Synaptic depression and short-term habituation are located in the sensory part of the mammalian startle pathway
- Nadine S Simons-Weidenmaier†1,
- Maruschka Weber†1, 2,
- Claudia F Plappert1,
- Peter KD Pilz1 and
- Susanne Schmid1Email author
© Simons-Weidenmaier et al; licensee BioMed Central Ltd. 2006
Received: 08 December 2005
Accepted: 09 May 2006
Published: 09 May 2006
Short-term habituation of the startle response represents an elementary form of learning in mammals. The underlying mechanism is located within the primary startle pathway, presumably at sensory synapses on giant neurons in the caudal pontine reticular nucleus (PnC). Short trains of action potentials in sensory afferent fibers induce depression of synaptic responses in PnC giant neurons, a phenomenon that has been proposed to be the cellular correlate for short-term habituation. We address here the question whether both this synaptic depression and the short-term habituation of the startle response are localized at the presynaptic terminals of sensory afferents. If this is confirmed, it would imply that these processes take place prior to multimodal signal integration, rather than occurring at postsynaptic sites on PnC giant neurons that directly drive motor neurons.
Patch-clamp recordings in vitro were combined with behavioral experiments; synaptic depression was specific for the input pathway stimulated and did not affect signals elicited by other sensory afferents. Concordant with this, short-term habituation of the acoustic startle response in behavioral experiments did not influence tactile startle response amplitudes and vice versa. Further electrophysiological analysis showed that the passive properties of the postsynaptic neuron were unchanged but revealed some alterations in short-term plasticity during depression. Moreover, depression was induced only by trains of presynaptic action potentials and not by single pulses. There was no evidence for transmitter receptor desensitization. In summary, the data indicates that the synaptic depression mechanism is located presynaptically.
Our electrophysiological and behavioral data strongly indicate that synaptic depression in the PnC as well as short-term habituation are located in the sensory part of the startle pathway, namely at the axon terminals of sensory afferents in the PnC. Our results further corroborate the link between synaptic depression and short-term habituation of the startle response.
The mammalian startle response is a protective response that results in the contraction of skeletal and facial muscles in response to a sudden acoustic, tactile or vestibular stimulus. This response is modulated by elementary forms of learning such as sensitization [1, 2] and habituation [3, 4]. Short-term habituation is an attenuation of the startle response upon repeated presentation of startle stimuli within one session that is reversible within several minutes [5, 6]. The degree of attenuation varies between different animal species and different mouse strains [7, 8].
We have previously shown that repeated short trains of action potentials (closely mirroring the activity of sensory afferent fibers during the presentation of a startle stimulus in vivo) induce an exponential decay of the synaptic response amplitudes in PnC giant neurons in rat brain slices. This form of synaptic depression was proposed to be the neural correlate for short-term habituation of the startle response [22, 28]. In the present study, we address the question whether the underlying mechanism for synaptic depression is localized at presynaptic sites belonging to the sensory branch of the startle pathway or rather at postsynaptic sites on the PnC giant neurons that directly activate motoneurons. This distinction is critical, since if synaptic depression occurs presynaptically, it would take place before multimodal integration of startle stimuli, whereas postsynaptic synaptic depression should be general for all sensory input. We performed patch-clamp recordings of PnC giant neurons in rat and mouse brain slices during stimulation of auditory and trigeminal afferent pathways. The depression induced by individual stimulation of these pathways in brain slices from rats and mice was examined for any possible interference arising from stimulation of the other pathway and the ensuing depression there. In parallel, behavioral experiments were performed with mice of the same strain used in vitro to investigate whether there is interference between short-term habituation to acoustic and tactile startle stimuli. Further electrophysiological studies included analysis of the passive membrane properties of PnC neurons and of short-term plasticity before and during synaptic depression. Additionally, the dynamic properties of the stimulated synapses were examined to provide more insight about the location of the synaptic depression mechanism.
The postsynaptic currents evoked by the single pulses within one burst summated strongly due to the large membrane time constant of giant neurons. Thus, burst stimulation of sensory afferents evoked compound synaptic responses in PnC neurons (see Fig. 2B) that have been shown to be mediated by ionotropic glutamate receptors . Peak amplitudes of the compound postsynaptic excitatory currents (cEPSCs) were measured with whole-cell patch clamp recordings at -70 mV. During a sequence of 100 bursts applied to sensory afferent fibers at a frequency of 1 Hz, the cEPSC peak amplitudes decreased to 56 ± 3 % of the initial response evoked when auditory fibers were stimulated (means of cEPSC amplitudes 91–100, n = 29) and dropped to 60 ± 2 % of the initial amplitude when trigeminal fibers were stimulated (n = 44, see Figs. 2B and 2C and). The depression of the cEPSCs lasted for about 10 minutes before amplitudes recovered to the initial value (data not shown, see [22, 28]). Resting membrane potentials and input resistances of the postsynaptic neurons were analyzed during the recordings. The resting potential was -54.7 ± 1.53 mV before and -53 ± 1.42 mV immediately after depression of burst responses was induced by 100 auditory burst stimuli at 1 Hz (n = 17). The input resistance of the recorded cells was 100 ± 17 MΩ before and 114 ± 19 MΩ during depression (n = 22), as assessed by the I/O function of current responses to three small hyperpolarizing voltage pulses. This shows that the postsynaptic cell parameters were quite stable during recordings and that there were no alterations in postsynaptic membrane permeability at or near rest during depression.
Interaction of auditory and trigeminal input in the PnC
Interaction of acoustic and tactile startle habituation
In summary, the data shows that both synaptic depression and short-term habituation are pathway/modality specific. This also corroborates the hypothesis that short-term habituation of the startle response is associated with synaptic depression in the PnC.
Depression of burst responses is accompanied by altered short-term plasticity
Multiple stimuli at high frequency are necessary to induce synaptic depression
Evidence for a presynaptic mechanism
As a whole, our results provided an abundance of evidence that presynaptically-located synaptic depression in the PnC is the mechanism responsible for short-term habituation of the startle response.
In this study, auditory and trigeminal synapses in the PnC were stimulated presynaptically by applying short, high frequency bursts to afferent fibers of secondary neurons in the respective sensory pathway. We chose the burst stimulus paradigm as a model for the in vivo activity of auditory neurons during an acoustic startle experiment. Primary and secondary auditory neurons have been shown to fire at high frequency during sound presentation [29–31] and our burst duration resembles the duration of a startle stimulus. Giant neurons have a slow membrane time constant, enabling them to integrate repetitive auditory inputs as well as other sensory or modulatory input arriving at the neuron at different latencies . Presynaptic bursts of action potentials produce compound synaptic currents whose amplitudes determine the probability that spiking will occur and influence the number of action potentials generated by PnC giant neurons . Such compound excitatory synaptic currents (cEPSCs) are therefore a decisive factor for the elicitation and amplitude of a startle response.
In the first two experiments, we showed that in C57/Bl6 mice (and to some extent in rats) both the tactile and acoustic startle responses decreased when repetitive stimuli of these modalities were presented and similarly demonstrated that synaptic depression is induced when acoustic or trigeminal fibers synapsing on PnC giant neurons are repeatedly stimulated.
There was a slight difference in absolute acoustic startle amplitudes in one group of animals tested before tactile habituation (Fig. 4A, block 1–10) and in two other groups of animals tested either after tactile habituation or after exposure to the 95 dB background noise only (Fig. 4B, block 11–15). This difference was small (180 and 150 mV, respectively) and statistically insignificant. The 95 dB background noise used during tactile stimulation could account for the slightly lower acoustic startle amplitudes in Fig. 4B. However, after exposure to background noise, both groups of animals in Fig. 4B still showed acoustic startle habituation not statistically different from the habituation in Fig. 4A. The critical factor in this experiment is the lack of difference between the acoustic startle amplitudes of the two groups of mice in Fig. 4B (blocks 11–15, t-values < 1), even though only one group had received prior tactile stimulation.
Interestingly, the decline in startle response amplitudes of the C57BL/6 mice was generally greater when the tactile (behavioral) or trigeminal (electrophysiological) afferents were stimulated than when acoustic/auditory fibers were stimulated. This implies that short-term habituation to acoustic stimuli is generally weaker in these animals compared to habituation to tactile stimuli. Indeed, it has been reported that the amount of short-term habituation varies enormously between different stimulus modalities and that the degree of habituation is also dependent on the mouse strain . However, we cannot completely exclude the possibility that habituation to the (perhaps fear and/or stress-inducing) background noise during tactile startle measurements summates with the tactile startle habituation, although the background noise was switched on 5 min. before measurements started and tactile habituation showed a perfect exponential decay. Moreover, background noise should actually lead to sensitization, a process that counteracts habituation . Additionally, the behavioral results closely parallel the electrophysiological findings, adding to the growing body of evidence that PnC giant neurons are indeed a vital station in the startle pathway [13, 16, 18–20]. The results also strongly indicate that habituation takes place inside this pathway, namely in the form of synaptic depression at the synapse of the sensory inputs to the giant neurons [5, 11, 25–28].
Localization of synaptic depression
The main goal of this study was to determine whether the cellular substrate for short-term habituation, which is presumably the result of synaptic depression in sensory synapses within the PnC, is located in the sensory part of the startle pathway (i.e. at the presynaptic terminals of sensory afferents), or if this is instead a postsynaptic feature. Given the association of synaptic depression with short-term habituation, a presynaptic mechanism would imply that short-term habituation occurs before signals from different pathways are integrated in the PnC. Habituation would therefore be specific for each stimulus modality and would not generalize between different modalities. We tested this in electrophysiological experiments with rats and mice and in behavioral experiments conducted with mice from the same strain (i.e. C57BL/6 mice, also commonly used to generate knock-out mice). This is vital, as large differences between different mouse strains have been found with respect to habituation [7, 8].
Both approaches showed that both synaptic depression and short-term habituation are pathway specific. This is also consistent with behavioral studies of other species and mouse strains, which demonstrated that short-term habituation is modality specific [7, 34]. The pathway specificity signals that a presynaptic mechanism is involved and further evidence is provided by our data showing that the paired pulse ratio changes during depression, since alterations in short-term plasticity are commonly thought to reflect presynaptic changes in the transmitter release machinery [34, 35]. However, it should be noted that the paired pulse ratio declined during synaptic depression, which is the opposite of what would be expected if the decrease in synaptic efficacy is due to a reduced probability of transmitter release. This is normally accompanied by an increase in the paired pulse ratio, since the accumulated calcium in the presynaptic terminal meets a larger pool of releasable transmitter [35, 36].
Different mechanisms could account for a reduced paired pulse ratio; either the desensitization of postsynaptic glutamate receptors or presynaptic mechanisms, such as the exhaustion of releasable transmitter in the presynaptic terminal.
Mechanism of depression
Only repeated activation by short trains of at least four presynaptic action potentials produced an exponential decay of the cEPSC amplitudes in PnC neurons. Since trains of presynaptic action potentials lead to a strong and sustained release of the neurotransmitter glutamate into the synaptic cleft, desensitization of postsynaptic glutamate receptors could easily account for the resulting synaptic depression. However, several results rule out receptor desensitization as the underlying mechanism; first, the time course and the degree of depression were comparable when bursts were applied either every second or only every 10 seconds. In contrast, recovery from receptor desensitization should occur completely within 10 sec. Second, synaptic responses to single pulses as well as the responses to the first pulse within a burst were not (or not equally) affected by synaptic depression, but desensitized postsynaptic receptors should have had a similar effect on both response types. Moreover, repeated uncaging of exogenous glutamate at 1 Hz evoked responses with no sign of desensitization.
In summary, all of our results clearly contradict the hypothesis that postsynaptic receptor desensitization or changes in postsynaptic passive conductances can account for synaptic depression. Instead, our data provide ample behavioral and electrophysiological evidence that synaptic depression is a presynaptic phenomenon. Future studies will have to identify the molecular processes responsible for the alterations in synaptic transmission described here.
We can conclude from our behavioral and electrophysiological data that synaptic depression and its behavioral correlate short-term habituation are features of the sensory branch of the startle pathway; specifically, they are a function of sensory synaptic terminals in the PnC. Synaptic depression/short-term habituation therefore occur prior to multimodal signal integration in the PnC, where signals from different pathways converge. Our data also further corroborate the association of short-term habituation and synaptic depression in the PnC.
Preparation of brain slices
Details of the preparation have been reported previously . In brief, Sprague-Dawley rats or C57BL/6 mice (P10–14, Charles River, Sulzfeld, Germany) were deeply anesthetized with halothane, decapitated, and the brains were rapidly removed and transferred into ice-cold preparation solution containing (in mM): 210 sucrose, 26 NaHCO3, 1.3 MgSO4, 1.2 KH2PO4, 2 MgCl2, 2 KCl, 2 CaCl2, 10 glucose, 3 myoinositol, 2 sodium-pyruvate, 0.4 ascorbic acid, and equilibrated with 95% O2/5% CO2. Coronal slices (400 μm) were then cut with a vibratome (HM 650 V, Microm, Germany) in a submerged chamber filled with ice-cold preparation solution. Slices were transferred into a holding chamber filled with ACSF containing (in mM): 124 NaCl, 26 NaHCO3, 1.2 KH2PO4, 1.3 MgSO4, 2 KCl and 10 glucose. CaCl2 (2 mM) was added a few minutes after the slices had been transferred. The holding chamber was heated for 1 h to 34°, after which slices were kept at room temperature. All experiments were carried out in accordance with German and European animal protection laws.
For recording, slices were transferred into a superfusion-recording chamber mounted on an upright, fixed stage microscope (Zeiss, Oberkochen, Germany) with infrared differential interference optics. Superfusion rate was 2–3 ml ACSF/min. Patch-clamp recordings were made at room temperature under visual guidance with an infrared-sensitive camera (Kappa, Germany). Patch electrodes were pulled from borosilicate capillaries (Science products, Hofheim, Germany) and filled with a solution containing (in mM): 130 potassium gluconate, 5 KCl, 0.6 EGTA, 10 HEPES, 2 MgCl2, pH 7.2 (KOH), 270–290 mOsm. Electrodes had a resistance of 2–5 MΩ. Giant neurons in the area of the PnC were identified by a soma diameter greater than 35 μm. All measurements were made in the voltage clamp configuration at -70 mV. Presynaptic stimuli were applied with bipolar concentric tungsten electrodes (SNEX, Science Products, Hofheim, Germany) connected to a stimulator (Isostim A320, wpi, Berlin, Germany). The stimulation electrodes were positioned in the area ventrolateral to the lateral superior olive (LSO) to stimulate auditory fibers arising from the cochlear nucleus and the cochlear root (see  for details and Fig. 2), and medial to the principal nucleus V (Pr5) in order to stimulate trigeminal fibers crossing from the Pr5 to the PnC (see [22, 33] and Fig. 2). Recordings were made using an Axopatch 200 B amplifier and digitized with a Digidata 1320 (both Axon Instruments, Union City, USA). The data were filtered with a 10 kHz low-pass filter with a sampling rate of 20 kHz. pClamp 8.0.2 software (Axon Instruments, Union City, USA) was used for data acquisition and analysis. Stimulus intensities were kept low to avoid spiking of the neurons. Stimulus duration was 150 μs and synaptic depression was induced by a sequence of 100 burst stimuli at 1 Hz (unless otherwise noted). One burst consisted of four stimuli given within 12 ms (spacing 4 ms). Paired pulses were applied with a 50 ms interstimulus interval (ISI). Measurements were repeated ten times at 0.2 Hz for each cell before (control) and during synaptic depression induced by a sequence of 100 bursts. Ten traces were averaged for each condition and the paired pulse ratio was determined for each cell from the average trace. At least 5 min. recovery time was always allowed before applying a sequence of 100 bursts. The measurements under synaptic depression conditions followed immediately after the end of the 100 burst sequence. Maximum cEPSC amplitudes were measured (pA) and values were expressed as means ± SEM. Access resistance and seal quality was monitored at the beginning and several times during recordings to assure constant measurement conditions. Recordings were discarded when access resistance was larger than 30 MΩ or leak current more than -300 pA, or when one of these parameters changed by more than 15% during recording.
Photolysis of caged glutamate
For the photolysis experiments, 5 mg of caged L-glutamic acid, (γ-CNB-caged L-glutamic acid, Molecular Probes, Leiden, the Netherlands) was dissolved in 10 ml oxygenated ACSF, corresponding to a concentration of 1.14 mM. The high concentration was chosen to avoid bleaching during 1 Hz photolysis. The solution was fed into a microcircuit perfusing the slice. The entire experimental setup was kept in a dark room illuminated only by flat screen computer monitors. Single UV flashes of ca. 10 μs duration and with 0–6 mJ energy were applied by a Flash Mic system (Rapp Opto Electronic, Hamburg, Germany), which was mounted on the microscope's epifluorescent optical pathway. The area of the slice exposed to the flash could be controlled by the aperture of the optical pathway; the soma of the recorded neuron was centered in the visual field and the aperture was set in such a way that the soma and the surrounding area of the PnC giant neuron under investigation were excited by photolyzed glutamate (size of illuminated spot: 150 μm diameter). Under the conditions described, CNB-caged glutamate had no effect on membrane potential, input resistance or spontaneous activity. CNB-caged glutamate containing ASCF could be used for two subsequent days without any sign of bleaching when stored in the dark overnight at 4°C.
Twelve naïve female C57BL/6 mice were obtained from Charles River, Sulzfeld. Mice were 7–8 weeks old at the beginning of the experiments. The mice were housed in groups of five in cages containing nesting material under a 12:12 hour light/dark schedule (lights on at 6 a.m.) and received food and tap water ad libidum. The cages were in an air-conditioned room (temperature: 24 ± 1°C, humidity: 60 ± 5%). The mice were adapted to the colony room for 14 days before testing began and all testing took place during the light period.
The apparatus for measurements of startle responses is described in detail elsewhere . In short, the startle responses were measured inside a sound-attenuated chamber using a wire mesh test cage (5 × 9 × 5 cm) that was mounted on a movement-sensitive piezo accelerometer platform (Startle-Messsytem, University of Tübingen). Movement-induced voltage changes were digitized (Microstar, DAP1200e). Startle amplitudes were calculated as the difference between peak-to-peak voltage during a time window of 80 ms after stimulus onset and peak-to-peak voltage in the 80 ms time window before stimulus onset.
The tactile stimuli were air puffs of 100 Pascal (measured at the center of the cage; the air pressure before the air valve solenoid was 1.5 bar) delivered through a PVC tube centered on the side of the test cage; the distance to the center of the test cage was 8 cm. The air puff characteristics were measured using a 1-inch microphone (Bruel & Kjaer, model 4145). The air puffs had a duration of 30 ms, plus a rise time of 8 ms and a decay time of about 40 ms. Because the air puffs were given in the time window where startle was measured, they caused a "startle" artifact of 17 mV in the mean if measured with a weight simulating a mouse in the cage. In order to reduce noise generated by the air valve solenoid, the air passed through a "silencer" (see ). In order to mask the sound of the air puff itself, all testing of the tactile startle response was performed with background noise containing frequencies between 250 Hz and 20 kHz, with maximum intensity at 2 kHz. The noise was produced by a DSP-controlled system (Medav: Elf-Board with Siggen Software), amplified and emitted by a loudspeaker (Craaft HT 1640) inside the sound-absorbing chamber. The background noise level was 95 dB SPL RMS ("root mean square"), which completely masked the sound of the airpuff.
Acoustic stimuli were 14 kHz tones of 20 ms duration including 0.4 ms rise-/decay times. The SPL of these stimuli were 105 dB. The intertrial interval of acoustic and tactile stimuli was 15 sec.
The mice were adapted to the experimental environment inside the sound-attenuated chamber for 5 minutes on two days preceding testing. During this adaptation, background noise remained steady at 75 dB SPL RMS. On each test day, the mice were additionally allowed to adapt for 5 minutes before testing began; the following four test conditions were used: 1) "tactile→acoustic": 5 min adaptation (background noise 95 dB SPL) followed by 100 tactile stimuli (background noise 95 dB SPL) followed by 50 acoustic stimuli (background noise 50 dB SPL). 2) "acoustic only": no tactile stimuli (30 min background noise 95 dB SPL) followed by 50 acoustic stimuli (background noise 50 dB SPL). 3) "acoustic→tactile": 5 min adaptation (background noise 50 dB SPL) followed by 100 acoustic stimuli (background noise 50 dB SPL) followed by 50 tactile stimuli (background noise 95 dB SPL). 4) "tactile only": no acoustic stimuli (30 min background noise 50 dB SPL) followed by 50 tactile stimuli (background noise 95 dB SPL). Over four days, each mouse was tested once in each of the four conditions in a pseudorandom order.
For each block of 10 stimuli and each mouse, the mean of the ten startle responses was calculated; these means were used to calculate parametric statistics (grand mean and SEM). To test whether the startle response to the first 100 stimuli habituates, a general linear model was calculated using the block mean values (block as continuous factor, mouse as nominal factor of repeated measures). To test whether the startle response to the last 50 stimuli was dependent on the preceding treatment, t-tests were calculated.
This study was funded by the German Research Council through a grant to Susanne Schmid (DFG: Schm 1710/1–2) and to Peter Pilz (Pi 450/-2)
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