No description available.

No description available.

No description available.

The present studies explore binding, distribution, and function of angiotensin II (AII) receptors (AT$\sb1$ and AT$\sb2)$ in the brain. The discovery that sulfhydryl reducing agents masked some but not all AII receptors in the brain prompts an evaluation of commonly used binding assay buffer constituents. EDTA enhances binding (40%) at both AT$\sb1$ and AT$\sb2$ nuclei, while bacitracin did not alter binding at either receptor subtype. Phenanthroline and BSA differentially altered binding at AT1 (220% of control) and AT$\sb2$ (118% of control) receptors. The results indicate that phenanthroline and BSA would be poor buffer constituents for studies comparing binding at AT$\sb1$ and AT$\sb2$ receptors. All receptors were mapped in normotensive and genetically hypertensive hamster brains and the subtype composition estimated for a number of brain nuclei and the pituitary. Binding in the hamster was similar to that previously observed in the rat brain with exceptions: (1) additional binding in the medial habenula and interpeduncular nuclei, (2) absence of binding in the inferior olive, suprachiasmatic nucleus, medial amygdala, piriform cortex, and subthalamic nucleus and (3) quantitative differences in the dorsomotor nucleus of the vagus, striatum, hippocampus and anterior pituitary. Unlike studies of the normotensive and spontaneously hypertensive rat, we found no significant differences in binding distribution, density or subtype composition when comparing normal and genetically hypertensive hamsters. Finally, the effects of brain angiotensin II (AII) on central catecholamine utilization were determined. We found no significant differences in norepinephrine, epinephrine or dopamine utilization in rat brain homogenates following intracerebroventricular injection of AII. Although there is evidence that AII alters catecholamine utilization in some brain nuclei, these alterations appear limited (anatomically and/or quantitatively) to a relatively small portion of the brain catecholaminergic system. The results indicate that the selection of buffer constituents is an important consideration for AII binding studies, that there are minor species differences in the distribution of AII receptors in the brain and that despite substantial functional and anatomical overlap, only a relatively small portion of the brain catecholaminergic system is modulated by angiotensin II.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. It is a disease with a broad spectrum of symptoms, both motor and non-motor, but is often only diagnosed when the motor symptoms begin to appear. By this time however, a large amount of the dopaminergic neurons of the substantia nigra pars compacta have already deteriorated. It is therefore of great interest to be able to diagnose the disease earlier on in its progression and perhaps slow down or halt its course. Recent literature has supported the idea that non-motor symptoms begin to appear years, perhaps even decades, before the motor symptoms are visible. This makes them a prime candidate for diagnosing PD earlier on. With the aim of assessing the prevalence of different NMS in prodromal and early Parkinson’s, 19 studies addressing different NMS were analyzed. It was found that NMS are prevalent in both prodromal and early PD. The strongest prodromal predictors for PD were found to be olfactory dysfunction and REM-sleep behavior disorder (RBD).

Over the last few years, antibody-mediated disorders of the central nervous system (CNS) have been a rapidly expanding field in neurology. The antibodies bind to extracellular domains of proteins expressed in the CNS and impair neuronal function. Patients with limbic encephalitis, Morvan’s syndrome have antibodies that bind to the voltage gated potassium channel (VGKC)-complex proteins, LGI1 and CASPR2, while patients with antibodies to the NMDAR have more complex encephalopathies. Clinical evidence suggests that these antibodies are pathogenic as immunotherapy reduces antibody levels, which correlate closely with clinical improvement. Antibodies can be detected in patient sera using human embryonic kidney (HEK) cells transfected with CASPR2, LGI1 and NMDAR subunits, or by binding to rodent brain sections and primary neuronal cultures. In vitro NMDAR-antibodies have been shown to cross-link synaptic NMDARs and cause their subsequent internalisation from the cell membrane. It is not known if passive transfer of NMDAR-antibodies can recapitulate features of disease or if these pathogenic mechanisms occur with VGKC-complex antibodies. The characteristics of LGI1 and CASPR2 antibodies were explored in vitro. IgG1 and IgG4 were identified as the predominant antibody subclasses, with all CASPR2 sera containing IgG1 antibodies and all LGI1 sera containing IgG4. On transfected cells both LGI1 and CASPR2 antibodies activated the classical pathway of the complement cascade. Furthermore CASPR2 antibody binding to transfected HEK cells showed a reduction in intensity over time which was most likely a result of internalisation of the CASPR2-antibody bound complex. Both CASPR2 and LGI1 antibodies bound strongly to the surface of live hippocampal neurons in culture, and this staining was reduced 24 hours after the removal of IgG, corresponding to a loss of antigen expressed at the cell surface. Patients with NMDAR-encephalitis present with a psychotic disturbance, memory loss and seizures, usually progressing to a reduced level of consciousness and a marked movement disorder. A single injection of IgG, purified from patients with NMDAR-encephalitis was administered into the lateral ventricle of mice. Animals were observed for 40 days and showed significant behavioural changes, including a deficit in spontaneous alternation, dyskinetic hind-limb clasping and visual signs of spontaneous seizures, which are reminiscent to features of the disease. Behavioural changes were not observed in animals injected with IgG from healthy individuals. These behavioural alterations appeared to be reversible and were no longer present at day 40, which was supported by protein analysis showing equivalent levels of the NMDAR expressed in the hippocampus in animals receiving patient and control IgG. In summary, these findings provide further evidence that supports a direct role of autoantibodies in NMDAR-encephalitis, limbic encephalitis and Morvan’s syndrome.

The 'local circuits' of the mammalian neocortex are defined within cortical columns less than 1mm across. There is mounting evidence that these fine-scale neural networks are an important organisational and functional unit. However, detailed study of the local circuitry is hampered by considerable technical difficulties; computer-based modelling therefore offers an important approach to understanding their basic properties. In this thesis, computer simulations are used to examine some of the fundamental questions associated with this class of neural network. We describe a spiking-network model which is inspired by anatomical and physiological study of local neocortical circuitry. Small, heterogeneous circuits are constructed from regular firing, rhythmic bursting and fast spiking neurons. These cells interact strongly through dynamic connections; synapses exhibit facilitation, depression, or a hybrid form of non-associative plasticity. A fast, asymmetric Hebbian process is also examined as a model of the 'Malsburg synapse', and is implemented in parallel with the non-associative fonns of plasticity. Exploration proceeds in three stages using a bottom-up methodology. First, we investigate the dynamical repertoire of the individual classes of circuit; the significance of architectural variation between circuits is addressed, and we examine the influence of fast adaptive processes in shaping network dynamics. Guided by available experimental data, circuits are connected in the second stage to create larger architectures; these are used to study interactions between the circuits. In the third stage, the inhibitory circuits implement surround and feedback inhibition, and local circuit effects of these two contrasting models are explored. Simulation results offer novel links between disparate experimental data. They also indicate how variation in the architecture of particular local circuits, and the different classes of connection between these circuits, might have functional pertinence. More generally, our findings suggest how this style of network may support a highly flexible, dynamically configurable computational architecture.

No description available.