RESUMEN
Motion-induced anxiety and agoraphobia are more frequent symptoms in patients with vestibular migraine (VM) than migraine without vertigo. The neuropeptide calcitonin gene-related peptide (CGRP) is a therapeutic target for migraine and VM, but the link between motion hypersensitivity, anxiety, and CGRP is relatively unexplored, especially in preclinical mouse models. To further examine this link, we tested the effects of systemic CGRP and off-vertical axis rotation (OVAR) on elevated plus maze (EPM) and rotarod performance in male and female C57BL/6J mice. Rotarod ability was assessed using two different dowel diameters: mouse dowel (r = 1.5â cm) versus rat dowel (r = 3.5â cm). EPM results indicate that CGRP alone or OVAR alone did not increase anxiety indices. However, the combination of CGRP and OVAR did elicit anxiety-like behavior. On the rotarod, CGRP reduced performance in both sexes on a mouse dowel but had no effect on a rat dowel, whereas OVAR had a significant effect on the rat dowel. These results suggest that only the combination of CGRP with vestibular stimulation induces anxiety-like behavior and that CGRP affects the dynamic balance function in mice depending on the type of challenge presented. These findings suggest that anxiety-like behaviors can be teased out from imbalance behaviors in a mouse model of "migraine." Future studies are aimed to determine if CGRP receptor antagonists that have been effective treating migraineurs and mouse "migraine" models may also reduce the anxiety observed in migraine.
Asunto(s)
Ansiedad , Péptido Relacionado con Gen de Calcitonina , Ratones Endogámicos C57BL , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Masculino , Ansiedad/metabolismo , Femenino , Modelos Animales de Enfermedad , Ratones , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante , Vestíbulo del Laberinto/efectos de los fármacos , Trastornos Migrañosos/metabolismoRESUMEN
Aging impacts the vestibular system and contributes to imbalance. In fact, imbalance precedes changes in cognition in the elderly. However, research is limited in assessing aging mouse models that are deficient in crucial neuromodulators like Calcitonin Gene-Related Peptide (CGRP). We studied the loss of CGRP and its effects in the aging mouse, namely its effect on both static and dynamic imbalances. Postural sway and rotarod testing were performed before and after a vestibular challenge (VC) in the 129S wild type and the αCGRP (-/-) null mice. Four age groups were tested that correspond to young adulthood, late adulthood, middle age, and senescence in humans. Our results suggest wild type mice experience a decline in rotarod ability due to aging after they reach their prime performance at 6-10 months of age, while the αCGRP (-/-) null mice perform poorly on rotarod early in life but improve with age as they get older, potentially due to vestibular compensation. Our postural sway study suggests that a vestibular challenge can lead to significantly reduced CoP ellipse areas (freezing behaviors) in older mice, and this change occurs earlier in the αCGRP (-/-) null but requires future studies to evaluate anxiety effects. These results indicate that αCGRP is an important component of proper balance and that the loss of αCGRP can contribute to balance complications that may compound with aging.
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Envejecimiento , Péptido Relacionado con Gen de Calcitonina , Ratones Noqueados , Equilibrio Postural , Animales , Envejecimiento/fisiología , Ratones , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/genética , Vestíbulo del Laberinto/metabolismo , Masculino , Prueba de Desempeño de Rotación con Aceleración Constante , FemeninoRESUMEN
COVID-19 can cause neurological symptoms such as fever, dizziness, and nausea. However, such neurological symptoms of SARS-CoV-2 infection have been hardly assessed in mouse models. In this study, we infected two commonly used wild-type mouse lines (C57BL/6J and 129/SvEv) and a 129S calcitonin gene-related peptide (αCGRP) null-line with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including fever, dizziness, and nausea. We then evaluated whether a CGRP receptor antagonist, olcegepant, a "gepant" antagonist used in migraine treatment, could mitigate acute neuroinflammatory and neurological signs of SARS-COV-2 infection. First, we determined whether CGRP receptor antagonism provided protection from permanent weight loss in older (>18 m) C57BL/6J and 129/SvEv mice. We also observed acute fever, dizziness, and nausea in all older mice, regardless of treatment. In both wild-type mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels with virtually no IL-6 release in mice lacking αCGRP. These findings suggest that migraine inhibitors such as those blocking CGRP receptor signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic or endemic coronavirus outbreaks.IMPORTANCECoronavirus disease (COVID-19) can cause neurological symptoms such as fever, headache, dizziness, and nausea. However, such neurological symptoms of severe acute respiratory syndrome CoV-2 (SARS-CoV-2) infection have been hardly assessed in mouse models. In this study, we first infected two commonly used wild-type mouse lines (C57BL/6J and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological symptoms including fever and nausea. Furthermore, we showed that the migraine treatment drug olcegepant could reduce long-term weight loss and IL-6 release associated with SARS-CoV-2 infection. These findings suggest that a migraine blocker can be protective for at least some acute SARS-CoV-2 infection signs and raise the possibility that it may also impact long-term outcomes.
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COVID-19 , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Modelos Animales de Enfermedad , Interleucina-6 , Ratones Endogámicos C57BL , Trastornos Migrañosos , SARS-CoV-2 , Pérdida de Peso , Animales , Ratones , Interleucina-6/metabolismo , COVID-19/virología , SARS-CoV-2/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/virología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Péptido Relacionado con Gen de Calcitonina/metabolismo , Masculino , Humanos , Femenino , PiperazinasRESUMEN
BACKGROUND: Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects â¼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. METHODS: We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. RESULTS: MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. CONCLUSIONS: These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.Trial Registration: Not Applicable.
Asunto(s)
Trastornos Migrañosos , Mareo por Movimiento , Humanos , Masculino , Adulto , Femenino , Ratones , Animales , Receptores de Péptido Relacionado con el Gen de Calcitonina/uso terapéutico , Péptido Relacionado con Gen de Calcitonina , Ratones Endogámicos C57BL , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/complicaciones , Mareo por Movimiento/tratamiento farmacológico , Mareo por Movimiento/complicaciones , NáuseaRESUMEN
COVID-19 can result in neurological symptoms such as fever, headache, dizziness, and nausea. However, neurological signs of SARS-CoV-2 infection have been hardly assessed in mouse models. Here, we infected two commonly used wildtype mice lines (C57BL/6 and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including motion-related dizziness. We then evaluated whether the Calcitonin Gene-Related Peptide (CGRP) receptor antagonist, olcegepant, used in migraine treatment could mitigate acute neuroinflammatory and neurological responses to SARS-COV-2 infection. We infected wildtype C57BL/6J and 129/SvEv mice, and a 129 αCGRP-null mouse line with a mouse-adapted SARS-CoV-2 virus, and evaluated the effect of CGRP receptor antagonism on the outcome of that infection. First, we determined that CGRP receptor antagonism provided protection from permanent weight loss in older (>12 m) C57BL/6J and 129 SvEv mice. We also observed acute fever and motion-induced dizziness in all older mice, regardless of treatment. However, in both wildtype mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels by half, with virtually no IL-6 release in mice lacking αCGRP. These findings suggest that migraine inhibitors such as those blocking CGRP signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic and/or endemic coronaviruses.
RESUMEN
Both enhanced motion-induced nausea and increased static imbalance are \observed symptoms in migraine and especially vestibular migraine (VM). Motion-induced nausea and static imbalance were investigated in a mouse model, nestin/hRAMP1, expressing elevated levels of human RAMP1 in the CNS, which enhances CGRP signaling in the nervous system. Behavioral surrogates such as the motion-induced thermoregulation and postural sway center of pressure (CoP) assays were used to assess motion sensitivity. Tail vasodilation analysis revealed that this model exhibits an increased sensitivity to CGRP's effects at lower doses compared to control mice. In addition, the nestin/hRAMP1 mice exhibit a higher dynamic range in postural sway than their wildtype counterparts, along with increased sway observed in nestin/hRAMP1 male mice that was not present in male littermate controls. Results from migraine blocker experiments were challenging to interpret, but the data suggests that olcegepant is incapable of reversing CGRP-induced alterations in the nestin/hRAMP1 mice, while rizatriptan was ineffective in both the nestin/hRAMP1 and control mice. The results indicate that overexpression of hRAMP1 leads to heightened endogenous CGRP signaling. Results also suggest that both olcegepant and rizatriptan are ineffective in reducing CGRP-triggered nausea and sway in this hypersensitive CGRP mouse model. This study suggests that hypersensitivity to CGRP may be a mouse model for difficult to treat cases of vestibular migraine.
RESUMEN
Motion-induced anxiety and agoraphobia are more frequent symptoms in patients with vestibular migraine than migraine without vertigo. The neuropeptide calcitonin gene-related peptide (CGRP) is a therapeutic target for migraine and vestibular migraine, but the link between motion hypersensitivity, anxiety, and CGRP is relatively unexplored, especially in preclinical mouse models. To further examine this link, we tested the effects of systemic CGRP and off-vertical axis rotation (OVAR) on elevated plus maze (EPM) and rotarod performance in male and female C57BL/6J mice. Rotarod ability was assessed using two different dowel diameters: mouse dowel (r = 1.5 cm) versus rat dowel (r = 3.5 cm). EPM results indicate CGRP increased anxiety indexes and time spent in the closed arms in females but not males, while OVAR increased anxiety indexes and time spent in the closed arms in both sexes. The combination of CGRP and OVAR elicited even greater anxiety-like behavior. On the rotarod, CGRP reduced performance in both sexes on a mouse dowel but had no effect on a rat dowel, whereas OVAR had a significant effect on the rat dowel. Rotarod performance is influenced by dowel diameter, with larger dowels presenting greater challenges on balance function. These results suggest that both CGRP and vestibular stimulation induce anxiety-like behavior and that CGRP affects dynamic balance function in mice depending on the type of challenge presented. Findings highlight the potential translation of anti-CGRP receptor signaling therapeutics for treating motion hypersensitivity and motion-induced anxiety that manifests in vestibular migraine. Significance statement: Anxiety is very common in patients with dizziness and vestibular migraine (VM). Elevated CGRP levels have been linked to migraine symptoms of increased light and touch sensitivity in mice and humans and we wondered if a systemic injection of CGRP into mice would increase anxiety and imbalance; and if mice further exposed to a vestibular stimulus would have their anxiety measures sharpened. We observed a female preponderance in both CGRP and motion-induced anxiety-like behaviors, suggesting that the role of CGRP in migraine's anxiety symptoms can be recapitulated in the mouse. Our findings suggest that CGRP signaling has a pertinent role in motion-induced anxiety and dynamic imbalance, and warrants the potential use of anti-CGRP therapies for the treatment of these symptoms.
RESUMEN
Aging impacts the vestibular system and contributes to imbalance. In fact, in the elderly balance deficits often precede changes in cognition. However, imbalance research is limited in assessing aging mouse models that are deficient in neuromodulators like Calcitonin Gene-Related Peptide (CGRP). We studied the loss of CGRP and its effects in the aging mouse, namely its effect on both static and dynamic imbalances. In addition, postural sway and rotarod testing were performed before and after a vestibular challenge (VC) in the 129S wildtype and the αCGRP (-/-) null mice. Four age groups were tested that correspond to young adulthood, late adulthood, middle age, and senescence in humans. Our results suggest wildtype mice experience a decline in rotarod ability with increased age, while the αCGRP (-/-) null mice perform poorly on rotarod early in life and do not improve. Our postural sway study suggests that a vestibular challenge can lead to significantly reduced CoP ellipse areas (freezing behaviors) in older mice, and this change occurs earlier in the αCGRP (-/-) null mouse. These results indicate that αCGRP is an important component of static and dynamic balance; and that the loss of αCGRP can contribute to balance complications that may compound with aging.
RESUMEN
Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by hearing loss that is not assessed on standard audiological examinations, such as reduced temporal processing acuity. To assess whether sound therapy may improve these deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. The DBA/2J mouse strain develops rapid, base to apex, progressive SNHL beginning at birth and is functionally deaf by six months of age. Hearing sensitivity and auditory brainstem function was measured using otoacoustic emissions, auditory brainstem response (ABR) and extracellular recording from the inferior colliculus (IC) in mice following exposure to 30 d of continuous AAE. Peripheral function and sound sensitivity in auditory midbrain neurons improved following exposure to both types of AAE. However, exposure to a novel, temporally complex AAE more strongly improved a measure of temporal processing acuity, neural gap-in-noise detection in the auditory midbrain. These experiments suggest that targeted sound therapy may be harnessed to improve hearing outcomes for children suffering from congenital SNHL.
Asunto(s)
Pérdida Auditiva Sensorineural , Percepción del Tiempo , Estimulación Acústica , Acústica , Animales , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico , Ratones , Ratones Endogámicos DBARESUMEN
Vestibular migraine (VM) is an increasingly recognized pathology yet remains as an underdiagnosed cause of vestibular disorders. While current diagnostic criteria are codified in the 2012 Barany Society document and included in the third edition of the international classification of headache disorders, the pathophysiology of this disorder is still elusive. The Association for Migraine Disorders hosted a multidisciplinary, international expert workshop in October 2020 and identified seven current care gaps that the scientific community needs to resolve, including a better understanding of the range of symptoms and phenotypes of VM, the lack of a diagnostic marker, a better understanding of pathophysiologic mechanisms, as well as the lack of clear recommendations for interventions (nonpharmacologic and pharmacologic) and finally, the need for specific outcome measures that will guide clinicians as well as research into the efficacy of interventions. The expert group issued several recommendations to address those areas including establishing a global VM registry, creating an improved diagnostic algorithm using available vestibular tests as well as others that are in development, conducting appropriate trials of high quality to validate current clinically available treatment and fostering collaborative efforts to elucidate the pathophysiologic mechanisms underlying VM, specifically the role of the trigemino-vascular pathways.
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Active mechanical amplification of sound occurs in cochlear outer hair cells (OHCs) that change their length with oscillations of their membrane potential. Such length changes are the proposed cellular source of the cochlear amplifier, and prestin is the motor protein responsible for OHC electromotility. Previous findings have shown that mice lacking prestin displayed a loss of OHC electromotility, subsequent loss of distortion-product otoacoustic emissions, and a 40-60 dB increase in hearing thresholds. In this study we were interested in studying the functional consequences of the complete loss of cochlear amplification on neural coding of frequency selectivity, tuning, and temporal processing in the auditory midbrain. We recorded near-field auditory evoked potentials and multi-unit activity from the inferior colliculus (IC) of prestin (-/-) null and prestin (+/+) wild-type control mice and determined frequency response areas (FRAs), tuning sharpness, and gap detection to tone bursts and silent gaps embedded in broadband noise. We were interested in determining if the moderate to severe sensorineural hearing loss associated with the loss of motor protein prestin would also impair auditory midbrain temporal-processing measures, or if compensatory mechanisms within the brainstem could compensate for the loss of prestin. In prestin knockout mice we observed that there are severe impairments in midbrain tuning, thresholds, excitatory drive, and gap detection suggesting that brainstem and midbrain processing could not overcome the auditory processing deficits afforded by the loss of OHC electromotility mediated by the prestin protein.
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Calcitonin gene-related peptide (CGRP) is a neuroactive peptide that is thought to play a role at efferent synapses in hair cell organs including the cochlea, lateral line, and semicircular canal. The deletion of CGRP in transgenic mice is associated with a significant reduction in suprathreshold cochlear nerve activity and vestibulo-ocular reflex (VOR) gain efficacy when compared to littermate controls. Here we asked whether the loss of CGRP also influences otolithic end organ function and contributes to balance impairments. Immunostaining for CGRP was absent in the otolithic end organs of αCGRP null (-/-) mice while choline acetyltransferase (ChAT) immunolabeling appeared unchanged suggesting the overall gross development of efferent innervation in otolithic organs was unaltered. Otolithic function was assessed by quantifying the thresholds, suprathreshold amplitudes, and latencies of vestibular sensory-evoked potentials (VsEPs) while general balance function was assessed using a modified rotarod assay. The loss of αCGRP in null (-/-) mice was associated with: (1) shorter VsEP latencies without a concomitant change in amplitude or thresholds, and (2) deficits in the rotarod balance assay. Our findings show that CGRP loss results in faster otolith afferent activation timing, suggesting that the CGRP component of the efferent vestibular system (EVS) also plays a role in otolithic organ dynamics, which when coupled with reduced VOR gain efficacy, impairs balance.
RESUMEN
Approximately 15% of American adults report some degree of difficulty hearing in a noisy environment or have auditory filtering difficulties. There are objective clinical tests of auditory filtering, yet few tests exist for mouse models that do not rely on extensive training. We have used reflex modification audiometry (RMA) and developed exclusion criteria for the mouse model. This RMA based test makes use of the acoustic startle response (ASR) and the ability of prepulses to inhibit the ASR [i.e., prepulse inhibition (PPI)] to assess the mouse's ability to detect prepulse signals presented in quiet or embedded in masking noise. We have studied PPI behavior across four inbred mouse strains with normal cochlear function and developed pre-testing exclusion criteria and test/retest reliability measures. Moreover, because both the medial (MOC) and the lateral (LOC) olivocochlear efferent feedback systems have been proposed to improve auditory behavior performance, especially in noisy backgrounds, we have examined PPI abilities in mice (with their littermate controls) either lacking the MOC receptor subunit α9 nicotinic acetylcholine receptor [α9 nAChR (-/-)] or expressing an overactive receptor [Ld'T mutation in α9 nAChR KI], or lacking an LOC efferent neuropeptide, alpha calcitonin gene-related peptide [αCGRP (-/-)] only in the CNS. Because CGRP receptor formation has been shown to mature from juvenile to adult ages, we also studied if this maturation would be reflected in PPI behavioral responses in juvenile and adult (+/+) controls and in adult αCGRP (-/-) animals. We show that 50% PPI response thresholds (sound level with 50% correct responses) in quiet are decreased in the (-/-) α9 nAChR animals, and 50% PPI responses are increased for mice with an overactive receptor (α9 nAChR KI) and are increased in adult mice lacking αCGRP (-/-). However, in background noise, only mice lacking αCGRP exhibited increased 50% PPI response thresholds, as there were no significant differences between α9 nAChR adult mouse lines and their littermate controls. These findings suggest that MOC and LOC olivocochlear neurotransmission work in tandem to improve behavioral responses to sound. These experiments further pave the way for rapid behavioral hearing assessments in other mouse models.
RESUMEN
Autism spectrum disorder (ASD) is a behaviorally diagnosed disorder of early onset characterized by impairment in social communication and restricted and repetitive behaviors. Some of the earliest signs of ASD involve auditory processing, and a recent study found that hearing thresholds in children with ASD in the mid-range frequencies were significantly related to receptive and expressive language measures. In addition, otoacoustic emissions have been used to detect reduced cochlear function in the presence of normal audiometric thresholds. We were interested then to know if otoacoustic emissions in children with normal audiometric thresholds would also reveal differences between children with ASD and typical developing (TD) controls in mid-frequency regions. Our objective was to specifically measure baseline afferent otoacoustic emissions (distortion-product otoacoustic emissions [DPOAEs]), transient-evoked otoacoustic emissions (TrOAEs), and efferent suppression, in 35 children with high-functioning ASD compared with 42 aged-matched TD controls. All participants were males 6-17 years old, with normal audiometry, and rigorously characterized via Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Children with ASD had greatly reduced DPOAE responses in the 1 kHz frequency range, yet had comparable DPOAE responses at 0.5 and 4-8 kHz regions. Furthermore, analysis of the spectral features of TrOAEs revealed significantly decreased emissions in ASD in similar frequencies. No significant differences were noted in DPOAE or TrOAE noise floors, middle ear muscle reflex activity, or efferent suppression between children with ASD and TD controls. In conclusion, attention to specific-frequency deficits using non-invasive measures of cochlear function may be important in auditory processing impairments found in ASD. Autism Res 2017, 10: 337-345. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Asunto(s)
Umbral Auditivo/fisiología , Trastorno del Espectro Autista/fisiopatología , Emisiones Otoacústicas Espontáneas/fisiología , Adolescente , Niño , Humanos , Lenguaje , MasculinoRESUMEN
In adult animals, the neuropeptide calcitonin gene-related peptide (CGRP) is contained in cochlear efferent fibers projecting out to the cochlea, and contributes to increased suprathreshold sound-evoked activity in the adult auditory nerve. Similarly, CGRP applied to the lateral-line organ (hair cell organ) increases afferent nerve activity in adult frogs (post-metamorphic day 30), yet this increase is developmentally delayed from post-metamorphic day 4-30. In this study, we discovered that there was also a developmental delay in increased suprathreshold sound-evoked activity auditory nerve between juvenile and adult mice similar to what had been observed previously in frog. Moreover, juvenile mice with a targeted deletion of the αCGRP gene [CGRP null (-/-)] did not show a similar developmental increase in nerve activity, suggesting CGRP signaling is involved. This developmental delay is not due to a delay in CGRP expression, but instead is due to a delay in receptor formation. We observed that the increase in sound-evoked nerve activity is correlated with increased formation of cochlear CGRP receptors, which require three complexed proteins (CLR, RAMP1, RCP) to be functional. CGRP receptor formation in the cochlea was incomplete at 1 month of age (juvenile), but complete by 3 months (adult), which corresponded to the onset of suprathreshold enhancement of sound-evoked activity in wild-type animals. Taken together, these data support a model for cochlear function that is enhanced by maturation of CGRP receptor complexes.
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Umbral Auditivo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Cóclea/inervación , Nervio Coclear/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Estimulación Acústica , Factores de Edad , Animales , Péptido Relacionado con Gen de Calcitonina/deficiencia , Péptido Relacionado con Gen de Calcitonina/genética , Proteína Similar al Receptor de Calcitonina/metabolismo , Cóclea/crecimiento & desarrollo , Cóclea/metabolismo , Nervio Coclear/crecimiento & desarrollo , Genotipo , Ratones de la Cepa 129 , Ratones Noqueados , Complejos Multiproteicos , Fenotipo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismoRESUMEN
2,3,7,8-tetrachorodibenzo-p-dioxin (TCDD), a ubiquitous and persistent environmental contaminant, is a potent teratogen. Whereas developmental TCDD toxicity is mediated by the aryl hydrocarbon receptor (AhR), the normal function of the AhR is poorly understood. We tested whether dioxin exposure during a critical period of hair cell development disrupts cochlear function in three mouse strains, (C57BL6, BalbC, and CBA) that contain high affinity AhR-b alleles. C57BL/6, BalbC, and CBA dams were exposed to 500 ng/kg TCDD or olive oil (vehicle) on embryonic day 12 by gavage. Cochlear function was analyzed at 1.5 months of age by measuring 1) auditory brainstem response (ABRs) to tone pips from 5.6 to 30 kHz, and 2) distortion-product otoacoustic emissions (DPOAEs) evoked by primaries with f2 at the same frequency values. Cochlear threshold sensitivity following TCDD exposure was significantly elevated in both female and male mice in the C57BL/6 strain, carrying the Ahb-1 allele, but not significantly elevated in the BalbC or CBA strains, carrying the Ahb-2 allele. These ABR threshold deficits in mice carrying the Ahb-1 allele parallels the cleft palate incidence to higher TCDD exposures, suggesting that ABR testing could serve as a sensitive indicator of TCDD toxicity in at-risk children. Moreover, DPOAEs were not affected following TCDD exposure in any of the mouse strains, suggesting that following TCDD exposure mice with the Ahb-1 allele exhibit a mild auditory neuropathy. The causes of many auditory neuropathies are unknown, yet a developmental exposure to dioxin may be a risk factor for this condition.
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Cóclea/efectos de los fármacos , Pérdida Auditiva Central/inducido químicamente , Pérdida Auditiva Central/fisiopatología , Exposición Materna/efectos adversos , Dibenzodioxinas Policloradas/efectos adversos , Alelos , Animales , Cóclea/fisiología , Dioxinas/química , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Hidrocarburos/química , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Emisiones Otoacústicas Espontáneas , Embarazo , Preñez , Receptores de Hidrocarburo de Aril/genética , Factores de Riesgo , TeratógenosRESUMEN
Cochlear damage caused by loud sounds can be attenuated by "sound-conditioning" methods. The amount of adaptation for distortion product otoacoustic emissions (DPOAEs) measured in alert rabbits previously predicted an ear's susceptibility to a subsequent noise exposure. The present study investigated if sound-conditioning influenced the robustness of such DPOAE adaptation, and if such conditioning elicited more protection by increasing the amount of DPOAE adaptation. Toward this end, rabbits were divided into two study groups: (1) experimental animals exposed to a sound-conditioning protocol, and (2) unconditioned control animals. After base-line measures, all rabbits were exposed to an overstimulation paradigm consisting of an octave band noise, and then re-assessed 3 weeks post-exposure to determine permanent changes in DPOAEs. A major result was that prior sound-conditioning protected reductions in DPOAE levels by an average of 10-15 dB. However, DPOAE adaptation decreased with sound-conditioning, so that such conditioning was no longer related to noise-induced reductions in DPOAEs. Together, these findings suggest that sound-conditioning affected neural pathways other than those that likely mediate DPOAE adaptation (e.g., medial olivocochlear efferent and/or middle-ear muscle reflexes).
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Adaptación Fisiológica/fisiología , Ruido , Emisiones Otoacústicas Espontáneas/fisiología , Distorsión de la Percepción/fisiología , Animales , Cóclea/fisiología , Condicionamiento Psicológico , Femenino , Masculino , Percepción de la Altura Tonal/fisiología , Conejos , Reflejo Acústico/fisiologíaRESUMEN
A noninvasive test was developed in rabbits based on fast adaptation measures for 2f1-f2 distortion-product otoacoustic emissions (DPOAEs). The goal was to evaluate the effective reflex activation, i.e., "functional strength," of both the descending medial olivocochlear efferent reflex (MOC-R) and the middle-ear muscle reflex (MEM-R) through sound activation. Classically, it is assumed that both reflexes contribute toward protecting the inner ear from cochlear damage caused by noise exposure. The DP-gram method described here evaluated the MOC-R effect on DPOAE levels over a two-octave (oct) frequency range. To estimate the related activation of the middle-ear muscles (MEMs), the MEM-R was measured by monitoring the level of the f1-primary tone throughout its duration. Following baseline measures, rabbits were subjected to noise over-exposure. A main finding was that the measured adaptive activity was highly variable between rabbits but less so between the ears of the same animal. Also, together, the MOC-R and MEM-R tests showed that, on average, DPOAE adaptation consisted of a combined contribution from both systems. Despite this shared involvement, the amount of DPOAE adaptation measured for a particular animal's ear predicted that ear's subsequent susceptibility to the noise over-exposure for alert but not for deeply anesthetized rabbits.
Asunto(s)
Nivel de Alerta , Vías Auditivas/fisiología , Cóclea/inervación , Oído Medio/inervación , Ruido/efectos adversos , Núcleo Olivar/fisiología , Emisiones Otoacústicas Espontáneas , Reflejo Acústico , Estimulación Acústica , Animales , Fatiga Auditiva , Retroalimentación Psicológica , Conejos , Factores de TiempoRESUMEN
The neuroactive peptide calcitonin-gene related peptide (CGRP) is known to act at efferent synapses and their targets in hair cell organs, including the cochlea and lateral line. CGRP is also expressed in vestibular efferent neurons as well as a number of central vestibular neurons. Although CGRP-null (-/-) mice demonstrate a significant reduction in cochlear nerve sound-evoked activity compared with wild-type mice, it is unknown whether and how the loss of CGRP influence vestibular system function. Vestibular function was assessed by quantifying the vestibulo-ocular reflex (VOR) in alert mice. The loss of CGRP in (-/-) mice was associated with a reduction of the VOR gain of ≈50% without a concomitant change in phase. Using immunohistochemistry, we confirmed that, although CGRP staining was absent in the vestibular end-organs of null (-/-) mice, cholinergic staining appeared normal, suggesting that the overall gross development of vestibular efferent innervation was unaltered. We further confirmed that the observed deficit in vestibular function of null (-/-) mice was not the result of nontargeted effects at the level of the extraocular motor neurons and/or their innervation of extraocular muscles. Analysis of the relationship between vestibular quick phase amplitude and peak velocity revealed that extraocular motor function was unchanged, and immunohistochemistry revealed no abnormalities in motor endplates. Together, our findings show that the neurotransmitter CGRP plays a key role in ensuring VOR efficacy.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/deficiencia , Reflejo Vestibuloocular/genética , Análisis de Varianza , Animales , Toxinas Botulínicas Tipo A/metabolismo , Calbindina 2/metabolismo , Péptido Relacionado con Gen de Calcitonina/genética , Colina O-Acetiltransferasa/metabolismo , Movimientos Oculares/genética , Femenino , Regulación de la Expresión Génica/genética , Masculino , Ratones , Ratones Noqueados , Miosina VIIa , Miosinas/metabolismo , Vestíbulo del Laberinto/metabolismoRESUMEN
It is well acknowledged from observations in humans that iron deficiency during pregnancy can be associated with a number of developmental problems in the newborn and developing child. Due to the obvious limitations of human studies, the stage during gestation at which maternal iron deficiency causes an apparent impairment in the offspring remains elusive. In order to begin to understand the time window(s) during pregnancy that is/are especially susceptible to suboptimal iron levels, which may result in negative effects on the development of the fetus, we developed a rat model in which we were able to manipulate and monitor the dietary iron intake during specific stages of pregnancy and analyzed the developing fetuses. We established four different dietary-feeding protocols that were designed to render the fetuses iron deficient at different gestational stages. Based on a functional analysis that employed Auditory Brainstem Response measurements, we found that maternal iron restriction initiated prior to conception and during the first trimester were associated with profound changes in the developing fetus compared to iron restriction initiated later in pregnancy. We also showed that the presence of iron deficiency anemia, low body weight, and changes in core body temperature were not defining factors in the establishment of neural impairment in the rodent offspring.Our data may have significant relevance for understanding the impact of suboptimal iron levels during pregnancy not only on the mother but also on the developing fetus and hence might lead to a more informed timing of iron supplementation during pregnancy.