Neuroanatomical And Neurochemical Organization Of Compartments In The Basal Ganglia Of The Rat

The structural and neurochemical organization of the basal ganglia of the rat was investigated with highly sensitive modern anterograde and retrograde tracing methods in combination with immunocytochemical identification of intrinsic neuronal substances with the optical and laser-confocal microscope to address the fundamental organization of these centers as an integrated system.;Based on the present results and other evidence, a functional model of the basal ganglia is proposed: The corticostriatal inputs activate a large population of striatal neurons. Among these, appropriate neurons are \u27selected\u27 within each functional domain by the dopaminergic, cholinergic, and GABAergic recurrent collateral inputs. The same corticostriatal input simultaneously activates type II spiny projection neurons from each functional domain, which inhibit a population of parvalbumin-containing GABAergic pallidal neurons. These pallidal neurons disinhibit a number of pallidostriatal neurons via axon collaterals. The appropriate population of pallidostriatal neurons is \u27selected\u27, probably by subthalamic afferents. The selected GABAergic pallidostriatal neurons then inhibit striatal functional domains, thereby \u27selecting\u27 only the appropriate functional unit. The selected population of striatal projection neurons then inhibits a number of GABAergic neurons of the basal ganglia output centers. Again, appropriate neurons are \u27selected\u27 by subthalamic afferents and recurrent collaterals. The selected GABAergic neurons then disinhibit the thalamus, pedunculopontine nucleus and/or the superior colliculus via axon collaterals. The information sent to the thalamus is used to program memory, whereas that directed to the pedunculopontine nucleus or the superior colliculus participates in motor execution. The dorsolateral striatal circuit operates during sensory-guided and self-paced movements, while the medial and ventral striatal circuit operates during memory-guided movements. Striatal interneurons, globus pallidus neurons, subthalamic nuclear neurons and dopaminergic neurons play a role in \u27selecting\u27 the appropriate sets of neurons at different levels. (Abstract shortened by UMI.

Growing new dendritic spines to correct cognitive deficits of schizophrenia

In this project, we will attempt to re-grow functional dendritic spines in an animal model of schizophrenia for the first time. By re-growing dendritic spines, we intend to restore glutamatergic neurotransmission and improve cognition.https://ir.lib.uwo.ca/brainscanprojectsummaries/1023/thumbnail.jp

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. The study focuses on the Cadherin/protocadherins encoded by a multi-gene family that serve as adhesion molecules and are involved in cell-cell communication in the mammalian brain. A number of these molecules have been implicated in the causation of schizophrenia and related disorders. RESULTS: The results show that olanzapine causes changes in DNA methylation, most specific to the promoter region of specific genes. This response is tissue specific and involves a number of cadherin genes, particularly in cerebellum. Also, the genes identified have led to the identification of several pathways significantly affected by DNA methylation in cerebellum, hippocampus and liver. These included the Gα12/13 Signalling (p = 9.2E-08) and Wnt signalling (p = 0.01) pathways as contributors to psychosis that is based on its responsiveness to antipsychotics used in its treatment. CONCLUSION: The results suggest that DNA methylation changes on the promoter regions of the Cadherin/protocadherin genes impact the response of olanzapine treatment. These impacts have been revealed through the identified pathways and particularly in the identification of pathways that have been previously implicated in psychosis

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

Previous studies have demonstrated altered brain activity in Alzheimer\u27s disease using task based functional MRI (fMRI), network based resting-state fMRI, and glucose metabolism from 18 F 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 F-18 FDG-PET. We studied 15 normal elderly controls (NEC) and 15 probable Alzheimer disease (AD) subjects from the AD Neuroimaging Initiative. An independent component analysis was applied to the RS-fMRI, followed by template matching to identify neuronal components (NC). A regional brain activity measurement was constructed based on the variation of the RS-fMRI signal of these NC. The standardized glucose uptake values of several brain regions relative to the cerebellum (SUVR) were measured from partial volume corrected FDG-PET images. Comparing the AD and NEC groups, the mean brain activity metric was significantly lower in the accumbens, while the glucose SUVR was significantly lower in the amygdala and hippocampus. The RS-fMRI brain activity metric was positively correlated with cognitive measures and amyloid beta 1-42 cerebral spinal fluid levels; however, these did not remain significant following Bonferroni correction. There was a significant linear correlation between the brain activity metric and the glucose SUVR measurements. This proof of concept study demonstrates that this novel and easy to implement RS-fMRI brain activity metric can differentiate a group of healthy elderly controls from a group of people with AD

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. Reduced connectivity was found between the anterior insulae and the medial prefrontal cortex in schizophrenia compared to controls, but contrary to some models emotion processing regions failed to demonstrate increased connectivity with the medial prefrontal cortex in MDD compared to controls. Although, not statistically significant after correction for multiple comparisons, patients with schizophrenia tended to demonstrate decreased connectivity between basal ganglia-thalamocortical regions and the medial prefrontal cortex compared to patients with MDD, which might be expected as these regions effect action. Results were interpreted to support anomalies in nodes associated with directed effort in schizophrenia and nodes associated with emotional encoding network in MDD compared to healthy controls

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. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning

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\u27s 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. Methods: Unilateral 6-hydroxydopamine lesioned parkinsonian rodents and controls received microinfusions of BoNT-A or vehicle into the ipsilateral internal globus pallidus (n = 8 per group). Changes in gait were measured by the CatWalk apparatus, along with assessment of apomorphine-induced rotational behaviour prior to and following BoNT-A injection. Immunofluorescent staining for markers of glutamatergic, GABAergic and total terminals was performed at the internal globus pallidus. Results: Administration of a single dose of BoNT-A (0.5 ng) significantly improved the rotational asymmetry and gait abnormalities. Ameliorations in speed, body speed variation, cadence and walking pattern were comparable to pre-lesioned animals, and persisted up to 1 month following BoNT-A injection. These changes are associated to BoNT-A\u27s ability to selectively target glutamatergic terminals. Conclusion: Blockade of subthalamic hyperactivity by BoNT-A leads to sufficient reorganization in the basal ganglia needed to generate a consistent rhythmic pattern of walking. This suggests the potential use of intracerebral BoNT-A to produce effective neuromodulation in the parkinsonian brain, as well as expansion into other neurodegenerative disorders linked to excitotoxity

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. NGF-infusion caused apoptosis of cells in the subplate layer. Adult rats that received neonatal infusions of NGF showed decreased grey matter thickness, and decreased levels of parvalbumin in prelimbic and infralimbic areas of the medial prefrontal cortex (mPFC). NGF-treated rats had difficulty completing the set-shifting and reversal learning tasks due to increased perseverance (ie, a failure to disengage from the previously-learned strategy once the rule contingencies were changed) compared to the control group. Collectively, these results identify the crucial role of the frontal cortical subplate layer in the structural and functional development of the mPFC relevant to schizophrenia. Furthermore, the present findings substantially advance the face and construct validity of this putative preclinical model of schizophrenia based on developmental disruption of the frontal cortical subplate

Semiautomated Assessment of the Anterior Cingulate Cortex in Alzheimer\u27s Disease

© 2019 by the American Society of Neuroimaging 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\u27s disease (AD). However, volumetric changes specific to the ACC in AD are not clear because of the difficulty in segmenting this region. The objectives of the current study were to develop a precise and high-throughput approach for measuring ACC volumes and to correlate the relationship between ACC volume and cognitive function in AD. METHODS: Structural T 1 -weighted magnetic resonance images of AD patients (n = 47) and age-matched controls (n = 47) at baseline and at 24 months were obtained from the Alzheimer\u27s disease neuroimaging initiative (ADNI) database and studied using a custom-designed semiautomated segmentation protocol. RESULTS: ACC volumes obtained using the semiautomated protocol were highly correlated to values obtained from manual segmentation (r =.98) and the semiautomated protocol was considerably faster. When comparing AD and control subjects, no significant differences were observed in baseline ACC volumes or in change in ACC volumes over 24 months using the two segmentation methods. However, a change in ACC volume over 24 months did not correlate with a change in mini-mental state examination scores. CONCLUSIONS: Our results indicate that the proposed semiautomated segmentation protocol is reliable for determining ACC volume in neurodegenerative conditions including AD