Assessment of executive function in a rodent model of Type 1 diabetes.

This study examined the impact of Type 1 Diabetes Mellitus (T1DM) on executive function using a series of operant conditioning-based tasks in rats. Sprague Dawley rats were randomized to either non-diabetic (n = 12; 6 male) or diabetic (n = 14; 6 male) groups. Diabetes was induced using multiple low-dose streptozotocin injections.

Partial ablation of frontal cortical subplate leads to developmental abnormalities in KCC2 in the prefrontal cortex.

During early brain development, the subplate relays thalamocortical afferents to the overlying cortex. Disconnection of thalamic inputs to the prefrontal cortex by lesions of the subplate of the developing prefrontal cortex at early neonatal periods result in adult-onset behavioral abnormalities reminiscent of positive, negative, and cognitive symptoms of schizophrenia. Delayed maturation of γ-amino butyric acid (GABA) function may contribute to certain abnormalities of the prefrontal cortex and clinical manifestations of schizophrenia.

Characterizing the autonomic neural connections between the abdominal aortic and superior hypogastric plexuses: A multimodal neuroanatomical study.

The aortic plexus serves as the primary gateway for sympathetic fibers innervating the pelvic viscera. Damage to this plexus and/or its associated branches can lead to an assortment of neurogenic complications such as bladder dysregulation or retrograde ejaculation. The neuroanatomy of this autonomic plexus has only recently been clarified in humans; as such, the precise function of its constituent fibers is still not clear.

Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats.

Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of neurodevelopment is a major risk factor for behavioral deficits and psychiatric illness in offspring. A spectrum of behavioral abnormalities can be recapitulated in rodents by inducing MIA using the viral mimetic, PolyI:C. Many studies have focused on long-term changes in brain structure and behavioral outcomes in offspring following maternal PolyI:C exposure, but acute changes in prenatal development are not well-characterized.

Botulinum toxin A injection into the entopeduncular nucleus improves dynamic locomotory parameters in hemiparkinsonian rats.

Parkinson's disease is associated with hyperactivity of the subthalamic nucleus (STN), contributing to motor and gait disturbances. Although deep brain stimulation of the STN alleviates certain motor dysfunction, its specific effect on gait abnormalities remains controversial. This study investigated the long-term changes in locomotion following direct infusions of botulinum toxin-A into the globus pallidus internal segment (GPi) to suppress the flow of information from the STN to the GPi in a hemiparkinsonian rat model.

Semiautomated Assessment of the Anterior Cingulate Cortex in Alzheimer's Disease.

Background And Purpose: The anterior cingulate cortex (ACC) is involved in several cognitive processes including executive function. Degenerative changes of ACC are consistently seen in Alzheimer's disease (AD). However, volumetric changes specific to the ACC in AD are not clear because of the difficulty in segmenting this region.

Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors.

The use of cannabis for therapeutic and recreational purposes is growing exponentially. Nevertheless, substantial questions remain concerning the potential cognitive and affective side-effects associated with cannabis exposure. In particular, the effects of specific marijuana-derived phytocannabinoids on neural regions such as the prefrontal cortex (PFC) are of concern, given the role of the PFC in both executive cognitive function and affective processing.

Temporoparietal Junction Functional Connectivity in Early Schizophrenia and Major Depressive Disorder.

Background: The temporoparietal junction (TPJ) has been linked to lower-level attentional and higher-level social processing, both of which are affected in schizophrenia (SZ) and major depressive disorder (MDD). We examined resting functional connectivity of bilateral anterior and posterior TPJ in SZ and MDD to evaluate potential anomalies in each disorder and differences between disorders.

Methods: Resting-state functional magnetic resonance imaging data were acquired from 24 patients with SZ, 24 patients with MDD, and 24 age-matched healthy controls.

Intrapallidal injection of botulinum toxin A recovers gait deficits in a parkinsonian rodent model.

Aim: Modulation of electrical activity in the subthalamic nucleus has been therapeutically effective in Parkinson's disease. Pharmacological manipulation of glutamate release from subthalamic neurons could also favourably alter basal ganglia activity to improve motor symptoms. This study investigates the efficacy of selective suppression of hyperactive glutamatergic input from the subthalamic nucleus to the globus pallidus internal segment by botulinum toxin A (BoNT-A) in a parkinsonian model.

Higher order thalamic nuclei resting network connectivity in early schizophrenia and major depressive disorder.

The pulvinar and the mediodorsal (MDN) nuclei of the thalamus are higher order nuclei which have been implicated in directed effort and corollary discharge systems. We used seed-based resting fMRI to examine functional connectivity to bilateral pulvinar and MDN in 24 schizophrenic patients (SZ), 24 major depressive disorder patients (MDD), and 24 age-matched healthy controls. SZ had less connectivity than controls between the left pulvinar and precuneus, left ventral-lateral prefrontal cortex (vlPFC), and superior and medial-frontal regions, between the right pulvinar and right frontal pole, and greater connectivity between the right MDN and left dorsolateral prefrontal cortex (dlPFC).

Infusions of Nerve Growth Factor Into the Developing Frontal Cortex Leads to Deficits in Behavioral Flexibility and Increased Perseverance.

In the pursuit of further establishing a neurodevelopmental animal model to investigate the mechanisms underlying impaired executive function, a core and severely debilitating symptom of schizophrenia, we sought to characterize the deficits in behavioral flexibility in adult rats following neonatal infusions of nerve growth factor (NGF) into the medial part of the developing frontal cortex. Our previous studies using this neonatal frontal cortical lesion model have shown that it leads to adult-onset positive and negative symptom-like features, and several neuropathological abnormalities of schizophrenia. In the present study, we used operant conditioning-based paradigms to investigate set-shifting ability and reversal learning performance in adult rats that received infusions of NGF into the developing frontal cortex on post-natal day 1.

Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression.

Alzheimer disease (AD) and stroke coexist and interact; yet how they interact is not sufficiently understood. Both AD and basal ganglia stroke can impair behavioural flexibility, which can be reliably modeled in rats using an established operant based set-shifting test. Transgenic Fischer 344-APP21 rats (TgF344) overexpress pathogenic human amyloid precursor protein (hAPP) but do not spontaneously develop overt pathology, hence TgF344 rats can be used to model the effect of vascular injury in the prodromal stages of Alzheimer disease.

Spontaneous low frequency BOLD signal variations from resting-state fMRI are decreased in Alzheimer disease.

Previous studies have demonstrated altered brain activity in Alzheimer's disease using task based functional MRI (fMRI), network based resting-state fMRI, and glucose metabolism from 18F fluorodeoxyglucose-PET (FDG-PET). Our goal was to define a novel indicator of neuronal activity based on a first-order textural feature of the resting state functional MRI (RS-fMRI) signal. Furthermore, we examined the association between this neuronal activity metric and glucose metabolism from 18F FDG-PET.

Neurometabolic abnormalities in schizophrenia and depression observed with magnetic resonance spectroscopy at 7 T.

Background: Examining neurometabolic abnormalities in critical brain areas in schizophrenia and major depressive disorder (MDD) may help guide future pharmacological interventions including glutamate-modulating treatments.

Aims: To measure metabolite concentrations within the anterior cingulate cortex (ACC) and thalamus of people with schizophrenia and people with MDD.

Methods: Spectra were acquired from 16 volunteers with schizophrenia, 17 with MDD and 18 healthy controls using magnetic resonance spectroscopy on a 7 Tesla scanner.

Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D receptor antagonists impairs executive function.

Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle.

Medial Prefrontal and Anterior Insular Connectivity in Early Schizophrenia and Major Depressive Disorder: A Resting Functional MRI Evaluation of Large-Scale Brain Network Models.

Anomalies in the medial prefrontal cortex, anterior insulae, and large-scale brain networks associated with them have been proposed to underlie the pathophysiology of schizophrenia and major depressive disorder (MDD). In this study, we examined the connectivity of the medial prefrontal cortices and anterior insulae in 24 healthy controls, 24 patients with schizophrenia, and 24 patients with MDD early in illness with seed-based resting state functional magnetic resonance imaging analysis using Statistical Probability Mapping. As hypothesized, reduced connectivity was found between the medial prefrontal cortex and the dorsal anterior cingulate cortex and other nodes associated with directed effort in patients with schizophrenia compared to controls while patients with MDD had reduced connectivity between the medial prefrontal cortex and ventral prefrontal emotional encoding regions compared to controls.

Functional magnetic resonance spectroscopy of glutamate in schizophrenia and major depressive disorder: anterior cingulate activity during a color-word Stroop task.

Background: Glutamate abnormalities have been suggested to be associated with symptoms of schizophrenia. Using functional magnetic resonance spectroscopy ((1)H-fMRS), it is possible to monitor glutamate dynamically in the activated brain areas, which has yet to be reported in schizophrenia. It was hypothesized that subjects with schizophrenia would have weaker glutamatergic responses in the anterior cingulate to a color-word Stroop Task.

Increased glutamate levels observed upon functional activation in the anterior cingulate cortex using the Stroop Task and functional spectroscopy.

It has been shown in recent studies that it is possible to detect changes in the main excitatory neurotransmitter, glutamate, upon functional activation with visual and motor paradigms using a 7 T MRI and functional magnetic resonance spectroscopy. A cognitive task would be desirable for this technique because it could then be used to examine psychiatric disorders that have cognitive deficiencies. The aim of the work presented here was to use functional magnetic resonance spectroscopy with a 7 T MRI to show that increases in glutamate can be observed within the anterior cingulate cortex using the Stroop Task as the activation paradigm in healthy controls.

Olanzapine-induced DNA methylation in the hippocampus and cerebellum in genes mapped to human 22q11 and implicated in schizophrenia.

Background: Although there is indirect evidence that the effects of antipsychotic drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects by epigenetic modulation. Here, we tested the effect of an antipsychotic, olanzapine, on the DNA methylation status of genes following chronic treatment using rat-specific methylation arrays.

Olanzapine-induced methylation alters cadherin gene families and associated pathways implicated in psychosis.

Background: The complex aetiology of most mental disorders involves gene-environment interactions that may operate using epigenetic mechanisms particularly DNA methylation. It may explain many of the features seen in mental disorders including transmission, expression and antipsychotic treatment responses. This report deals with the assessment of DNA methylation in response to an antipsychotic drug (olanzapine) on brain (cerebellum and hippocampus), and liver as a non-neural reference in a rat model.

Automated algorithm to measure changes in medial temporal lobe volume in Alzheimer disease.

Background: The change in volume of anatomic structures is as a sensitive indicator of Alzheimer disease (AD) progression. Although several methods are available to measure brain volumes, improvements in speed and automation are required. Our objective was to develop a fully automated, fast, and reliable approach to measure change in medial temporal lobe (MTL) volume, including primarily hippocampus.

The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum.

Background: The mechanism of action of olanzapine in treating schizophrenia is not clear. This research reports the effects of a therapeutic equivalent treatment of olanzapine on DNA methylation in a rat model in vivo.Genome-wide DNA methylation was assessed using a MeDIP-chip analysis.

Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus.

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats.

Progressive membrane phospholipid changes in first episode schizophrenia with high field magnetic resonance spectroscopy.

Patients with a first episode of schizophrenia generally have increased phospholipid membrane breakdown products within the brain, while findings in chronic patients have been inconsistent. In this study we examine progressive changes in phosphorus membrane metabolites in the same patient group through the early years of schizophrenia in brain regions associated with the disease. Sixteen never-treated and medicated first episode schizophrenic patients were assessed at 10 months and 52 months after diagnosis.

Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia.

Background: Thalamic glutamine loss and grey matter reduction suggest neurodegeneration in first-episode schizophrenia, but the duration is unknown.

Aims: To observe glutamine and glutamate levels, grey matter volumes and social functioning in patients with schizophrenia followed to 80 months after diagnosis.

Method: Grey matter volumes and proton magnetic resonance spectroscopy metabolites in left anterior cingulate and left thalamus were measured in 17 patients with schizophrenia before medication and 10 and 80 months after diagnosis.