Magnitude Of Prepulse Inhibition Research Articles

Unraveling the role of Slc10a4 in auditory processing and sensory motor gating: Implications for neuropsychiatric disorders?

BackgroundPsychiatric disorders, such as schizophrenia, are complex and challenging to study, partly due to the lack of suitable animal models. However, the absence of the Slc10a4 gene, which codes for a monoaminergic and cholinergic associated vesicular transporter protein, in knockout mice (Slc10a4−/−), leads to the accumulation of extracellular dopamine. A major challenge for studying schizophrenia is the lack of suitable animal models that accurately represent the disorder. We sought to overcome this challenge by using Slc10a4−/− mice as a potential model, considering their altered dopamine levels. This makes them a potential animal model for schizophrenia, a disorder known to be associated with altered dopamine signaling in the brain. MethodsThe locomotion, auditory sensory filtering and prepulse inhibition (PPI) of Slc10a4−/− mice were quantified and compared to wildtype (WT) littermates. Intrahippocampal electrodes were used to record auditory event-related potentials (aERPs) for quantifying sensory filtering in response to paired-clicks. The channel above aERPs phase reversal was chosen for reliably comparing results between animals, and aERPs amplitude and latency of click responses were quantified. WT and Slc10a4−/− mice were also administered subanesthetic doses of ketamine to provoke psychomimetic behavior. ResultsBaseline locomotion during auditory stimulation was similar between Slc10a4−/− mice and WT littermates. In WT animals, normal auditory processing was observed after i.p saline injections, and it was maintained under the influence of 5 mg/kg ketamine, but disrupted by 20 mg/kg ketamine. On the other hand, Slc10a4−/− mice did not show significant differences between N40 S1 and S2 amplitude responses in saline or low dose ketamine treatment. Auditory gating was considered preserved since the second N40 peak was consistently suppressed, but with increased latency. The P80 component showed higher amplitude, with shorter S2 latency under saline and 5 mg/kg ketamine treatment in Slc10a4−/− mice, which was not observed in WT littermates. Prepulse inhibition was also decreased in Slc10a4−/− mice when the longer interstimulus interval of 100 ms was applied, compared to WT littermates. ConclusionThe Slc10a4−/− mice responses indicate that cholinergic and monoaminergic systems participate in the PPI magnitude, in the temporal coding (response latency) of the auditory sensory gating component N40, and in the amplitude of aERPs P80 component. These results suggest that Slc10a4−/− mice can be considered as potential models for neuropsychiatric conditions.

Individual difference in prepulse inhibition does not predict spatial learning and memory performance in C57BL/6 mice

The startle reflex to an intense acoustic pulse stimulus is attenuated if the pulse stimulus is shortly preceded by a weak non-startling prepulse stimulus. This attenuation of the startle reflex represents a form of pre-attentional sensory gating known as prepulse inhibition (PPI). Although PPI does not require learning, its expression is regulated by higher cognitive processes. PPI deficits have been detected in several psychiatric conditions including schizophrenia where they co-exist with cognitive deficits. A potential link between PPI expression and cognitive performance has therefore been suggested such that poor PPI may predict, or may be mechanistically linked to, overt cognitive impairments. A positive relationship between PPI and strategy formation, planning efficiency, and execution speed has been observed in healthy humans. However, parallel studies in healthy animals are rare. It thus remains unclear what cognitive domains may be associated with, or orthogonal to, sensory gating in the form of PPI in healthy animals. The present study evaluated a potential link between the magnitude of PPI and spatial memory performance by comparing two subgroups of animals differing substantially in baseline PPI expression (low-PPI vs high-PPI) within a homogenous cohort of 100 male adult C57BL/6 mice. Assessment of spatial reference memory in the Morris water maze and spatial recognition memory in the Y-maze failed to reveal any difference between low-PPI and high-PPI subjects. These negative findings contrast with our previous reports that individual difference in PPI correlated with sustained attention and working memory performance in C57BL/6 mice.

Prenatal IV nicotine exposure produces a sex difference in sensorimotor gating of the auditory startle reflex in adult rats

Maternal smoking during pregnancy is associated with auditory processing deficits in children; these effects have been confirmed with animal models of continuous high-dose prenatal nicotine exposure. The present experiments utilized a novel, low-dose, intermittent, intravenous (IV) gestational nicotine exposure model to investigate potential deficits on the preattentive process of sensorimotor gating, as indexed by prepulse inhibition (PPI), in preweanling and adult rat offspring. Pregnant dams received bolus IV injections of nicotine (0.05mg/kg/injection) 3×/day on gestational days 8–21. Auditory and tactile stimulus modalities were probed with tone and air puff prepulse stimuli, respectively. These prepulse stimuli preceded a 100dB(A) startle tone by six different interstimulus intervals (ISIs; 0, 8, 40, 80, 120, 4000ms) to define a curve of response inhibition. The magnitude of PPI increased with age, from 59 to 81% inhibition. Preweanlings (PNDs 14 and 18) and adults (PND 75) gestationally exposed to nicotine exhibited altered startle responding relative to controls, but the nature of the deficit became more localized at later ages. The entire curve of response inhibition in preweanlings exposed to prenatal nicotine (PND 14) was shifted up relative to controls, and notably, did not interact with prepulse stimulus modality, suggesting a generalized increased sensorimotor responsiveness as a function of prenatal nicotine. At PND 18, a shift in the response curve across all ISIs was again noted, but varied as a function of prepulse stimulus modality; the increased sensorimotor responsiveness was specific to the auditory, but not tactile, sensory modality. In adulthood, male and female animals prenatally exposed to nicotine were differentially sensitive to modulation by the ISIs, relative to control male and female animals. Specifically, despite robust PPI, adult females exposed to gestational nicotine were relatively insensitive to changes in ISI from 8 to 120ms; in contrast, the robust PPI of nicotine-exposed males demonstrated a clear focal point of inhibition at 40ms. These findings indicate that a low, daily dosing of IV prenatal nicotine produces long-lasting alterations in auditory PPI. An important implication of this research is that “chipping” with smoked-tobacco products during pregnancy may produce enduring changes in sensorimotor processing.

Acoustic startle and disruption of prepulse inhibition by dizocilpine in selectively bred mice.

In this study we examined the relationship between genetically produced differences in the magnitude of prepulse inhibition (PPI) of the acoustic startle response (ASR) and stress induced swim analgesia in genetically different strains of mice. Prepulse inhibition of the ASR and its changes due to dizocilpine (MK-801) injection were studied in 180 mice. The animals used in this study were obtained from our colony of 54 generation, Swiss-Webster mice selectively bred for high and low magnitude of analgesia. Three month old male mice of the high analgesia (HA) and the low analgesia (LA) lines, in addition to randomly bred controls (C) were used in the experiment. Thirty minutes before the ASR session the mice were injected intraperitoneally with saline or with 0.15, 0.25, 0.5 mg÷kg of dizocilpine maleate. Prepulses suppressed the acoustic startle response in all lines in a prepulse intensity-dependent manner, but only the differences between the weakest and the strongest prepulses appeared significant. Two-way ANCOVA performed separately for each line revealed a significant effect of dizocilpine and prepulse intensity. Only in the HA line, however, the disruption of PPI from the injection of dizocilpine was evidenced by significant treatment by prepulse interaction. That means the prepulses decreased ASR significantly less in dizocilpine- treated animals than in saline-treated animals. The results confirmed that the mouse lines manifesting differential ASR magnitudes along with different degrees of PPI sensitivity to dizocilpine, might be suitable for pharmacogenetic studies on the glutaminergic mechanism of the startle response.

Acute or subchronic clozapine treatment does not ameliorate prepulse inhibition (PPI) deficits in CPB-K mice with low levels of hippocampal NMDA receptor density

The hypo-glutamatergic hypothesis of schizophrenia is based on clinical similarities between schizophrenia and phencyclidine (PCP)-induced psychosis in mentally healthy humans. Sensorimotor gating, as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), is impaired in schizophrenic patients. In animals, noncompetitive N-methyl-D: -aspartate (NMDA) antagonists such as PCP disrupt PPI in a way that resembles the defect seen in schizophrenia. In a previous study with inbred mouse strains, low PPI levels have been demonstrated in CPB-K mice possessing low levels of hippocampal NMDA receptor densities. The present study was performed to test whether the low magnitude of PPI in CPB-K mice can be reversed by the atypical antipsychotic drug clozapine (CLZ). Before any treatment, CPB-K mice displayed a significant (p < 0.001) lower level in PPI and a significant (p < 0.001) higher ASR when compared to BALB/cJ mice known to have high hippocampal NMDA receptor densities. Acute and subchronic effects of a 2-week treatment with CLZ at daily doses of 5 and 10 mg/kg intraperitoneally, respectively, did not reveal any significant alteration of PPI levels in CPB-K mice. Nevertheless, the examination of motor behavior during nonstimulus trials provided a positive control for the drug's effectiveness. In summary, (1) this study confirmed our working hypothesis: Lower levels of hippocampal glutamatergic receptor densities correspond to lower sensorimotor gating in CPB-K mice, and (2) acute or subchronic treatment with CLZ did not elevate low PPI levels in CPB-K mice. Thus, further experiments will concentrate on other antipsychotic drugs to prove the predictive validity of this animal model.

The monotonic dependency of prepulse inhibition of the acoustic startle reflex on the intensity of the startle-eliciting stimulus

Prepulse inhibition (PPI) of the acoustic startle reflex is a translational behavioural paradigm for the assessment of sensorimotor gating deficit which has been demonstrated in a number of neuropsychiatric conditions. PPI refers to the reduction of the reflexive startle response to a ‘pulse’ stimulus when its presentation is shortly preceded by a weak ‘prepulse’ stimulus. We have recently examined the expression of PPI as a function of the startle-eliciting ‘pulse’ stimulus intensity in mice and in humans. One major discrepancy that emerged was the finding that healthy human subjects, unlike normal mice, did not show a clear monotonic reduction of PPI magnitude (as indexed by % reduction in startle reactivity) with increasingly intense pulse stimulus. This lack of correspondence between species may potentially weaken the translational power of the PPI paradigm. Here, we re-examined this issue in 31 healthy subjects across three levels of pulse stimulus intensity (95, 105 and 115 dB). A clear linear reduction of PPI as a function of pulse intensity was revealed when subjects failing to respond to the lowest pulse stimulus were excluded. Inclusion of such non-responders, on the other hand, resulted in a trend towards an inverted U-shape function as reported previously. The present study thus clarifies an apparent divergence between mouse and man, and provides important qualification to the “First Law of Reflex Modification” proposed by Hoffman and Ison which suggests that the absolute reduction in startle reactivity resulting from a prepulse stimulus preceding the startle-eliciting pulse stimulus is fixed by the prepulse intensity regardless of the pulse stimulus intensity.

Attentional blink and prepulse inhibition of startle are positively correlated

Although a link between the attentional blink and prepulse startle inhibition has been considered, no evidence of this relationship has been reported. We delivered acoustic startle probes during rapid serial visual presentations in which the relative positions of two targets (targets 1 and 2) was varied within a stream of distractors. Startle probes were presented at 100 ms lead intervals relative to onset of a target or distractor. We found positive correlations between visual prepulse inhibition and attentional blink effects across participants. As the magnitude of prepulse inhibition with target and distractor lead stimuli increased, deficits in identifying target 2 during the attentional blink increased, suggesting similar processes underlying these phenomena. Whereas prepulse inhibition may reveal the strength of inhibition to protect stimulus processing, attentional blink may index the rate of recovery from similar inhibitory processes.

Prepulse inhibition is different in two inbred mouse strains (CPB-K and BALB/cJ) with different hippocampal NMDA receptor densities

Objective The hypo-glutamatergic hypothesis of schizophrenia is not only based on the phencyclidine-(PCP)-induced psychosis in mentally healthy humans but also on studies with schizophrenic patients showing deficits in post mortem hippocampal N-methyl- d-aspartate (NMDA) receptor gene expression and deficits in prepulse inhibition. The inbred mouse strains CPB-K and BALB/cJ display considerable differences in hippocampal NMDA receptor densities. Therefore, our working hypothesis was based on the assumption that the CPB-K mouse strain, which has a lower NMDA receptor density in hippocampal CA1, might be a possible animal model for schizophrenia. For this purpose, the inbred mouse strains CPB-K and BALB/cJ were compared by using a sensorimotor gating paradigm. Methods Acoustic startle response (ASR) and prepulse inhibition (PPI) of the startle reflex were measured. Results CPB-K mice displayed a significantly higher ASR and a significantly lower magnitude of PPI as compared to BALB/cJ mice. The test–retest reliability was approved for PPI in both mouse strains, which was performed in repeated sessions over 13 weeks. In summary, our working hypothesis was confirmed that lower levels of hippocampal NMDA receptor densities correspond to lower sensorimotor gating in CPB-K mice. Based on this finding, further experiments using different behavioral paradigms have to be carried out to establish the CPB-K mouse strain as an animal model of schizophrenia.

Apomorphine-Induced Prepulse Inhibition Disruption is Associated with a Paradoxical Enhancement of Prepulse Stimulus Reactivity

Prepulse inhibition (PPI) refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. PPI has been extensively employed as an assay for sensorimotor gating, and its disruption has been characterized in specific disease conditions, including schizophrenia. In animals, dopamine agonists disrupt PPI, and this disruption can be antagonized by antipsychotic drug treatment. The present study extended these fundamental findings to C57BL6 mice, and further evaluated the subjects' reaction to the prepulse stimulus alone in relation to the expression of PPI. Not only did apomorphine (2.0 mg/kg, intraperitoneal (i.p.)) attenuate PPI but it also enhanced reactivity to the prepulse stimulus. The dual effects of apomorphine appear paradoxical in view of the positive correlation, detectable in both the control and apomorphine groups, between prepulse reactivity and PPI magnitude. The present findings contradict the hypothesis that apomorphine disrupts PPI via reduced detectability or perception of the prepulse, and we further propose that enhanced distractibility may provide a parsimonious account for the dual effects of apomorphine. Moreover, haloperidol pretreatment (0.4 mg/kg, i.p.) fully antagonized the effects of apomorphine upon prepulse reactivity as well as on PPI. The present results add to our understanding of the relevance and applicability of the PPI paradigm in modeling schizophrenia-like symptoms in animals.

Immediate and long-lasting effects of chronic stress in the prepubertal age on the startle reflex

The immediate and long-lasting effects of two models of chronic stress during the prepubertal period of life (21–32 days) on the acoustic startle response (ASR) were studied in outbred Wistar normotensives and rats with inherited stress-induced arterial hypertension (ISIAH) derived from them. Chronic variable stress (CVS) and repeated handling were used as chronic treatment. The obtained data showed a significantly attenuated ASR and a greater magnitude of prepulse inhibition (PPI) in juvenile and adult ISIAH compared to Wistar rats. The immediate effects of prolonged stress on the ASR were genotype-dependent. Young ISIAH rats exposed to both types of prepubertal stimulation had higher ASR than the age-matched controls. No significant stress-induced changes in the ASR were found in young Wistar rats. The long-lasting consequences of prolonged prepubertal stress were similar in the two strains and were determined by the specificity of stress stimulation: chronic handling had no effect on the ASR, while CVS enhanced it. The long-lasting effect of CVS experienced in prepubertal life appears to produce ASR changes similar to those seen in patients with posttraumatic stress disorder (PTSD). The magnitude of PPI increased from early age to adulthood and it was tolerant to environmental influences. The two rat strains did not differ in the rate of short-term habituation to repeated acoustic stimuli, which was unaffected by prepubertal stress. Evidence was obtained indicating that genetic and environmental background in childhood may contribute to the truncation of the startle response.

Neural plasticity in the mouse inferior colliculus: relationship to hearing loss, augmented acoustic stimulation, and prepulse inhibition

C57BL/6J (C57) and DBA/2J (DBA) mice exhibit progressive high-frequency hearing loss. Extracellular recordings of responses of neurons in the inferior colliculus (IC) evoked by 70-dB SPL tones indicated that normal tonotopic organization was greatly disrupted in both strains: still-audible lower frequencies (4–12 kHz) evoked responses in a large percentage of recording sites in ventral tonotopic regions that normally respond strongly to high frequencies only. To relate the IC responses to an auditory behavior, prepulse inhibition (PPI) was measured using 70-dB tones as prepulses. As high-frequency hearing loss progressed in C57 mice, prepulses of 4–12 kHz elicited stronger PPI, and this was significantly correlated with changes in the percentage of IC recording sites responding to 70-dB tones (the neural pathway for PPI includes the IC). The analysis was extended to DBA mice that had been exposed to an augmented acoustic environment (AAE) – a procedure that improves PPI. In these mice, a higher percentage of IC recording sites responded to 70-dB tones, and this was correlated with improved PPI. The data suggest that responses of IC neurons reflect both hearing loss-induced plasticity and changes induced by exposure to an AAE, and these neural changes are correlated with the magnitude of PPI.

Inbred mouse strains differ in the regulation of startle and prepulse inhibition of the startle response.

The startle response and adaptability of the startle response (prepulse inhibition and habituation) have been observed in animals. The studies reported here screened 8 inbred mouse strains to determine whether genetic factors influence these behaviors. Strain differences were found in both the sensitivity to acoustic startle and the magnitude of both the auditory and tactile startle as well as the magnitude of prepulse inhibition (PPI) of both tactile and acoustic startle. Neither the 2 startle responses nor the 2 forms of PPI were significantly correlated with one another, suggesting that different genes regulate these 2 forms of startle and PPI. Acoustic-acoustic PPI was significantly correlated, however, with hippocampal auditory gating (TC ratio) suggesting an overlap in the genes that regulate these 2 forms of sensory gating.