Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Abstract

Significance Here, we model a positive symptom of schizophrenia, hallucination-like activity, in a mouse model of an environmental risk factor of schizophrenia, maternal immune activation (MIA). MIA offspring display an enhanced susceptibility to the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI) and demonstrate elevated DOI-induced brain activity as measured by induction of immediate early genes and manganese-enhanced MRI. High sensitivity to DOI in MIA offspring can be explained by an increased level of serotonin receptor 2A (5-HT2AR) that mediates the effect of DOI on the prefrontal cortex. Chronic treatment with the 5-HT2AR antagonist ketanserin reduces DOI-induction of head twitching in MIA offspring. Our data demonstrate that DOI-induced hallucination-like activity can be modeled in the MIA mouse model and suggest 5-HT2AR as a potential therapeutic target for schizophrenia.

Maternal lipopolysaccharide treatment differentially affects 5-HT2A and mGlu2/3 receptor function in the adult male and female rat offspring

“…Similar findings have also been observed in adult mice exposed to prenatal stress as well as in offspring born to influenza virus infected mothers (Moreno et al, 2011;Holloway et al, 2013). Additionally, prenatally immune-challenged mice displayed an elevated DOI-induced neuronal activity in several brain regions, including the PFC, thalamus and striatum, as revealed by manganese-enhanced magnetic resonance imaging (Malkova et al, 2014).…”

Automated Computational Processing of 3‐D MR Images of Mouse Brain for Phenotyping of Living Animals

“…modal_scale_nii.m is a MATLAB routine developed in the Jacobs’ lab, and has been applied in a variety of papers (Bearer et al, 2007a; Bearer et al, 2007b; Delora et al, 2016; Gallagher et al, 2013; Gallagher et al, 2012; Malkova et al, 2014; Zhang et al, 2010a) although the actual processing code is previously unpublished. The “modal_scale” code is provided here with this protocol for the first time (see Supplemental Materials).…”

“…With MEMRI images captured over time we were able to show the role of kinesin-1 in axonal transport in the living brain for the first time (Medina et al, 2017). Using this protocol for alignment we have also shown the effect of psychoactive drugs on neuronal activation, particularly focusing on treatments in a mouse model of schizophrenia (Malkova et al, 2014). …”

“…This is especially useful when imaging living animals because imaging time must be short (Pautler, 2004; Pautler and Koretsky, 2002; Pautler et al, 2003; Pautler et al, 1998; Silva and Bock, 2008; Silva et al, 2004). MEMRI has been used to observe functional circuitry and axonal transport dynamics in the living brain (Bearer et al, 2007a; Bearer et al, 2007b; Bearer et al, 2009; Gallagher et al, 2013; Gallagher et al, 2012; Medina et al, 2017; Pautler, 2004; Van der Linden et al, 2004; Zhang et al, 2010a), and localized neuronal activity (Malkova et al, 2014; Yu et al, 2005). Multiple studies have been done to determine a non-toxic dose of Mn 2+ (Bearer et al, 2007a; Eschenko et al, 2012; Lindsey et al, 2013).…”

An ontologically consistent MRI-based atlas of the mouse diencephalon

“…Recently, there has been an increase in the number of studies investigating the mouse thalamus using functional, structural, and diffusion-weighted imaging (DWI) techniques to examine neurological disorders and map brain connectivity (Ferris et al, 2014;Keifer et al, 2015;Maheswaran et al, 2009;Malkova et al, 2014;Nessler et al, 2007;Richards et al, 2014;Shu et al, 2013). However, these studies have relied upon manual segmentation of the diencephalon or have used atlases that identify only a limited number of diencephalic structures (Dorr et al, 2008;Kovacevic et al, 2005;Ma et al, 2005;MacKenzieGraham et al, 2004;Ullmann et al, 2012;Ullmann et al, 2014;Ullmann et al, 2013).…”