Biomedical subjects

Timothy A Jones

Publications and source records attributed to Timothy A Jones.

13 recordsLinked to original sources

PubMed2006

Afferent synapses are present in utricular hair cells from otoconia-deficient mice.

The head tilt mouse (het/het, abbr. het) is a naturally occurring mutant whose salient phenotypic traits include the complete absence of otoconia in both the utricle and saccule. Cursory histologic evaluation has indicated that the neuroepithelia exhibit a normal appearance. Though evidence exists indicating that utricular function is severely if not completely compromised in these animals, it is not yet known whether afferent synapses exist within utricular hair cells of otoconia-deficient mutants. The absence of synapses would be suggestive of a trophic relationship between stimulus-evoked hair cell activation and the afferent synapse. To address this question, we have conducted an ultrastructural survey of utricular sensory epithelia from confirmed het mice. The specific objective was to determine whether utricular hair cells made synaptic contact with afferent neurons. We found that both type I and II hair cells from utricles of het mice exhibited afferent synapses that were found at numerous sites distributed throughout the utricle. These results indicate that afferent synapses within vestibular hair cells do not critically depend upon stimulus-evoked activity.

Animals↗

PubMed2006

Emergence of hearing in the chicken embryo.

It is commonly held that hearing generally begins on incubation day 12 (E12) in the chicken embryo (Gallus domesticus). However, little is known about the response properties of cochlear ganglion neurons for ages younger than E18. We studied ganglion neurons innervating the basilar papilla of embryos (E12-E18) and hatchlings (P13-P15). We asked first, when do primary afferent neurons begin to encode sounds? Second, when do afferents evidence frequency selectivity? Third, what range of characteristic frequencies (CFs) is represented in the late embryo? Finally, how does sound transfer from air to the cochlea affect responses in the embryo and hatchling? Responses to airborne sound were compared with responses to direct columella footplate stimulation of the cochlea. Cochlear ganglion neurons exhibited a profound insensitivity to sound from E12 to E16 (stages 39-42). Responses to sound and frequency selectivity emerged at about E15. Frequency selectivity matured rapidly from E16 to E18 (stages 42 and 44) to reflect a mature range of CFs (170-4,478 Hz) and response sensitivity to footplate stimulation. Limited high-frequency sound transfer from air to the cochlea restricted the response to airborne sound in the late embryo. Two periods of ontogeny are proposed. First is a prehearing period (roughly E12-E16) of endogenous cochlear signaling that provides neurotrophic support and guides normal developmental refinements in central binaural processing pathways followed by a period (roughly E16-E19) wherein the cochlea begins to detect and encode sound.

Afferent Pathways↗

PubMed2006

A comparison of vestibular and auditory phenotypes in inbred mouse strains.

The purposes of this research were to quantify gravity receptor function in inbred mouse strains and compare vestibular and auditory function for strain- and age-matched animals. Vestibular evoked potentials (VsEPs) were collected for 19 inbred strains at ages from 35 to 389 days old. On average, C57BL/6J (35 to 190 days), BALB/cByJ, C3H/HeSnJ, CBA/J, and young LP/J mice had VsEP thresholds comparable to normal. Elevated VsEP thresholds were found for elderly C57BL/6J, NOD.NONH2(kb), BUB/BnJ, A/J, DBA/2J, NOD/LtJ, A/WySnJ, MRL/MpJ, A/HeJ, CAST/Ei, SJL/J, elderly LP/J, and CE/J. These results suggest that otolithic function varies among inbred strains and several strains displayed gravity receptor deficits by 90 days old. Auditory brainstem response (ABR) thresholds were compared to VsEP thresholds for 14 age-matched strains. C57BL/6J mice (up to 190 days) showed normal VsEPs with normal to mildly elevated ABR thresholds. Four strains (BUB/BnJ, NOD/LtJ, A/J, elderly LP/J) had significant hearing loss and elevated VsEP thresholds. Four strains (DBA/2J, A/WySnJ, NOD.NONH2(kb), A/HeJ) had elevated VsEP thresholds (including absent VsEPs) with mild to moderate elevations in ABR thresholds. Three strains (MRL/MpJ, Ce/J, SJL/J) had significant vestibular loss with no concomitant hearing loss. These results suggest that functional change in one sensory system does not obligate change in the other. We hypothesize that genes responsible for early onset hearing loss may affect otolithic function, yet the time course of functional change may vary. In addition, some genetic mutations may produce primarily gravity receptor deficits. Potential genes responsible for selective gravity receptor impairment demonstrated herein remain to be identified.

Age Factors↗

PubMed2006

Columella footplate motion and the cochlear microphonic potential in the embryo and hatchling chicken.

A piezoelectric (PZE) vibrator was used to mechanically drive the columella footplate and stimulate the cochlea of chicken embryos and hatchlings. Our objectives were to characterize the motion of the PZE driver and determine the relationship between columella footplate motion (displacement/ velocity) and the cochlear microphonic recorded from the recessus scala tympani (CMrst). At each frequency, displacement of the PZE driver probe tip was linearly related to the applied voltage over a wide range of attenuation levels (-60 to -20 dBre:50 Vp-p). The mean displacement across frequencies (100-4000 Hz) was 0.221+/-0.042 micromp-p for a constant applied voltage level of -20 dBre:50 Vp-p. Displacement was within 1.5 dB of the mean for this stimulus level at all frequencies except for 4000 Hz, where it was approximately 3 dB higher (p < 0.01). CMrst amplitudes in hatchlings were larger than amplitudes in embryos (p=0.003). For a given frequency, CM was linearly related to footplate displacement and velocity at both ages. The transform ratio of CMrst/A (CM amplitude/displacement) increased at approximately 6 dB/octave at frequencies between 100 and 1000 Hz in hatchlings suggesting that cochlear impedance (Zc) was resistive at these frequencies. In a large fraction of the embryos, Zc exhibited reactive behavior.

Animals↗

PubMed2005

A quantitative survey of gravity receptor function in mutant mouse strains.

The purpose of this research was to identify vestibular deficits in mice using linear vestibular evoked potentials (VsEPs). VsEP thresholds, peak latencies, and peak amplitudes from 24 strains with known genetic mutations and 6 inbred background strains were analyzed and descriptive statistics generated for each strain. Response parameters from mutant homozygotes were compared with heterozygote and/or background controls and all strain averages were contrasted to normative ranges. Homozygotes of the following recessive mutations had absent VsEPs at the ages tested: Espn(je), Atp2b2dfw-2J, Spnb4qv-lnd2J, Spnb4qv-3J, Myo7ash1, Tmie(sr), Myo6sv, jc, Pcdh15av-J, Pcdh15av-2J, Pcdh15av-3J, Cdh23v-2J, Sans(js), hr, Kcne1pkr and Pou3f4del. These results suggest profound gravity receptor deficits for these homozygotes, which is consistent with the structural deficits that have been documented for many of these strains. Homozygotes of Catna2cdf, Grid2ho4J, Wnt1sw, qk, and Mbpshi strains and heterozygotes of Grid2lc had measurable VsEPs but one or more response parameters differed from the respective control group (heterozygote or background strain) or were outside normal ranges. For example, qk and Mbpshi homozygotes showed significantly prolonged latencies consistent with the abnormal myelin that has been described for these strains. Prolonged latencies may suggest deficits in neural conduction; elevated thresholds suggest reduced sensitivity, and reduced amplitudes may be suggestive for reduced neural synchrony. One mutation, Otx1jv, had all VsEP response parameters within normal limits--an expected finding because the abnormality in Otxljv is presumably restricted to the lateral semicircular canal. Interestingly, some heterozygote groups also showed abnormalities in one or more VsEP response parameters, suggesting that vestibular dysfunction, although less severe, may be present in some heterozygous animals.

Animals↗

PubMed2004

Diminished baroreflex control of heart rate responses in otoconia-deficient C57BL/6JEi head tilt mice.

The maintenance of stable blood pressure during postural changes is known to involve integration of vestibular and cardiovascular central regulatory mechanisms. Sensory activity in the vestibular system plays an important role in cardiovascular regulation. The purpose of this study was to determine the role of vestibular gravity receptors in normal baroreflex function. Baroreflex heart rate (HR) responses to changes in blood pressure (BP) in otoconia-deficient head tilt (het) mice (n = 8) were compared with their wild-type littermates (n = 12). The study was carried out in conscious male mice chronically implanted with arterial and venous catheters for recording BP and HR and for the infusion of vasoactive drugs. Resting HR was higher in the het mice (661 +/- 13 beats/min) than in the wild-type mice (579 +/- 20 beats/min). BP was comparable in the het (113 +/- 4 mmHg) and wild-type mice (104 +/- 4 mmHg). The slopes of reflex decreases in HR in response to phenylephrine (PE) were blunted in the het mice (-5.5 +/- 1.5 beats x min(-1) x mmHg(-1)) compared with the wild-type mice (-8.5 +/- 0.9 beats x min(-1) x mmHg(-1)). Likewise, reflex tachycardic responses to decreases in BP with sodium nitroprusside (SNP) were significantly blunted in the het mice (-0.8 +/- 0.3 beats x min(-1) x mmHg(-1)) versus the wild-type mice (-2.2 +/- 0.6 beats x min(-1) x mmHg(-1)). Frequency-domain analysis of the HR variability suggests that under resting conditions, parasympathetic contribution was lower in the het versus wild-type mice. Mapping of the expression of immediate-early gene product, c-Fos, in forebrain and brain stem nuclei in response to a BP challenge showed no differences between the wild-type and het mice. These results suggest that tonic activity of gravity receptors modulates and is required for normal function of the cardiac baroreflexes.

Animals↗

PubMed2004

Gravity receptor function in mice with graded otoconial deficiencies.

The purpose of the present study was to examine gravity receptor function in mutant mouse strains with variable deficits in otoconia: lethal milk (lm), pallid (pa), tilted (tlt), mocha (mh), and muted (mu). Control animals were either age-matched heterozygotes or C57BL/6J (abbr. B6) mice. Gravity receptor function was measured using linear vestibular evoked potentials (VsEPs). Cage and swimming behaviors were also documented. Temporal bones were cleared to assess the overall otoconial deficit and to correlate structure and function for lm mice. Results confirmed the absence of VsEPs for mice that lacked otoconia completely. VsEP thresholds and amplitudes varied in mouse strains with variable loss of otoconia. Some heterozygotes also showed elevated VsEP thresholds in comparison to B6 mice. In lm mice, which have absent otoconia in the utricle and a variable loss of otoconia in the saccule, VsEPs were present and average P1/N1 amplitudes were highly correlated with the average loss of saccular otoconia (R = 0.77,p < 0.001). Cage and swimming behavior were not adversely affected in those animals with recordable VsEPs. Most, but not all, mice with absent VsEPs were unable to swim. Some animals were able to swim despite having no measurable gravity receptor response. The latter finding underscores the remarkable adaptive potential exhibited by neurobehavioral systems following profound sensory loss. It also shows that behavior alone may be an unreliable indicator of the extent of gravity receptor deficits.

Animals↗

PubMed2004

Effects of selected pharmacological agents on avian auditory and vestibular compound action potentials.

Glutamate is currently the consensus candidate for the hair cell transmitter in the inner ear of vertebrates. However, other candidate transmitter systems have been proposed and there may be differences in this regard for auditory and vestibular neuroepithelia. In the present study, perilymphatic perfusion was used to deliver prescribed concentrations of ten drugs to the interstitial fluids of the inner ear of hatchling chickens (n = 124). Dose-response curves were obtained for four of these pharmacological agents. The work was carried out in part to distinguish further the neuroepithelial chemical receptors mediating auditory and vestibular compound action potentials (CAPs). Kainic acid (KA) eliminated both auditory and vestibular responses. D-alpha-Aminoadipic acid (DAA) and dizocilpine maleate (MK-801), both NMDA-specific antagonists, failed to alter vestibular CAPs at any concentration. MK-801 significantly and selectively reduced auditory CAPs at concentrations equal to or greater than 1 mM. Similarly, kynurenic acid (4-hydroxyquinoline-2-carboxylic acid, 1 mM), a glutamate antagonist, significantly reduced auditory but not vestibular CAPs. A non-NMDA glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), reduced vestibular CAPs significantly but only at the highest concentration tested (1 mM). In contrast, CNQX reduced auditory responses at concentration as low as 1 microM. The CNQX concentration effective in reducing auditory CAPs by 50% (EC(50)) was approximately 20 microM. Glutamate (1 mM) as well as alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), a glutamate agonist, significantly reduced auditory CAPs (AMPA EC(50)=100 microM). Bicuculline, a GABA(A) receptor antagonist, and L-NAME, a nitric oxide synthase inhibitor, failed to alter responses from either modality. These findings support the hypothesis that glutamate receptors mediate auditory CAPs in birds. However, the results underscore a remarkable difference in sensitivity of the vestibular neuroepithelium (here gravity receptors) to non-NMDA receptor antagonists. The basis of the vestibular insensitivity to glutamate blockers is unknown but it may reflect differences in receptors themselves, differences in the transmission modes available to vestibular synapses or differences in the access of compounds to vestibular neuroepithelial receptors from the interstitial-perilymphatic fluid spaces.

Action Potentials↗

PubMed2003

The simultaneous in vivo perilymphatic perfusion of avian auditory and vestibular end organs.

Perilymphatic perfusion is a method that allows the control of fluid parameters throughout the perilymphatic space of the inner ear. We have evaluated a new method for continuous perilymphatic perfusion of the auditory and vestibular end organs with artificial perilymph (APL) in chickens. Perfusate temperature (39.0 degrees C), pH (7.4), osmolarity (328 +/- 2 mosm), and flow rate (2 microl/min) were carefully controlled. Independent functional tests of vestibular and auditory sensory systems were made throughout perfusion periods by recording peripheral compound action potentials (CAPs). The recordings provided a means of monitoring the status of hair cell transduction, synaptic transmission and collective primary afferent activation in response to auditory or vestibular gravity receptor stimuli. Auditory and vestibular responses were stable during perfusion. No significant changes occurred in vestibular or auditory CAP amplitudes during long-term perfusion (50-80 min, n=7) and responses remained stable in one animal perfused for over 3 h. To our knowledge, there have been no reports evaluating vestibular function under these conditions. This technique enables us to systematically study receptor pharmacology in the peripheral vestibular and auditory systems virtually simultaneously in vivo. The model is well suited for use in the study of the pharmacology and toxicology of inner ear sensory systems.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

Malleal processus brevis is dispensable for normal hearing in mice.

The mammalian middle ear cavity contains a chain of three ossicles (the malleus, incus, and stapes), which develop from the mesenchyme of the first two branchial arches. Mice deficient in the Msx1 homeobox gene exhibit craniofacial abnormalities, including the absence of the malleal processus brevis that is normally attached to the upper part of the tympanic membrane. Here, we show that the expression of Msx1 and Msx2 overlaps in the malleal primordium during early embryonic development. A functional redundancy of Msx1 and Msx2 in the development of the middle ear is suggested by the stronger hypomorphism in the malleus of Msx1(-/-)/Msx2(-/-) embryos, including the absence of the malleal manubrium and the malleal processus brevis. The expression of Bmp4, a known downstream target of Msx1 in several developing craniofacial organs, was down-regulated in the malleal primordium, particularly in the region of the developing malleal manubrium, of Msx1 and Msx1(-/-)/Msx2(-/-) embryos. Msx genes, thus, appear to act in a cell autonomous manner, possibly by regulating Bmp4 expression, in the formation of the malleus. Transgenic rescue of the cleft palate of Msx1(-/-) mice overcame the neonatal lethality and allowed Msx1(-/-) mice to grow into adulthood but retain the phenotype of the absence of the malleal processus brevis. The availability of this animal model for the first time allowed us to measure auditory evoked potentials to assess the functional significance of the malleal processus brevis. The results demonstrated unimpaired auditory function in Msx1(-/-) mice. In addition, mutant mice appeared normal in balance behavior and in the vestibular evoked potential screening test. These results indicate that the malleal processus brevis is not necessary for sound transmission and seems dispensable for normal hearing and balance in mammals.

Animals↗

PubMed2003

An evaluation of the histological effects of intra-articular methadone in the canine model.

Methadone hydrochloride is an opiate that has pharmacodynamic and pharmacokinetic properties that suggest it may provide longer analgesia than morphine when administered via the intra-articular route. However, no studies to date have been conducted examining the effects of intra-articular methadone hydrochloride on local tissues. Therefore, the purpose of this study was to determine the histopathologic effects of intra-articular methadone hydrochloride on local tissues in the canine knee. Nine canines, 1 to 4 years old, weighing between 20 kg and 23 kg were used. All canines had their knees randomized to receive either bupivacaine, 0.5% with epinephrine 1:200,000 (4.5 mL), and 5 mg methadone hydrochloride (0.5 mL) for the study knee, or bupivacaine, 0.5% with epinephrine 1:200,000 (4.5 mL), and 0.5 mL normal saline for the control knee. Serum methadone hydrochloride levels were obtained on all canines at 6 and 24 hours. Canines were randomly assigned to 1 of 3 groups to be euthanized at either 24 hours, 14 days, or 28 days. Following euthanization and necropsy, synovial fluid levels and tissue samples were obtained and examined for histopathologic changes. Synovial fluid samples noted a few white blood cells at 24 hours and none at 14 and 28 days. Tissue samples showed no histopathologic changes, and serum concentration levels of methadone hydrochloride were negligible.

Analgesics, Opioid↗

PubMed2002

Neurovestibular modulation of circadian and homeostatic regulation: vestibulohypothalamic connection?

Chronic exposure to increased force environments (+G) has pronounced effects on the circadian and homeostatic regulation of body temperature (T(b)), ambulatory activity (Act), heart rate, feeding, and adiposity. By using the Brn 3.1 knockout mouse, which lacks vestibular hair cells, we recently described a major role of the vestibular system in mediating some of these adaptive responses. The present study used the C57BL6JEi-het mouse strain (het), which lacks macular otoconia, to elucidate the contribution of specific vestibular receptors. In this study, eight het and eight WT mice were exposed to 2G for 8 weeks by means of chronic centrifugation. In addition, eight het and eight WT mice were maintained as 1G controls in similar conditions. Upon 2G exposure, the WT exhibited a decrease in T(b) and an attenuated T(b) circadian rhythm. Act means and rhythms also were attenuated. Body mass and food intake were significantly lower than the 1G controls. After 8 weeks, percent body fat was significantly lower in the WT mice (P < 0.0001). In contrast, the het mice did not exhibit a decrease in mean T(b) and only a slight decrease in T(b) circadian amplitude. het Act levels were attenuated similarly to the WT mice. Body mass and food intake were only slightly attenuated in the het mice, and percent body fat, after 8 weeks, was not different in the 2G het group. These results link the vestibular macular receptors with specific alterations in homeostatic and circadian regulation.

Acceleration↗

PubMed2002

Stimulus and recording variables and their effects on mammalian vestibular evoked potentials.

Linear vestibular evoked potentials (VsEPs) measure the collective neural activity of the gravity receptor organs in the inner ear that respond to linear acceleration transients. The present study examined the effects of electrode placement, analog filtering, stimulus polarity and stimulus rate on linear VsEP thresholds, latencies and amplitudes recorded from mice. Two electrode-recording montages were evaluated, rostral (forebrain) to 'mastoid' and caudal (cerebellum) to 'mastoid'. VsEP thresholds and peak latencies were identical between the two recording sites; however, peak amplitudes were larger for the caudal recording montage. VsEPs were also affected by filtering. Results suggest optimum high pass filter cutoff at 100-300 Hz, and low pass filter cutoff at 10,000 Hz. To evaluate stimulus rate, linear jerk pulses were presented at 9.2, 16, 25, 40 and 80 Hz. At 80 Hz, mean latencies were longer (0.350-0.450 ms) and mean amplitudes reduced (0.8-1.8 microV) for all response peaks. In 50% of animals, late peaks (P3, N3) disappeared at 80 Hz. The results offer options for VsEP recording protocols.

Animals↗