In this thesis, we explore the density of the microglia in the cerebral and cerebellar cortices of individuals with autism to investigate the hypothesis that neuroinflammation is involved in autism. We describe in our findings an increase in microglial density in two disparate cortical regions, frontal insular cortex and visual cortex, in individuals with autism (Tetreault et al., 2012). Our results imply that there is a global increase in the microglial density and neuroinflammation in the cerebral cortex of individuals with autism.
We expanded our cerebellar study to additional neurodevelopmental disorders that exhibit similar behaviors to autism spectrum disorder and have known cerebellar pathology. We subsequently found a more than threefold increase in the microglial density specific to the molecular layer of the cerebellum, which is the region of the Purkinje and parallel fiber synapses, in individuals with autism and Rett syndrome. Moreover, we report that not only is there an increase in microglia density in the molecular layer, the microglial cell bodies are significantly larger in perimeter and area in individuals with autism spectrum disorder and Rett syndrome compared to controls that implies that the microglia are activated. Additionally, an individual with Angelman syndrome and the sibling of an individual with autism have microglial densities similar to the individuals with autism and Rett syndrome. By contrast, an individual with Joubert syndrome, which is a developmental hypoplasia of the cerebellar vermis, had a normal density of microglia, indicating the specific pathology in the cerebellum does not necessarily result in increased microglial densities. We found a significant decrease in Purkinje cells specific to the cerebellar vermis in individuals with autism.
These findings indicate the importance for investigation of the Purkinje synapses in autism and that the relationship between the microglia and the synapses is of great utility in understanding the pathology in autism. Together, these data provide further evidence for the neuroinflammation hypothesis in autism and a basis for future investigation of neuroinflammation in autism. In particular, investigating the function of microglia in modifying synaptic connectivity in the cerebellum may provide key insights into developing therapeutics in autism spectrum disorder.
}, address = {1200 East California Boulevard, Pasadena, California 91125}, advisor = {Allman, John Morgan}, } @phdthesis{10.7907/FZ94-DW76, author = {Watson, Karli Kiiko}, title = {The Von Economo Neurons: From Cells to Behavior}, school = {California Institute of Technology}, year = {2006}, doi = {10.7907/FZ94-DW76}, url = {https://resolver.caltech.edu/CaltechETD:etd-05252006-224259}, abstract = {The von Economo neurons are one of the few known specializations to hominoid cortical microcircuitry. The recent emergence of this cell type, as well as its localization to subregions of the frontal cortex, suggest its involvement in sophisticated cognitive behaviors. Studies of this cell may thus provide insights into human uniqueness and origin and may additionally be relevant to the treatment and understanding of mental illness.
The first section of this thesis investigates the anatomical details of these cells, including their structure and surface receptor expression. Using a Golgi preparation of a human postmortem brain, I describe the dendritic architecture of this unique population of neurons. We found that, in contrast to layer 5 pyramidal neurons, the von Economo neurons have sparse dendritic trees with symmetric apical and basal components. This confirms that the von Economo cells in both ACC and FI share the architectural characteristics of a single population, and that this population is distinct from other layer 5 neurons. I additionally used immunohistochemistry to probe the receptor expression on these cells, and found that the von Economo neurons strongly express the dopamine D3 and D5 receptors, as well as serotonin-1b and serotonin-2b receptors. Together, these results provide the first detailed anatomical description of a neuron type unique to great apes and humans.
In the second part of this thesis, I explore whether a behavioral stimulus, humor, activates the regions in which this cell occurs. Humor is a hallmark of social discourse and usually depends on the convergence of fast, intuitive assessments with a slow “re-interpretation” of the humor. Because of these characteristics, we thought it likely that humor would activate FI and ACC in addition to other regions in the brain. I used event-related fMRI to differentiate brain activity induced by the hedonic similarities and cognitive differences inherent in cartoons depicting two kinds of humor: visual humor (sight gags) and language-based humor. I found that the brain networks recruited during a humorous experience did indeed include FI and ACC, and that the profile of activation differs according to the type of humor being processed.
Taken together, these projects significantly expand on our knowledge of these unusual cells, and provide a basis that allows us to hypothesize about their function. In the conclusion of this paper, we propose that the role of the von Economo neurons is to facilitate fast decision making in the context of high uncertainty, such as during social interaction.
}, address = {1200 East California Boulevard, Pasadena, California 91125}, advisor = {Allman, John Morgan}, } @phdthesis{10.7907/P9FG-7K79, author = {Bush, Eliot Christen}, title = {Evolution and Scaling in Mammalian Brains}, school = {California Institute of Technology}, year = {2004}, doi = {10.7907/P9FG-7K79}, url = {https://resolver.caltech.edu/CaltechETD:etd-03292004-144927}, abstract = {Here I look at three stages in the evolutionary development of mammalian brains. Chapter one addresses how connectivity in neocortex scales with brain size. This is of evolutionary interest because it helps define the basic mammalian condition. Neocortical white matter increases disproportionately in large brains. This might reflect increases in the number of connections per neuron. It might also reflect scaling in axon diameter. I compare these hypotheses by examining white matter-gray matter scaling in cerebellum. Because the white matter of cerebellum lacks cortico-cortical connections, the connectivity theory predicts that cerebellar white matter should not hyperscale relative to gray matter. I have measured white matter and gray matter volume in a large sample of mammals and I find that cerebellar white matter does not hyperscale. This supports the proposition that neocortical hyperscaling reflects an increase in the number of connections per neuron in large brains.
In chapter two I use independent contrasts analysis to examine the scaling of frontal cortex in a large sample of mammals. I find significant differences in scaling between primates and carnivores. Primate frontal cortex hyperscales relative to the rest of neocortex and the rest of the brain, and the primate slope is significantly greater than that for carnivores. This suggests that there are substantial differences in frontal cortex structure and development between the two groups. Combined with with anatomical differences, it suggests that primates have evolved a number of unique adaptations in frontal cortex.
Chapter three examines the evolution of brain size in anthropoid primates. Living anthropoids have larger brains than strepsirrhines. What about early anthropoid fossils? I measure brain size in the early anthropoid Parapithecus grangeri using computed tomography. I find that relative to the living anthropoids, Parapithecus had a small brain for its body size. Thus large brains did not develop at the same time as a number of other anthropoid adaptations.
}, address = {1200 East California Boulevard, Pasadena, California 91125}, advisor = {Allman, John Morgan}, } @phdthesis{10.7907/jnhb-e433, author = {Rosenbluth, David}, title = {Eye Position Modulation of Visual Cortex and the Sensory Set Hypothesis}, school = {California Institute of Technology}, year = {2002}, doi = {10.7907/jnhb-e433}, url = {https://resolver.caltech.edu/CaltechTHESIS:01312012-161153127}, abstract = {What we see depends on where we look. This is obvious as a statement about the nonuniformity of our external visual environment. But it is also true, in a much less obvious sense, as a statement about the internal neurophysiology of the visual system. What we see depends on where we look in the neurophysiological sense that eye position signals have a dramatic effect on the responsiveness of visual cortical neurons. This thesis empirically studies the way in which point of regard (what point in space the eyes are fixating) influences neurons in visual cortical areas V1 and V4 and then presents a theoretical exploration of how these two different ways in which “What we see depends on where we look” might be functionally intertwined.
The empirical data presented here adds to the growing body of evidence that eye position signals are ubiquitous in visual cortex, an observation which reopens speculation about the functional role that these signals might play in different visual cortical areas. The presence of eye position signals in visual areas of the ventral visual processing stream raises the possibility that these signals might facilitate object identity. Eye position signals might be exploited by visual cortex as a conditioned stimulus, which can become functionally linked to the responses of visual cortical neurons (unconditional response) through repeated pairing with the unconditioned stimulus, the retinal stimulus, in a classical conditioning paradigm. In this way the visual system would be capable of learning systematic relationships between point of regard and statistical characteristics of the visual environment. The learned response to the conditioned stimulus could then be exploited as a preparatory signal, to speed or otherwise alter visual processing to suit the current context. In exploring this theoretical viewpoint, we discuss the circumstances under which context dependent coding provides advantages and how a code switching strategy might be implemented through physiological parcellation mediated by gain control. Eye position signals are here considered to be one among many different types of extra-retinal signals, present in visual cortical areas, whose presence might be similarly exploited. As such, the data and theory presented here should be considered as contributing to the broader literature on the influence of signals from outside the classical receptive field.
}, address = {1200 East California Boulevard, Pasadena, California 91125}, advisor = {Allman, John Morgan}, } @phdthesis{10.7907/7V43-WY98, author = {Sivertsen, Dave William}, title = {The Physiology of High-Order Visual Neurons in the Jumping Spider (Salticidae) and the Vocalizations of Free Ranging Owl Monkeys}, school = {California Institute of Technology}, year = {1989}, doi = {10.7907/7V43-WY98}, url = {https://resolver.caltech.edu/CaltechETD:etd-12092008-091408}, abstract = {Jumping spiders have a highly specialized visual system for the detection and analysis of prey. The retina of each of the anterior medial eyes has a compact, high-resolution, three-dimensional array of receptors that can scan, saccade, and engage in slow tracking. Qualitative study, computer-controlled data collection, and randomized stimulus presentation were used in an electrophysiological study of the properties of high-order visual neurons.
Receptive field mapping revealed neurons with well-defined, positionally stable, receptive fields. Some of these receptive fields had an angular extent greater than that of the static retinal array. The stability with respect to the cephalothorax and the angular extent of these receptive fields suggest integration of retinal information and eye position, to yield position constancy. Most neurons had receptive fields of constant angular subtense as the distance to the tangent screen varied. Some neurons have receptive fields that remain relatively constant in absolute physical size (changing in angular extent) as screen distance varies. Such size constant cells may be useful in assessing prey suitability. These characteristics require integration of depth information. These cells are driven monocularly, ruling out disparity cues. Jumping spiders do not use muscular accommodation. Instead, the retina has a layered, tiered structure. Depth of focus cues are probably the source of this information, as hypothesized previously by Land (1969a).
Quantitative assessment of velocity preferences revealed cells with medial eye input responding optimally to velocities of 16°/second, and other cells responding to higher velocities. Tuning for direction of movement orientation was also observed and quantified. The degree of tuning correlates with a measure of latency.
Results are also presented in a separate section from a primate behavior study on the vocalizations of the owl monkey, in which the vocal repertoire of two populations was recorded. Field recordings were analyzed for temporal and spectral properties of both the vocalizations and the acoustic context. We found no systematic variations of calls between populations, except for the number of syllables in the loud call. We examined behavioral context and probable function of inter and intragroup vocalizations. We found that the loud call may carry gender information, with a bimodal distribution of the spectral bandwidth of the fundamental.
This work was supported in part by a National Research Service Award (T32 GM 07737) from the National Institute of General Medical Sciences, and a Lawrence A. Hanson Fellowship.
}, address = {1200 East California Boulevard, Pasadena, California 91125}, advisor = {Allman, John Morgan}, } @phdthesis{10.7907/j0a4-ne77, author = {Petersen, Steven Elery}, title = {Visual Response Properties of Neurons in Extrastriate Cortex of the Owl Monkey}, school = {California Institute of Technology}, year = {1982}, doi = {10.7907/j0a4-ne77}, url = {https://resolver.caltech.edu/CaltechTHESIS:05142018-121737381}, abstract = {The neurophysiological response properties of single neurons were studied quantitatively in four extrastriate areas of the owl monkey: the medial (M), dorsomedial (DM), dorsolateral (DL), and the middle temporal (MT) areas. Directionality was computed by comparing the responses to stimuli moved in the optimal and opposing directions; MT cells had much higher directionality to moving bars than cells in the other areas. Cells in all four areas were sharply tuned to the orientation of stationary flashed bars. Tuning for moving bars was broader than for flashed bars; DM cells were more sharply tuned to moving bars than were cells in the other areas. Tuning was broader to spots than to bars, while directionality was relatively unaffected. A moving array of random dots was the best stimulus for many MT neurons. Random dot stimuli were also effective in M, but evoked weak or no response from DM and DL cells. Extrastriate receptive fields were much larger than striate receptive fields. Eccentricity was correlated with receptive field size, but was uncorrelated with other variables.
Neurons in these four areas were tested for their selectivity to the spatial dimensions, the length and width, of visual stimuli. Cells in DL were much more selective for the spatial dimension than were cells in the other areas. The dimensional selectivity of DL cells is independent of the amount or sign of contrast in the receptive field, and the position of the stimulus within the receptive field. The optimal lengths and widths of visual stimuli are specified independently, and have a wide range of optimal dimensions from 1 to 30° in length, and from 0.25 to 7° in width.
Since many of the neurons of MT show strong directionality, it has been hypothesized that MT contributes to the perception of motion. A well-known aspect of motion perception is the phenomenon of direction-specific adaptation. We tested the neurons of MT for changes in responsiveness due to prolonged adaptation to stimuli moving in various directions. For directional cells, the response to a bar was suppressed following adaptation in the best direction, and enhanced following adaptation in the opposite direction, when compared to the response to a bar following a period of stationary stimulation. For nondirection cells, the effects were much weaker, or absent.
These results support the notion of a localization of function among the various extrastriate areas.
}, address = {1200 East California Boulevard, Pasadena, California 91125}, advisor = {Allman, John Morgan}, } @phdthesis{10.7907/N9F5-SV06, author = {Newsome, William Thomas}, title = {Studies on primate extrastriate visual cortex. I. The interhemispheric connections of visual cortex in the owl monkey, Aotus trivergatus, and the bushbaby, Galago senegalensis. II. A functional localization of neuronal response properties in extrastriate cortex of the owl monkey, Aotus trivirgatus}, school = {California Institute of Technology}, year = {1980}, doi = {10.7907/N9F5-SV06}, url = {https://resolver.caltech.edu/CaltechETD:etd-09152004-141810}, abstract = {Anatomical techniques have been used to map within visual cortex the pattern of degenerating axonal terminals produced by surgical section of the selenium of the corpus callosum in the owl monkey, Aotus trivirgatus, and the bushbaby, Galago senegalensis: To the extent to which degenerating callosal terminals correspond to physiological representations of the visual vertical meridian, the pattern of interhemispheric connections can be used as a powerful aid in locating visual area boundaries. The goals of this study have been 1) to assess the degree of correspondence between degenerating callosal terminals and anatomically identifiable vertical meridian representations, and 2) to gain information concerning the existence and organization of as yet unknown extrastriate visual areas. In both the owl monkey and the bushbaby, a discrete band of degeneration corresponds precisely to the vertical meridian representation at the V1-V2 border, and a less precise increase in the density of axonal terminals corresponds to the vertical meridian representation of extrastriate area MT. A well-defined band of degeneration on the ventral surface of the owl monkey’s cerebral hemisphere corresponds to a previously unknown vertical meridian representation which is shared by two newly defined extrastriate visual areas. Over much of areas DL and DI in the owl monkey, and in the region where the center-of-gaze representations of V2, DL and MT are in close proximity in both the owl monkey and the bushbaby, the pattern of callosal terminals is complex and has little value for determining precise areal boundaries.
The response properties of 275 single neurons from four extrastriate visual areas have been quantitatively studied in chronically prepared, sedated owl monkeys. During experimental sessions, computer controlled visual stimuli were presented to the animal while the computer recorded the responses of single cortical neurons. The responses were stored on magnetic tape for later analysis. The major result of this study is the demonstration of a striking localization of direction-selective neurons to extrastriate area MT of the owl monkey. MT neurons responded maximally to stimuli tuned to a single optimal direction of motion whereas neurons of the medial third tier areas (DM, DI and M) responded maximally to oriented stimuli moving in either of two directions perpendicular to the optimal axis of orientation. Other differences were noted between neurons of MT and neurons of the medial third tier areas. A systematic difference exists in the tightness of tuning to the optimal direction of motion. Neurons in MT tended to be less well tuned to the optimal direction of motion than did neurons of the medial third tier areas. Neurons in MT also exhibited a different pattern of preferences for stimulus velocity than did neurons of the medial third tier areas. A distinct group of MT cells preferred velocities of 10-25 degrees/second, while neurons of the medial third tier areas had a broad distribution of preferred velocities ranging from 10-100 degrees/second. There was no systematic difference in tuning to preferred velocity for the two regions.
}, address = {1200 East California Boulevard, Pasadena, California 91125}, advisor = {Allman, John Morgan}, }