Sensorimotor Gating Processes Research Articles

Neonatal lesions in the amygdala or ventral hippocampus disrupt prepulse inhibition of the acoustic startle response; implications for an animal model of neurodevelopmental disorders like schizophrenia

Prepulse inhibition of the acoustic startle response is a behavioural tool applied to assess sensorimotor gating processes in humans and rats. Schizophrenic patients show deficits in prepulse inhibition of the acoustic startle response. The animal model of neurodevelopmental disorders such as schizophrenia, as purported in earlier reports and the present study, is based on the assumption that damage to brain structures early in life (on day 7) disrupts brain maturation of structures connected to the damaged areas, measurable by behavioural changes, whereas similar damage later in life (on day 21) does not result in these behavioural changes. Locomotor activity, the acoustic startle response and its prepulse inhibition were investigated in adult rats lesioned in the amygdala or ventral hippocampus on day 7 or 21 of life. The acoustic startle response was increased in animals lesioned in the amygdala on day 7 or 21 of life, but not in animals lesioned in the ventral hippocampus. Prepulse inhibition was impaired and locomotor activity enhanced in animals lesioned in the amygdala or ventral hippocampus on day 7, but not in animals lesioned in these structures on day 21 of life. The results on the acoustic startle response are suggestive of amygdaloid influences on modulation of the acoustic startle response. The effects of early postnatal lesions on prepulse inhibition and locomotor activity are in support of the animal model of neurodevelopmental disorders like schizophrenia.

A neural network approach to the acoustic startle reflex and prepulse inhibition

Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense stimulus is preceded by a weak non-startling prestimulus. PPI is widely used as a model for sensorimotor gating processes and has been shown to be impaired in various neuropsychiatric disorders, including schizophrenia. We have reproduced startle-like behavior and basic PPI modifications with a neural network. The network design was constrained by the attempt (1) to use as few connections as possible and (2) to relate neuroanatomical structures to the simulated network. Performance of the network was evaluated by the behavior of the simulated motor neurons in response to prepulse and pulse stimuli presented with various lead intervals and prepulse intensities. A delayed inhibitory pathway via the pedunculopontine nucleus (PPTg) to the caudal pontine reticular nucleus was found to be a necessary but insufficient requirement to reproduce basic PPI output patterns. Additional requirements included (a) a low threshold at or below the caudal pontine reticular formation, (b) signal amplification in the inhibitory pathway and (c) prolongation of activity in the inhibitory pathway. On the grounds of the most appropriate output patterns of the simulations, we propose a mechanism of sustained activation in the PPTg due to recursive connections. Relations between stimuli, behavior (motor output) and the underlying architecture are discussed. Potentially, this modeling technique can be extended to investigate the impact of drugs and higher brain regions on PPI.

Environmental animal models for sensorimotor gating deficiencies in schizophrenia: a review.

In schizophrenia research, the study of animal models has received considerable attention in the past 20 years. The value of animal models in pre-clinical research is widely recognised, largely because they can provide precious knowledge regarding the neurobiology of schizophrenia and can also be used for developing antipsychotic drugs. Prepulse inhibition (PPI; reduction in startle reflex induced by a prestimulus) is impaired in schizophrenic patients, a finding that has been associated with a loss of sensorimotor gating abilities. In rats, the schizophrenic-like PPI deficit can be induced by pharmacological or surgical manipulations targeting mainly the cortico-meso-limbic circuitry. The literature was critically reviewed in an effort to determine the robustness and the relevance for schizophrenia of another category of animal models, based purely on manipulations of the social environment, that encompasses the neurodevelopmental hypothesis of schizophrenia. Specifically, we focused our attention on the long-term effects of such environmental models on sensorimotor gating processes as assessed in the PPI paradigm, with an attempt to evaluate their face, predictive and construct validity. Our review of the literature leads to the conclusion that social deprivation performed directly after weaning (approximately 21 days of age) is more likely to be a relevant model for PPI impairments in schizophrenia than pre-weaning manipulations. Although the robustness of such environmental models requires further study, these animal models offer the advantage of avoiding invasive manipulations, which allows for a variety of anatomical, electrophysiological, neuroendocrine or neurochemical investigations in the absence of confounding pharmacological or surgical effects.

Microinfusion of the non-competitive N-methyl- d-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity

Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl- d-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25 μg/0.5 μl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague–Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394–8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113–121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field. From our results, we suggest that N-methyl- d-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.

On the clinical and cognitive meaning of impaired sensorimotor gating in schizophrenia

Schizophrenia patients have been shown to have a defective sensorimotor gating process as indexed by impaired prepulse inhibition of the startle eyeblink reflex. Moreover, we have previously reported that schizophrenia patients have dysfunctional attentional modulation of prepulse inhibition. The present experiment combined our previous sample of 14 schizophrenia outpatients and 12 demographically matched control subjects with a new sample of 10 outpatients and 6 control subjects. All participants performed a tone-length judgement task that involved attending to one pitch of tone (the attended prepulse) and ignoring another pitch of tone (the ignored prepulse). During this task the acoustic startle eyeblink reflex was electromyographically recorded from the orbicularis oculi muscle. The results replicated the finding of impaired attentional modulation of prepulse inhibition in the new sample of schizophrenia outpatients compared to demographically matched control subjects. Specifically, the new control group exhibited greater startle modification during the attended prepulse, whereas the new patient group failed to show this differential effect. In addition, impaired prepulse inhibition following the attended prepulse was significantly correlated with heightened delusions, conceptual disorganization, and suspiciousness as measured with the expanded Brief Psychiatric Rating Scale. These correlations were significant with prepulse inhibition to the attended prepulse but not with prepulse inhibition to the ignored prepulse. Impaired prepulse inhibition was not correlated with negative symptoms. All in all, the results support the hypothesis that impaired attentional modulation of startle prepulse inhibition reflects basic neurocognitive processes related to thought disorder in schizophrenia.

Novel anticoagulants based on inhibition of the factor VIIa/tissue factor pathway

Prepulse inhibition (PPI) of the acoustic startle response is a behavioural tool used to assess sensorimotor gating processes and its disturbances in rats and in humans. PPI in rats is reduced by an overactivity of the dopamine (DA) system. Because there are functional interactions between DA and adenosine receptors, we tested whether PPI can be influenced by the mixed DA receptor agonist apomorphine (APO) and by the unselective adenosine antagonist theophylline (THEO). Combined administration of APO (0.5 mg/kg, i.p.) and THEO (20 mg/kg, i.p.) in doses devoid of significant effects on their own significantly reduced PPI. The PPI-disrupting effect of the combined THEO plus APO treatment was dose-dependently antagonized by co-administration of the selective adenosine A1 agonist CPA (0.15–1.5 mg/kg, i.p.), but not by the A2A agonist CGS21680 (0.1–2 mg/kg, i.p.). These data demonstrate that antagonistic interactions between DA and adenosine, involving adenosine A1 receptors, play an important role in the regulation of PPI. The possible implications of these findings for the use of adenosine agonists in the treatment of schizophrenia are discussed.

The psychological significance of human startle eyeblink modification: a review

The human startle eyeblink reflex is reliably modified by both cognitive and emotional processes. This review provides a comprehensive survey of the current literature on human startle modification and its psychological significance. Issues raised for short lead interval startle inhibition include its interpretation as a measure of protection of processing, sensorimotor gating and early attentional processing. For long lead interval effects, interpretations related to attentional and emotional processing are discussed. Also reviewed are clinical applications to information processing dysfunctions in the schizophrenia spectrum disorders, and to emotional processing disorders. Finally, an integrative summary that incorporates most of the cognitive findings is presented and directions for future research are identified regarding both cognitive and emotional modification of startle.

Adafenoxate: A monoamine oxidase and biogenic monoamine uptake inhibitor

St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects.Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders.The effects of acute (500 mg/kg) and chronic (200 mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas.Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200 mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit.The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.

Responding to acoustic startle during chronic ethanol intoxication and withdrawal.

Ethanol (EtOH) withdrawal is characterized by a hyperexcitable state that includes anxiety, tremor, muscle rigidity and seizures. The present three experiments examined the effects of EtOH dependence and withdrawal on the acoustic startle response, an easily quantifiable measure of behavioral reactivity to exteroceptive stimuli. Two intensities of startle stimuli, 105 and 120 dB pulses, were presented to rats during chronic EtOH exposure and during EtOH withdrawal. Prepulse inhibition, which is a sensitive measure of sensorimotor gating processes associated with filtering sensory stimulation, was also assessed during chronic EtOH exposure and withdrawal. Prepulse inhibition was induced by the presentation of a weak 80 dB acoustic stimulus 100 ms prior to a 120 dB stimulus pulse. After 14 days of EtOH liquid diet administration the magnitude of responses elicited by 105 and 120 dB startle stimuli was less in ethanol-treated subjects during continued EtOH access than in animals fed a control liquid diet. When EtOH liquid diet treatment was continued for an additional 3-day period and animals were tested 8 h after withdrawal from EtOH, withdrawn animals were more reactive to startle stimuli at both intensities than were animals maintained on the EtOH liquid diet. A time-course experiment with repeated startle testing at 4, 8, and 12 h post-EtOH exposure revealed significant increases in responding to the 105 dB startle intensity at 8 h post-EtOH exposure. The ability of animals to respond to a prepulse stimulus was not affected during chronic EtOH treatment, but was reduced during withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)