Manfred Kössl

Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice

The transient receptor potential vanilloid type 1 channel (TRPV1) (formerly called vanilloid receptor VR1) is known for its key role of functions in sensory nerves such as perception of inflammatory and thermal pain. Much less is known about the physiological significance of the TRPV1 expression in the brain. Here we demonstrate that TRPV1 knock-out mice (TRPV1-KO) show less anxiety-related behavior in the light–dark test and in the elevated plus maze than their wild-type littermates with no differences in locomotion. Furthermore, TRPV1-KO mice showed less freezing to a tone after auditory fear conditioning and stress sensitization. This reduction of conditioned and sensitized fear could not be explained by alterations in nociception. Also, tone perception per se was unaffected, as revealed by determination of auditory thresholds through auditory brainstem responses and distortion-product otoacoustic emissions. TRPV1-KO showed also less contextual fear if assessed 1 d or 1 month after strong conditioning protocols. These impairments in hippocampus-dependent learning were mirrored by a decrease in long-term potentiation in the Schaffer collateral–commissural pathway to CA1 hippocampal neurons. Our data provide first evidence for fear-promoting effects of TRPV1 with respect to both innate and conditioned fear and for a decisive role of this receptor in synaptic plasticity.

A Targeted Deletion in α-Tectorin Reveals that the Tectorial Membrane Is Required for the Gain and Timing of Cochlear Feedback

alpha-tectorin is an extracellular matrix molecule of the inner ear. Mice homozygous for a targeted deletion in a-tectorin have tectorial membranes that are detached from the cochlear epithelium and lack all noncollagenous matrix, but the architecture of the organ of Corti is otherwise normal. The basilar membranes of wild-type and alpha-tectorin mutant mice are tuned, but the alpha-tectorin mutants are 35 dB less sensitive. Basilar membrane responses of wild-type mice exhibit a second resonance, indicating that the tectorial membrane provides an inertial mass against which outer hair cells can exert forces. Cochlear microphonics recorded in alpha-tectorin mutants differ in both phase and symmetry relative to those of wild-type mice. Thus, the tectorial membrane ensures that outer hair cells can effectively respond to basilar membrane motion and that feedback is delivered with the appropriate gain and timing required for amplification.

The functional role of GABA and glycine in monaural and binaural processing in the inferior colliculus of horseshoe bats

SummaryThe functional role of GABA and glycine in monaural and binaural signal analysis was studied in single unit recordings from the central nucleus of the inferior colliculus (IC) of horseshoe bats (Rhinolophus rouxi) employing microiontophoresis of the putative neurotransmitters and their antagonists bicuculline and strychnine.Most neurons were inhibited by GABA (98%; N=107) and glycine (92%; N=118). Both neurotransmitters appear involved in several functional contexts, but to different degrees.Bicuculline-induced increases of discharge activity (99% of cells; N=191) were accompanied by changes of temporal response patterns in 35% of neurons distributed throughout the IC. Strychnine enhanced activity in only 53% of neurons (N=147); cells exhibiting response pattern changes were rare (9%) and confined to greater recording depths. In individual cells, the effects of both antagonists could markedly differ, suggesting a differential supply by GABAergic and glycinergic networks.Bicuculline changed the shape of the excitatory tuning curve by antagonizing lateral inhibition at neighboring frequencies and/or inhibition at high stimulation levels. Such effects were rarely observed with strychnine.Binaural response properties of single units were influenced either by antagonization of inhibition mediated by ipsilateral stimulation (bicuculline) or by changing the strength of the main excitatory input (bicuculline and strychnine).

Correlating Stimulus-Specific Adaptation of Cortical Neurons and Local Field Potentials in the Awake Rat

Changes in the sensory environment are good indicators for behaviorally relevant events and strong triggers for the reallocation of attention. In the auditory domain, violations of a pattern of repetitive stimuli precipitate in the event-related potentials as mismatch negativity (MMN). Stimulus-specific adaptation (SSA) of single neurons in the auditory cortex has been proposed to be the cellular substrate of MMN (Nelken and Ulanovsky, 2007). However, until now, the existence of SSA in the awake auditory cortex has not been shown. In the present study, we recorded single and multiunits in parallel with evoked local field potentials (eLFPs) in the primary auditory cortex of the awake rat. Both neurons and eLFPs in the awake animal adapted in a stimulus-specific manner, and SSA was controlled by stimulus probability and frequency separation. SSA of isolated units was significant during the first stimulus-evoked “on” response but not in the following inhibition and rebound of activity. The eLFPs exhibited SSA in the first negative deflection and, to a lesser degree, in a slower positive deflection but no MMN. Spike adaptation correlated closely with adaptation of the fast negative deflection but not the positive deflection. Therefore, we conclude that single neurons in the auditory cortex of the awake rat adapt in a stimulus-specific manner and contribute to corresponding changes in eLFP but do not generate a late deviant response component directly equivalent to the human MMN. Nevertheless, the described effect may reflect a certain part of the process needed for sound discrimination.

The acoustic two-tone distortions 2f1-f2 and f2-f1 and their possible relation to changes in the operating point of the cochlear amplifier

Acoustic two-tone distortions are generated during non-linear mechanical amplification in the cochlea. Generation of the cubic distortion 2f1-f2 depends on asymmetric components of a non-linear transfer function whereas the difference tone f2-f1 relies on symmetric components. Therefore, a change of the operating point and hence the symmetry of the cochlear amplifier could be strongly reflected in the level of the f2-f1 distortion. To test this hypothesis, low-frequency tones (5 Hz) were used to bias the position of the cochlear partition in the gerbil. Phase-correlated changes of f2-f1 occurred at bias tone levels where there were almost no effects on 2f1-f2. Higher levels of the bias tone induced pronounced changes of both distortions. These results are qualitatively in good agreement with the results of a simulation in which the operating point of a Boltzman function was shifted. This function is similar to those used to describe outer hair cell (OHC) transduction. To influence OHC motility, salicylate was injected. It caused a decrease of the 2f1-f2 level and an increase in the level of f2-f1. Such reciprocal changes of both distortions, again, can be interpreted in terms of a shift of the operating point of the cochlear amplifier along a non-linear transfer characteristic. To directly influence the cochlear amplifier, DC current was injected into the scala media. Large negative currents (> -2 microA) caused a pronounced decrease of 2f1-f2 (> 15 dB) and positive currents had more complex effects with increasing and/or decreasing 2f1-f2 distortion level. The effects were time and primary level dependent. Changes of f2-f1 for DC currents > magnitude of mu 2A were in most cases larger compared to 2f1-f2 and reversed for certain primary levels. The current effects probably result from a combination of changing the endocochlear potential and shifting the operating point along a non-linear transfer function.

The cochlear frequency map of the mustache bat, Pteronotus parnellii.

SummaryThe frequency-place map of the cochlea of mustache bats was constructed by the analysis of HRP-transport patterns in spiral ganglion cells following iontophoretic tracer injections into cochlear nucleus regions responsive to different frequencies.The cochlea consists of 5 half turns (total length 14.3 mm) and the representation of certain frequency bands can be assigned to specific cochlear regions:1.The broad high frequency range between 70 and 111 kHz is represented in the most basal half turn within only 3.2 mm. This region is terminated apically by a distinct narrowing of the scala vestibuli that coincides with a pronounced increase in basilar membrane (BM) thickness.2.The narrow intermediate frequency range between 54 and 70 kHz is expanded onto 50% of cochlear length between 4.0 and 11.1 mm distance from apex. The frequency range around 60 kHz, where the tuning characteristics of the auditory system are exceptionally sharp, is located in the center of this expanded BM-region in the second half turn within a maximum of innervation density. These data can account for the vast overrepresentation of neurons sharply tuned to about 60 kHz at central stations of the auditory pathway. In the cochlear region just basal to the innervation maximum, where label from injections at 66 and 70 kHz was found, a number of morphological specializations coincide: the BM is maximally thickened, innervation density is low, the spiral ligament is locally enlarged, and the ‘thick lining’, a dense covering of the scala tympani throughout the basal halfturn, suddenly disappears.3.Low frequencies up to 54 kHz are represented within the apical half turns over a 4 mm span of the basilar membrane. The data are compared to the cochlea of horseshoe bats and the possible functional role of the morphological discontinuities for sharp tuning and the generation of otoacoustic emissions is discussed.

Evoked acoustic emissions and cochlear microphonics in the mustache bat, Pteronotus parnellii.

In the echolocating bat, Pteronotus parnellii, otoacoustic responses at a frequency of 62 kHz are measurable in the external ear canal during continuous and after transient acoustic stimulation. These responses are interpreted to represent emissions from the cochlea. They can reach an amplitude as large as 70 dB SPL and occur in the frequency range most important for echolocation, namely on the average about 700 Hz above the constant frequency component of the orientation calls. A sharp maximum of the amplitude of cochlear microphonic potentials at about 62 kHz could be correlated with the emission frequency. In one bat an evoked otoacoustic response changed to a spontaneous otoacoustic emission. The frequency and amplitude of the evoked otoacoustic responses reversibly decreased after exposure for 1 min to continuous sounds of more than 85 dB SPL with frequencies of about 2.5-7.5 kHz above the emission frequency. Similar effects occurred during anaesthesia or cooling. A possible relation between the existence of otoacoustic emissions and morphological specializations of the cochlea is discussed.

Stimulus-Specific Adaptation in the Gerbil Primary Auditory Thalamus Is the Result of a Fast Frequency-Specific Habituation and Is Regulated by the Corticofugal System

The detection of novel and therefore potentially behavioral relevant stimuli is of fundamental importance for animals. In the auditory system, stimulus-specific adaptation (SSA) resulting in stronger responses to rare compared with frequent stimuli was proposed as such a novelty detection mechanism. SSA is a now well established phenomenon found at different levels along the mammalian auditory pathway. It depends on various stimulus features, such as deviant probability, and may be an essential mechanism underlying perception of changes in sound statistics. We recorded neuronal responses from the ventral part of the medial geniculate body (vMGB) in Mongolian gerbils to determine details of the adaptation process that might indicate underlying neuronal mechanisms. Neurons in the vMGB exhibited a median spike rate change of 15.4% attributable to a fast habituation to the frequently presented standard stimulus. Accordingly, the main habituation effect could also be induced by the repetition of a few uniform tonal stimuli. The degree of habituation was frequency-specific, and comparison across simultaneously recorded units indicated that adaptation effects were apparently topographically organized. At the population level, stronger habituation effects were on average associated with the border regions of the frequency response areas. Finally, the pharmacological inactivation of the auditory cortex demonstrated that SSA in the vMGB is mainly regulated by the corticofugal system. Hence, these results indicate a more general function of SSA in the processing and analysis of auditory information than the term novelty detection suggests.

Comparative aspects of cochlear functional organization in mammals.

This review addresses the functional organization of the mammalian cochlea under a comparative and evolutionary perspective. A comparison of the monotreme cochlea with that of marsupial and placental mammals highlights important evolutionary steps towards a hearing organ dedicated to process higher frequencies and a larger frequency range than found in non-mammalian vertebrates. Among placental mammals, there are numerous cochlear specializations which relate to hearing range in adaptation to specific habitats that are superimposed on a common basic design. These are illustrated by examples of specialist ears which evolved excellent high frequency hearing and echolocation (bats and dolphins) and by the example of subterranean rodents with ears devoted to processing low frequencies. Furthermore, structural functional correlations important for tonotopic cochlear organization and predictions of hearing capabilities are discussed.

Otoacoustic emissions from the cochlea of the ‘constant frequency’ bats, Pteronotus parnellii and Rhinolophus rouxi

During stimulation with continuous pure tones, the cochlea of each individual of the mustached bat, Pteronotus parnellii, produces a strong evoked stimulus-frequency otoacoustic emission (SFOAE) at about 62 kHz. The SFOAEs were on average 480 Hz above the dominant constant frequency component of the echolocation call (resting frequency, RF). In two out of nine individuals of Pteronotus the SFOAEs changed into spontaneous otoacoustic emissions of 25-40 dB SPL. In the rufuous horseshoe bat, Rhinolophus rouxi spontaneous emissions were not detected and only in two out of seven animals were there weak SFOAEs about 300 Hz above the RF of 78 kHz. This difference may be due to a stronger damping of underlying resonant processes in Rhinolophus (Henson et al., 1985a). Acoustic distortion products behaved quite similar in both species. The first lower sideband distortion 2f1-f2 was measurable over a wide frequency range between 10 and 100 kHz. The optimum frequency separation delta f of the two primary tones to evoke maximum 2f1-f2 distortion was 0.8 to 5.8 kHz in Pteronotus and 1 to 7 kHz in Rhinolophus for frequencies outside the range of the constant frequency components of the call. This corresponds to ratios f2/f1 of about 1.03 to 1.2. At the frequency of the SFOAE in Pteronotus (480 Hz above the RF) and about 300 Hz above the RF in Rhinolophus the optimum delta f decreased sharply to values of 31-63 Hz in Pteronotus (ratio f2/f1 of 1.0005-1.001), and to 39-590 Hz in Rhinolophus (ratio f2/f1 of 1.0005-1.007). In Pteronotus a second minimum of delta f was found at about 90 kHz (values of 180-620 Hz, ratios f2/f1 of 1.002-1.007). In both bat species, the respective minima of delta f are located at or close to frequencies where neuronal tuning sharpness is exceptionally high. This indicates a mechanical origin of enhanced tuning. After adjusting the frequency of f2 to match the optimum delta fs, 2f1-f2 threshold curves were obtained. The distortion product threshold approximately parallels neuronal data and is in both species characterized by a pronounced insensitivity at the RF followed by a steep threshold minimum at frequencies 0.3-3 kHz above the RF. These features may be involved in reducing the cochlear response to the call such that the bats are able to focus on the Doppler-shifted echos which are slightly higher in frequency and thus within the range of the threshold minimum.