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1.
Neurobiol Aging ; 56: 87-99, 2017 08.
Article in English | MEDLINE | ID: mdl-28532644

ABSTRACT

A key feature of age-related hearing loss is a reduction in the expression of inhibitory neurotransmitters in the central auditory system. This loss is partially responsible for changes in central auditory processing, as inhibitory receptive fields play a critical role in shaping neural responses to sound stimuli. Vigabatrin (VGB), an antiepileptic agent that irreversibly inhibits γ-amino butyric acid (GABA) transaminase, leads to increased availability of GABA throughout the brain. This study used multi-channel electrophysiology measurements to assess the excitatory frequency response areas in old CBA mice to which VGB had been administered. We found a significant post-VGB reduction in the proportion of V-type shapes, and an increase in primary-like excitatory frequency response areas. There was also a significant increase in the mean maximum driven spike rates across the tonotopic frequency range of all treated animals, consistent with observations that GABA buildup within the central auditory system increases spike counts of neural receptive fields. This increased spiking is also seen in the rate-level functions and seems to explain the improved low-frequency thresholds.


Subject(s)
Aging/genetics , Aging/metabolism , Auditory Perception/genetics , Auditory Perception/physiology , Cochlear Nerve/metabolism , Mesencephalon/metabolism , Neurons/metabolism , gamma-Aminobutyric Acid/metabolism , 4-Aminobutyrate Transaminase/antagonists & inhibitors , 4-Aminobutyrate Transaminase/physiology , Acoustic Stimulation , Animals , Anticonvulsants/pharmacology , Cochlear Nerve/cytology , Female , Hearing Loss/etiology , Hearing Loss/genetics , Inferior Colliculi/metabolism , Male , Mice, Inbred CBA , Neural Inhibition/genetics , Neural Inhibition/physiology , Presbycusis/metabolism , Vigabatrin/pharmacology
2.
J Neurosci ; 37(7): 1873-1887, 2017 02 15.
Article in English | MEDLINE | ID: mdl-28093476

ABSTRACT

Stimulation of vestibular efferent neurons excites calyx and dimorphic (CD) afferents. This excitation consists of fast and slow components that differ >100-fold in activation kinetics and response duration. In the turtle, efferent-mediated fast excitation arises in CD afferents when the predominant efferent neurotransmitter acetylcholine (ACh) activates calyceal nicotinic ACh receptors (nAChRs); however, it is unclear whether the accompanying efferent-mediated slow excitation is also attributed to cholinergic mechanisms. To identify synaptic processes underlying efferent-mediated slow excitation, we recorded from CD afferents innervating the turtle posterior crista during electrical stimulation of efferent neurons, in combination with pharmacological probes and mechanical stimulation. Efferent-mediated slow excitation was unaffected by nAChR compounds that block efferent-mediated fast excitation, but were mimicked by muscarine and antagonized by atropine, indicating that it requires ACh and muscarinic ACh receptor (mAChR) activation. Efferent-mediated slow excitation or muscarine application enhanced the sensitivity of CD afferents to mechanical stimulation, suggesting that mAChR activation increases afferent input impedance by closing calyceal potassium channels. These observations were consistent with suppression of a muscarinic-sensitive K+-current, or M-current. Immunohistochemistry for putative M-current candidates suggested that turtle CD afferents express KCNQ3, KCNQ4, and ERG1-3 potassium channel subunits. KCNQ channels were favored as application of the selective antagonist XE991 mimicked and occluded efferent-mediated slow excitation in CD afferents. These data highlight an efferent-mediated mechanism for enhancing afferent sensitivity. They further suggest that the clinical effectiveness of mAChR antagonists in treating balance disorders may also target synaptic mechanisms in the vestibular periphery, and that KCNQ channel modulators might offer similar therapeutic value.SIGNIFICANCE STATEMENT Targeting the efferent vestibular system (EVS) pharmacologically might prove useful in ameliorating some forms of vestibular dysfunction by modifying ongoing primary vestibular input. EVS activation engages several kinetically distinct synaptic processes that profoundly alter the discharge rate and sensitivity of first-order vestibular neurons. Efferent-mediated slow excitation of vestibular afferents is of considerable interest given its ability to elevate afferent activity over an extended time course. We demonstrate for the first time that efferent-mediated slow excitation of vestibular afferents is mediated by muscarinic acetylcholine receptor (mAChR) activation and the subsequent closure of KCNQ potassium channels. The clinical effectiveness of some anti-mAChR drugs in treating motion sickness suggest that we may, in fact, already be targeting the peripheral EVS.


Subject(s)
Cholinergic Agents/pharmacology , Excitatory Postsynaptic Potentials/physiology , Neurons, Afferent/physiology , Neurons, Efferent/physiology , Receptors, Muscarinic/metabolism , Synaptic Transmission/physiology , Vestibule, Labyrinth/cytology , Analysis of Variance , Animals , Biophysics , Calbindin 2/metabolism , Electric Stimulation , Ether-A-Go-Go Potassium Channels/metabolism , Evoked Potentials/drug effects , Excitatory Postsynaptic Potentials/drug effects , Female , KCNQ Potassium Channels/metabolism , Male , Neural Pathways/physiology , Neurons, Afferent/drug effects , Neurons, Efferent/drug effects , Patch-Clamp Techniques , Synaptic Transmission/drug effects , Turtles
3.
Neurobiol Aging ; 32(1): 168-78, 2011 Jan.
Article in English | MEDLINE | ID: mdl-19246123

ABSTRACT

Reduced frequency selectivity is associated with an age-related decline in speech recognition in background noise and reverberant environments. To elucidate neural correlates of age-related alteration in frequency selectivity, the present study examined frequency response areas (FRAs) of multi-unit clusters in the inferior colliculus of young, middle-aged, and old CBA/CaJ mice. The FRAs in middle-aged and old mice were found to be broader and more asymmetric in shape. In addition to a decrease of closed/complex FRAs in both middle age and old groups, there was a transient decrease in V-shaped FRAs and a concomitant increase in multipeak FRAs in middle age. Intensity coding was also affected by age, as observed in an increase of monotonic responses in middle-aged and old mice. While a decline in low-level activity began in middle age, reduced driven rates at suprathreshold levels occurred later in old age. Collectively, these results support the view that aging alters frequency selectivity by widening excitatory FRAs and that these changes begin to appear in middle age.


Subject(s)
Aging , Evoked Potentials, Auditory/physiology , Inferior Colliculi/cytology , Inferior Colliculi/physiology , Neurons/physiology , Acoustic Stimulation/methods , Action Potentials/physiology , Age Factors , Animals , Auditory Threshold/physiology , Brain Mapping , Chi-Square Distribution , Mice , Mice, Inbred CBA , Psychoacoustics
4.
J Assoc Res Otolaryngol ; 9(1): 90-101, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17994264

ABSTRACT

Perception of complex sounds depends on the encoding of the dynamic and static structures within the ongoing stimulus by the auditory system. Aging has been associated with deficits in both areas, thus, the difficulty that the elderly have in speech comprehension could due to hearing loss, or to a loss of temporal sensitivity, or some combination of both. We investigated the effects of sensorineural hearing loss (SNHL) on neural correlates of temporal resolution by recording the responses of inferior colliculus neurons to a gap detection paradigm. We used C57BL/6 (C57) strain of laboratory mouse, which carries the Ahl deafness gene that initiates a progressive high frequency SNHL beginning at about 2 months of age and rapidly progresses to total deafness by 18 months. We compared gap encoding from inferior collicular neurons from young, normal-hearing C57 mice and middle-aged, hearing-impaired, C57 mice, quantifying minimal gap threshold, and recovery functions. The proportion of unit types, spontaneous rates and degree of monotonicity were comparable between young and middle-aged C57 mice. As expected, single unit thresholds were elevated by 30-40 dB in middle-aged C57 mice. However, no significant differences in mean minimal gap thresholds or in the slopes of the gap recovery functions were found between the two age groups. Thus, the results suggest that moderate high frequency SNHL does not affect temporal processing as measured by the gap detection paradigm.


Subject(s)
Aging/physiology , Hearing Loss, Sensorineural/physiopathology , Inferior Colliculi/physiopathology , Action Potentials , Animals , Auditory Perception/physiology , Mice , Mice, Inbred C57BL
5.
Neurobiol Aging ; 23(4): 565-78, 2002.
Article in English | MEDLINE | ID: mdl-12009506

ABSTRACT

Three experiments compared auditory temporal acuity in humans and in the behavior and single cells in the inferior colliculus (IC) of mice, to establish the comparability of aging effects on temporal acuity across species, and to suggest a neural foundation. The thresholds for silent gaps placed in white noise (MGTs) were similar in young mice and young humans, and increased in some but not all old humans and old mice. Neural MGT in the most sensitive cells of both young and old mice was comparable to behavioral MGT in the young of both species, but older mice had more cells with very high MGT. Human listeners were selected to have minimal absolute hearing loss. Older mice had significant hearing loss that was correlated with MGT in behavioral, but not in neural, measures. Some old mice and some old IC cells, however, had low MGTs coupled with elevated absolute hearing thresholds. Age-related changes in temporal acuity appear comparable in humans and mice. The data suggest a common deficit in neural mechanisms.


Subject(s)
Aging/psychology , Auditory Perception/physiology , Behavior, Animal/physiology , Neurons/physiology , Time Perception/physiology , Acoustic Stimulation , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Auditory Threshold/physiology , Evoked Potentials, Auditory/physiology , Female , Humans , Male , Mice , Mice, Inbred CBA , Middle Aged , Psychophysics , Species Specificity
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