Ultrasound (US) has become a standard procedure used during pregnancy to document the health and development of a fetus. When ultrasound was first developed, some researchers urged caution, suggesting that the possibility of hazard should be kept under constant review. Given the routine application of fetal ultrasound imaging, any possibility of deleterious developmental effects resulting from its use is an important public health issue. Rats have a well characterized central nervous system whose neurochemical pathways and neuronal electrophysiology qualitatively correspond to those of humans. Because of this, we opted to use Wistar rats as an animal model to document effects from ultrasound exposure. We exposed one group of rats on prenatal days 15 and 20 for fifteen minutes. A control group was exposed subjected to similar conditions, however no ultrasound exposure was given. A third group was exposed for ten minutes each on post natal days (PND) 2 and 3 while a fourth control group was exposed to the same conditions as group three with no ultrasound exposure. The rats were then watched for developmental delays. When the rats reached the appropriate age, they were given a locomotor task to test for appropriate motor responses. Acoustic startle and prepulse inhibition tests were administered to test for sensorimotor gating, hearing, and motor response. Finally, a brainstem auditory evoke potential test was given to track auditory threshold and appropriate neural firing at various auditory nuclei. Postnatally US exposed rats showed a decreased acoustic startle response and prenatally exposed rats exhibited a speeding up in components of the brainstem auditory evoked potential test.

The vertebrate hypothalamus is a central node within multiple interwoven neural networks that integrate external and internal cues to control homeostasis, endocrine functions and social behavior. The neuropeptide hormone arginine-vasopressin (AVP) is produced in both the supraoptic and paraventricular nuclei of the hypothalamus. Expression within these nuclei is conserved across species, and species differences in the expression of AVP and its cognate receptors correlate with differences in social behavior. As a central node within the social behavior network, chemogenetic manipulation of AVP+ cells in the paraventricular nucleus (pvn) of the hypothalamus provides a unique opportunity to investigate the relationship between social behavior and the regulation of stress responses. Here, we show that reversibly inducing excitatory activity in vasopressin neurons in the PVN results in reduced motivation for social interaction and increased grooming behavior in males. Chronic activation of PVN AVP neurons reduced social motivation in male mice that persisted even without CNO administration. These results highlight the role PVN AVP+ neurons play in the modulation of male social motivation.

Progesterone regulates female reproduction in many ways, yet it is still unclear how signals are conveyed through nuclear and extranuclear receptors. The traditional notion was that progesterone binds classical progesterone receptors to alter gene transcription. This view has been challenged by the discovery of additional progesterone signaling molecules important for progesterone actions in non-neural cells. In granulosa cells, the progesterone receptor membrane component 1 (Pgrmc1) mediates progesterone effects by forming a receptor complex with binding partner, Serpine mRNA binding protein 1, but it is unknown whether these molecules function similarly in the brain. To begin to address these issues, I investigated the neural role of Pgrmc1 in female mouse brain, rat brain and in neural cells. By examining the neuroanatomical localization, hormonal regulation, and colocalization of Pgrmc1 within key neurons in the neural control of ovulation, Pgrmc1 emerged as a candidate signaling molecule likely to mediate progesterone functions. Furthermore, Pgrmc1 levels regulate the expression of several diverse genes and signaling pathways in neural cells. Taken together, these results demonstrate that Pgrmc1 function is likely to impact diverse neural functions.

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Brain maturation is an important factor in cognitive, emotional, behavioural and motor development during childhood and adolescence. This study uses multi-modal magnetic resonance imaging (MRI) techniques to assess neural representations of devel opment in both healthy and abnormally developing populations. A novel face emotion stimulus set, designed to assess distinct dimensions of facial emotion, particularly to assess the e ect of averted faces, is introduced in a pilot functional MRI study of an adult cohort. Results from this pilot study show that interactions between face direction and emotion can infuence which brain areas are recruited for emo- tion processing, suggesting that the neural correlates of judging facial emotion content are modulated by face direction. Facial emotion perception was assessed as a neural task to investigate dimensions of emotion processing, and emotion processing development, in a group of children and adolescents. A number of correlations were found between dimensions of the task and developmental measures such as age, pubertal development and intelligence. In particular, intelligence was shown to be positively associated with the increasing utilization of regions associated with cognitive control, such as the prefrontal cortex. A voxel-based morphometry (VBM) study explored potential structural correlates of adolescent development. Age was found to correlate with changes in local brain regions, however pubertal development was shown to be a more accurate measure of those changes. A diusion tensor imaging assessment of white matter using fractional anisotropy has demonstrated important developmental di erences in white matter be- tween males and females over childhood and adolescence. Findings also suggest diff erent relationships between intelligence and white matter for males and females. Developmental Coordination Disorder, a common childhood disorder characterised by deficits in learning and automating motor skills, was assessed as an example of ab normal brain development. VBM was used to show that kinematic metrics of a simple visuomotor task correlated with regional grey matter volumes.

Prototoxin proteins have been identified as members of the Ly6/uPAR super family whose three-finger motif resembles that of α-bungarotoxin. Though they are known to modify the function of nAChRs, their specificity is still unclear. Our lab identified three prototoxin proteins in the chicken ciliary ganglion: Ch3ly, Ch5ly, and Ch6ly. Ch6ly was later identified as prostate stem cell antigen (PSCA), and specifically decreased the amount of calcium influx through the homomeric α7 nAChR subtype. I then identifiedCh3ly and Ch5ly as LY6E and LYPD6B, respectively. I focused my attention onLYPD6B because of its expression in the brain. This dissertation tests whether LYPD6Bis a prototoxin protein that specifically co-localizes with and modifies the function of the heteromeric α3β4* nAChRs (the other nAChR subtype expressed in the chicken ciliary ganglia). In the first part of my dissertation I performed intracellular two-electrode voltage clamp on Xenopus oocytes co-expressing human LYPD6B and different stoichiometries of the α3β4* nAChR, these included two (α3)2(β4)3 withβ4−α3−β4−β4−α3 and β4−α3−β4−α3−β4 stoichiometries, two (α3)3(β4)2 with stoichiometries β4−α3−α3−β4−α3 and β4−α3−β4−α3−α3, two (α3β4)2(α5D)β4−α3−α5D−β4−α3 and β4−α3−β4−α3−α5D, and (α3β4)2(α5N) with stoichiometries β4−α3−α5N−β4−α3 and β4−α3−β4−α3−α5N. Concatemeric constructs are designed to link nAChR subunits, thus when translated it is done so as a single polypeptide. LYPD6Bincreased the acetylcholine (ACh) potency and desensitization rate, but decreased the maximum current response (Imax) for the (α3)3(β4)2 nAChR subtype. Yet, LYPD6Bonly decreased the Imax for the (α3β4)2α5 D-variant and not the N-variant (associated with increase nicotine consumption). For the second part of my dissertation, I determined if the expression of LYPD6B correlated with nAChRs in an activity dependent manner. Though LYPD6B mRNA expression correlates with nAChR subunit mRNA expression levels, it seemed to be independent of nAChR activity. To determine if fluorescent colocalization occurs between LYPD6B and a specific nAChR subtype, I genetically engineered LYPD6B to express a human influenza hemagglutinin (HA) epitope tag and cloned into a chicken retrovirus. LYPD6B was shown to co-localize only with the α3β4*heteromeric and not the homomeric α7 nAChRs, in a nAChR activity dependent manner. This study adds to the complexity of a prototoxin’s function by suggesting that the specificity is dependent on nAChR type and stoichiometry. It is the first in identifying a prototoxin protein, LYPD6B, which specifically modulates the function of the(α3)3(β4)2 and (α3β4)2(α5 D-variant) heteromeric nAChR subtypes. For the (α3β4)2(α5D-variant) nAChR subtype LYPD6B decreased the Imax. Such observation may be telling of a novel mechanism involved with nicotine dependence. For the(α3)3(β4)2 nAChR subtype LYPD6B increases its ACh sensitivity, desensitization rate, while decreasing Imax. Additionally, the co-localization of LYPD6B and α3β4* nAChRsin the lack of nAChR activity highlights the relevance of the functional effects α3β4*nAChRs exhibit due to LYPD6B. Such relevance may be the utilization of limiting Ach amounts.

Ph.D., Faculty of Science, University of the Witwatersrand, 2011 / This study investigated the effect of exogenous melatonin administration on transient global cerebral ischemia and adult neurogenesis in adult male Sprague- Dawley rats. It also determined serum melatonin concentrations in all the experimental groups and established any effect of melatonin on estimated total granule cell numbers. Adult male Sprague-Dawley rats were divided into eight groups with each group consisting of 6 rats (n = 6). Post-induction time durations of 72 hours and 7 days was used. Single dose of 5 mg/kg exogenous melatonin was administered at each phases of 30 minutes before and after a 10 minutes transient bilateral occlusion of the common carotid arteries in the different groups, followed by reperfusion. Rats were anesthetized with 20 mg/kg of ketamine and 2.5 mls of blood was collected via cardiac puncture for estimation of serum melatonin concentration using commercially prepared radioimmunoassay ELISA kit. Free floating brain sections cut at 50 μm were immunostained for Ki-67, marker for proliferating cells. The total granule cell number in the dentate gyrus was estimated using the optical fractionator method on plastic embedded brain sections. Mean melatonin concentration (pg/mol) was 268.54 ± 28.73 (72 hours) and 277.83 ± 28.73 (7 days) compared to the sham control; 266.94 ± 37.6 and non surgical 262.96 ± 23.85 respectively. Differences in the concentration were not statistically significant (P<0.05). Histological finding indicated neuropil disruption with potentiation of restoration as the post ischemia days progressed in the melatonin administered groups. The estimated total granule cell number in the dentate gyrus of the hippocampus was not affected by exogenous melatonin administration. However, there was potentiation in proliferations of the neurogenic niche in the dentate gyrus of the hippocampus demonstrating a very strong indications that melatonin enhanced the generations of proliferating cells in adult male Sprague-Dawley rats.

Personality is something that sets every human being apart, yet it is something that has been quite hard to pinpoint. Recently, neuroscientists have begun pinning down the neural correlates of personality traits – with focus on the Big Five, sparking a whole new subfield within personality research, known as personality neuroscience. By using neuroscientific methods and techniques to find the underpinnings of the Big Five have led to a deeper and broader understanding of how genetics and the environment integrate into making individuals who they are. This research has also been helpful in the prediction of various outcomes e.g. academic performance and achievement and neuropsychological disorders. In this thesis, the supposed neural correlates of the Big Five are examined through thorough and critical investigations, where evidence from some of the existing relevant studies is reviewed and compared, as well as the different problems and complexities that the field of personality neuroscience is dealing with. The findings in this thesis shows that extraversion has neurobiological basis in the frontal areas of the brain, neuroticism with reduced volume in the frontal areas, agreeableness with frontoparietal areas that are related to theory of mind as well as temporal regions, conscientiousness with frontal parts that are associated with planning and goal-orientation, and openness/intellect with frontoparietal areas as well as subcortical regions, which have been linked with intelligence and creativity. However, some of the correlations were inconsistent and scattered and further research needs to be done. The analysis of academic achievement and performance, as well as neuropsychological disorders and the Big Five with neuroimaging as a method, have shown to be limited, thus much more research is needed.