Thesis (Ph. D.)--University of California, San Diego, 2009. / Title from first page of PDF file (viewed January 13, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 194-211).

Thesis (Ph.D.)--University of Melbourne, Dept. of Optometry & Vision Sciences, 2009. / Typescript. Includes bibliographical references (p. 195-230)

Thesis (Ph. D.)--University of Chicago, Committee on Neurobiology, August 1999. / Includes bibliographical references. Also available on the Internet.

Thesis (B.A. (Hons.)) - University of Queensland, 2005. / Includes bibliography.

Neuroimmune proteins are involved in a wide array of biological functions throughout brain development. Importantly, these molecular mechanisms regulate the activity-dependent sculpting of neural circuits during the critical period. Abnormal expression of these molecular mechanisms, especially in early development, is linked to the emergence of neurodevelopmental disorders. Despite having central roles in both normal and pathological conditions, very little is known about the lifespan expression of neuroimmune proteins in the human cortex. As studies exploring the relationship between inflammation and disease tend to rely on animal models, unpacking immune lifespan trajectories in the human brain will be essential for translational research. Furthermore, it will aid the development of timely and effective therapeutic interventions for neurodevelopmental disorders. In my thesis, I characterize the development of 72 neuroimmune proteins in 30 postmortem tissue samples of the human primary visual cortex. These samples cover the lifespan from 20 days to 79 years. I compare the developmental profiles of these immune markers to those of well-studied classic neural proteins including glutamatergic, GABAergic and other synaptic plasticity-related markers. Using a data-driven approach, I found that the 72 neuroimmune proteins share approximately eight developmental patterns, most of which undulate across the lifespan. Furthermore, I used unsupervised hierarchical clustering to show that the development of neuroimmune proteins in the human visual cortex varies from that of classic neural proteins. These findings facilitate a deeper understanding of human cortical development through two classes of proteins involved in brain development and plasticity. / Thesis / Master of Science (MSc) / The human brain develops across the lifespan. This ability of the brain to change and adapt to the environment is called plasticity and it is essential for normal brain functions, such as processing visual information. Immune proteins play important roles in the visual cortex- the brain region responsible for visual information processing. They help establish brain circuits in early development and regulate ongoing neural processes important to brain plasticity. In my thesis, I measure the expression of neuroimmune proteins to unpack their developmental patterns in the human visual cortex. I found that these proteins have fluctuating levels across development, with many displaying heightened expression levels in early childhood. Additionally, I found eight common trajectory patterns that were shared between the proteins. These findings enable a better understanding of how regulators of human brain development mature.

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Understanding how human and animal visual systems work is an important and still largely unsolved problem. The neural mechanisms for low-level visual processing have been studied in detail, focusing on early visual areas. Much less is known about the neural basis of high-level perception, particularly in humans. An important issue is whether and how lessons learned from low-level studies, such as how neurons in the primary visual cortex respond to oriented edges, can be applied to understanding highlevel perception, such as human processing of faces. Visual aftereffects are a useful tool for investigating how stimuli are represented, because they reveal aspects of the underlying neural organisation. This thesis focuses on identifying neural mechanisms involved in high-level visual processing, by studying the relationship between low- and high-level visual aftereffects. Previous psychophysical studies have shown that humans exhibit reliable orientation (tilt) aftereffects, wherein prolonged exposure to an oriented visual pattern systematically biases perception of other orientations. Humans also show face identity aftereffects, wherein prolonged exposure to one face systematically biases perception of other faces. Despite these apparent similarities, previous studies have argued that the two effects reflect different mechanisms, in part because tilt aftereffects show a characteristic S-shaped curve, with the effect magnitude increasing and then decreasing with orientation difference, while face aftereffects appeared to increase monotonically (in various units of face morphing strengths) with difference from a norm (average) face. Using computational models of orientation and face processing in the visual cortex, I show that the same computational mechanisms derived from early cortical processing, applied to either orientation-selective or face-selective neurons, are sufficient to replicate both types of effects. However, the models predict that face aftereffects would also be S-shaped, if tested on a sufficiently wide range of face stimuli. Based on the modelling work, I designed psychophysical experiments to test this theory. An identical experimental paradigm was used to test both face gender and tilt aftereffects, with strikingly similar S-shape curves obtained for both conditions. Combined with the modelling results, this result provides evidence that low- and high level visual adaptation reflect similar neural mechanisms. Other psychophysical experiments have recently shown interactions between low and high-level aftereffects, whereby orientation and line curvature processing (in early visual area) can influence judgements of facial emotion (by high-level face-selective neurons). An extended multi-level version of the face processing model replicates this interaction across levels, but again predicts that the cross-level effects will show similar S-shaped aftereffect curves. Future psychophysical experiments can test these predictions. Together, these results help us to understand how stimuli are represented and processed at each level of the visual cortex. They suggest that similar adaptation mechanisms may underlie both high-level and low-level visual processing, which would allow us to apply much of what we know from low-level studies to help understand high-level processing.

O estudo da acuidade Vernier (VRN) revela a capacidade do sistema visual humano em detectar deslocamentos espaciais de poucos arcos de segundos, menores que a distância entre dois cones foveais adjacentes. Tal fato desperta interesse teórico sobre o tema, além de futuras aplicações na área clínica. A acuidade VRN pode ser medida tanto psicofisicamente quanto eletrofisiologicamente. Para a detecção de quebras de colinearidade (acuidade VRN), alguns autores hipotetizam que as células ganglionares (CGs) M da retina provêem sinal adequado da retina ao córtex, e dão suporte ao desempenho psicofísico da tarefa VRN. Em condições de estímulos semelhantes, as células ganglionares magnocelulares (M) em primatas parecem ter precisão espacial com razão sinal-ruído mais alta do que as células parvocelulares (P) . A dependência ao contraste (C) das células M na precisão espacial, frequência espacial, frequência temporal e velocidade do estímulo é mais similar ao desempenho psicofísico em humanos do que comparados aos dados das células P (Rüttiger et al., 2002; Sun et al., 2004). Nós utilizamos o Potencial Provocado Cortical Visual de Varredura (sVEP) para avaliar esta hipótese no nível de processamento intermediário entre as respostas de célula única na retina e a detecção psicofísica. Nós medimos os limiares corticais VRN em função do contraste (14 participantes, média de 28,21 ± 2,8) e lacunas (9 participantes, média de 29,7 ± 5,9). As quebras verticais VRN na colinearidade foram introduzidas em uma grade de onda quadrada horizontal. O estímulo VRN alternou entre um estado alinhado (grades sem quebras) e desalinhado (grades com quebras) a 6 Hz. Durante cada uma das 10 tentativas, o deslocamento aumentou em passos logarítmicos iguais de 0,5 a 7,5. O limiar VRN foi definido no momento do deslocamento em que a extrapolação linear da média vetorial das respostas em 1F atinge zero uV. Os contrastes testados foram: 4, 8, 16, 32, 64, 80%. Os resultados mostram que (1) aos limiares VRN em Log, medidos com sVEP, com o C em Log, diminuíram de forma linear (com uma inclinação de -0,5), similiares às células ganglionares M mas não P (Sun et al., 2004) e próximo às medidas psicofísicas (Sun et al., 2004; Wehrhahn e Westheimer, 1990); (2) Para C 16% obtivemos limiares de hiperacuidade (menor que 1 arcmin). Em altos contrastes a média do limiar foi de 0,37(erro padrão de 0,06 unidades logarítmicas); (3) Os limiares para o 2F tiveram uma dependência para o contraste diferente, com poucos efeitos para contraste abaixo de 16%. (4) As inclinações das linhas de extrapolação dos sVEP para o 1F1 foram 2 a 3 vezes maiores que as inclinações para 2F; (5) No protocolo controle, deslocamentos bidirecionais e simétricos geraram somente respostas no 2F. Os resultados 3 a 5 implicam que os componentes 1F e 2F derivam de neurônios distintos e fundamentam que respostas no 2F refletem respostas de movimento cortical simétrico. A dependência dos limiares de contraste do sVEP VRN (1F) é similiar aos estudos prévios psicofísicos (Sun et al., 2004; Wehrhahn e Westheimer, 1990), e repete a dependência ao contraste das células M (Sun et al., 2004). Estes resultados fundamentam a hipótese que o córtex extrai informações da posição relativa com precisão de hiperacuidade dos sinais advindos das células M / The human visual system is able to detect spatial displacements of a few arcsec, much smaller than the distance between two adjacent foveal cones. Hyperacuity tasks such as Vernier (VRN) have both theoretical importance as well as clinical application. VRN can be measured psychophysically and with sVEP. Some authors hypothesize that M ganglion cells provide the retinal signal to cortex adequate to support Vernier performance. Under stimulus conditions analogous to detection of Vernier offsets, primate magnocellular (M) ganglion cells appear to have more precise spatial localization (with higher Signal to Noise Ratio) than parvocellular (P) cells, and the dependence of M cell spatial precision on contrast (C), spatial frequency, temporal frequency and stimulus velocity is more similar to human psychophysical performance than comparable data from P cells (Ruttiger et al, 2002; Sun et al., 2003, 2004) (Rüttiger et al., 2002; Sun et al., 2004). We measured the C-dependence of cortical VRN thresholds (thd) using the Sweep VEP (sVEP) to help evaluate this hypothesis at a processing level intermediate between single-cell retinal responses and psychophysical detection. We measured Vernier thds using sVEP as function of constrast (12 young adults, age means 28.21 yrs ± 2.8) and Gaps (9 participants, 29.7 ± 5.9) with normal vision. Vertical VRN breaks in colinearity were introduced to a horizontal squarewave grating. The VRN stimulus alternated between aligned (grating w/o breaks) and misaligned (w/breaks) states at 6 (or 10) Hz. During each of ten, 10-s trials, displacement (D) was increased in equal logarithmic steps from 0.5 to 7.5. Vernier thd was defined as the D at which the rising slope of the vector averaged 1F response extrapolated to zero V. The Cs tested were: 4, 8, 16, 32, 64, 80%. We Found: (1) Log Vernier thd measuered with sVEP decreased linearly with log C similar to M- (but not P-) ganglion cells (Sun et al., 2004) with a slope of -0.5, close to that measured psychophysically (Rüttiger et al., 2002; Sun et al., 2004); (2) For C 16% , thds were true hyperacuities (less than 1). At high C, mean thd was 0.37(S.E = 0.06 log units); (3) Thds for 2F had a different C dependence, with little effect of C below 16 %. Thds for 2F were < 1F thds below 16 % C, but were 1F thds beyond 16 %; (4) The slopes of the sVEP extrapolation lines for 1F were 2-3 times > 2F slopes; (5) In a control protocol, symmetric, bidirectional displacements only generated 2F responses. Results 3-5 imply that the 1F and 2F components derive from distinct neurons, and support the notion that 2F responses reflect symmetric cortical motion responses. The C-dependence of sVEP Vernier (1F) thresholds is similar to prior psychophysics (Sun et al., 2004; Wehrhahn e Westheimer, 1990), and recapitulates Mcell C-dependence (Sun et al., 2004). This results support the hypothesis that cortex extracts relative position information with hyperacuity precision preferentially from M cell signals

It has long been known that attending to the right place at the right time can improve performance and reaction time in a wide variety of the tasks that humans engage in. If attention is defined as a general mechanism by which a nervous system’s economy of resources and information are distributed to enable a perceptual state that is well-aligned with the goals of the biological system, then changes in visual attention should emerge as changes in the distribution of resources and information in the visual cortex. A growing body of evidence supports this proposition in non-human primates, and suggests that visual spatial attention affects perceptual state through top-down signaling that refines the neural representation of the attended stimulus (Desimone and Duncan, Chelazzi and Reyonlds, Mayo). This refinement is correlated with, and often believed to cause, the change in behavioral performance accompanied by visual spatial attention. To test whether similar mechanisms of visual spatial attention affect perceptual state in mice (our central hypothesis), we recorded neuronal activity in the primary visual cortex while mice engaged in a contrast detection task. This task was designed to induce endogenous shifts in visual spatial attention by changing the probability that a stimulus would appear at a particular location on the monitor. We found that our subject’s contrast detection threshold did not depend on this manipulation, suggesting that either: our subject was unable to distinguish between different probability conditions, AND/OR there was no advantage in attending to the side of higher probability, AND/OR visual spatial attention does not affect perceptual state in mice in ways similar to that of non-human primates. Analyses of pupil recordings have helped us learn more about the subject’s strategy and the ways in which we can modify the task to encourage sizeable shifts in visual spatial attention. In parallel with this experiment, a process was developed to aggregate neuronal data from the same population of neurons across days. Although difficult and time-consuming, this strategy enables analyses of individual neurons across many days and trial types. Once we are successful in designing a task to induce shifts in visual spatial attention, this routine will allow us to determine whether mice and non-human primates share a common mechanism of visual spatial attention. Doing so will elucidate whether the mouse model should be used to study the physiology and pathophysiology of visual spatial attention.

Spatial attention enhances perception at specific locations in the visual field, measured behaviorally as improved task performance and faster reaction times. In visual cortex, neurons with receptive fields at attended locations display enhanced responses. This neural modulation is presumed to underlie the associated behavioral benefit, although the mechanisms linking sensory cortical modulation to perceptual enhancement remain unclear. In studies of spatial attention, experimentalists persuade animals to attend to particular locations by associating them with a higher probability or magnitude of reward. Notably, these manipulations alter in tandem both the absolute expectation of reward at a particular location, as well as the expectation of reward relative to other locations in the visual field. We reasoned that independently changing absolute and relative reward expectations could provide insight into the mechanisms of attention. We trained monkeys to discriminate the orientation of two stimuli presented simultaneously in different hemifields while independently varying the reward magnitude associated with correct discrimination at each location. Behavioral measures of attention were controlled by the relative value of each location. By contrast, neurons in visual area V4 were consistently modulated by absolute reward value, exhibiting increased firing rates, increased gamma-band power, and decreased trial-to-trial variability whenever receptive field locations were associated with large rewards. Thus, neural modulation in V4 can be robustly dissociated from the perceptual benefits of spatial attention; performance could be enhanced without neural modulation, and neural activity could be modulated without substantial perceptual improvement. These data challenge the notion that the perceptual benefits of spatial attention rely on increased signal-to-noise in V4. Instead, these benefits likely derive from downstream selection mechanisms. In identifying brain areas involved with attention, a distinction is generally made between sensory areas like V4— where the representation of the visual field is modulated by attentional state— and attentional “source" areas, primarily in the oculomotor system, that determine and control the locus of attention. The amygdala, long recognized for its role in mediating emotional responses, may also play a role in the control of attention. The amygdala sends prominent feedback projections to visual cortex, and recent physiological studies demonstrate that amygdala neurons carry spatial signals sufficient to guide attention. To characterize the role of the amygdala in the control of attention, we recorded neural activity in the amygdala and V4 simultaneously during performance of the orientation discrimination task. In preliminary data analysis, we note two sets of findings. First, consistent with prior work, we found that amygdala neurons combine information about space and value. Rewards both contralateral and ipsilateral to amygdala neurons modulated responses, but contralateral rewards had a larger effect. Therefore, notably distinct from known attentional control sources in the oculomotor system, spatial-reward responses in the amygdala do not reflect the relative value of locations. Second, we found signatures of functional connectivity between the amygdala and V4 during task performance. Reward cue presentation was associated with elevated alpha and beta coherence, and attention to locations contralateral to the amygdala and inside the receptive field of V4 neurons was associated with elevated inter-area gamma coherence. These results suggest that the amygdala may serve a unique role in the control of spatial attention. Together, these experiments contribute towards an understanding of the brain-to-behavior mechanisms linking neural activity in V4 and the amygdala to the dramatic perceptual and behavioral improvement associated with attention.