Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume

Abstract

Prepulse inhibition (PPI) of startle response is a measure of sensorimotor gating that is impaired in schizophrenia and in many other clinical conditions. Rat models using pharmacological or surgical strategies reveal that PPI is modulated by the cortico-striatalpallido-thalamic (CSPT) circuit. Here, we explore whether spontaneous variation in PPI in intact inbred and outbred rats is associated with functional and structural differences in the CSPT circuit. Inbred Roman High-(RHA) and Low-avoidance (RLA) and outbred heterogeneous stock (HS) rats were assessed for PPI, brain activity, and brain volume. Brain activity was assessed by c-Fos expression and brain volume by magnetic resonance imaging. Relevant structures of the CSPT circuit were evaluated, such as the medial prefrontal cortex (mPFC), cingulate cortex, hippocampus (HPC), amygdala, nucleus accumbens (NAc), and dorsal striatum. RHA showed lower PPI than RLA rats, while HS rats were stratified by their PPI levels in three groups. Reduced PPI was accompanied by decreased mPFC activity in Roman and HS rats and increased NAc shell activity in HS rats. Low PPI was also associated with decreased mPFC and HPC volumes in Roman and HS rats. This study reports a consistent relationship between decreased function and volume of the mPFC and spontaneous low-PPI levels in inbred and outbred intact rats. Moreover, our findings suggest that, apart from a hypoactive and smaller mPFC, a hyperactive NAc and smaller HPC may underlie reduced PPI levels. Our results support the notion that sensorimotor gating is modulated by forebrain structures and highlight the importance of the mPFC in its regulation.

A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats

“…In line with these strain-related differences in LI, we have shown in a series of studies that RHA rats display clear and consistent deficits of PPI of the acoustic startle response compared with RLAs (Del Rio et al, 2014; Oliveras et al, 2015, 2016, 2017; Río-Alamos et al, 2015; Río-Álamos et al, 2017a,b, 2019; Tapias-Espinosa et al, 2018, 2019) and that PPI deficits predict spatial working memory impairments (Oliveras et al, 2015). Altogether, the above mentioned cognitive and attentional profiles of RHA vs. RLA rats suggest that the former may represent a model of schizophrenia-relevant features.…”

“…Finally, it has recently been shown that, compared with their RLA counterparts, RHA rats exhibit significant reductions of the volumes of the mPFCx and HC [measured by means of magnetic resonance imaging (MRI)] as well as dramatically enlarged lateral ventricles (Río-Álamos et al, 2017a, 2019). In addition, PPI-elicited neural activity of the prefrontal cortex (as measured by c-fos activation) is lower in RHA than RLA rats (Tapias-Espinosa et al, 2019). These neuroanatomical and functional alterations are reminiscent of those observed in schizophrenic patients and provide further support to the contention that RHA rats may constitute a genetic model of schizophrenia-relevant features with face, construct, and predictive validity (reviewed by Río-Álamos et al, 2019).…”

“…Accordingly, in RHA rats behaviorally sensitized following chronic treatment with cocaine, but not in their RLA counterparts, the dopaminergic transmission in the mPFCx is markedly reduced (Giorgi et al, in preparation). Furthermore, compared with their RLA counterparts, RHA rats show a smaller frontocortical volume (Roberti, 2004; Río-Álamos et al, 2019) and a reduced activation of the mPFCx upon exposure to PPI testing and a variety of novelty-related situations (Meyza et al, 2009; Río-Álamos et al, 2019; Tapias-Espinosa et al, 2019).…”

“…We acknowledge that the proposed model is a simplification and does not take into account the role of other neurotransmitters that may be involved in the neurobehavioral traits that distinguish the Roman lines. It is hypothesized that the lower activity and volume of the mPFC, the HC, and the AMY, together with the higher density of 5-HT2A receptors and the dramatically decreased density of mGlu2 receptors in the frontal cortex of RHA vs. RLA rats may determine a hyper-functional glutamatergic cortical system in RHA rats (Meyza et al, 2009; Klein et al, 2014; Río-Álamos et al, 2017a, 2019; Wood et al, 2017; Tapias-Espinosa et al, 2019). This in turn would elicit an increment in the functional tone of the dopaminergic VTA neurons projecting to the Acb (Elert, 2014) and a decrease in the functional tone of the mesocortical dopaminergic system of RHA rats (Dalley et al, 2007; Giorgi et al, 2007; Probst and van Eimeren, 2013; Tournier et al, 2013; Elert, 2014; Klein et al, 2014; Dalley and Robbins, 2017; Fomsgaard et al, 2018).…”

“…In addition, the decreased density of DA D2 receptors together with the increased density in DA D1 receptors in the limbic system of RHAs relative to RLA rats (Giorgi et al, 1994, 2007; Guitart-Masip et al, 2006) may also contribute to the more robust functional tone of the mesolimbic dopaminergic system of the former line. It is proposed that this integrated neural circuitry underlies novelty seeking (Tournier et al, 2013), impaired impulse control (Dalley et al, 2007), vulnerability to drug sensitization and abuse (Giorgi et al, 2007; Fattore et al, 2009; Tournier et al, 2013) and schizophrenia-relevant attentional/cognitive impairments (Wakabayashi et al, 2015; Río-Álamos et al, 2019; Tapias-Espinosa et al, 2019; for a review see Swerdlow and Light, 2016). Hence, compared with RLA and heterogeneous/outbred rats, RHAs appear to be unique in that they include all the phenotypes mentioned above, and this makes this rat strain a promising heuristic tool to investigate relationships among these traits and their underlying neurobiological/genetic bases.…”