Acoustic prepulse inhibition in male and female prairie voles: Implications for models of neuropsychiatric illness

Abstract

Sensory gating, the ability to suppress sensory information of irrelevant stimuli, is affected in several neuropsychiatric diseases, notably schizophrenia and autism. It is currently unclear how these deficits interact with other hallmark symptoms of these disorders, such as social withdrawal and difficulty with interpersonal relationships. The highly affiliative prairie vole (Microtus ochrogaster) may be an ideal model organism to study the neurobiology underlying social behavior. In this study, we assessed unimodal acoustic sensory gating in male and female prairie voles using the prepulse inhibition (PPI) paradigm, whereby a lower amplitude sound (prepulse) decreases the startle response to a high amplitude sound (pulse) compared to the high amplitude sound alone. Prairie voles showed evidence of PPI at all prepulse levels compared to pulse alone, with both males and females showing similar levels of inhibition. However, unlike what has been reported in other rodent species, prairie voles did not show a within-session decrease in startle response to the pulse alone, nor did they show a decrease in startle response to the pulse over multiple days, highlighting their inability to habituate to startling stimuli (short- and long-term). When contrasted with a cohort of male wildtype C57Bl/6J mice that underwent a comparable PPI protocol, individual voles showed significantly higher trial-by-trial variability as well as longer latency to startle than mice. The benefits and caveats to using prairie voles in future sensory gating experiments are discussed.

Introduction

The prairie vole (Microtus ochrogaster) has been used extensively in research on monogamy and pair-bonding due to its robust affiliative behaviors [1,2] and the relationship of the neuropeptides oxytocin and vasopressin with such behaviors [3]. Despite this strong rationale for use as a model studying social behaviors, voles have been underutilized to model social deficits in neuropsychiatric illnesses, likely due to their high behavioral and genetic heterogeneity compared to other laboratory rodents [2]. However, as recent treatments for schizophrenia and autism spectrum disorder (ASD) have targeted oxytocin as a potential therapeutic target [[4], [5], [6], [7]], the prairie vole may offer valuable insight into the neurochemistry of such mental illnesses [6,[8], [9], [10]].

The ability of the nervous system to filter out irrelevant stimuli (e.g. sensory gating) is a fundamental feature of attention and is compromised in neuropsychiatric disorders [[11], [12], [13], [14]]. Sensory gating can be seen throughout the animal kingdom, from simple invertebrates to humans [15]. The fundamentally conserved nature of sensory gating allows the systematic comparison of animal models to more complex human conditions. Prepulse inhibition (PPI), a measure of the ability to inhibit response to a startling stimulus if preceded by a weaker non-startling stimulus, is commonly used as a biomarker for disorders with dysfunctional sensory gating, such as schizophrenia, where patients show significantly less inhibition than controls [16].

In this paper, we characterize sensory gating behavior in prairie voles using the PPI procedure, a necessary first step towards modeling social and attentional deficits in ASD and schizophrenia. Habituation to the startle reflex, which is also compromised in schizophrenic patients, was assessed in the short-term (within-session) and long-term (over multiple sessions). We also compared male and female voles to determine if there were sex differences, as has been found in some strains of rodents and in humans [17,18]. Finally, we compared voles with an inbred mouse line, C57BL/6J, to determine differences in individual variability in startle responsiveness.