The Functional Networks of Prepulse Inhibition: Neuronal Connectivity Analysis Based on FDG-PET in Awake and Unrestrained Rats.

Cathrin Rohleder,Rudolf Graf,Alexander Drzezga,Heike Endepols,Lars Timmermann,Dirk Wiedermann,F Markus Leweke,Bernd Neumaier

doi:10.3389/fnbeh.2016.00148

Abstract

Prepulse inhibition (PPI) is a neuropsychological process during which a weak sensory stimulus (“prepulse”) attenuates the motor response (“startle reaction”) to a subsequent strong startling stimulus. It is measured as a surrogate marker of sensorimotor gating in patients suffering from neuropsychological diseases such as schizophrenia, as well as in corresponding animal models. A variety of studies has shown that PPI of the acoustical startle reaction comprises three brain circuitries for: (i) startle mediation, (ii) PPI mediation, and (iii) modulation of PPI mediation. While anatomical connections and information flow in the startle and PPI mediation pathways are well known, spatial and temporal interactions of the numerous regions involved in PPI modulation are incompletely understood. We therefore combined [18F]fluoro-2-deoxyglucose positron-emission-tomography (FDG-PET) with PPI and resting state control paradigms in awake rats. A battery of subtractive, correlative as well as seed-based functional connectivity analyses revealed a default mode-like network (DMN) active during resting state only. Furthermore, two functional networks were observed during PPI: Metabolic activity in the lateral circuitry was positively correlated with PPI effectiveness and involved the auditory system and emotional regions. The medial network was negatively correlated with PPI effectiveness, i.e., associated with startle, and recruited a spatial/cognitive network. Our study provides evidence for two distinct neuronal networks, whose continuous interplay determines PPI effectiveness in rats, probably by either protecting the prepulse or facilitating startle processing. Discovering similar networks affected in neuropsychological disorders may help to better understand mechanisms of sensorimotor gating deficits and provide new perspectives for therapeutic strategies.

Highlights

Prepulse inhibition (PPI) of the acoustic startle response is a measure of sensorimotor gating, and implies a reduction of the startle response, when a non-startling stimulus is presented within a certain time frame before the startling stimulus (Hoffman and Searle, 1967; Hoffman and Ison, 1980)
Deficient PPI modulation is associated with symptom severity in schizophrenia (Hazlett et al, 2007), little is known about the exact function of the modulation network
In order to examine its functional importance and the interplay between PPI-modulating brain areas, we performed functional connectivity analysis with the positron emission tomography (PET) images described in Rohleder et al (2014), as this methodological approach allows delineating distinct networks associated with different aspects of the behavioral paradigm

Summary

Introduction

Prepulse inhibition (PPI) of the acoustic startle response is a measure of sensorimotor gating, and implies a reduction of the startle response, when a non-startling stimulus (prepulse) is presented within a certain time frame before the startling stimulus (Hoffman and Searle, 1967; Hoffman and Ison, 1980). Deficient PPI modulation is associated with symptom severity in schizophrenia (Hazlett et al, 2007), little is known about the exact function of the modulation network. We hypothesized that it continuously adjusts sensorimotor gating, since it is active even if no selective attention to prepulse or startle stimuli is required (Rohleder et al, 2014). In order to examine its functional importance and the interplay between PPI-modulating brain areas, we performed functional connectivity analysis with the PET images described in Rohleder et al (2014), as this methodological approach allows delineating distinct networks associated with different aspects of the behavioral paradigm. For that purpose the olfactory bulb was chosen as reference area (Rohleder et al, 2014) since its activity was supposed to be similar in both conditions (rats were both times exposed to the smell of diluted acetic acid)

Methods

Results

Discussion

Conclusion