Includes bibliographical references / Major depression is a heterogeneous neuropsychiatric disorder with a significant genetic - stress interaction. The Wistar - Kyoto (WKY) rat displays hypersensitivity to stress and depression - like behaviour and is used as a genetic model of major depression. However, the depression - and anxiety - like behaviour of WKY has not yet been compared between the WKY/NCrl and WKY/NHsd substrains when characterizing WKY as a rat model of depression. WKY rats respond to noradrenergic and dopaminergic drugs but not to selective serotonin reuptake inhibitors (SSRIs) and are therefore suggested to model treatment resistant depression. The early life stress of maternal separation (MS) has been used to produce a rodent model of depression in Sprague - Dawley (SD) rats but results have been variable. It was therefore considered that WKY subjected to MS might produce a more robust model of depression than either WKY or MS alone. The widely used MS SD rat model of depression, as well as MS SD rats subjected to restraint stress in adult life, were evaluated as appropriate comparator models of depression. Furthermore, changes in the biochemistry in relevant brain areas of MS SD rats exposed to restraint stress in adulthood is still elusive and was further explored. The glutamate N - methyl - D - aspartate (NMDA) receptor antagonist, ketamine, has been found to be clinically useful. The acute effects of ketamine have not been previously tested in male WKY or MS SD rats and it was therefore decided to study the behavioural effects of ketamine in these rat models of depression. The aim of the first study was to characterize the WKY rat model of depression and to select the appropriate substrain of WKY best suited as a model of depression. The WKY/NCrl and WKY/NHsd substrains of WKY were tested for optimal depression - /anxiety - like behaviour in the forced swim test (FST), open field test (OFT) and elevated plus maze (EPM) and compared to the Wistar reference strain. Both WKY/NCrl and WKY/NHsd were less active than Wistar rats in the OFT and FST and WKY/NCrl were les s activ e than WKY/ NHsd. Therefore, the initial study identified WKY/NCrl as the appropriate substrain of WKY to model depression. The WKY/NCrl rats were further characterized in terms of their response to an optimal dose of the antidepressant drug, desipramine in the FST. Desipramine has been shown to be effective in reducing the depression - like behaviour of WKY and was therefore chosen as the antidepressant drug for this study. A dose of 15 mg/kg desipramine attenuated the depression - like behaviour as evide nced by decreased immobility in the FST and was therefore used for subsequent experiments. Desipramine had no effect on opioid receptors (μ - and κ - opioid receptors, MOR and KOR, respectively) , and tyrosine hydroxylase in the nucleus accumbens ( NAc ) or prefrontal cortex ( PFC ) of WKY rats.

Epilepsy directly affects approximately 50 million people globally and is the most common neurological disorder in sub-Saharan Africa, mainly due to high rates of neuroinfections and head trauma experienced by people in the region. A common factor in these causes of acquired epilepsy is their association with significant neuroinflammation, which is thought to drive the epileptogenic process. Although epilepsy exerts a heavy toll on the health, wellbeing and socio-economic outcomes of Africans, there are still major deficits in our understanding of how infections and inflammatory processes drive seizure development. Using the hippocampal organotypic brain slice culture model in mouse brains, I investigated the effects of classical immune activation on circuit excitability and cell viability. To initiate inflammation, I administered lipopolysaccharide (LPS), an endotoxin derived from gramnegative bacteria, and interferon-gamma (IFNy), a cytokine typically released by lymphocytes, to brain slices on varying time scales. I used enzyme-linked immune-sorbent assays to show that this reliably induced the release of the proinflammatory cytokines TNFα and IL-6 from the brain slices. I used patch-clamp electrophysiology to assess both the intrinsic electrical characteristics as well as the synaptic strength between pyramidal neurons after immune activation. I found no changes in the basic membrane properties of pyramidal neurons after short term neuroinflammation, but I did observe changes to the function of hippocampal networks at intermediate (24 hours) and lengthy (72 hours) time scales of immune activation in the form of significantly reduced spontaneous excitatory and inhibitory postsynaptic current frequencies and amplitudes. In addition, I developed an assay to determine neuronal survival to monitor the health of neurons in brain slices after immune activation and report that hippocampal organotypic brain slice cultures that were immuneactivated for 72 hours do not appear to experience either apoptotic or necrotic cell death. Taken together, these data constitute a valuable contribution towards understanding how inflammatory mechanisms drive changes to neuronal function, which could be relevant for understanding epileptogenesis in infectious and inflammatory causes of epilepsy.

Although HIV and antiretroviral drugs have been shown to cause damage in the brain, the long-term impacts of perinatal infection, early treatment and exposure in children at 11 years, remain unclear. The effects of HIV and antiretroviral therapy (ART), whilst indistinguishable, can be investigated at a chemical level through proton magnetic resonance spectroscopy (1H-MRS). Previous studies in children have largely focused on individual metabolite changes. However, several adult studies have now advanced beyond this to address patterns of metabolic activity that are altered with HIV infection. Using a 3T Skyra scanner, 136 children (76 HIV+, 30 HEU, 30 HU; 71 males) between the ages of 11.0- 12.5 years, and from a similar socioeconomic background, were scanned. In this study metabolite concentrations were quantified within the basal ganglia (BG), midfrontal gray matter (MFGM) and peritrigonal white matter (PWM). We utilised linear regression to investigate individual metabolite differences, comparing HIV-infected (HIV+) children from the Children with HIV Early Antiretroviral Therapy (CHER) trial, and HIV-exposed-uninfected (HEU) children, to HIV-unexposed (HU) children. Pearson's correlation analysis, factor analysis and logistic regression were then used to study alterations in metabolic patterns between HIV+ and HIV-uninfected (HIV-) children. Analysis of the data was carried out in R. We found elevated total choline in the BG (p = 0.03) and MFGM (p < 0.001) of HIV+ children, as well as reduced PWM total NAA (p = 0.03) and total creatine (p = 0.01). Altered metabolite concentrations were further observed in HEU children. Additionally, we identified a cross-regional coupling of choline which distinguishes HIV+ from HIV- children (p < 0.001). These findings indicate that multiregional inflammation and PWM axonal damage are occurring in HIV+ children at 11 years. Ultimately, the consequences of perinatal HIV acquisition, in spite of early treatment, continue to be seen at 11 years, as do the impacts of exposure.

Objective: Individuals with posttraumatic stress disorder (PTSD) have been found to exhibit emotional regulation difficulties. However, much remains to be learned about the specific neural mechanisms that underlie such difficulties. This study aimed to use eye tracking to investigate the mechanisms underlying emotional regulation difficulties in individuals with PTSD. Method: A total of 87 trauma-exposed mothers (34 PTSD positive and 53 non-PTSD controls) completed an eye tracking assessment in which pupillary dilation in response to emotionally valenced stimuli was measured. The participants also completed two self-report measures of emotional regulation. Results: The PTSD group exhibited increased pupillary dilation to positively valenced stimuli compared to the trauma-exposed, non-PTSD group. In contrast, there was no difference between the two groups using self-report measures of emotional regulation. Additionally, there were no associations between self-report measures and pupillary response to emotionally valenced stimuli. Conclusion: The findings may reflect impaired parasympathetic nervous system processes in individuals with PTSD. The finding that eye tracking, but not emotional regulation questionnaires, differentiated the groups may reflect the point that self-report measures are biased by an individual's ability and willingness to respond. These findings need to be followed up with additional experiments to delineate parasympathetic and other mechanisms involved in underpinning emotional regulation difficulties in PTSD.

Developmental Venous Anomalies are a normal variant that may be associated with other cerebral vascular malformation they have bean previously referred to Venous angiomas. DVAs are the most frequently encountered cerebral vascular malformation and their incidence is reported to be high as 2.6%. DVAs are classified into two types based on draining veins. Either deep or superficial. Those that drain into subependymal veins are classified as deep and those that drain into cortical pial veins are classified as superficial. The trans-cerebral veins join either the deep or superficial venous systems by crossing a varying length of the brain parenchyma. Controversy surrounds their exact clinical significance, as DVAs are rarely symptomatic. The symptoms displayed by a patient can be related to a lesion that is associated with DVAs, such as a cavernoma. Study Aim: To describe the patients presenting to a single unit over a 10-year period with symptoms attributable to a DVA. Results: Out of 19 patients in the database with the diagnosis of DVA, 10 were identified where the clinical presentation was directly related to the DVA. Seven of the patients presented with haemorrhage, 6 had parenchymal bleeds and one was intraventricular. Two patients had neurological deficit, 1 was transient and one was progressive. One patient had sudden severe headache with no evidence of haemorrhage on CT scan. The age range was from 14 to 55 with a mean of 32,7 years. Four patients were male and 6 were female. Of the patients that presented with haemorrhage only one had a fistula, three other patients with haemorrhage had evidence on DSA of stenosis of the large collector vein, In the remaining 3 patients no reason for the bleed could be detected. One patient presented with left hemianopia that resolved after several hours, DSA showed minimal caput medusa with delayed filling of the collector vein. The other patient that presented with progressive neurological deficit in the form of progressive leg spasticity and dysarthria, Angiography showed a large collecting vein that drains in the jugular bulb was stenosed. The last patient that presented with sudden sever headaches, with no haemorrhage identified on CT scan, On DSA there was early filling of the DVA veins compared to other cerebral veins and two prominent posterior communicating thalamoperforating vessels were seen. Conclusion: Developmental venous anomalies are the commonest vascular malformation, and are rarely symptomatic unless associated with a cavernoma. In patients that have symptoms linked to DVAs (Haemorrhage, neurological deficit, sudden sever headaches) overall they have a good outcome, and the deficit related to a DVA tend to improve overtime, except for one patient that we had in our group, the DVA draining the pons and the cerebellar hemisphere had a tight outflow stenosis, that lead to progressive neurological deficit. In general, the majority of DVAs that are symptomatic do well.

Includes bibliographical references. / This study aimed to determine whether highly active antiretroviral therapy (HAART) improved cognitive function in HIV positive people in South Africa, and whether this effect differed according to the CNS penetration-effectiveness (CPE) of the regimen used. I also investigated potential HIV-Associated Neurocognitive Disorders (HAND) biomarkers (serum neopterin, osteopontin and neurofilament H) to determine their relationship to the severity of cognitive impairment at baseline in HAART-naïve patients, and whether initial levels of these biomarkers related to the change in cognitive function a year later.

The neuromuscular junction (NMJ) is a synapse with one of the highest safety margins in the human body. The use of neuromuscular blocking agents to inhibit neuromuscular transmission is sufficient to produce skeletal muscle paralysis, a mechanism used to facilitate muscle relaxation during surgery. Residual neuromuscular block postoperatively has been found to be a major risk factor for postoperative complications. Sudden reinstatement of neuromuscular block (recurarisation), through use of magnesium, has also been observed clinically. This has led to a reluctance to use magnesium postoperatively for fear of recurarisation. Recurarisation following reversal of neuromuscular blockade with neostigmine or sugammadex has not been evaluated in a formal study, and for this reason, this study investigated recurarisation after 30 mg/kg magnesium sulphate (MgSO4) following reversal of neuromuscular blockade with neostigmine, two dosages of sugammadex or when reversal was omitted. Prior to investigating recurarisation, the effects of magnesium on neuromuscular transmission in the absence of neuromuscular blocking agents was investigated, in order to determine a standard clinical dose that did not produce detectable, by Train-of-Four Ratio (TOF-R) or Twitch 1 height (%T1), neuromuscular impairment.

Introduction: Schizophrenia is a chronic, debilitating mental disorder characterised by positive, negative and cognitive symptoms. Current treatment regimens fail to adequately address the cognitive and negative symptoms of the disorder. Social isolation rearing (SIR) is a well-established developmental adversity paradigm which is used as an animal model of schizophrenia and usually studied in male rats. Previous SIR studies have found attentional abnormalities in isolated rats in behavioural tests which correspond to the results of studies investigating the cognitive symptoms of schizophrenia in patient trials. Isolated rats also display abnormal social responses which may be of relevance to the negative symptoms of schizophrenia. The primary aim of this study was to build on existing SIR literature by performing behavioural tests in socially isolated rats to address attentional function. Neurochemical investigations were performed on projections of the locus coeruleus norepinephrine system, known to be involved in attentional function, as research on this system is surprisingly sparse. The secondary aim of the study was to address the negative symptoms of schizophrenia using ultrasonic vocalisation recording to investigate the calling behaviour of isolated rats in response to a novel context. The study included both male and female rats so that sex differences could be studied in the context of social isolation. Methodology: Sprague-Dawley rats were weaned at postnatal day (p) 21 and randomly allocated to one of four housing groups; female socialised (n=50), female isolated (n=50), male socialised (n=38) and male isolated (n=38). Socialised animals were housed 4 per cage (single sex) and isolated animals were housed alone. Animals were weighed and cages cleaned weekly as part of a minimal handling protocol required for SIR. After 8 weeks in their housing conditions (p78-82) rats underwent one of two behavioural paradigms: three phase novel object recognition or ultrasonic vocalisation recordings. Between p90-94 animals were rapidly decapitated and the hippocampus and prefrontal cortex were dissected out for use in one of two neurochemical analyses. For in-vitro superfusion experiments the tissue was used immediately to quantify functional release of radioactively-labelled norepinephrine when stimulated with glutamate under varying conditions. Enzyme linked immunosorbent assays (ELISA) and bicinchoninic acid (BCA) protein assays was performed to quantify norepinephrine and glutamate concentrations expressed in relation to the wet weight of the tissue and amount of protein in the tissue. Results: Behavioural and neurochemical changes were induced by the SIR model. Isolated animals were found to respond to novel objects abnormally compared to control animals. During initial exposure to a novel environment in the first phase of the novel object recognition test isolated animals demonstrated hypoactivity. An overall reduction in the fractional release of norepinephrine when stimulated with combinations of glutamate and gamma-aminobutyric acid (GABA) was demonstrated in the hippocampus of isolated rats. Sex differences were evident in a number of experiments. Female rats were found to be hyperactive in the three phases of the novel object recognition test compared to males and also had elevated hippocampal norepinephrine activity as well as an increased concentration of norepinephrine in this area. Male rats on the other hand had an elevated prefrontal cortex norepinephrine activity and concentration. Conclusion: The SIR paradigm is able to induce behavioural and neurochemical changes in both female and male rats. The results of this study reinforce the usefulness of SIR as a model for schizophrenia as the way in which isolated animals responded to novel objects was different to their socialised counterparts. This difference implies an abnormal attentional response which corresponds to the cognitive symptoms described in schizophrenia. Furthermore, the neurochemical experiments performed in this study are the first of their kind and provide preliminary evidence for the GABAergic mechanisms underlying attentional abnormalities associated with SIR. The prevalence of sex differences throughout testing also provides strong evidence for the inclusion of both sexes in future studies to avoid the omission of potentially important findings. Future studies to refine and build on neurochemical analyses in developmental models of schizophrenia, such as SIR will potentially provide a mechanistic understanding of cognitive dysfunction as well as useful translational information for treating the human disorder.

Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl ions via activated GABAA and glycine receptors. As a result, changes to the neuronal driving force for Cl- are thought to play pivotal roles in many physiological and pathological brain processes. Established theories regarding the determinants of Cl- driving force have recently been questioned based on new experimental data. However, it is experimentally difficult to distinguish the respective contributions of the multiple, dynamically interacting mechanisms which may be important in Cl- homeostasis. Here I present biophysical models of Cl- homeostasis using the pump-leak formulation. By means of numerical and novel analytic solutions, I demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Importantly, I show that while impermeant anions can contribute to setting [Cl- ]i in neurons, they have a negligible effect on the driving force for Cl locally and cell-wide. In contrast, I demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. This prediction is supported by a meta-analysis of multiple experimental studies, which demonstrates a strong correlation between the expression of the cationchloride cotransporter KCC2 and intracellular Cl concentration. My findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

As an important hemodynamic mechanism, pressure autoregulation protects the brain against inappropriate fluctuations in cerebral blood flow subject to changing cerebral perfusion pressures. In acute neurological illnesses, including traumatic brain injury in children, impaired autoregulation is associated with a worse prognosis. It also has important clinical implications for managing blood pressure and intracranial pressure. Two common methods of measuring pressure autoregulation reported in the adult literature have been rarely reported in children. This pilot study aimed to examine the relationship between two autoregulatory indices, namely PRx (pressure reactivity index) and ARI (autoregulatory index) in children with severe TBI. The study also examined their relationship with the response of clinically relevant variables such as intracranial pressure (ICP), brain oxygenation (PbtO2) and local cerebral blood flow (loCBF) to dynamic testing. The study is a retrospective cohort study of prospectively collected data conducted at the Red Cross Children Hospital. We analyzed the results of 18 patients in 28 tests of autoregulation to determine the static state of autoregulation by calculating the autoregulatory index (ARI). These tests were done by controlled elevation of blood pressure to evaluate changes in transcranial Doppler-derived flow velocity of the middle cerebral artery. Concomitant recordings were made of ICP, PbtO2, and loCBF. Secondly, we also calculated the PRx as a moving correlation co-efficient between slow changes in blood pressure and ICP. Two time epochs of PRx were examined in relation to the static tests: 1 hour before and after the test, and 12 hours before and after the test. The results included 28 tests done for ARI and 27 calculations for PRx epochs; all tests had ICP and PbtO2 data and 23 had loCBF. PRx and ARI showed no significant relationship between them. However, there was a significant relationship between ARI and ΔICP (p=0.04), i.e. when autoregulation was weak the change in ICP with a change in blood pressure was greater; and between PRx and ΔPbtO2 (p=0.04). There was a trend in correlation analysis between loCBF and PRx but not in the linear mixed effects model In conclusion, the study showed no correlation between the two autoregulatory indices, PRx and ARI, probably because they assess different aspects of autoregulation. However, significant relationships exist between ARI and ΔICP as well as PRx and ΔPbtO2, which generate interesting hypotheses about autoregulation and have clinical implications. Both autoregulatory indices have benefits and limitations. Further studies on such relationships, taking into consideration a larger sample group, inclusion of unstable patients, and utilization of the same range in BP for calculating the indices, are recommended.