Habituation Of Startle Response Research Articles

The common neural parasite Pseudoloma neurophilia is associated with altered startle response habituation in adult zebrafish (Danio rerio): Implications for the zebrafish as a model organism

The zebrafish’s potential as a model for human neurobehavioral research appears nearly limitless despite its relatively recent emergence as an experimental organism. Since the zebrafish has only been part of the research community for a handful of decades, pathogens from its commercial origins continue to plague laboratory stocks. One such pathogen is Pseudoloma neurophilia, a common microparasite in zebrafish laboratories world-wide that generally produces subclinical infections. Given its high prevalence, its predilection for the host’s brain and spinal cord, and the delicate nature of neurobehavioral research, the behavioral consequences of subclinical P. neurophilia infection must be explored. Fish infected via cohabitation were tested for startle response habituation in parallel with controls in a device that administered ten taps over 10min along with taps at 18 and 60min to evaluate habituation extinction. After testing, fish were euthanized and evaluated for infection via histopathology. Infected fish had a significantly smaller reduction in startle velocity during habituation compared to uninfected tankmates and controls. Habituation was eliminated in infected and control fish at 18min, whereas exposed negative fish retained partial habituation at 18min. Infection was also associated with enhanced capture evasion: Despite the absence of external symptoms, infected fish tended to be caught later than uninfected fish netted from the same tank. The combination of decreased overall habituation, early extinction of habituation compared to uninfected cohorts, and enhanced netting evasion indicates that P. neurophilia infection is associated with a behavioral phenotype distinct from that of controls and uninfected cohorts. Because of its prevalence in zebrafish facilities, P. neurophilia has the potential to insidiously influence a wide range of neurobehavioral studies if these associations are causative. Rigorous health screening is therefore vital to the improvement of the zebrafish as a translational model for human behavior.

Effect of L‐theanine on sensorimotor gating in healthy human subjects

l-Theanine (N-ethyl-l-glutamine) is an amino acid uniquely found in green tea. Growing evidence has suggested the possible effects of l-theanine on cognition. Previously, we found that l-theanine attenuates MK-801-induced deficit in prepulse inhibition (PPI) in mice. In this study, we examined the effect of l-theanine in increasing the PPI in healthy humans. The subjects were 14 healthy adults who underwent PPI testing as a measure of sensorimotor gating 90 min after an oral intake of l-theanine (0, 200, 400, or 600 mg). PPI tests were done by examiners who were blind to the dose. The administration of 200 mg of l-theanine and that of 400 mg, but not 600 mg, significantly increased the % PPI compared to the baseline (0 mg). There was no significant relation between the dose of l-theanine and the startle magnitude or the habituation of startle response. The plasma concentrations of l-theanine correlated with the dose of l-theanine. The observed effect with 200-400 mg of l-theanine on PPI suggested that l-theanine at a particular dose range increases sensorimotor gating in humans.

Aggression and acoustic startle response in adult and infant rats with genetically defined aggression towards man and its absence

The aim of the current study was to investigate the association between expression of acoustic startle response and fear-induced aggression. The intensity of aggressive response towards man and acoustic startle response in adult and 15-day old Norway rats selectively bred for 70 generation for high level or the lack of fear-induced aggression was studied. Adult rats of aggressive strain demonstrated high aggression and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. It was found that, in contrast to infant rats of tame strain, 15-day old rat pups of aggressive strain demonstrated distinct aggressive response towards man, although this response was not as intensive as in adult rats of this strain. There was no considerable difference between aggressive and tame infants in amplitude of acoustic startle response. Significant habituation of startle response was shown in adult rats of aggressive strain, whereas in 15-day old rat pups of aggressive rat strain amplitude of startle response remained unaltered. Both adult and infant rats of tame strain demonstrated considerable habituation of startle response. Thus, defensive aggression in rats with genetic predisposition to fear-induced aggression appears quite early--at eyes opening they demonstrate a pronounced aggressive response toward man. The acoustic startle reflex is one of the elements of complex behavior--fear-induced aggression, and this element is involved in the enhancement of aggressive response towards man in adult rats but does not play any essential role in infant aggressiveness.

Do transmembrane domain neuregulin 1 mutant mice exhibit a reliable sensorimotor gating deficit?

Evidence suggests that the heterozygous transmembrane domain mutant mouse model for the schizophrenia candidate gene neuregulin 1 ( Nrg1 HET) exhibits a deficit in prepulse inhibition (PPI). However, not all mouse models for Nrg1 exhibit PPI deficits. Thus, our study intended to clarify the severity of the initially described PPI deficit in Nrg1 HET mice. For this, Nrg1 mutant mice and wild type-like littermates of one breeding colony were tested for PPI in four different phenotyping facilities in Australia employing a variety of different PPI protocols with fixed and variable interstimulus intervals (ISIs). Testing mutant and wild type-like mice in three Australian phenotyping facilities using PPI protocols with variable ISIs revealed no effect of mutant transmembrane domain Nrg1 on sensorimotor gating. Changes to the startle response and startle response habituation were site/protocol-specific. The employment of two different PPI protocols at the same phenotyping facility revealed a protocol-dependent and site-specific facilitation of PPI in Nrg1 mutant mice compared to wild type-like mice. In conclusion, the often-noted PPI phenotype of the transmembrane domain Nrg1 mutant mouse model is highly PPI protocol-specific and appears sensitive to the particular conditions of the test laboratory. Our study describes wild type-like PPI under most test conditions and across three different laboratories. The research suggests that analysing one of the alleged hallmarks of animal models for schizophrenia must be done carefully: to obtain reliable PPI data it seems necessary to use more than one particular PPI protocol.

Group III Metabotropic Glutamate Receptors Inhibit Startle-Mediating Giant Neurons in the Caudal Pontine Reticular Nucleus But Do Not Mediate Synaptic Depression/Short-Term Habituation of Startle

Short-term habituation is a basic form of learning that is analyzed in different species and using different behavioral models. Previous studies on mechanisms of short-term habituation yielded evidence for a potential role of group III metabotropic glutamate receptors (mGluRIIIs). Here we tested the hypothesis that mGluRIII mediate short-term habituation of startle in rats, combining electrophysiological experiments in vitro with behavioral studies in vivo. We applied different mGluRIII agonists and antagonists on rat brainstem slices while recording from startle-mediating neurons in the caudal pontine reticular nucleus (PnC) and monitoring synaptic depression presumably underlying habituation. Furthermore, we injected the mGluRIII antagonist (RS)-alpha-phosphonophenylglycine (MPPG) and the agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) into the PnC of rats in vivo and measured its effect on startle habituation. Our results show that activation of mGluRIIIs in the PnC strongly inhibits startle-mediating giant neurons in vitro. Accordingly, L-AP4 reduced startle responses in vivo. However, synaptic depression in the slice was not disrupted by mGluRIII antagonists or agonists. Correspondingly, the in vivo application of the mGluRIII antagonist MPPG failed to show any effect on short-term habituation of startle responses. We therefore conclude that mGluRs are expressed within the primary startle pathway and that they inhibit startle responses upon activation; however, this inhibition does not play any role in synaptic depression and short-term habituation of startle. This is in contrast to the role of mGluRIIIs in other forms of habituation and supports the notion that there are different mechanisms involved in habituation of sensory-evoked behaviors.

Somatostatin-28 modulates prepulse inhibition of the acoustic startle response, reward processes and spontaneous locomotor activity in rats

Somatostatins have been shown to be involved in the pathophysiology of motor and affective disorders, as well as psychiatric disorders, including schizophrenia. We hypothesized that in addition to motor function, somatostatin may be involved in somatosensory gating and reward processes that have been shown to be dysregulated in schizophrenia. Accordingly, we evaluated the effects of intracerebroventricular administration of somatostatin-28 on spontaneous locomotor and exploratory behavior measured in a behavioral pattern monitor, sensorimotor gating, prepulse inhibition (PPI) of the acoustic startle reflex, and brain reward function (measured in a discrete trial intracranial self-stimulation procedure) in rats. Somatostatin-28 decreased spontaneous locomotor activity during the first 10 min of a 60 min testing session with no apparent changes in the exploratory activity of rats. The highest somatostatin-28 dose (10 microg/5 microl/side) induced PPI deficits with no effect on the acoustic startle response or startle response habituation. The somatostatin-induced PPI deficit was partially reversed by administration of SRA-880, a selective somatostatin 1 (sst(1)) receptor antagonist. Somatostatin-28 also induced elevations in brain reward thresholds, reflecting an anhedonic-like state. The non-peptide sst(1) receptor antagonist SRA-880 had no effect on brain reward function under baseline conditions. Altogether these findings suggest that somatostatin-28 modulates PPI and brain reward function but does not have a robust effect on spontaneous exploratory activity. Thus, increases in somatostatin transmission may represent one of the neurochemical mechanisms underlying anhedonia, one of the negative symptoms of schizophrenia, and sensorimotor gating deficits associated with cognitive impairments in schizophrenia patients.

Prepulse inhibition of acoustic startle in Japanese patients with chronic schizophrenia

Prepulse inhibition (PPI) of acoustic startle reflex has been suggested as a neurophysiologic measure of information processing abnormalities in schizophrenia. However, there has been little information on PPI and related measures in Asian patients with schizophrenia. We examined startle response to acoustic stimuli, its habituation, and PPI in 20 Japanese patients with chronic schizophrenia under antipsychotic medication and 16 healthy controls matched for age and sex. We measured PPI with 115 dB of pulse (40 ms), 82, 86, or 90 dB of prepulse (20 ms) and 30, 60, or 120 ms of lead interval (LI). The startle response to pulse alone trials was significantly smaller in schizophrenics than in controls, which may be due, at least in part, to medication. There was no significant difference in habituation of startle response during the test session between the two groups. PPI differed significantly between the two groups when LI was 120 ms. No significant relationship was found on startle response or PPI with age of onset, number of previous admission, medication dosages, or symptom scores assessed with the Positive and Negative Syndrome Scale (PANSS). Our results confirm impaired PPI in chronic schizophrenia patients compared with controls in Japanese.

Synaptic depression and short-term habituation are located in the sensory part of the mammalian startle pathway

BackgroundShort-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.ResultsPatch-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.ConclusionOur 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.

Sensorimotor Gating and Habituation of the Startle Response in Schizophrenic Patients Randomly Treated With Amisulpride or Olanzapine

Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia. The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise. Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect. Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.

Sensorimotor gating and habituation of the startle response in the prodrome of schizophrenia

Patients with schizophrenia exhibit impairments in habituation and sensorimotor gating of the acoustic startle response (ASR). Animal data suggested that a deficit in prepulse inhibition (PPI) of the ASR, which is used as an operational measure for sensorimotor gating, is genetically determined. To test the assumption, that both gating and habituation are candidate endophenotypes of schizophrenia, we investigated startle reactivity, habituation and PPI of the ASR in 51 subjects with prodromal symptoms of schizophrenia, in 28 first episode schizophrenics and in 33 healthy volunteers. Subjects in early prodromal stages and unmedicated patients with first episode schizophrenia did show a PPI deficit, whereas antipsychotically treated subjects showed almost normal PPI. In contrast, startle reactivity and habituation decreased with proceeding of the illness (controls > early prodromal group > late prodromal group > first episode schizophrenics). Antipsychotic medication improved also startle reactivity and habituation in schizophrenic patients. Our findings suggest that PPI is possibly an endophenotype of schizophrenia, because it occurs already at an early stage of the prodromal phase, whereas startle reactivity and habituation deficits are rather symptoms of schizophrenia, because they are getting worse with process of the illness. Funded by the German Federal Ministry for Education and Research BMBF (grant 01-GI–9934).

Rat strain-dependent effects of repeated stress on the acoustic startle response

Amplitude and habituation of the acoustic startle response were assessed in four recombinant inbred (RI) rat strains. One group from each strain underwent repeated restraint stress, the last session of which was 24 h before startle testing while, a second group from each strain was not stressed prior to testing. Additionally, prepulse inhibition of the acoustic startle response, and anxiety behavior in the elevated plus-maze were assessed in separate, non-stressed groups of each strain. In the non-stressed condition, these RI strains differed significantly from each other on all behaviors measured. In the two RI strains that showed the greatest habituation of the startle response, repeated stress resulted in significantly lower acoustic startle amplitude than that seen in non-stressed controls of those strains. In the strains showing low levels of habituation, repeated stressed increased the level. Neither genotype-dependent levels of startle amplitude, prepulse inhibition of the startle response, nor anxiety in the plus-maze were closely related to the effect of stress on either startle amplitude or habituation. The results suggest that genotype-dependent habituation of the startle response may be important in determining whether stress will alter startle amplitude.

The relationship of age to prepulse inhibition and habituation of the acoustic startle response

Prepulse inhibition (PPI) of the startle response reflects an early stage of information processing that is abnormal in schizophrenia and certain other specific neuropsychiatric disorders that are distinguished by the inability to inhibit redundant or relatively irrelevant sensory, cognitive, or motor information. The goal of the present study was to characterize the effect of normal aging on PPI and habituation of the startle response and to examine the hypothesis that normal aging is characterized by a global decline in inhibitory function. Ninety-seven non-psychiatric controls (age range 18–88) were tested for startle eyeblink response using electromyogram (EMG) recording. Startle magnitude decreased and startle latency increased with aging. PPI demonstrated an inverted U-shaped function with age (greatest PPI at intermediate ages) while there was no significant effect of age on startle habituation. The results do not support the theory that aging is associated with a general decline in inhibitory function and contrast with previous studies that have compared only extreme age groups and have found no effects of age on PPI.

Estrogen increases prepulse inhibition of acoustic startle in rats

Epidemiological studies have shown gender differences in the age of onset and symptoms of schizophrenia. Because sensorimotor gating mechanisms are deficient in schizophrenia, we studied the effect of administration of estrogen on prepulse inhibition of startle in rats, an animal model of sensorimotor gating. Rats were tested in an automated startle apparatus for their responses to random combinations of 115-dB sound pulses and prepulses of various intensity. Startle responses were reduced by increasing intensities of prepulses, indicating prepulse inhibition. Repeated administration of startle pulses caused gradual habituation of startle responses. Ovariectomy did not induce significant changes in either habituation of the startle response or prepulse inhibition of startle. Treatment with 17β-estradiol caused an increase in percentage prepulse inhibition at all prepulse intensities at 18 h, but only at higher prepulse intensities at 30 min after injection. Habituation of startle responses was not affected. The enhancing effect of estradiol on prepulse inhibition was mimicked by testosterone, but not by dihydrotestosterone. Estradiol treatment increased prepulse inhibition similarly in controls or after disruption of prepulse inhibition induced by treatment with apomorphine or dizocilpine (MK-801). Our results may help to explain gender differences in schizophrenia and some of the beneficial clinical effects of estrogen treatment in this disease.

Involvement of the human medial cerebellum in long-term habituation of the acoustic startle response.

Animal studies have shown an involvement of the cerebellar vermis in long-term habituation of the acoustic startle response, but not in short-term habituation. The aim of the present study was to investigate whether short-term and long-term habituation of the acoustic startle response are impaired in patients with medial cerebellar lesions. Five patients with midline cerebellar lesions due to surgery for astrocytoma and ten healthy, age- and sex-matched subjects were studied. Subjects received 40 acoustic startle stimuli each day on five successive days. Peak amplitudes of the startle response recorded at the orbicularis oculi and the sternomastoid muscles were obtained. Data were analyzed for response decrement within the training session of one day (short-term habituation) and for a decrease in the startle response across the five training days (long-term habituation). Short- and long-term habituation of the startle response recorded at the sternomastoid muscles could be achieved in controls and in cerebellar patients. However, long-term habituation of the blink component of the acoustic startle response recorded at the orbicularis oculi muscles was significantly impaired in patients with cerebellar lesions compared with control subjects, whereas short-term habituation was preserved in both groups. The present findings suggest that the medial cerebellum is involved in long-term habituation of the blink component of the startle response in humans.

Startle response models of sensorimotor gating and habituation deficits in schizophrenia

Studies of prepulse inhibition and habituation of startle responses elicited by intense stimuli provide some unusual opportunities for cross-species explorations of attentional deficits characteristic of schizophrenic patients. Schizophrenic patients exhibit deficits in both the prepulse inhibition of startle and the habituation of startle. The behavioral plasticity of startle responses and the comparability of the test paradigms used in rats and humans greatly facilitates the development of animal models of specifiable behavioral abnormalities in schizophrenic patients. This review describes two such examples of parallel animal and human models, one involving sensorimotor gating and the other examining behavioral habituation. Evidence is presented supporting the involvement of mesolimbic dopaminergic systems in the modulation of prepulse inhibition or sensorimotor gating and the importance of central serotonergic systems in the habituation of startle.

Long-term habituation of the acoustic startle response: Role of the cerebellar vermis

The cerebellar vermis has been recognized as a key region of a circuit essential for long-term habituation of the acoustic startle response in rats. The removal of this neuronal structure before training prevents the build-up of this long-term behavioral change. Our data show that, when the same lesion is performed after training for long-term habituation, the learned behavior is not affected. These results indicate that the cerebellar vermis is essential for the acquisition, but not for the retention of long-term habituation of the startle response.

Behavioral teratogenic insult of methylmercury assessed by using sets of measures: Reanalysis of data from the Collaborative Behavioral Teratology Study of National Center for Toxicological Research

The data of the Collaborative Behavioral Teratology Study were analyzed by using sets of measures simultaneously. A set of preweaning measures offered far more information as to treatment effects than a set of postweaning measures. The treatment effect observed in behavioral measures was also explained considerably by physical measures. However, the effect explained by uniquely behavioral measures (i.e., magnitude of semipartial R 2) was also observed in some degree. A sex-related difference was observed in auditory startle response habituation appearing only later or earlier in life. The usefulness of using a set of measures and assessing the relationship among sets in behavioral teratology, in addition to conventional single measure analysis, was discussed.

Age, sex and strain comparison of habituation of the startle response in the rat

Habituation and sensitization of the acoustic startle response were studied in young (3 month) and aged (26 month) male and female Fischer 344 rats and in young (3 month) and aged (32 month) male Sprague Dawley rats. Tones were presented on 25 consecutive trials for a session, one session on each of four consecutive days. An air puff stimulus immediately preceded trial 20 on each day to test sensitization. All aged rats demonstrated greater short-term (within session) relative habituation than their younger counterparts. Across sessions, aged male rats of both strains habituated more quickly than younger males. Aged female rats habituated more slowly. Sensitization was more likely to occur in younger rats.

Locomotor activity, auditory startle and shock thresholds in spontaneously hypertensive rats

A group of SHRs and a group of WKY normotensive controls were compared sequentially on open-field behavior, Y-maze activity, responsiveness and habituation of the auditory startle response, and shock thresholds. In the open field and Y maze the SHRs were more active than the WKYs, but the locomotor activity of the SHRs decreased more within sessions. However, the SHRs could be described as showing more, less or the same between-session habituation depending upon the apparatus and the portion of the session analyzed. The SHRs were less responsive than controls on the auditory startle response measure, and they did not differ from controls on startle-response habituation. The SHRs were less responsive than controls at low shock levels but more responsive at high shock levels. The relationship between SHRs and WKYs on the responsiveness dimension depended upon the modality and intensity of the stimulus, the response characteristics of the test situation, and the time sample of behavior taken.

Central injections of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS): Effects on brain [ 14C]2-Deoxy- d-glucose uptake and behavior in rats

Brain glucose utilization was examined 24 h after single intracisternal injections of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS) in rats. Quallitative autoradiography indicated a pronounced and homogeneous depression in [ 14C]2-deoxy- d-glucose ([ 14C]2DG) uptake throughout the brains of rats treated with 200 or 400 μg EOS. Quantitative scintillation counting of 14C in 9 brain areas of other rats confirmed the marked, generalized decrease in label uptake 24 h after EOS. Food intake measurements confirmed previous reports of dose-dependent anorexia after EOS. Rats treated with the 200 μg dose showed decreased open-field activity 24 h after injection but no other deficits in various tests of sensorimotor function or in tail-pinch-induced feeding. Rats treated with the 400 μg dose also showed deficits in open-field activity, plus deficits in orientation to touch stimuli, longer latencies than controls in catalepsy tests, and faster habituation of startle responses to sound. This group showed normal feeding responses to tail-pinch stimulation in the presence of solid food but not in the presence of liquid food. It was concluded that sensorimotor deficits may play some role in the anorexigenic effects of EOS but are probably not their primary cause. The discrepancy between the apparent degree of depression of brain glucose utilization and the comparatively mild behavioral deficits observed would suggest the possibility that metabolic fuels other than glucose may be mobilized following central EOS treatment.