Prepulse Inhibition Of Acoustic Startle Research Articles

Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat

Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies. This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone. Forty-two male Lister-hooded rat pups received the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n = 11 or PCP-treated n = 10) or isolation (saline n = 10 or PCP n = 11). Six weeks post-weaning, novelty- and PCP-induced (3.2mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded. Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment. Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone.

EPA-0476 – Comparative study of P50 suppression, PPI and antisaccade measures in first episode and chronic schizophrenia patients

The aim of the study was to compare P50 suppression, prepulse inhibition (PPI) and antisaccade (AS) measures in first episode and chronic schizophrenia patients to assess the predictive validity and progressive changes of selected parameters. Unmedicated first-episode (15 subjects) and chronic (15 subjects) schizophrenia patients participated in the study. The patients’ symptomatology was rated with the Positive and Negative Syndrome Scale (PANSS). Control group included 21 healthy subjects. P50 suppression and acoustic startle prepulse inhibition (PPI) were estimated according to standard protocols (Olincy et al., 2010; Calkins et al., 2007). In AS task subjects had to look as quickly as possible at the horizontal mirror position of the peripheral target. Saccade and contingent negative variation (CNV) parameters were evaluated. Higher PANSS scales values were found in chronic patients compared to first episode ones. Both patients’ groups displayed significantly reduced P50 suppression (p<0,001) and prepulse inhibition deficit at 60 ms lead interval (p<0,05) compared to controls. Patients of both groups exhibited increase in the correct AS latency and larger number of errors in AS task compared to controls (p<0,05). The pronounced decline of CNV amplitude in frontal regions was found in chronic patients only ( Group x Area interaction , p<0,05). Results of the study corroborate the evidences of P50, PPI and AS measures predicting validity. The CNV analysis revealed pronounced prefrontal cortex dysfunction in chronic patients only. These data are compatible with the hypothesis of progressive brain changes in schizophrenia.

Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

EPA-0460 – Effects of comt val158/met polymorphism on sensory-motor gating and blood monoamines level in russian schizophrenia patients and healthy persons

Catechol-O-methyltransferase (COMT) is candidate gene for schizophrenia, as it encodes enzyme involved in dopamine and noradrenaline methabolism. However, data concerning association of COMT polymorphism with schizophrenia onset in different ethnic groups are controversial. Impaired acoustic startle prepulse inhibition (PPI) is potential hallmark of vulnerability to schizophrenia, but a few investigations of COMT polymorphism effects on PPI revealed controversial results (Liu et al., 2013). To estimate effects of COMT polymorphism on PPI and blood monoamines level in Russian populations of schizophrenia patients and healthy persons. (males 22–55 years old): 39 schizophrenia patients and 32 healthy persons. PPI was estimated according to standard protocol (Calkins et al., 2007). Blood monoamnes estimated using HPLC with electrochemical detection. COMT polymorphism was detected by real-time PCR. There were significantly (p<0,05) lower heterozygotes frequency, impaired PPI, increased baseline startle latency, decreased plasma DOPAC in patients relatively to controls. Group x Genotype interaction was revealed for PPI and startle latency. In controls VAL/VAL carriers displayed the lowest PPI. In patients the lowest PPI showed VAL/ME T and the longest startle latency - MET/MET carriers. In controls PPI positively correlated with dopamine turnover ratio whereas in patients - with plasma adrenaline level. In Russian population effects of COMT VAL158/MET polymorphism on PPI significantly differ at healthy and schizophrenia persons. One can propose that PPI level in healthy subjects more strictly depends on dopamine turnover than in schizophrenia patients. Further investigations are needed to clear this problem. Supported by RHF grant 12-06-00809a

Long-lasting sensitization induced by repeated risperidone treatment in adolescent Sprague-Dawley rats: a possible D2 receptor mediated phenomenon?

Risperidone use in children and adolescents for the treatment of various neuropsychiatric disorders (e.g., schizophrenia, autism, disruptive behavior, etc.) has increased substantially in recent decades. However, its long-term effect on the brain and behavioral functions is not well understood. The present study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response in adulthood in the conditioned avoidance response and phencyclidine (PCP)-induced hyperlocomotion tests. Male adolescent Sprague-Dawley rats (postnatal days [P] 40-44 or 43-48) were first treated with risperidone (0.3, 0.5, or 1.0 mg/kg, subcutaneously (sc)) and tested in the conditioned avoidance or PCP (3.2 mg/kg, sc)-induced hyperlocomotion model daily for five consecutive days. After they became adults (~P 76-80), they were challenged with risperidone (0.3 mg/kg, sc) to assess their sensitivity to risperidone reexposure. A quinpirole (a D2/3 receptor agonist, 1.0 mg/kg, sc)-induced hyperlocomotion test was later conducted to assess the risperidone-induced functional changes in D2 receptor. In the risperidone challenge test in adulthood, adult rats previously treated with risperidone in adolescence made significantly fewer avoidance responses and exhibited significantly lower PCP-induced hyperlocomotion than those previously treated with vehicle. They also appeared to be more hyperactive than the vehicle-pretreated ones in the quinpirole-induced hyperlocomotion test. Prepulse inhibition of acoustic startle or fear-induced 22 kHz ultrasonic vocalizations in adulthood was not altered by adolescence risperidone treatment. Adolescent risperidone exposure induces a long-term increase in behavioral sensitivity to risperidone that persists into adulthood. This long-lasting change might be due to functional upregulation of D2-mediated neurotransmission.

동물 이명 검사용 GPIAS 측정 장치 구현과 이를 통한 자극 배경음의 시작 시점이 놀람 반응에 주는 영향

As one of the effective methods for researching the objective tinnitus detection, the GPIAS (Gap Pre-pulse Inhibition of Acoustic Startle) measurement has been used to verify the existence of animal tinnitus objectively. The level and pattern of the background sound presented prior to a startle pulse are closely related with the GPIAS results. But the effect of the starting point of the background sound on animal startle responses has not been reported yet. In this paper, we present the implementation of a GPIAS measurement system based on an unconstrained enclosure to avoid animals' excessive constraint stress and deal with the animals' growth. After the performance of our implemented system has been tested through the animal experiment using 4 SD-rats, the effect of starting point of stimulus background sound on the startle response has been studied by the use of our implemented system. Through the results, it is verified that our system can measure the inhibition of animal startle responses due the gap pre-pulse for GPIAS calculation and the background sound starting point does not significantly effect on the startle response and the GPIAS values if the background sound continues for more than 300msec before a gap pre-pulse is presented.

MitoPark mice, an animal model of Parkinson’s disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A2A antagonist SCH 412348

Psychoses are debilitating side effects associated with current dopaminergic treatments for Parkinson's disease (PD). Prepulse inhibition (PPI), in which a non-startling stimulus reduces startle response to a subsequent startle-eliciting stimulus, is important in filtering out extraneous sensory stimuli. PPI deficits induced by dopamine agonists can model symptoms of psychosis. Adenosine A(2A) receptor antagonists, being developed as novel PD treatments, indirectly modulate dopamine signaling in the basal ganglia and may have an improved psychosis profile which could be detected using the PPI model. The aims of this study is to characterize PPI in MitoPark mice, which exhibit progressive loss of dopamine signaling and develop a Parkinson-like motor phenotype, and assess standard and novel PD treatment effects on PPI in MitoPark mice, which more closely mimic the basal ganglia dopamine status of PD patients. MitoPark mice displayed enhanced PPI as dopamine tone decreased with age, consistent with studies in intact mice that show enhanced PPI in response to dopamine antagonists. Paradoxically, older MitoParks were more sensitive to PPI disruption when challenged with dopamine agonists such as apomorphine or pramipexole. Alternatively, SCH 412348, an adenosine A(2A) antagonist, did not disrupt PPI in MitoPark mice at doses that normalized hypoactivity. Use of MitoPark mice in the PPI assay to assess the potential for PD treatment to produce psychoses likely represents a more disease-relevant model. SCH 412348 does not differentially disrupt PPI as do dopamine agonists, perhaps indicative of an improved psychosis profile of adenosine A(2A) antagonists, even in PD patients with decreased dopamine tone in the basal ganglia.

Effects of Salicylate on the Inflammatory Genes Expression and Synaptic Ultrastructure in the Cochlear Nucleus of Rats

Aspirin (salicylate), as a common drug that is frequently used for long-term treatment in a clinical setting, has the potential to cause reversible tinnitus. However, few reports have examined the inflammatory cytokines expression and alteration of synaptic ultrastructure in the cochlear nucleus (CN) in a rat model of tinnitus. The tinnitus-like behavior of rats were detected by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. We investigated the expression levels of the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), N-methyl D-aspartate receptor subunit 2A (NR2A) mRNA and protein in the CN and compared synapses ultrastructure in the CN of tinnitus rats with normal ones. GPIAS showed that rats with long-term administration of salicylate were experiencing tinnitus, and the mRNA and protein expression levels of TNF-α and NR2A were up-regulated in chronic treatment groups, and they returned to baseline 14 days after cessation of treatment. Furthermore, compared to normal rats, repetitive salicylate-treated rats showed a greater number of presynaptic vesicles, thicker and longer postsynaptic densities, increased synaptic interface curvature. These data revealed that chronic salicylate administration markedly, but reversibly, induces tinnitus possibly via augmentation of the expression of TNF-α and NR2A and cause changes in synaptic ultrastructure in the CN. Long-term administration of salicylate causes neural plasticity changes at the CN level.

Neuronal nitric oxide synthase and NADPH oxidase interact to affect cognitive, affective, and social behaviors in mice

Both nitric oxide (NO) and reactive oxygen species (ROS) generated by nNOS and NADPH oxidase (NOX), respectively, in the brain have been implicated in an array of behaviors ranging from learning and memory to social interactions. Although recent work has elucidated how these separate redox pathways regulate neural function and behavior, the interaction of these two pathways in the regulation of neural function and behavior remains unspecified. Toward this end, the p47phox subunit of NOX, and nNOS were deleted to generate double knockout mice that were used to characterize the behavioral outcomes of concurrent impairment of the NO and ROS pathways in the brain. Mice were tested in a battery of behavioral tasks to evaluate learning and memory, as well as social, affective, and cognitive behaviors. p47phox deletion did not affect depressive-like behavior, whereas nNOS deletion abolished it. Both p47phox and nNOS deletion singly reduced anxiety-like behavior, increased general locomotor activity, impaired spatial learning and memory, and impaired preference for social novelty. Deletion of both genes concurrently had synergistic effects to elevate locomotor activity, impair spatial learning and memory, and disrupt prepulse inhibition of acoustic startle. Although preference for social novelty was impaired in single knockouts, double knockout mice displayed elevated levels of preference for social novelty above that of wild type littermates. These data demonstrate that, depending upon modality, deletion of p47phox and nNOS genes have dissimilar, similar, or additive effects. The current findings provide evidence that the NOX and nNOS redox signaling cascades interact in the brain to affect both cognitive function and social behavior.

Trans-canal laser irradiation reduces tinnitus perception of salicylate treated rat

The aim of this study was to find out the effect of low-level laser therapy (LLLT) on salicylate-induced tinnitus in the rat model. Fourteen Sprague-Dawley rats (8 weeks; 240–280gm) were divided into 2 groups (study group, control group). Rats of both groups were treated with 400mg/kg/day of sodium salicylate for 8 consecutive days. Tinnitus was monitored using GPIAS (Gap Prepulse Inhibition of Acoustic Startle) 2h after first salicylate treatment, and every 24h during 9 days of treatment. Rats in laser group were irradiated to each ear with wavelength of 830nm diode laser (165mW/cm2) for 30min daily for 8 days. During salicylate treatment, rats of study group irradiated with low level laser showed significantly higher GPIAS values throughout the experiment. Therapeutic effect of LLLT is demonstrated in animal tinnitus model by means of GPIAS. Further experimental studies are needed to find possible mechanisms and better methods to improve LLLT efficacy.

Impaired prepulse inhibition of acoustic startle in Chinese patients with first-episode, medication-naïve schizophrenia

Background Patients with schizophrenia have prominent abnormality in information processing that can be observed by measures of prepulse inhibition (PPI) of acoustic startle reflex and PPI deficits have been considered as a candidate endophenotypic marker of schizophrenia. However, there has been little information on PPI and related measures in Chinese patients with schizophrenia. The research was to explore the deficits of acoustic startle reflex that might exist in Chinese patients with schizophrenia. Methods Startle response to acoustic stimuli, habituation, and PPI were examined in 31 Chinese patients with first-episode, medication-naïve schizophrenia and 30 age- and sex- matched healthy Chinese controls. At the same day of startle testing, psychopathological symptoms of the patients were assessed with the Positive and Negative Syndrome Scale (PANSS). Results Compared with healthy controls, patients exhibited the significant reduction in startle response and PPI deficits at 60 milliseconds (ms) intervals (PPI60, P &lt;0.05) but not at 30 or 120 ms intervals. Furthermore, there was a relatively strong correlation between PPI60 (P &lt;0.05) and scores of positive scale of PANSS in patients with schizophrenia. Conclusion Our findings confirmed impaired PPI in Chinese patients with schizophrenia and suggested that a relationship between sensorimotor gating deficits and clinical symptoms of patients with schizophrenia might exist.

Kalrnplays key roles within and outside of the nervous system

BackgroundThe human KALRN gene, which encodes a complex, multifunctional Rho GDP/GTP exchange factor, has been linked to cardiovascular disease, psychiatric disorders and neurodegeneration. Examination of existing Kalrn knockout mouse models has focused only on neuronal phenotypes. However, Kalirin was first identified through its interaction with an enzyme involved in the synthesis and secretion of multiple bioactive peptides, and studies in C.elegans revealed roles for its orthologue in neurosecretion.ResultsWe used a broad array of tests to evaluate the effects of ablating a single exon in the spectrin repeat region of Kalrn (KalSRKO/KO); transcripts encoding Kalrn isoforms containing only the second GEF domain can still be produced from the single remaining functional Kalrn promoter. As expected, KalSRKO/KO mice showed a decrease in anxiety-like behavior and a passive avoidance deficit. No changes were observed in prepulse inhibition of acoustic startle or tests of depression-like behavior. Growth rate, parturition and pituitary secretion of growth hormone and prolactin were deficient in the KalSRKO/KO mice. Based on the fact that a subset of Kalrn isoforms is expressed in mouse skeletal muscle and the observation that muscle function in C.elegans requires its Kalrn orthologue, KalSRKO/KO mice were evaluated in the rotarod and wire hang tests. KalSRKO/KO mice showed a profound decrease in neuromuscular function, with deficits apparent in KalSR+/KO mice; these deficits were not as marked when loss of Kalrn expression was restricted to the nervous system. Pre- and postsynaptic deficits in the neuromuscular junction were observed, along with alterations in sarcomere length.ConclusionsMany of the widespread and diverse deficits observed both within and outside of the nervous system when expression of Kalrn is eliminated may reflect its role in secretory granule function and its expression outside of the nervous system.

Altered Neuronal Intrinsic Properties and Reduced Synaptic Transmission of the Rat's Medial Geniculate Body in Salicylate-Induced Tinnitus

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.

The Effect of Injury Severity on Behavior: A Phenotypic Study of Cognitive and Emotional Deficits after Mild, Moderate, and Severe Controlled Cortical Impact Injury in Mice

Traumatic brain injury (TBI) can cause a broad array of behavioral problems including cognitive and emotional deficits. Human studies comparing neurobehavioral outcomes after TBI suggest that cognitive impairments increase with injury severity, but emotional problems such as anxiety and depression do not. To determine whether cognitive and emotional impairments increase as a function of injury severity we exposed mice to sham, mild, moderate, or severe controlled cortical impact (CCI) and evaluated performance on a variety of neurobehavioral tests in the same animals before assessing lesion volume as a histological measure of injury severity. Increasing cortical impact depth successfully produced lesions of increasing severity in our model. We found that cognitive impairments in the Morris water maze increased with injury severity, as did the degree of contralateral torso flexion, a measure of unilateral striatal damage. TBI also caused deficits in emotional behavior as quantified in the forced swim test, elevated-plus maze, and prepulse inhibition of acoustic startle, but these deficits were not dependent on injury severity. Stepwise regression analyses revealed that Morris water maze performance and torso flexion predicted the majority of the variability in lesion volume. In summary, we find that cognitive deficits increase in relation to injury severity, but emotional deficits do not. Our data suggest that the threshold for emotional changes after experimental TBI is low, with no variation in behavioral deficits seen between mild and severe brain injury.

Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine

Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α7 nACh receptor antagonist methyllycaconitine or WAY100635, while the α4β2 nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Prepulse Inhibition of Acoustic Startle and the Influence of Methylphenidate in Children With ADHD

Objective: ADHD is common among children with comorbidity of enuresis. Findings concerning prepulse inhibition (PPI) of startle reflexes are controversial. Although PPI is improved through desamino-arginine vasopressin (dDAVP) in enuresis, some patients also improve concomitant ADHD through dDAVP. This study aims to evaluate whether methylphenidate (MPH) also improves PPI in ADHD. Method: Nineteen ADHD patients were investigated in a prospective, double-blind, crossover study with MPH versus placebo. PPI was measured as a reduction of acoustic startle reflexes. Subgroups of gender, ADHD subtype, and baseline PPI were analyzed. Results: Median baseline PPI of ADHD patients (51.7%) was below the value of age-matched normal controls (73%, p = .090). MPH showed no improvement in the whole group, or the subgroups gender or subtype. Reduced baseline PPI was significantly improved (22.5%-39.3%, p = .039). Conclusion: Heterogeneity of ADHD is confirmed with a wide range of baseline PPI. The improvement of reduced baseline PPI through MPH suggests impaired sensorimotor gating in this subgroup.

Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route‐based learning as a function of maternal body weight gain after prenatal exposure to poly IC

Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).

Time course of tinnitus development following noise exposure in mice

Gap-induced prepulse inhibition of acoustic startle (GPIAS) has been used in rats and mice to study the problem of tinnitus. The current study demonstrates that similar methods can be used to study the temporal development of tinnitus over time in middle-aged mice. Six-month-old mice on a mixed C57Bl6 × 129 background were anesthetized with isoflurane and exposed to unilateral noise (n = 15), or sham exposure for controls (n = 8), for 1 hr (16-kHz octave band signal, 116-dB SPL). Tinnitus was tested in eight different sound frequency bands before and at postexposure time points of 1, 3-4, 7, 14, 21, and 30 days and monthly thereafter until 7 months postexposure. Noise-exposed mice displayed a number of changes in GPIAS consistent with the presence of hyperacusis and tinnitus. Noise exposure was associated with acute tinnitus measured 1 day later at several frequencies at and above the exposure frequency center. Consistent, chronic tinnitus then emerged in the 24-kHz range. Several time points following noise exposure suggested evidence of hyperacusis, often followed temporally by the development of deficits in GPIAS (reflecting tinnitus). Temporal development of these changes following noise exposure are discussed in the context of the interactions among aging, noise exposure, and the associated neurochemical changes that occur at early stages of auditory processing.

Habituation and Prepulse Inhibition of Acoustic Startle in Rodents

The acoustic startle response is a protective response, elicited by a sudden and intense acoustic stimulus. Facial and skeletal muscles are activated within a few milliseconds, leading to a whole body flinch in rodents(1). Although startle responses are reflexive responses that can be reliably elicited, they are not stereotypic. They can be modulated by emotions such as fear (fear potentiated startle) and joy (joy attenuated startle), by non-associative learning processes such as habituation and sensitization, and by other sensory stimuli through sensory gating processes (prepulse inhibition), turning startle responses into an excellent tool for assessing emotions, learning, and sensory gating, for review see( 2, 3). The primary pathway mediating startle responses is very short and well described, qualifying startle also as an excellent model for studying the underlying mechanisms for behavioural plasticity on a cellular/molecular level(3). We here describe a method for assessing short-term habituation, long-term habituation and prepulse inhibition of acoustic startle responses in rodents. Habituation describes the decrease of the startle response magnitude upon repeated presentation of the same stimulus. Habituation within a testing session is called short-term habituation (STH) and is reversible upon a period of several minutes without stimulation. Habituation between testing sessions is called long-term habituation (LTH)(4). Habituation is stimulus specific(5). Prepulse inhibition is the attenuation of a startle response by a preceding non-startling sensory stimulus(6). The interval between prepulse and startle stimulus can vary from 6 to up to 2000 ms. The prepulse can be any modality, however, acoustic prepulses are the most commonly used. Habituation is a form of non-associative learning. It can also be viewed as a form of sensory filtering, since it reduces the organisms' response to a non-threatening stimulus. Prepulse inhibition (PPI) was originally developed in human neuropsychiatric research as an operational measure for sensory gating(7). PPI deficits may represent the interface of "psychosis and cognition" as they seem to predict cognitive impairment(8-10). Both habituation and PPI are disrupted in patients suffering from schizophrenia(11), and PPI disruptions have shown to be, at least in some cases, amenable to treatment with mostly atypical antipsychotics(12, 13). However, other mental and neurodegenerative diseases are also accompanied by disruption in habituation and/or PPI, such as autism spectrum disorders (slower habituation), obsessive compulsive disorder, Tourette's syndrome, Huntington's disease, Parkinson's disease, and Alzheimer's Disease (PPI)(11, 14, 15) Dopamine induced PPI deficits are a commonly used animal model for the screening of antipsychotic drugs(16), but PPI deficits can also be induced by many other psychomimetic drugs, environmental modifications and surgical procedures.

Habituation and Prepulse Inhibition of Acoustic Startle in Rodents

The acoustic startle response is a protective response, elicited by a sudden and intense acoustic stimulus. Facial and skeletal muscles are activated within a few milliseconds, leading to a whole body flinch in rodents1. Although startle responses are reflexive responses that can be reliably elicited, they are not stereotypic. They can be modulated by emotions such as fear (fear potentiated startle) and joy (joy attenuated startle), by non-associative learning processes such as habituation and sensitization, and by other sensory stimuli through sensory gating processes (prepulse inhibition), turning startle responses into an excellent tool for assessing emotions, learning, and sensory gating, for review see 2, 3. The primary pathway mediating startle responses is very short and well described, qualifying startle also as an excellent model for studying the underlying mechanisms for behavioural plasticity on a cellular/molecular level3. We here describe a method for assessing short-term habituation, long-term habituation and prepulse inhibition of acoustic startle responses in rodents. Habituation describes the decrease of the startle response magnitude upon repeated presentation of the same stimulus. Habituation within a testing session is called short-term habituation (STH) and is reversible upon a period of several minutes without stimulation. Habituation between testing sessions is called long-term habituation (LTH)4. Habituation is stimulus specific5. Prepulse inhibition is the attenuation of a startle response by a preceding non-startling sensory stimulus6. The interval between prepulse and startle stimulus can vary from 6 to up to 2000 ms. The prepulse can be any modality, however, acoustic prepulses are the most commonly used. Habituation is a form of non-associative learning. It can also be viewed as a form of sensory filtering, since it reduces the organisms' response to a non-threatening stimulus. Prepulse inhibition (PPI) was originally developed in human neuropsychiatric research as an operational measure for sensory gating7. PPI deficits may represent the interface of "psychosis and cognition" as they seem to predict cognitive impairment8-10. Both habituation and PPI are disrupted in patients suffering from schizophrenia11, and PPI disruptions have shown to be, at least in some cases, amenable to treatment with mostly atypical antipsychotics12, 13. However, other mental and neurodegenerative diseases are also accompanied by disruption in habituation and/or PPI, such as autism spectrum disorders (slower habituation), obsessive compulsive disorder, Tourette's syndrome, Huntington's disease, Parkinson's disease, and Alzheimer's Disease (PPI)11, 14, 15 Dopamine induced PPI deficits are a commonly used animal model for the screening of antipsychotic drugs16, but PPI deficits can also be induced by many other psychomimetic drugs, environmental modifications and surgical procedures.