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1.
Otolaryngol Head Neck Surg ; 151(4): 667-74, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25113508

ABSTRACT

OBJECTIVE: Examine prophylactic effects of dexamethasone (Dex) in retrocochlear auditory centers in a noise-induced hearing loss (NIHL) mouse model. STUDY DESIGN: Prospective animal study. SETTING: Academic research center. SUBJECTS AND METHODS: Thirty-two mice were divided into control, untreated, saline (2 and 10 µL), and Dex (2 and 10 µL) groups. Dex was applied intratympanically (IT) prior to 110 to 120 dB noise over 6 hours. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) were performed at 1 day, 1 week, 1 month, and 2 months. Retrocochlear neuronal cells were labeled with FluoroGold and counted. Hair cells of the organ of Corti were labeled with fluorescein isothiocyanate-conjugated phalloidin and counted. RESULTS: Auditory brainstem response thresholds of untreated NIHL, 2 and 10 µL IT saline, and 2 and 10 µL IT Dex were 21.7 ± 2.9 dB, 20 ± 0 dB, 20 ± 5 dB, 18.3 ± 2.9 dB, and 18.3 ± 2.9 dB, respectively. At 1-day post NIHL, all groups demonstrated profound hearing loss. At 2 weeks, 2 and 10 µL Dex thresholds improved to 47.5 ± 3.5 dB and 48.8 ± 18.9 dB, respectively, whereas the untreated and saline groups remained unchanged. Mean cell counts in the cochlear nucleus (CN), superior olivary complex (SOC), and lateral lemniscus (LL) of control mice were 1483 ± 190, 2807 ± 67, and 112 ± 20, respectively. After acoustic trauma, the untreated, saline, and 2 µL Dex groups yielded decreased neuronal counts in the SOC. In contrast, the 10 µL Dex group had 1883 ± 186 (CN), 2774 ± 182 (SOC), and 166 ± 18 (LL). There was sporadic hair cell loss for all traumatized groups. CONCLUSION: Our NIHL mouse model demonstrated dose-dependent Dex pretreatment otoprotection against NIHL with preservation of retrocochlear auditory neurons.


Subject(s)
Cochlear Nucleus/drug effects , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Hearing Loss, Noise-Induced/prevention & control , Superior Olivary Complex/drug effects , Animals , Cochlear Nucleus/pathology , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem/drug effects , Hair Cells, Auditory/drug effects , Hair Cells, Auditory/pathology , Hearing Loss, Noise-Induced/pathology , Male , Mice , Mice, Inbred CBA , Otoacoustic Emissions, Spontaneous/drug effects , Superior Olivary Complex/pathology
2.
Laryngoscope ; 123(12): 3185-93, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23817980

ABSTRACT

OBJECTIVES/HYPOTHESIS: To examine the relationship between hearing and connexin 43, a dominant gap junctional protein in the central nervous system. STUDY DESIGN: Original research. METHODS: Connexin 43 heterozygous mice are used to assess its mutational effect on hearing. Results are compared to controls consisting of connexin 43, wild type and CBA/J mice. Hearing is assessed using auditory brainstem response and distortion product otoacoustic emissions tests. Distribution of connexin 43 in the organ of Corti and the retrocochlear auditory centers (eight nerve, cochlear nucleus, olivary complex, lateral lemniscus, inferior colliculus, respectively) is examined. Fluorescent markers are used to elucidate cell types. RESULTS: Mean click auditory brainstem response threshold for the young connexin 43 heterozygous mice (3-4 months) was 36.7 ± 12.6 dB compared to 25 ± 0 dB for control mice (P < 0.05). Mean threshold difference became more pronounced (68 ± 7.5 dB vs. 31 ± 2.2 dB) at 10 months (P < 0.05). Tonal auditory brainstem response testing showed elevated thresholds (>60 dB) at all frequencies (4-32 kHz) compared to the controls. Distortion product otoacoustic emissions (DPOAE) were present in all the mice, although the older connexin 43 heterozygous mice responded at higher thresholds. The pattern of connexin 43 immunoreactivity was distinctive from connexin 26 and 30, showing minimal presence in the organ of Corti but robustly present in the retrocochlear centers. CONCLUSION: Connexin 43 heterozygous mice demonstrated greater degree of hearing loss compared to age-matched controls. It is abundantly found in the retrocochlear auditory centers. The mechanism of hearing loss in these mice does not appear to be related to hair cell loss.


Subject(s)
Cochlea/metabolism , Connexin 43/physiology , Hearing Loss/metabolism , Hearing/physiology , Acoustic Stimulation , Animals , Audiometry, Pure-Tone , Auditory Threshold/physiology , Cochlea/physiopathology , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem/physiology , Hearing Loss/physiopathology , Mice , Mice, Inbred CBA , Otoacoustic Emissions, Spontaneous/physiology
3.
Otol Neurotol ; 33(6): 1085-91, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22772010

ABSTRACT

HYPOTHESIS: Optimal pharmacotherapy entails a safe delivery method that specifically targets auditory structure(s) of interest. A retrocochlear neuronal tracer may enable comparison of various pharmacotherapy delivery methods and localization of the drug along the auditory pathway. BACKGROUND: Sensorineural hearing loss (SNHL) can involve cochlear hair cell or neural cell death, which often is accompanied by secondary degeneration of central auditory neurons. Targeting the precise location of nerve degeneration is important for treatment success. To be clinically relevant, the method of drug delivery must be safe and reliable while being maximally absorbed by the relevant inner ear structures of interest. METHODS: We compared 3 methods of FluoroGold (FG) delivery, a retrograde neuronal tracer, in delineating the retrocochlear auditory pathway using a normal-hearing strain of CBA mice. FG was delivered either intratympanic (IT), intracochlear (IC), or through the round window (RW). Five days after FG injection, mice were sacrificed for cell counts in the cochlear nucleus (CN), superior olivary complex (SOC), and the lateral lemniscus (LL). RESULTS: Although neurons in the CN and SOC were abundantly labeled by FG in all 3 injection methods, the IT method was the most reproducible and specific. The average cells for the CN, SOC, and LL were 851 ± 121, 2629 ± 367, and 112 ± 30, respectively. Accurate cell counts could not be established for the IC and RW injection methods because of nonspecific cell staining. Only 1 of the 5 IC-injected mice had specific labeling along the retrocochlear auditory pathway. Cell counts for the single mouse with specific IC staining in the CN, SOC, and LL were 177, 1839, and 56, respectively. Similarly, 2 of the 5 RW-injected mice had specific labeling, whereas the rest were nonspecific. The average cell counts for the 2 mice with specific labeling in the CN, SOC, and LL was 723.5 ± 580.0, 2173.5 ± 998.0, and 131.5 ± 8.0, respectively. CONCLUSION: The IT injection method resulted in reproducible, specific staining of neuronal cells along the retrocochlear auditory pathway compared with the RW or IC route of delivery.


Subject(s)
Auditory Pathways/anatomy & histology , Cochlear Nerve/anatomy & histology , Drug Delivery Systems , Hearing Loss, Sensorineural/drug therapy , Neuronal Tract-Tracers , Animals , Cell Count , Cochlear Nucleus/anatomy & histology , Ear, Inner/anatomy & histology , Fluorescent Dyes , Mice , Mice, Inbred CBA , Olivary Nucleus/anatomy & histology , Reproducibility of Results , Round Window, Ear/anatomy & histology , Stilbamidines , Tympanic Membrane/anatomy & histology
4.
Proc Natl Acad Sci U S A ; 109(7): 2585-9, 2012 Feb 14.
Article in English | MEDLINE | ID: mdl-22308470

ABSTRACT

Spreading depression (SD), a slow diffusion-mediated self-sustained wave of depolarization that severely disrupts neuronal function, has been implicated as a cause of cellular injury in a number of central nervous system pathologies, including blind spots in the retina. Here we show that in the hypoglycemic chicken retina, spontaneous episodes of SD can occur, resulting in irreversible punctate lesions in the macula, the region of highest visual acuity in the central region of the retina. These lesions in turn can act as sites of origin for secondary self-sustained reentrant spiral waves of SD that progressively enlarge the lesions. Furthermore, we show that the degeneration of the macula under hypoglycemic conditions can be prevented by blocking reentrant spiral SDs or by blocking caspases. The observation that spontaneous formation of reentrant spiral SD waves leads to the development of progressive retinal lesions under conditions of hypoglycemia establishes a potential role of SD in initiation and progression of macular degeneration, one of the leading causes of visual disability worldwide.


Subject(s)
Hypoglycemia/pathology , Macular Degeneration/pathology , Retina/pathology , Animals , Blotting, Western , Chickens , Immunohistochemistry
5.
Am J Psychiatry ; 159(1): 59-65, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11772691

ABSTRACT

OBJECTIVE: The authors assessed schizophrenia-associated changes in volume and neuronal number in the mediodorsal nucleus and the pulvinar regions of the thalamus. METHOD: Right-hemisphere thalami obtained at autopsy from 14 schizophrenic and eight comparison subjects were examined. Computer-assisted morphometric techniques were used to determine volumes for the mediodorsal nucleus, pulvinar, and the anterior and centromedian nuclei as well as the parvocellular, magnocellular, and caudodorsal subdivisions of the mediodorsal nucleus. Neurons in the mediodorsal nucleus and pulvinar were counted and measured by using a stereology-based sampling strategy. RESULTS: Four schizophrenic and three comparison subjects had Alzheimer's type pathology, leaving 10 schizophrenic and five comparison subjects without other documented neuropathological changes. In analyses that included either the full cohort or only the subjects without Alzheimer's type pathology, volumes of the mediodorsal nucleus and pulvinar, but not the anterior or centromedian nuclei, were significantly smaller in the schizophrenic subjects. For the schizophrenic subjects, neuronal number in the mediodorsal nucleus, parvocellular subdivision, and pulvinar was significantly lower, and neuronal size in the mediodorsal nucleus, caudodorsal subdivision, and pulvinar was significantly smaller. CONCLUSIONS: Schizophrenia is associated with volume and neuronal changes in the mediodorsal nucleus and pulvinar, the major association nuclei of the thalamus, whereas total thalamic volume and the volumes of anterior and centromedian nuclei were not significantly altered.


Subject(s)
Schizophrenia/pathology , Thalamic Nuclei/pathology , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Anterior Thalamic Nuclei/pathology , Female , Humans , Image Processing, Computer-Assisted , Intralaminar Thalamic Nuclei/pathology , Male , Mediodorsal Thalamic Nucleus/pathology , Middle Aged , Neurons/pathology , Pulvinar/pathology , Reference Values
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