Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats.

BACKGROUND: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. METHODS: In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. RESULTS: Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. CONCLUSIONS: These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice.

There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.

The effect of maternal diabetes on the expression of gamma-aminobutyric acid and metabotropic glutamate receptors in male newborn rats' inferior colliculi.

OBJECTIVES: Few studies have examined the molecular alterations in the auditory pathway of infants of diabetic mothers, notwithstanding the fact that maternal diabetes may have an impact on the development of the neonatal peripheral and central nervous systems. Male newborn rats were studied to determine how maternal diabetes affected the expression of gamma-aminobutyric acid (GABAAα1 and GABAB1) and metabotropic glutamate (mGlu2) receptors in the inferior colliculus (IC) in this research. METHODS: Female rats were given a single intraperitoneal injection of streptozotocin (STZ) at a 65 mg/kg dose to develop a model of diabetic mothers. The study population was split into sham, diabetes without treatment, and diabetes with insulin groups. Their male neonatal rats were anesthetized on P0, P7, and P14 after mating and delivery. The receptors' distribution pattern was studied using immunohistochemistry (IHC). RESULTS: Pairwise comparison in the groups revealed that the GABA receptors (Aα1 and B1) were significantly downregulated in the diabetes without treatment group (p<0.001). Furthermore, pairwise comparison in the groups indicated significant mGlu2 upregulation in the diabetes without treatment group (p<0.001). Regarding the concentration of all receptors, there was no discernible distinction between the diabetes with insulin and sham groups. CONCLUSIONS: This investigation showed that the concentration of GABAAα1 and GABAB1 receptors decreased significantly over time, whereas the concentration of mGlu2 receptors increased significantly over time in male neonatal rats born to streptozotocin-induced diabetic mothers.

The embryonic patterning gene Dbx1 governs the survival of the auditory midbrain via Tcf7l2-Ap2δ transcriptional cascade.

At the top of the midbrain is the inferior colliculus (IC), which functions as the major hub for processing auditory information. Despite the functional significance of neurons in the IC, our understanding of their formation is limited. In this study, we identify the embryonic patterning gene Dbx1 as a key molecular player that governs genetic programs for IC survival. We find that Dbx1 plays a critical role in preventing apoptotic cell death in postnatal IC by transcriptionally repressing c-Jun and pro-apoptotic BH3 only factors. Furthermore, by employing combined approaches, we uncover that Tcf7l2 functions downstream of Dbx1. Loss of Tcf7l2 function causes IC phenotypes with striking similarity to those of Dbx1 mutant mice, which include defective embryonic maturation and postnatal deletion of the IC. Finally, we demonstrate that the Dbx1-Tcf7l2 cascade functions upstream of Ap-2δ, which is essential for IC development and survival. Together, these results unravel a novel molecular mechanism for IC maintenance, which is indispensable for normal brain development.

Synaptoporin and parathyroid hormone 2 as markers of multimodal inputs to the auditory brainstem.

The distribution of the synaptic vesicle protein synaptoporin was investigated by immunofluorescence in the central auditory system of the mouse brainstem. Synaptoporin immunostaining displayed region-specific differences. High and moderate accumulations of were seen in the superficial layer of the dorsal cochlear nucleus, dorsal and external regions of the inferior colliculus, the medial and dorsal divisions of the medial geniculate body and in periolivary regions of the superior olivary complex (SOC). Low or absent labeling was observed in the more central parts of these structures such as the principal nuclei of the SOC. It was conspicuous that dense synaptoporin immunoreactivity was detected predominantly in areas, which are known to be synaptic fields of multimodal, extra-auditory inputs. Target neurons of synaptoporin-positive synapses in the SOC were then identified by double-labelling immunofluorescence microscopy. We thereby detected synaptoporin puncta perisomatically at nitrergic, glutamatergic and serotonergic neurons but none next to neurons immunoreactive for choline-acetyltransferase and calcitonin-gene related peptide. These results leave open whether functionally distinct neuronal groups are accessed in the SOC by synaptoporin-containing neurons. The last part of our study sought to find out whether synaptoporin-positive neurons originate in the medial paralemniscal nucleus (MPL), which is characterized by expression of the peptide parathyroid hormone 2 (PTH2). Anterograde neuronal tracing upon injection into the MPL in combination with synaptoporin- and PTH2-immunodetection showed that (1) the MPL projects to the periolivary SOC using PTH2 as transmitter, (2) synaptoporin-positive neurons do not originate in the MPL, and (3) the close juxtaposition of synaptoporin-staining with either the anterograde tracer or PTH2 reflect concerted action of the different inputs to the SOC.

Targeted Inhibition of Upregulated Sodium-Calcium Exchanger in Rat Inferior Colliculus Suppresses Alcohol Withdrawal Seizures.

The inferior colliculus (IC) is critical in initiating acoustically evoked alcohol withdrawal-induced seizures (AWSs). Recently, we reported that systemic inhibition of Ca2+ entry via the reverse mode activity of the Na+/Ca2+ exchanger (NCXrev) suppressed AWSs, suggesting remodeling of NCX expression and function, at least in the IC, the site of AWS initiation. Here, we probe putative changes in protein expression in the IC of NCX isoforms, including NCX type 1 (NCX1), 2 (NCX2), and 3 (NCX3). We also evaluated the efficacy of targeted inhibition of NCX1rev and NCX3rev activity in the IC on the occurrence and severity of AWSs using SN-6 and KB-R943, respectively. We used our well-characterized alcohol intoxication/withdrawal model associated with enhanced AWS susceptibility. IC tissues from the alcohol-treated group were collected 3 h (before the onset of AWS susceptibility), 24 h (when AWS susceptibility is maximal), and 48 h (when AWS susceptibility is resolved) following alcohol withdrawal; in comparison, IC tissues from the control-treated group were collected at 24 h after the last gavage. Analysis shows that NCX1 protein levels were markedly higher 3 and 24 h following alcohol withdrawal. However, NCX3 protein levels were only higher 3 h following alcohol withdrawal. The analysis also reveals that bilateral microinjections of SN-6 (but not KB-R7943) within the IC markedly suppressed the occurrence and severity of AWSs. Together, these findings indicate that NCX1 is a novel molecular target that may play an essential role in the pathogenesis and pathophysiology of AWSs.

Age-related ultrastructural changes in the lateral cortex of the inferior colliculus.

Temporal precision, a key component of sound and speech processing in the inferior colliculus (IC), depends on a balance of inhibition and excitation, and this balance degrades during aging. The cause of disrupted excitatory-inhibitory balance in aging is unknown, however changes at the synapse are a likely candidate. We sought to determine whether synaptic changes occur in the lateral cortex of the IC (IClc), a multimodal nucleus that processes lemniscal, intrinsic, somatosensory, and descending auditory input. Using electron microscopic techniques across young, middle age and old Fisher Brown Norway rats, our results demonstrate minimal loss of synapses in middle age, but significant (∼28%) loss during old age. However, in middle age, targeting of GABAergic dendrites by GABAergic synapses is increased and the active zones of excitatory synapses (that predominantly target GABA-negative dendrites) are lengthened. These synaptic changes likely result in a net increase of excitation in the IClc during middle age. Thus, disruption of excitatory-inhibitory balance in the aging IClc may be due to synaptic changes that begin in middle age.

Downregulated miRNAs associated with auditory deafferentation and compensatory neural plastic changes following single-sided deafness in the inferior colliculi of rats.

BACKGROUND AND AIMS: Deafferentation and compensatory neural plastic changes in the inferior colliculus (IC) have been suggested following single-sided deafness (SSD). We explored related miRNA changes in the IC of SSD rats using miRNA microarray analyses. METHODS: Eight-week-old rats were divided into control and SSD rats (n = 8 for each group). SSD rats underwent right-side cochlear ablation surgery, with the IC harvested two weeks post-surgery. miRNA microarray analysis was performed using GeneChip miRNA 4.0, microarray (Affymetrix Inc.). miRNAs whose expression levels differed between SSD and control rats with a fold-change ≥ 1.5 and P < 0.05 were examined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target genes of differentially expressed miRNAs were predicted using TargetScan software. The pathways related to predicted target genes were analyzed. mRNA levels of predicted target genes were estimated using qRT-PCR. RESULTS: The expression of miR-15b-5p, miR-202-5p, and miR-212-3p was lower in the contralateral (left) IC of SSD rats than that of control rats. In SSD rats, miRNA expression levels in the contralateral IC were 0.45-, 0.25-, and 0.50-fold lower for miR-15b-5p, miR-202-5p, and miR-212-3p, respectively (P < 0.05). The expression of predicted target genes (Spred1, Rasa1, Lsm11, and Srsf1) was higher in the contralateral IC of SSD rats than in control rats. The targets were predicted to be related with cleavage of growing transcripts in the termination region, mitogen-activated protein kinase family signaling cascades, RAF/AMP kinase cascade, regulation of RAS by GTPase activating proteins (GAPs), and RNA polymerase II transcription termination. For ipsilateral ICs, miR-425-3p, miR-199a-5p, and miR-134-3p showed lower expressions in SSD rats than in control rats, which were 0.55-, 0.61-, and 0.69-fold lower, respectively (P < 0.05). The expression of predicted target genes (Atp2b2, Grin2b, Foxp1, Ztbt20, Zfp91, and Strn) was higher in the ipsilateral IC of SSD rats; the regulation of synaptic plasticity, cAMP signaling pathway, metal ion binding, and calcium ion transport can be associated with these target genes. CONCLUSION: Adult rats with unilateral auditory deprivation showed miRNA changes in the IC. The contralateral IC showed decreased miRNA expression predicted to be related to MAPK and RAS signaling, whereas the ipsilateral IC revealed decreased miRNA expression predicted to be associated with synaptic plasticity and calcium ion transport.

Structural arrangement of auditory brainstem nuclei in the bats Phyllostomus discolor and Carollia perspicillata.

The structure of the mammalian auditory brainstem is evolutionarily highly plastic, and distinct nuclei arrange in a species-dependent manner. Such anatomical variability is present in the superior olivary complex (SOC) and the nuclei of the lateral lemniscus (LL). Due to the structure-function relationship in the auditory brainstem, the identification of individual nuclei supports the understanding of sound processing. Here, we comparatively describe the nucleus arrangement and the expression of functional markers in the auditory brainstem of the two bat species Phyllostomus discolor and Carollia perspicillata. Using immunofluorescent labeling, we describe the arrangement and identity of the SOC and LL nuclei based on the expression of synaptic markers (vesicular glutamate transporter 1 and glycine transporter 2), calcium-binding proteins, as well as the voltage-gated ion channel subunits Kv1.1 and HCN1. The distribution of excitatory and inhibitory synaptic labeling appears similar between both species and matches with that of other mammals. The detection of calcium-binding proteins indicates species-dependent differences and deviations from other mammals. Kv1.1 and HCN1 show largely the same expression pattern in both species, which diverges from other mammals, indicating functional adaptations in the cellular physiology of bat neurons.

Segregation of Multimodal Inputs Into Discrete Midbrain Compartments During an Early Critical Period.

The lateral cortex of the inferior colliculus (LCIC) is a multimodal subdivision of the midbrain inferior colliculus (IC) that plays a key role in sensory integration. The LCIC is compartmentally-organized, exhibiting a series of discontinuous patches or modules surrounded by an extramodular matrix. In adult mice, somatosensory afferents target LCIC modular zones, while auditory afferents terminate throughout the encompassing matrix. Recently, we defined an early LCIC critical period (birth: postnatal day 0 to P12) based upon the concurrent emergence of its neurochemical compartments (modules: glutamic acid decarboxylase, GAD+; matrix: calretinin, CR+), matching Eph-ephrin guidance patterns, and specificity of auditory inputs for its matrix. Currently lacking are analogous experiments that address somatosensory afferent shaping and the construction of discrete LCIC multisensory maps. Combining living slice tract-tracing and immunocytochemical approaches in a developmental series of GAD67-GFP knock-in mice, the present study characterizes: (1) the targeting of somatosensory terminals for emerging LCIC modular fields; and (2) the relative separation of somatosensory and auditory inputs over the course of its established critical period. Results indicate a similar time course and progression of LCIC projection shaping for both somatosensory (corticocollicular) and auditory (intracollicular) inputs. While somewhat sparse and intermingling at birth, modality-specific projection patterns soon emerge (P4-P8), coincident with peak guidance expression and the appearance of LCIC compartments. By P12, an adult-like arrangement is in place, with fully segregated multimodal afferent arrays. Quantitative measures confirm increasingly distinct input maps, exhibiting less projection overlap with age. Potential mechanisms whereby multisensory LCIC afferent systems recognize and interface with its emerging modular-matrix framework are discussed.

Compromised fractalkine signaling delays microglial occupancy of emerging modules in the multisensory midbrain.

Microglial cells (MGCs) are highly dynamic and have been implicated in shaping discrete neural maps in several unimodal systems. MGCs respond to numerous cues in their microenvironment, including the neuronally expressed chemokine, fractalkine (CX3CL1), via interactions with its corresponding fractalkine receptor (CX3CR1). The present study examines microglial and CX3CL1 patterns with regard to the emerging modular-extramodular matrix organization within the lateral cortex of the inferior colliculus (LCIC). The LCIC is a multisensory shell region of the midbrain inferior colliculus where discrete compartments receive modality-specific connections. Somatosensory inputs terminate within modular confines, while auditory inputs target the surrounding matrix. Glutamic acid decarboxylase (GAD) is an established marker of LCIC modules in developing mouse. During early postnatal development, multimodal LCIC afferents segregate into discrete, neurochemically defined compartments. Here, we analyzed neonatal GAD67-GFP (GFP is defined as green fluorescent protein) and CX3CR1-GFP mice to assess: (1) whether MGCs are recruited to distinct LCIC compartments known to be undergoing active circuit assembly, and (2) if such behaviors are fractalkine signaling-dependent. MGCs colonize the nascent LCIC by birth and increase in density until postnatal day 12 (P12). At the peak critical period (P4-P8), MGCs conspicuously border emerging LCIC modules, prior to their subsequent invasion by P12. CX3CL1 expression becomes distinctly modular at P12, in keeping with the notion of fractalkine-mediated recruitment of microglia to modular centers. In CX3CR1GFP/GFP mice with compromised fractalkine signaling, microglial recruitment into modules is delayed. Taken together, these results suggest a potential role for microglia and fractalkine signaling in sculpting multisensory LCIC maps during an early critical period.

α3ß4∗ Nicotinic Acetylcholine Receptors Strongly Modulate the Excitability of VIP Neurons in the Mouse Inferior Colliculus.

The inferior colliculus (IC), the midbrain hub of the central auditory system, receives extensive cholinergic input from the pontomesencephalic tegmentum. Activation of nicotinic acetylcholine receptors (nAChRs) in the IC can alter acoustic processing and enhance auditory task performance. However, how nAChRs affect the excitability of specific classes of IC neurons remains unknown. Recently, we identified vasoactive intestinal peptide (VIP) neurons as a distinct class of glutamatergic principal neurons in the IC. Here, in experiments using male and female mice, we show that cholinergic terminals are routinely located adjacent to the somas and dendrites of VIP neurons. Using whole-cell electrophysiology in brain slices, we found that acetylcholine drives surprisingly strong and long-lasting excitation and inward currents in VIP neurons. This excitation was unaffected by the muscarinic receptor antagonist atropine. Application of nAChR antagonists revealed that acetylcholine excites VIP neurons mainly via activation of α3ß4∗ nAChRs, a nAChR subtype that is rare in the brain. Furthermore, we show that acetylcholine excites VIP neurons directly and does not require intermediate activation of presynaptic inputs that might express nAChRs. Lastly, we found that low frequency trains of acetylcholine puffs elicited temporal summation in VIP neurons, suggesting that in vivo-like patterns of cholinergic input can reshape activity for prolonged periods. These results reveal the first cellular mechanisms of nAChR regulation in the IC, identify a functional role for α3ß4∗ nAChRs in the auditory system, and suggest that cholinergic input can potently influence auditory processing by increasing excitability in VIP neurons and their postsynaptic targets.

Cholinergic boutons are closely associated with excitatory cells and four subtypes of inhibitory cells in the inferior colliculus.

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.

Overexpression of Isl1 under the Pax2 Promoter, Leads to Impaired Sound Processing and Increased Inhibition in the Inferior Colliculus.

The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

Inferior Colliculus's Hypermetabolism: A New Finding on Brain FDG PET and Perfusion MRI in a Patient With COVID-19.

ABSTRACT: We present the case of a 64-year-old man presenting an episode of confusion during SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection with a positive oropharyngeal swab polymerase chain reaction test. He was hospitalized for dyspnea related to pneumonia demonstrated on chest CT. FDG PET performed after the confusion phase, but still in the COVID-19 (coronavirus disease 2019)-positive phase, showed high glucose metabolism of the inferior colliculi. Morphological MRI was normal. The first-pass perfusion MRI shows hyperperfusion of the inferior colliculi, corresponding to FDG PET hypermetabolism.

Changes in the Gene Expression Profiles of the Inferior Colliculus Following Unilateral Cochlear Ablation in Adult Rats.

This study aimed to explore gene expression changes in the inferior colliculus (IC) after single-sided deafness (SSD). Forty 8-week-old female Sprague-Dawley rats were used. Twenty rats underwent right-side cochlear ablation, and IC tissues were harvested after 2 weeks (SSD 2-week group). Twenty rats underwent a sham operation and were sacrificed after 2 weeks (control group). Both sides of the IC were analyzed using a gene expression array. Pathway analyses were performed on genes that were differentially expressed compared with their levels in the control group. The expression levels of genes involved in the candidate pathways were confirmed using reverse transcription polymerase chain reaction (RT-PCR). Among the genes with ≥ 1.5-fold changes in expression levels and P < 0.05, there were 7 and 9 genes with increased and decreased expression, respectively, in the ipsilateral IC and 10 and 12 genes with increased and decreased expression, respectively, in the contralateral IC. The pathway analysis did not identify significantly related pathway. In the bilateral analysis, a total of 14 genes were ≥ 1.3-fold downregulated in both the ipsilateral and contralateral IC in the SSD 2-week group compared with their expression in the control group. Pathway analyses of these 14 genes included 7 genes, namely, amine compound solute carrier (Slc)5a7; Slc18a3; Slc6a5; synaptic vesicle glycoprotein 2C (Sv2c); S100 calcium binding protein A10 (S100a10); a gene with sequence similarity to family 111, member A (Fam111a); and peripherin (Prph), that were related to the acetylcholine neurotransmitter release cycle, SLC transporters, and the neurotransmitter release cycle pathways. RT-PCR showed reduced expression of Slc5a7, Sv2c, and Prph in the contralateral IC and Slc18a3 and Slc6a5 in the ipsilateral IC of the SSD 2-week group compared with that in the control group.

Resveratrol noncompetitively inhibits glycine receptor-mediated currents in neurons of rat central auditory neurons.

Resveratrol, a naturally occurring stilbene found in red wine, is known to modulate the activity of several types of ion channels and membrane receptors, including Ca2+, K+, and Na+ ion channels. However, little is known about the effects of resveratrol on some important receptors, such as glycine receptors and GABAA receptors, in the central nervous system (CNS). In the present study, the effects of resveratrol on glycine receptor or GABAA receptor-mediated currents in cultured rat inferior colliculus (IC) and auditory cortex (AC) neurons were studied using whole-cell voltage-clamp recordings. Resveratrol itself did not evoke any currents in IC neurons but it reversibly decreased the amplitude of glycine-induced current (IGly) in a concentration-dependent manner. Resveratrol did not change the reversal potential of IGly but it shifted the concentration-response relationship to the right without changing the Hill coefficient and with decreasing the maximum response of IGly. Interestingly, resveratrol inhibited the amplitude of IGly but not that of GABA-induced current (IGABA) in AC neurons. More importantly, resveratrol inhibited GlyR-mediated but not GABAAR-mediated inhibitory postsynaptic currents in IC neurons using brain slice recordings. Together, these results demonstrate that resveratrol noncompetitively inhibits IGly in auditory neurons by decreasing the affinity of glycine to its receptor. These findings suggest that the native glycine receptors but not GABAA receptors in central neurons are targets of resveratrol during clinical administrations.

Distribution and co-expression of adrenergic receptor-encoding mRNA in the mouse inferior colliculus.

Adrenergic receptors are mediators of adrenergic and noradrenergic modulation throughout the brain. Previous studies have provided evidence for the expression of adrenergic receptors in the midbrain auditory nucleus, the inferior colliculus (IC), but have not examined the cellular patterns of expression in detail. Here, we utilize multichannel fluorescent in situ hybridization to detect the expression of adrenergic receptor-encoding mRNA in the inferior colliculus of male and female mice. We found expression of α1 , α2A , and ß2 receptor-encoding mRNA throughout all areas of the IC. While we observed similar levels of expression of α1 receptor-encoding mRNA across the subregions of the IC, α2A and ß2 receptor-encoding mRNA was expressed differentially. To account for developmental changes in noradrenergic receptor expression, we measured expression levels in mice aged P15, P20, and P60. We observed little change in levels of expression across these ages. To ascertain the modulatory potential of multiple adrenergic receptor subtypes in a single IC cell, we measured co-expression of α1 , α2A , and ß2 receptor-encoding mRNA. We found greater proportions of cells in the IC that expressed no adrenergic receptor-encoding mRNA, α1 and α2A adrenergic receptor-encoding mRNA, and α1, α2A, and ß2 receptor-encoding mRNA than would be predicted by independent expression of each receptor subtype. These data suggest a coordinated pattern of adrenergic receptor expression in the IC and provide the first evidence for adrenergic receptor expression and co-expression in the subregions of the mouse auditory midbrain.

MPTP toxicity causes vocal, auditory, orientation and movement defects in the echolocation bat.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can damage dopaminergic neurons in the substantia nigra in many mammals with biochemical and cellular changes that are relatively similar to those observed in Parkinson's disease. Our study examined whether MPTP-treated echolocation bats can cause changes in bat echolocation system. By considering ultrasound spectrums, auditory brainstem-evoked potentials and flight trajectories of normal bats, we observed that the vocal, auditory, orientation and movement functions of MPTP-treated bats were significantly impaired, and they exhibited various symptoms resembling those in patients with Parkinson's disease. Our immunohistochemistry and western blot analyses further indicated that expression of vocal-related FOXP2 in the superior colliculus, auditory-related otoferlin in the inferior colliculus, dopamine synthesis-related aromatic l-amino acid decarboxylase in the substantia nigra and dopamine receptor in the striatum was significantly decreased. Furthermore, protein expression related to inflammation, oxidative stress and apoptosis in the substantia nigra was significantly increased in MPTP-treated bats. These results indicate that inflammation, oxidative stress and apoptosis may be instrumental in dopaminergic neurodegeneration in the substantia nigra. The vocal, auditory and orientation and movement dysfunctions of MPTP-treated bats are relatively consistent with symptoms of Parkinson's disease.

Changes in microRNA Expression in the Cochlear Nucleus and Inferior Colliculus after Acute Noise-Induced Hearing Loss.

Noise-induced hearing loss (NIHL) can lead to secondary changes that induce neural plasticity in the central auditory pathway. These changes include decreases in the number of synapses, the degeneration of auditory nerve fibers, and reorganization of the cochlear nucleus (CN) and inferior colliculus (IC) in the brain. This study investigated the role of microRNAs (miRNAs) in the neural plasticity of the central auditory pathway after acute NIHL. Male Sprague-Dawley rats were exposed to white band noise at 115 dB for 2 h, and the auditory brainstem response (ABR) and morphology of the organ of Corti were evaluated on days 1 and 3. Following noise exposure, the ABR threshold shift was significantly smaller in the day 3 group, while wave II amplitudes were significantly larger in the day 3 group compared to the day 1 group. The organ of Corti on the basal turn showed evidence of damage and the number of surviving outer hair cells was significantly lower in the basal and middle turn areas of the hearing loss groups relative to controls. Five and three candidate miRNAs for each CN and IC were selected based on microarray analysis and quantitative reverse transcription PCR (RT-qPCR). The data confirmed that even short-term acoustic stimulation can lead to changes in neuroplasticity. Further studies are needed to validate the role of these candidate miRNAs. Such miRNAs may be used in the early diagnosis and treatment of neural plasticity of the central auditory pathway after acute NIHL.