit mapping, we found that VIP neurons 17 integrate input from the contralateral IC and the dorsal cochlear nucleus. The dorsal cochlear nucleus 18 also drove feedforward inhibition to VIP neurons, indicating that inhibitory circuits within the IC shape 19 the temporal integration of ascending inputs. Thus, VIP neurons are well-positioned to influence 20 auditory computations in a number of brain regions. 21 Results 67The VIP-IRES-Cre mouse line labels neurons in multiple subdivisions of the IC 68 By crossing VIP-IRES-Cre mice with Ai14 reporter mice, we obtained mice in which VIP + neurons 69 expressed the fluorescent protein tdTomato. VIP + neurons in these animals were visible in numerous 70 brain regions; the present report focuses on the IC. Figure 1 shows the distribution of VIP + neurons 71 (magenta) in transverse sections through the IC. Labeled neurons were present throughout most of the 72 rostro-caudal extent of the IC, but were most numerous in the caudal regions. Labeled neurons were 73 rare or absent in the IC rostral pole and intercollicular tegmentum. 74 75 VIP neurons are glutamatergic and represent 1.8% of IC neurons 76 Previous studies have shown that IC neurons are either glutamatergic or GABAergic (Merchán et al., 77 2005; Oliver et al. , 1994). To investigate the neurotransmitter content of VIP neurons, we performed 78 immunohistochemical staining against GAD67, a marker for GABAergic neurons, in brain slices from 79 three VIP-IRES-Cre x Ai14 animals, aged P58 (Figure 2A). We then counted tdTomato + neurons and 80 GAD67-labeled cell bodies in one caudal and one rostral IC slice per animal. Neurons located in the ICc, 81ICd, and IClc were combined for this analysis. Across 793 tdTomato + neurons, only 10 neurons co-82 VIP neurons exhibit sustained firing patterns and their intrinsic physiology varies along 101the tonotopic axis of the ICc 102Next, we investigated the firing pattern and intrinsic physiology of VIP neurons by targeting whole cell 103 patch clamp recordings to tdTomato + neurons in brain slices from VIP-IRES-Cre x Ai14 mice. Recordings 104 made from the ICc, ICd, and IClc were lumped together for this experiment because there were no clear 105 differences in VIP neuron physiology across these subdivisions of the IC. VIP neurons had a resting 106 membrane potential of -69.5 mV ± 4.4 mV (n = 216, correc...
The superior colliculus (SC) contains an auditory space map that is shaped by projections from several subcortical auditory nuclei. Both GABAergic (inhibitory) and excitatory cells contribute to these inputs, but there are contradictory reports regarding the sources of these inputs. We used retrograde tracing techniques in guinea pigs to identify cells in the auditory brainstem that project to the SC. We combined retrograde tracing with immunohistochemistry for glutamic acid decarboxylase (GAD) to identify putative GABAergic cells that participate in this pathway. Following a tracer injection in the SC, the nucleus of the brachium of the inferior colliculus (NBIC) contained the most labeled cells, followed by the inferior colliculus (IC). Smaller populations were observed in the sagulum, paralemniscal area, periolivary nuclei and ventrolateral tegmental nucleus. Overall, only 10% of the retrogradely labeled cells were GAD immunopositive. The presumptive inhibitory cells were observed in the NBIC, IC, superior paraolivary nucleus, sagulum and paralemniscal area. We conclude that the guinea pig SC receives input from a diverse set of auditory brainstem nuclei, some of which provide GABAergic input. These diverse origins of input to the SC likely represent a variety of functions. Inputs from the NBIC and IC likely provide spatial information for guiding orienting behaviors. Inputs from subcollicular nuclei are less likely to provide spatial information; rather, they may provide a shorter route for auditory information to reach the SC, and could generate avoidance or escape responses to an external threat.
The inferior colliculus occupies a central position in ascending and descending auditory pathways. A substantial proportion of its neurons are GABAergic, and these neurons contribute to intracollicular circuits as well as to extrinsic projections to numerous targets. A variety of types of evidence -morphology, physiology, molecul ar markers -indicate that the GABAergic cells can be divided into at least four subtypes that serve different functions. However, there has yet to emerge a unified scheme for distinguishing these subtypes. The present review discusses these criteria and, where possible, relates the different properties. In contrast to GABAergic cells in cerebral cortex, where subtypes are much more thoroughly characterized, those in the inferior colliculus contribute substantially to numerous long range extrinsic projections. At present, the best characterized subtype is a GABAergic cell with a large soma, dense perisomatic synaptic inputs and a large axon that provides rapid auditory input to the thalamus. This large GABAergic subtype projects to additional targets, and other subtypes also project to the thalamus. The eventual characterization of these subtypes can be expected to reveal multiple functions of these inhibitory cells and the many circuits to which they contribute.
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 a7 nAChRs in rat SOC, suggesting possible engagement of ACh-mediated modulation of neural activity in the MNTB. However, the existence and nature of this putative modulation have 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 multibarrel electrodes enabled pharmacological manipulation of nAChRs by reversibly applying antagonists to two receptor types, a7 and a4b2. 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 anatomic evidence revealing novel cholinergic projections to MNTB arising from pontine and superior olivary nuclei.
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.
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