Enhancement of prepulse inhibition after blockade of GABA activity within the superior colliculus

doi:10.1016/S0006-8993(99)01525-5

Brain Research

Volume 833, Issue 1, 26 June 1999, Pages 81-85

https://doi.org/10.1016/S0006-8993(99)01525-5 Get rights and content

Abstract

The present study examined the effects of local microinjections of the GABA chloride channel blocker Picrotoxin into the superior colliculus (SC) on prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. PPI is a useful model for the investigation of the neuronal basis of sensorimotor gating which is deficient in some psychiatric disorders, such as schizophrenia. Blockade of GABA activity within the SC by Picrotoxin injections (leading to a moderate stimulation of the SC) significantly enhanced PPI without affecting the ASR baseline amplitude or the spontaneous motor activity. Based on these results we discuss the role of the SC in a hypothetical neuronal circuit mediating PPI of the ASR.

Introduction

Sensorimotor gating reflects the ability of the brain to protect brain functions—ranging from perception, coordinated motion to cognition—from disturbing influences [26]. One of the most useful models for the study of sensorimotor processing is prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats 11, 13, 24, 25. In this isomorphic model, the ASR amplitude is markedly reduced by a weak stimulus presented 15–500 ms before the startle eliciting stimulus occurs 8, 9, 25. The identification of the neuroanatomical and neurochemical substrate of PPI may be a prerequisite for the development of strategies to treat human disorders characterized by a deficit in sensorimotor gating, such as schizophrenia, Huntington's disease, Tourette syndrome and obsessive compulsive disorders [25]. A series of experiments suggested that PPI can be reduced by a modulating circuit including the nucleus accumbens, the medial prefrontal cortex, the ventral tegmental area and the septohippocampal system 11, 13, 25.

Although a good deal of information about the PPI modulating circuit is available, less is known about the PPI mediating circuit. The pedunculopontine tegmental nucleus (PPTg) seems to be the brain structure where modulating and mediating PPI pathways converge 7, 11, 13, 26. It has been suggested that auditory prepulses are mediated by a pathway from the central auditory system via the colliculus inferior and the superior colliculus (SC) to the PPTg 2, 7, 11, 13, 18. From there, an inhibitory cholinergic projection to the primary startle circuit mediates PPI 6, 12, 26. Furthermore, the PPTg receives GABAergic projections from the nucleus accumbens and the ventral pallidum, the output structures of the PPI modulating circuit [14].

The present study tested the hypothesis that the SC is involved in the mediation of PPI of the ASR. We suggest that a blockade of GABA activity within the SC leads to an enhancement of PPI without affecting the baseline ASR. Therefore, we locally injected different doses of Picrotoxin into the SC and tested the effects of these injections on the baseline ASR and on PPI. Picrotoxin is a GABA chloride channel blocker and should block GABA activity within the SC leading to a moderate chemical excitation of the SC.

Section snippets

Materials and methods

Eighteen male Sprague–Dawley rats weighing 280–360 g at the time of the surgery were used for this study. They were housed in groups of six animals under a continuous light/dark cycle (lights on from 0700 to 1900 h). The rats received 12 g rat chow/animal/day and water was freely available. The experiments were done in accordance with ethical guidelines for the care and use of experimental animals and were approved by the local council of animal care (Regierungspräsidium Tübingen, ZP 4/96).

The

Results

Histological analysis revealed that 17 rats had received bilateral injections into the different layers of the SC (injection sites are shown in Fig. 1). One animal died during the surgery.

Injections of Picrotoxin into the SC led to a significant enhancement of PPI (Fig. 2A; ANOVA: F_3,48=4.2, p=0.01). Post-hoc Tukey tests revealed a p<0.01 (t=−3.52) for the pairwise comparison between the PPI after injections of saline and 5 ng Picrotoxin. No effect of Picrotoxin injections into the SC were

Discussion

The present study tested the hypothesis that the SC is involved in the mediation of PPI. Pharmacological blockade of GABA activity within the SC by local injections of Picrotoxin enhanced PPI using auditory prepulses. The PPI increase observed in the present study (from 79.3±4.6 to 90.7±1.6% PPI) leads to an almost total (100%) blockade of the ASR in prepulse–pulse trials. The baseline ASR amplitude and the spontaneous motor activity of the rats were not influenced. These results support an

Acknowledgements

This research was supported by the Deutsche Forschungsgemeinschaft (SFB 307/C2 and Fe 483/1-1). I am grateful to Dr. Michael Koch for his help throughout several phases of this study and Helga Zillus for technical assistance.

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The role of the deeper layers of the superior colliculus in attentional modulations of prepulse inhibition
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Citation Excerpt :
In rats, the fear-conditioning-induced PPI enhancement is mediated by the lateral nucleus of the amygdala (LA), and the perceptual-separation-induced PPI enhancement is mediated by the posterior parietal cortex (PPC), indicating that the LA and the PPC contribute to the attentional modulation of PPI differently [37]. More importantly for motivating the present study, both the LA and the PPC have either direct or indirect neural connections with the DpSC [43–45], which may also be a relay site in the pathway mediating PPI [18,19,46]. Previous animal studies have also suggested that PPI is modulated by the cortico-striatal-pallido-thalamic circuitry [47].
Prepulse inhibition (PPI) is the suppression of the startle reflex, when a weaker non-startling sensory stimulus (the prepulse) precedes the intense startling stimulus. Although the basic PPI neural circuitry resides in the brainstem, PPI can be enhanced by selective attention to the prepulse, indicating that this sensorimotor-gating process is influenced by higher-order perceptual/cognitive processes. Along with the auditory cortex, the brain structures involved in attentional modulations of PPI include both the lateral nucleus of the amygdala (LA), which contributes to the fear-conditioning modulation, and the posterior parietal cortex (PPC), which contributes to the spatially attentional modulation. The deeper layers of the superior colliculus (DpSC), which has been suggested as a midbrain component in the PPI circuitry, receive descending axonal projections from some forebrain structures associated with auditory perception, emotional conditioning, or spatial attention. This study was to examine whether the DpSC are also involved in attentional modulations of PPI in rats. The results showed that both fear conditioning of a prepulse sound and precedence-effect-induced perceptual separation between the conditioned prepulse and a noise masker facilitated selective attention to the prepulse and consequently enhanced PPI. Reversibly blocking glutamate receptors in the DpSC with 2-mM kynurenic acid eliminated both the conditioning-induced and the perceptual-separation-induced PPI enhancements. However, the baseline magnitudes of startle and PPI were not affected. The results suggest that the DpSC play a role in mediating the attentional enhancements of PPI, probably through both receiving top-down signals from certain forebrain structures and modulating the midbrain representations of prepulse signals.
Top-down modulation of prepulse inhibition of the startle reflex in humans and rats
2009, Neuroscience and Biobehavioral Reviews
Prepulse inhibition (PPI) is the attenuation of the startle reflex when the sudden intense startling stimulus is shortly preceded by a weaker, non-startling sensory stimulus (prepulse). PPI reflects a protective function of reducing disruptive influences to the processing of prepulse signals and is recognized as a model of sensorimotor gating. In humans, PPI is modulated by both attentional and emotional responses to prepulse, indicating that this early-stage gating is top–down modulated by higher-order cognitive processes. Recent studies have confirmed top–down modulation of PPI in animals, because PPI in rats is enhanced by auditory fear conditioning and perceived separation between fear-conditioned prepulse and masker. This review summarizes recent studies of top–down modulation of PPI conducted in humans and those in rats. Since both baseline PPI and attentional modulation of PPI in patients with schizophrenia are impaired, and both baseline PPI and conditional modulation of PPI in rats with isolation rearing are impaired, this review emphasizes that investigation of top–down modulation of PPI is critical for establishing new animal models for studying both cognitive features and neural bases of schizophrenia. Deficits in either baseline PPI or attentional modulation of PPI in either patients with attention-deficit/hyperactivity disorder (ADHD) or ADHD-modeling rats are also discussed.
5,7-Dihydroxytryptamine injections into the prefrontal cortex and nucleus accumbens differently affect prepulse inhibition and baseline startle magnitude in rats
2009, Behavioural Brain Research
The prefrontal cortex and the nucleus accumbens are two brain sites which are known to be involved in the modulation of the acoustic startle response. In particular, the release of monoaminergic transmitters within these brain sites plays an important role in prepulse inhibition of the startle response which serves as an operational measure of sensorimotor gating. Like for dopamine, it is well established that serotonin transmission plays an important role in prepulse inhibition. However, there are only few studies investigating the effects of local manipulation of serotonin transmission on prepulse inhibition. The aim of the present study was to test whether prepulse inhibition or the startle response itself was affected by serotonergic depletion of either the prefrontal cortex or the nucleus accumbens. Serotonergic depletion was induced by local injections of 5,7-dihydroxytryptamine and verified by ex vivo analysis of transmitter levels by high pressure liquid chromatography. In our behavioural tests, we found that 5,7-dihydroxytryptamine into the prefrontal cortex decreased prepulse inhibition, whereas injections into the nucleus accumbens facilitated prepulse inhibition. The time course of these behavioural effects, as well as the transmitter level changes within the different brain sites was very different. Most interestingly, 5,7-dihydroxytryptamine injections into the nucleus accumbens affect serotonin and dopamine levels in both, nucleus accumbens and prefrontal cortex. Taken together, the present study supports an important role of serotonin in the modulation of prepulse inhibition and baseline startle magnitude. However, the observed changes cannot be attributed to a specific brain site since our data clearly show that local 5,7-dihydroxytryptamine injections also affect transmitter levels in brain sites away from the injection site.
Ethanol withdrawal and proclivity are inversely related in rats selectively bred for differential saccharin intake
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Grillon et al. (2000, 1994) have reported that nonalcoholic people with a family history of alcoholism show generally lower acoustic startle and reduced prepulse inhibition relative to people with a family history of anxiety disorders; this pattern was observed in both the presence and absence of alcohol. Possible mechanisms for enhanced prepulse inhibition among ethanol-exposed LoS rats and humans whom they model include reduced gamma-aminobutyric acid (Fendt, 1999) or dopamine (Swerdlow et al., 2005; Zhang et al., 2000) activity. Additional work is necessary to understand the nature of this intriguing line difference in connection with alcohol.
Withdrawal severity and voluntary alcohol consumption are inversely related in rats and mice. The present study demonstrated this empirical relation and extended it in two ways. First, the rats were selectively bred for low (LoS) and high (HiS) saccharin intake, a phenotype that correlates positively with ethanol intake and inversely with emotional reactivity. Withdrawal has not yet been studied in these rats. Second, proclivity to consume ethanol was measured as conditioned preference for an ethanol-paired flavor. After 2 weeks of forced exposure to ethanol and a period of abstinence, LoS rats showed elevated acoustic startle; HiS rats did not (Exp. 1). When ethanol- and no-ethanol solutions were available freely during conditioning, both LoS and HiS rats preferred a flavor paired with 4% ethanol, but only HiS rats preferred a flavor paired with 10% ethanol (Exp. 2A); when exposure to the two solutions was controlled, all groups except LoS males preferred flavors paired with 4% or 10% ethanol (Exp. 2B). Thus, as predicted, withdrawal was more severe in the line with less ethanol proclivity (LoS). These results implicate basic associative and affective processes in individual differences in patterns of alcohol use.
Urotensin II acts as a modulator of mesopontine cholinergic neurons
2005, Brain Research
Citation Excerpt :
Garcia-Rill et al. [16] predicted that activation of neurons in the mesopontine would reduce habituation of the startle reflex to a loud auditory stimulus. MPCh neurons are also intimately involved in prepulse inhibition (PPI), a phenomenon in which the amplitude of the startle reflex is reduced by the presence of a preceding muted warning stimulus (for review see [10,20]). Elucidating the role of MPCh neurons in PPI is of great interest because PPI deficits are a hallmark and diagnostic symptom in many neuropsychiatric disorders (for review see [20]).
Urotensin II (UII) is a vasomodulatory peptide that was not predicted to elicit CNS activity. However, because we have recently shown that the urotensin II receptor (UII-R) is selectively expressed in rat mesopontine cholinergic (MPCh) neurons, we hypothesize that UII may have a central function. The present study demonstrates that the UII system is able to modulate MPCh neuron activity. Brain slice experiments demonstrate that UII excites MPCh neurons of the mouse laterodorsal tegmentum (LDTg) by activating a slow inward current. Furthermore, microinfusion of UII into the ventral tegmental area produces a sustained increase in dopamine efflux in the nucleus accumbens, as measured by in vivo chronoamperometry. In agreement with UII activation of MPCh neurons, intracerebroventricular injections of UII significantly modulate ambulatory movements in both rats and mice but do not significantly affect startle habituation or prepulse inhibition. The present study establishes that UII is a neuromodulator that may be exploited to target disorders involving MPCh dysfunction.
Gabaergic regulation of the neural organization of fear in the midbrain tectum
2005, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Moderate, but not high, levels of fear enhance the amplitude of the startle response (Davis and Astrachan, 1978; Walker et al., 1997; Santos et al., 2005). While separate evidence has been provided for the involvement of GABA-mediated mechanisms in startle and acoustically evoked potentials (AEP) (Bagri et al., 1989; Brandão et al., 2001; Fendt, 1999), studies combining sensory processing and motor responses are lacking in this field of research. Thus, taking advantage of the properties of BIC and SMC in producing distinct defensive behavior, we were also interested in measuring the sensory changes (AEP) concomitant to freezing induced by SMC.
In midbrain tectum (MT) structures, such as the dorsal periaqueductal gray (dPAG), the superior colliculus (SC) and the inferior colliculus (IC) GABAergic neurons exert a tonic control on the neural substrates involved in the expression of defensive reactions. In this review, we summarize behavioral, immunohistochemical (brain Fos distribution) and electrophysiological (auditory evoked potentials) data obtained with the reduction of GABA transmission by local injections of a GABA receptor blocker (bicuculline, BIC) or a glutamic acid decarboxylase inhibitor (semicarbazide, SMC) into the MT. Distinct patterns of Fos distribution were obtained following the freezing and escape reactions induced by MT injections of SMC and BIC, respectively. While only the laterodorsal nucleus of the thalamus was labeled after SMC-induced freezing, a widespread increase in Fos expression in the brain occurred after BIC-induced escape. Also, injections of SMC into the IC increased the auditory evoked potentials recorded from this structure. It is suggested that GABAergic mechanisms of MT are also called into play when sensory gating of the MT is activated during different emotional states.

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Research reportEnhancement of prepulse inhibition after blockade of GABA activity within the superior colliculus

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Hear. Res.

Eur. J. Pharmacol.

Trends Neurosci.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Prog. Neurobiol.

Behav. Brain Res.

Brain Res. Bull.

Physiol. Behav.

Physiol. Behav.

Physiol. Behav.

Conformational specifity of GABA binding to the presynaptic GABAA receptor

NeuroReport

Different regions of the periaqueductal grey are involved differently in the expression and conditioned inhibition of fear-potentiated startle

Eur. J. Neurosci.

Sensorimotor gating deficits after lesions of the superior colliculus

NeuroReport

Research report
Enhancement of prepulse inhibition after blockade of GABA activity within the superior colliculus

Conformational specifity of GABA binding to the presynaptic GABA_A receptor