Habituation Of Acoustic Startle Response Research Articles

A Computational Model for the Simulation of Prepulse Inhibition and Its Modulation by Cortical and Subcortical Units.

The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.

Auditory Behavior in Adult-Blinded Mice.

Cross-modal plasticity occurs when the function of remaining senses is enhanced following deprivation or loss of a sensory modality. Auditory neural responses are enhanced in the auditory cortex, including increased sensitivity and frequency selectivity, following short-term visual deprivation in adult mice (Petrus et al. Neuron 81:664-673, 2014). Whether or not these visual deprivation-induced neural changes translate into improved auditory perception and performance remains unclear. As an initial investigation of the effects of adult visual deprivation on auditory behaviors, CBA/CaJ mice underwent binocular enucleation at 3-4weeks old and were tested on a battery of learned behavioral tasks, acoustic startle response (ASR), and prepulse inhibition (PPI) tests beginning at least 2weeks after the enucleation procedure. Auditory brain stem responses (ABRs) were also measured to screen for potential effects of visual deprivation on non-behavioral hearing function. Control and enucleated mice showed similar tone detection sensitivity and frequency discrimination in a conditioned lick suppression test. Both groups showed normal reactivity to sound as measured by ASR in a quiet background. However, when startle-eliciting stimuli were presented in noise, enucleated mice showed decreased ASR amplitude relative to controls. Control and enucleated mice displayed no significant differences in ASR habituation, PPI tests, or ABR thresholds, or wave morphology. Our findings suggest that while adult-onset visual deprivation induces cross-modal plasticity at the synaptic and circuit levels, it does not substantially influence simple auditory behavioral performance.

Rapid Effects of Selection on Brain-wide Activity and Behavior

Interindividual variation in behavior and brain activity is universal and provides substrates for natural selection [1-9]. Selective pressures shift the expression of behavioral traits at the population level [10, 11], but the accompanying changes of the underlying neural circuitry have rarely been identified [12, 13]. Selection likely acts through the genetic and/or epigenetic underpinnings of neural activity controlling the selected behavior [14]. Endocrine and neuromodulatory systems participate in behavioral diversity and could provide the substrate for evolutionary modifications [15-21]. Here, we examined brain-wide patterns of activity in larval zebrafish selectively bred over two generations for extreme differences in habituation of the acoustic startle response (ASR) [22]. The ASR is an evolutionarily conserved defensive behavior induced by strong acoustic/vibrational stimuli. ASR habituation shows great individual variability that is stable over days and heritable [4, 22]. Selection for high ASR habituation leads to stronger sound-evoked activation of ASR-processing brain areas. In contrast, animals selected for low habituation displayed stronger spontaneous activity in ASR-processing centers. Ablation of dopaminergic tyrosine hydroxylase (TH) neurons decreased ASR sensitivity. Independently selected ASR habituation lineages link the effect of behavioral selection to dopaminergic caudal hypothalamus (HC) neurons [23]. High ASR habituation co-segregated with decreased spontaneous swimming phenotypes, but visual startle responses were unaffected. Furthermore, high- and low-habituation larvae differed in stress responses as adults. Thus, selective pressure over a couple of generations on ASR habituation behavior is able to induce substantial differences in brain activity, carrying along additional behaviors as piggyback traits that might further affect fitness in the wild. VIDEO ABSTRACT.

Prepulse inhibition and acoustic startle response in young healthy Chinese.

Prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR) are considered to be effective neurobiological measures of sensorimotor gating and information processing. The deficit of PPI and habituation of ASR has been proposed to be candidate endophenotypes of schizophrenia spectrum disorders. However, there has been little information on PPI and ASR measures in Chinese. The present study aimed to provide more information about the characteristics of PPI and ASR in young healthy Chinese and investigate their sensitivity to experimental parameters and characteristics of population. In this study, we examined the PPI and habituation of ASR in 41 young healthy adults (21 males and 20 females), using an acoustic startle stimulus of 115 dB and a prepulse of 75 dB at a lead interval (LI) of 60 ms and 120 ms, respectively. The behavioral performance demonstrated that the PPI and habituation of ASR in all the young participants were robust. The significant difference was not observed in PPI and habituation between male and female. The block effect on PPI was significant; PPI reduces with increasing training. Latency facilitation was observed under prepulse conditions, with a significant effect of LI. Compared to previous studies in Caucasians, Chinese in this study shows a higher habituation and PPI. In conclusion, this research provides more data of behavioral characteristics of PPI and ASR in young healthy Chinese. Chinese in this study shows a higher habituation and PPI than Caucasians in previous studies.

Neuromodulatory Regulation of Behavioral Individuality in Zebrafish

Inter-individual behavioral variation is thought to increase fitness and aid adaptation to environmental change, but the underlying mechanisms are poorly understood. We find that variation between individuals in neuromodulatory input contributes to individuality in short-term habituation of the zebrafish (Danio Rerio) acoustic startle response (ASR). ASR habituation varies greatly between individuals, but differences are stable over days and are heritable. Acoustic stimuli that activate ASR-command Mauthner cells also activate dorsal raphe nucleus (DRN) serotonergic neurons, which project to the vicinity of the Mauthner cells and their inputs. DRN neuron activity decreases during habituation in proportion to habituation and a genetic manipulation that reduces serotonin content in DRN neurons increases habituation, whereas serotonergic agonism or DRN activation with ChR2 reduces habituation. Finally, level of rundown of DRN activity co-segregates with extent of behavioral habituation across generations. Thus, variation between individuals in neuromodulatory input contributes to individuality in a core adaptive behavior. VIDEO ABSTRACT.

Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats

Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.

Estradiol Treatment and Hormonal Fluctuations During the Estrous Cycle Modulate the Expression of Estrogen Receptors in the Auditory System and the Prepulse Inhibition of Acoustic Startle Response

Estrogens' effects on hearing are documented across species, but the responsible molecular mechanisms remain unknown. The presence of estrogen receptors (ER) throughout the auditory system offers a potential pathway of direct estrogenic effects on auditory function, but little is known about how each ER's expression is regulated by the overall hormonal status of the body. In the present study, we determined the effects of ovariectomy and chronic 17β-estradiol treatment on mRNA and protein expression of ERα and ERβ in peripheral (cochlea) and central (inferior colliculus) auditory structures of mice, as well as on auditory-related behavior using the acoustic startle response (ASR), prepulse inhibition (PPI), and habituation of the startle response. 17β-Estradiol treatment down-regulated ERα but not ERβ and increased PPI and latency of the ASR. Neither the magnitude nor the habituation of ASR was affected. Furthermore, ER's mRNA and protein expression in the inner ear were analyzed throughout the estrous cycle (proestrus, estrus, metestrus, and diestrus), revealing a negative correlation of circulating estrogens with ERα expression, whereas ERβ was stable. Our findings show that ER not only are present in both the peripheral and central auditory system but also that circulating estrogen levels down-regulate ERα expression in the auditory system and affect PPI and the latency of ASR, suggesting a key role of ERα as a hormone-induced modulator of the auditory system and behavior.

Dopaminergic mechanisms underlying involvement of the prefrontal cortex and amygdala in acoustique startle modificftion during the action of stimulus associated with positive reinforcement

We studied the neurochemical mechanisms underlying the action of the conditioned stimulus associated with positive reinforcement on the amplitude of the acoustic startle response (ASR). To this aim, we injected a blocker of dopamine D2 receptors, sulpiride, into the rat medial prefrontal cortex or basolateral amygdala during the repeated procedure of ASR habituation. We have shown that, after the injection of saline to control rats into both the prefrontal cortex and amygdala, the change in ASR amplitude after an increase in illumination depends on the preliminary learning of a behavioral skill associated with a conditioned light signal. We found that if an acoustic signal appeared immediately after the change in the illumination the blockage of D2 dopamine receptors in the medial prefrontal cortex induced an increase in ASR amplitude. This disturbed the habituation of animals that were preliminarily subjected to associative training before this procedure. The injection of sulpiride into the basolateral amygdala during the increase in illumination did not affect the dynamics of ASR amplitude. This effect of the drug did not depend on the preliminary acquirement of positive conditioning to light. Our data suggest that D2 dopamine receptors of the medial prefrontal cortex, but not the basolateral amygdala, are involved in the reproduction of previously acquired skills associated with positive reinforcement under conditions of current defensive behavior.

Acoustic startle response and sensorimotor gating in a genetic mouse model for the Y1 receptor

Recent research has highlighted a potential role for neuropeptide Y (NPY) and its Y(1) receptor in the development of schizophrenia. Genetic as well as molecular biological studies have demonstrated reduced levels of NPY in schizophrenia patients. Importantly, Y(1) receptors may mediate some of the potential effects of NPY on schizophrenia, as decreased Y(1) receptor expression has been found in the lymphocytes of schizophrenia patients. To clarify NPY's role in schizophrenia, we investigated a genetic animal model for Y(1) deficiency in regard to (i) acoustic startle response (ASR), (ii) habituation to ASR and (iii) sensorimotor gating [i.e. prepulse inhibition (PPI)] using two different PPI protocols. Mutant and wild type-like mice were screened for baseline behaviours and after pharmacological challenge with the psychotropic drugs dexamphetamine (DEX) and MK-801. Y(1) knockout mice (Y(1)(-/-)) showed a moderate reduction of the ASR and an impaired ASR habituation at baseline and after DEX treatment. The baseline PPI performance of Y(1) mutant mice was unaltered their response to DEX and MK-801 challenge was moderately different compared to control mice, which was dependent on the PPI protocol used. MK-801 challenge had a protocol-dependent differential effect in Y(1)(-/-) mice and DEX a more pronounced impact at the highest prepulse intensities. In conclusion, it appears that the Y(1) receptor influences the acoustic startle response and its habituation but does not play a major role in sensorimotor gating. Further explorations into the effects of Y(1) deficiency seem valid.

Impaired prepulse inhibition and habituation of acoustic startle response in Japanese patients with schizophrenia

Prepulse inhibition (PPI) and habituation of the acoustic startle reflex (ASR) are considered to be candidate endophenotypes of schizophrenia. However, to our knowledge, only one group has investigated these startle measures in Asian patients with schizophrenia. In the present study, we evaluated these startle measures in 51 Japanese patients with schizophrenia and compared them with those of 55 healthy age- and sex-matched Japanese controls. A human startle response monitoring system was used to deliver acoustic startle stimuli, and record and score the electromyographic activity of the orbicularis oculi muscle. The startle measures examined were mean magnitude of ASR to pulse alone trials in initial block (SR), habituation of ASR during the session (HAB), and PPI at prepulse intensities of 82 dB (PPI82), 86 dB (PPI86), and 90 dB (PPI90) sound pressure level. SR was not significantly different between the patients and controls. Patients displayed significantly reduced HAB and PPI for all prepulse intensities compared to controls. The greatest statistical difference in PPI between patients and controls was found with PPI86. This did not correlate with any clinical variable in each group. Our results indicate that PPI and habituation of ASR are impaired in Asian patients with schizophrenia.

Normal prepulse inhibition and habituation of acoustic startle response in suicidal depressive patients without psychotic symptoms

Background Until now, there is a lack of useful biological markers to predict suicidal behavior in depressive patients. However, it is consistently found that suicidality is associated with a central serotonin deficit. Animal data suggest that prepulse inhibition (PPI) as well as habituation of the acoustic startle response (ASR), which are established as operational measures for sensorimotor gating, decreases after serotonin depletion. Thus, we investigated PPI and habituation of ASR in suicidal patients with depressive disorders as potential biological markers for suicidal behavior. Methods PPI and habituation of ASR was measured in 20 depressive patients who had at least one suicide attempt within the last three month. Eighteen healthy matched controls were examined likewise. Results Suicidal depressive patients did not differ from healthy controls in PPI, startle reactivity and habituation of ASR. Subgroup analyses showed that factors such as severity of depression, impulsiveness, gender, smoking, lethality of the last suicide attempt, number of suicide attempts, and medication had no influence on the results. Conclusions These results suggest that neither PPI nor habituation of ASR could serve as useful markers for suicidality.

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.

Attenuation of the prepulse inhibition of the acoustic startle response within and between sessions

Prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR) are widely used biological markers in the study of psychiatric disorders and have been shown to be homologous across species. Previous studies in humans suggested that PPI is a stable and reliable measure between test sessions, but that PPI decreases within sessions. The purpose of this study was to explore the short- and long-term decrease in PPI as a potential confound in the measurement and interpretation of PPI. We investigated the progression of PPI and habituation of ASR in three test sessions spaced 4 weeks apart in a group of 20 healthy participants. Analysis revealed a significant decrease in the percent PPI within and between the test sessions. Nevertheless, PPI was reliable across three test sessions, indicating that the significant attenuation of PPI over time was a consistent phenomenon. These results suggest that PPI exhibits short- and long-term attenuation.

Prepulse inhibition and habituation of acoustic startle response in male MDMA ('ecstasy') users, cannabis users, and healthy controls.

Chronic administration of 3,4-methylenedioxymethamphetamine (MDMA) is associated with long-term depletion of serotonin (5-HT) and loss of 5-HT axons in the brains of rodents and nonhuman primates. Despite the broad database concerning the selective serotonergic neurotoxicity of recreational MDMA consumption by humans, controversy still exists with respect to the question of whether the well-known functional consequences of these neurotoxic effects, such as memory impairment, were caused by chronic 5-HT deficiency. Habituation and prepulse inhibition (PPI) of the acoustic startle response (ASR) can be used as a marker of central serotonergic functioning in rodents and humans. Thus, we investigated the functional status of the central serotonergic system in chronic but abstinent MDMA users by measuring PPI and habituation of ASR. PPI and habituation of ASR were measured in three groups. The first group (MDMA group) included 20 male drug-free chronic users of MDMA; the second group (cannabis group) consisted of 20 male drug-free chronic users of cannabis; and the third group (healthy controls) comprised 20 male participants with no history of illicit drug use. Analysis revealed significantly increased PPI of MDMA users compared to those of cannabis users and healthy controls. Cannabis users and healthy controls showed comparable patterns of PPI. There were no differences in habituation among the three groups. These results suggest that the functional consequences of chronic MDMA use may be explained by 5-HT receptor changes rather than by a chronic 5-HT deficiency condition. Use of cannabis does not lead to alterations of amplitude, habituation, or PPI of ASR.

The effects of perinatal AZT exposure on the acoustic startle response in adult rats

AZT (azidothymidine, zidovudine, ZDV) has become the standard medication to prevent the transmission of the human immunodeficiency virus from mother to fetus. The present study was designed to assess the acoustic startle response (ASR) in adult rats that had been perinatally exposed to AZT. Each litter was randomly assigned to a treatment group: nontreated, AZT 0, 50, 100 or 150 mg/kg. Once daily gastric intubation began prenatally between gestational day (G) 19 and 22 and then continued postnatally between postnatal day (PND) 2 and 20. Between PND75 and PND80, animals were tested for habituation to the acoustic stimuli and prepulse inhibition following a challenge of either saline or 1.0 mg/kg amphetamine (AMP) intraperitoneally. Amphetamine increased ASR and startle latencies throughout the session. The AZT100 dose increased ASR habituation. AZT treatment did not affect prepulse inhibition. Females treated with AZT150 continued to show high ASRs at the end of the startle session. AZT-treated animals showed a dose-dependent increase in peak latency, suggesting a possible abnormal conduction velocity. These effects are independent of handling and intubation effects. Therefore, perinatal AZT treatment results in long-term changes within the primary acoustic startle pathway.

Synaptic plasticity in the acoustic startle pathway: the neuronal basis for short-term habituation?

The aim of the present study was to analyse the cellular mechanism underlying short-term habituation of the acoustic startle response (ASR). We explored distinct synapses of the neuronal startle pathway in rat brain slices by patch-clamp recordings of giant neurons in the caudal pontine reticular formation. Presynaptic stimulation of auditory afferents by repeated bursts at 0.1 and 1 Hz led to an exponential decay of EPSC magnitudes. This homosynaptic depression (HSD) was reversible and repeatedly inducible after recovery. Many parameters of HSD in vitro match those of ASR habituation in vivo. The mechanisms underlying HSD are distinct from classical short-term plasticity: paired-pulse as well as paired-burst stimulation revealed a facilitation of the second EPSC, occurring in a much smaller time window up to interstimulus intervals of 200 ms. Pharmacological experiments demonstrated that HSD could be completely blocked by the group II and III metabotropic glutamate receptor antagonist MPPG. Similar results were obtained by CPPG, another group II and III antagonist. In contrast, HSD was not affected by the group I and II antagonist MCPG. We conclude that we found a form of synaptic depression in synapses within the primary startle pathway which correlates in many respects with short-term habituation of the ASR and which is presumably mediated by group III metabotropic glutamate receptors.

Neural transplants: effects on startle responses in neonatally MSG-treated rats

Neonatal monosodium glutamate (MSG) treatment has been associated with disfunctions in stress responses. Therefore, the present study aimed at examining the acoustic startle response (ASR) in MSG-treated rats and the effects of fetal neural transplantation. Male and female rats were given MSG (4 mg/g) or saline on alternate days from days 2–10 after birth. To determine whether fetal transplants could reverse behavioral impairments observed in MSG-treated rats, at 12 days of age MSG-treated rats received either arcuate nucleus (AN), cortical fetal grafts, or sham surgery into the third ventricle. ASR amplitude was measured at 35–40 days of age, and again in adulthood. MSG produced the expected decrease in the density of hypothalamic neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the AN area. Corticotropin-releasing factor (CRF) neurons/fibers were not affected by MSG. Pituitary atrophy was observed in all MSG rats. We report a permanent increase in the amplitude and reduction in short-term habituation of ASR in all MSG-treated rats. No effect was observed on long-term habituation in male rats. Cortical, but not AN tissue significantly reduced the magnitude of ASR in MSG animals. The results are discussed in terms of the central pathways mediating ASR, in particular hypothalamo-amygdala connections. It is considered that nonspecific factors mediate recovery produced by cortical tissue grafts, as observed in other models of neural transplan-tation.

Concurrent assessment of acoustic startle and auditory P50 evoked potential measures of sensory inhibition

The acoustic startle response (ASR) and midlatency auditory evoked potentials (AEP) have been utilized in the measurement of sensory inhibition. Using these different paradigms, abnormalities suggesting a lack of normal inhibition have been noted in a number of psychiatric syndromes. To date, the most commonly used sensory inhibition paradigms have not been studied in the same individuals, making generalizations across studies tenuous. In this report, reduction of ASR over multiple trials (habituation), prepulse inhibition (PPI) of ASR (decrease in ASR caused by low intensity prepulses) and P50 suppression (P50 AEP amplitude reduction in a paired-click paradigm) were measured in the same individuals. Relationships between these measures of acoustic startle and AEP inhibition were then assessed. Twenty subjects with no personal history of psychiatric disorder were tested and exhibited significant habituation and PPI of ASR as well as P50 suppression. Habituation of ASR was significantly and positively correlated with P50 suppression early, but not late, in AEP testing. Only a modest trend for a positive association between PPI and P50 suppression was noted. Habituation and PPI of startle were both highly correlated (positively) with P50 AEP amplitude. Habituation of startle remained significantly predictive of P50 suppression after controlling for P50 amplitude, whereas the modest association between PPI and P50 suppression was removed when P50 amplitude was factored out. Results indicate that habituation of acoustic startle, but not PPI, is highly associated with P50 suppression in control subjects. An unexpected finding was a robust positive correlation between P50 amplitude and both measures of startle inhibition. These findings and methodologic issues are discussed in terms of possible neural substrates involved in differrent measures of sensory inhibition.

Refractory period and habituation of acoustic startle response in rats.

The time course of the recovery cycle (refractory period) of the acoustic startle response in rats was determined. The refractory effect was shown to be highly dependent upon the interval between two startle stimuli but independent of the intensity of the stimuli at a given interval, provided that the intensity of both stimuli was the same. A model based on summation of refractory effects to repetitive stimulation did not predict habituation to repetitive stimulation. The interaction between refractory effect and habituation was discussed, and it was suggested that short interstimulus intervals reduce the effective intensity of the habituation stimulus so that the effects of frequency and intensity become confounded in habituation studies where the interval between habituation stimuli invades the refractory period of the response being studied.