A combined DTI-fMRI approach for optimizing the delineation of posteromedial vs. anterolateral entorhinal cortex

In the entorhinal cortex (EC), attempts have been made to identify the human homologue regions of the medial (MEC) and lateral (LEC) subdivision using either functional magnetic resonance imaging (fMRI) or diffusion tensor imaging (DTI). However, there are still discrepancies between entorhinal subdivisions depending on the choice of connectivity seed regions and the imaging modality used. While DTI can be used to follow the white matter tracts of the brain, fMRI can identify functionally connected brain regions. In this study, we used both DTI and resting-state fMRI in 103 healthy adults to investigate both structural and functional connectivity between the EC and associated cortical brain regions. Differential connectivity with these regions was then used to predict the locations of the human homologues of MEC and LEC. Our results from combining DTI and fMRI support a subdivision into posteromedial (pmEC) and anterolateral (alEC) EC and reveal a discrete border between the pmEC and alEC. Furthermore, the EC subregions obtained by either imaging modality showed similar distinct connectivity patterns: While pmEC showed increased connectivity preferentially with the default mode network, the alEC exhibited increased connectivity with regions in the dorsal attention and salience networks. Optimizing the delineation of the human homologues of MEC and LEC with a combined, cross-validated DTI-fMRI approach allows to define a likely border between the two subdivisions and has implications for both cognitive and translational neuroscience research

Investigation of Memory Related Cortical Thalamic Circuitry in the Human Brain

This dissertation examined the role of medial prefrontal cortex (mPFC) and the hippocampus (HC) in episodic memory, and provides a novel approach to identify the midline thalamus mediating mPFC-HC interactions in humans. The mPFC and HC are critical to the temporal organization of episodic memory, and these interactions are disrupted in several mental health and neurological disorders. In the first study, I provide evidence that the mPFC is involved in ordinal retrieval, and the HC is active in temporal context retrieval in remembering the order of when events happen. In the second study, I focus on the anatomical basis of the mPFC-HC interactions which is reliant on the midline thalamus. I review in detail the anatomy of the midline thalamus both in location, and connectivity profile with the rest of the brain comparing the extensive anatomical evidence in rodents with the available evidence in monkeys and humans. This section also elaborates on the role of the midline thalamus in memory, stress regulation, wakefulness, and feeding behavior, and how pathological markers along the midline thalamus are a vanguard of several neurological disorders including Alzheimer’s Disease, schizophrenia, depression, and drug addiction. Lastly, I devised a new approach to identify the midline thalamus in humans in vivo using diffusion weighted imaging, capitalizing on known fiber connections gleaned from non-human animals, focusing on connections between the midline thalamus and the mPFC, medial temporal lobe and the nucleus accumbens. The success of this approach is promising for translational imaging. Overall, this dissertation provides new evidence on 1) complementary functional roles of the mPFC and HC in sequence memory, 2) a cross-species anatomical framework for understanding the midline thalamus in humans and neurological disorders, and 3) a new method for non-invasive identification of the midline thalamus in humans in vivo. Thus, this dissertation provides a new fundamental understanding of mPFC-midline thalamic-HC circuit in humans and tools for its non-invasive study in human disease

Altered NMDA and GABA-A Receptor Subunit Expression in the Hypothalamic Paraventricular Nucleus of Hypertensive and Pregnant Rats

Hypertension and pregnancy are both accompanied by increases in sympathetic nerve activity. This has been attributed in part, to changes in the neurochemistry of the hypothalamic paraventricular nucleus (PVN). In hypertension, physiological studies have revealed that decreases in GABAergic inhibition and increases in glutamatergic excitation within the PVN contribute to this sympathoexcitation. In late-term pregnancy however, the sympathoexcitation appears to be mediated by decreases in GABAergic inhibition, with no glutamatergic contribution. This study aimed to examine the molecular characteristics of the GABAA and NMDA receptor to ascertain whether changes in their subunit expression in the PVN could contribute to the sympathoexcitation observed in these physiological states. Whole PVN micropunches subjected to quantitative immunoblotting were combined with semi-quantitative analysis of immunohistochemistry to ascertain which subunits were altered, and whether the alteration was confined to specific parvocellular subnuclei of the PVN. The results of this study show that both hypertension and pregnancy are accompanied by significant decreases in both the α1 and α5 subunit of the GABAA receptor in the PVN. Furthermore, hypertension is also accompanied by a significant increase in the expression of the GluN2A subunit of the NMDA receptor, which was associated with increases in the number of GluN2A-immunoreactive neurones in specific parvocellular subnuclei of the PVN. Conversely, pregnancy was associated with a significant increase in GluN2B subunit expression which was not associated with changes in cell immunoreactivity in any parvocellular subnuclei. The results from this study suggest that decreases in α1 and α5 subunits of the GABAA receptor may be important in mediating the sympathoexcitation observed in both of these physiological states, with the greater level of sympathoexcitation observed in hypertension possibly attributed to increases in GluN2A-mediated NMDA receptor expression

An ontologically consistent MRI-based atlas of the mouse diencephalon

In topological terms, the diencephalon lies between the hypothalamus and the midbrain. It is made up of three segments, prosomere 1 (pretectum), prosomere 2 (thalamus), and prosomere 3 (the prethalamus). A number of MRI-based atlases of different parts of the mouse brain have already been published, but none of them displays the segments the diencephalon and their component nuclei. In this study we present a new volumetric atlas identifying 89 structures in the diencephalon of the male C57BL/6J 12 week mouse. This atlas is based on an average of MR scans of 18 mouse brains imaged with a 16.4T scanner. This atlas is available for download at www.imaging.org.au/AMBMC. Additionally, we have created an FSL package to enable nonlinear registration of novel data sets to the AMBMC model and subsequent automatic segmentation

Cingulate Cortex Networks : Role in learning and memory and Alzheimer's disease related changes

VRIJE UNIVERSITEIT CINGULATE CORTEX NETWORKS Role in learning and memory and Alzheimer’s disease related changesScheltens, P. [Promotor]Witter, M.P. [Promotor