Advancing rodent models of the behaviours and the neurobiological pathology associated with schizophrenia

Schizophrenia is a psychiatric illness affecting roughly 1% of the population worldwide. The symptomatology is generally classified in terms of the enhancement or absence of otherwise normally-functioning features, and has been partially recreated in rodents and non-human primates for research purposes. The overarching goal of this thesis is to address some of the shortcomings of rat models of the behaviours and the neurobiological pathology associated with schizophrenia. Specifically, we examined the effects of estradiol on dopamine release to address the potential role of sex differences in schizophrenia development and response to treatment. Furthermore, we explored the effects of prenatal glutamatergic blockade on cognition and locomotor activity at two different stages in rat adult development. Finally, we investigated the involvement of prefronto-cortical dopamine transmission on working memory, a cognitive function disrupted in schizophrenia. When paired with estradiol, chronic haloperidol treatment was effective in blocking the hyperlocomotor-inducing effects of amphetamine, supporting clinical findings. Although we attributed this effect, in part, to dopamine transmission within the nucleus accumbens, supplementary studies offer a complete map of possible estradiol-dopamine interactions within the central nervous system. In an effort to further investigate the developmental and glutamatergic aspect of schizophrenia, we found that prenatal glutamatergic blockade results in impairments similar to those seen in other animal models, as well as patients with schizophrenia. In investigating the role of prefronto-cortical dopamine transmission vis-a-vis of working memory function in the rat, we found that working memory as measured by a delay-non-match to place task, is not driven by prefronto-cortical dopamine transmission

Intra-Accumbens Injection of a Dopamine Aptamer Abates MK-801-Induced Cognitive Dysfunction in a Model of Schizophrenia

Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other µ opioid agonists

Author Correction: A consensus protocol for functional connectivity analysis in the rat brain (Nature Neuroscience, (2023), 26, 4, (673-681), 10.1038/s41593-023-01286-8)

In the version of this article initially published, Clément M. Garin was presented in the author list without a middle initial. The name has been amended in the HTML and PDF versions of the article