The dorsal and ventral white matter tracts believed to connect the anterior and posterior language cortices have been investigated in previous studies, but not extensively in children and adolescents. Magnetic resonance diffusion tensor imaging (DTI) tractography was used in order to examine the asymmetry of dorsal and ventral language white matter tracts of 34 typically developing children ages 8 to 18, and the relationship of these asymmetries with language development and ability. In our sample of participants, the dorsal and ventral tracts both demonstrated lateralization to the left hemisphere in fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD), but not for tract volume or axial diffusivity (AD). We found no correlations between tract asymmetries and age or language level.

How does the visual cortex learn invariant object categories as an observer scans a depthful scene? Two neural processes that contribute to this ability are modeled in this thesis. The first model clarifies how an object is represented in depth. Cortical area V1 computes absolute disparity, which is the horizontal difference in retinal location of an image in the left and right foveas. Many cells in cortical area V2 compute relative disparity, which is the difference in absolute disparity of two visible features. Relative, but not absolute, disparity is unaffected by the distance of visual stimuli from an observer, and by vergence eye movements. A laminar cortical model of V2 that includes shunting lateral inhibition of disparity-sensitive layer 4 cells causes a peak shift in cell responses that transforms absolute disparity from V1 into relative disparity in V2. The second model simulates how the brain maintains stable percepts of a 3D scene during binocular movements. The visual cortex initiates the formation of a 3D boundary and surface representation by binocularly fusing corresponding features from the left and right retinotopic images. However, after each saccadic eye movement, every scenic feature projects to a different combination of retinal positions than before the saccade. Yet the 3D representation, resulting from the prior fusion, is stable through the post-saccadic re-fusion. One key to stability is predictive remapping: the system anticipates the new retinal positions of features entailed by eye movements by using gain fields that are updated by eye movement commands. The 3D ARTSCAN model developed here simulates how perceptual, attentional, and cognitive interactions across different brain regions within the What and Where visual processing streams interact to coordinate predictive remapping, stable 3D boundary and surface perception, spatial attention, and the learning of object categories that are invariant to changes in an object's retinal projections. Such invariant learning helps the system to avoid treating each new view of the same object as a distinct object to be learned. The thesis hereby shows how a process that enables invariant object category learning can be extended to also enable stable 3D scene perception.

Multiple brain disorders are associated with hypoinhibition of neural circuits that are controlled by inhibitory neurons using the neurotransmitter γ-aminobutyric acid (GABA). GABA activates type A receptors (GABARs) to mediate the majority of inhibitory neurotransmission and changes in GABAR subunit composition have profound effects on brain function. In fact, down-regulation of one of the three β isoforms, β1, is associated with alcoholism, autism, epilepsy, schizophrenia, and bipolar disorder. These conditions also present with mitochondrial defects and metabolic dysregulation. In the first Aim of my thesis, I ask whether the core promoter of the human GABAR β1 subunit gene (GABRB1) can be regulated by the same transcription factor, the nuclear respiratory factor 1 (NRF-1) that controls oxidative phosphorylation and mitochondrial biogenesis in neurons. The ENCODE database of NRF-1 binding in human embryonic stem cells was used to identify an interaction of NRF-1 with GABRB1. Using a variety of approaches: electro mobility shift, promoter/reporter luciferase assays, gene silencing and bioinformatics, we demonstrate that GABRB1 contains a canonical NRF-1 element responsible for the majority of GABRB1 promoter- luciferase activity in transfected primary neurons. Moreover, we show that endogenous NRF-1 is responsible for a substantial amount of luciferase activity in our studies. Altogether, our results suggest GABRB1 is a target gene for NRF-1, providing a possible link between mitochondria related energy metabolism and transcriptional regulation of β1-containing GABARs in neurological disease. Synthesis of NRF-1 is regulated by the transcription factor cAMP response element binding protein (CREB), an important memory molecule implicated in multiple brain disorders. The second Aim of my thesis was to develop a molecular sensor that can be used in living neurons to signal the presence of CREB dependent gene regulation. We employ a split complement bioluminescent sensor to monitor interaction of protein surfaces that link CREB with its co-factor CBP and demonstrate that it can detect activation of CREB via its serine 133 phosphorylation site and activation through an undiscovered mechanism. We also show that this sensor can be used to monitor BDNF signaling providing the foundation for its future use in in vivo models of disease where BDNF is implicated.

Understanding how information is encoded, processed, and decoded to produce behavior is a fundamental goal of neuroscience. In this dissertation, we aim to expand our understanding of our human decision-making processes at the single-neuronal level. We describe three studies exploring the neural substrate of decision-making in three separate brain regions. First, we describe a method for recording the activity of individual neurons in human subjects. The unique combination of behavioral and neurophysiological data will allow us to better understand the neural substrate of cognitive functions in humans. Second, we explored how decisions are represented in the brain. We recorded single neuronal responses in the human nucleus accumbens while subjects engaged in a financial decision-making task. We found that neurons in the nucleus accumbens predicted upcoming decisions well before the behavior was manifested. In addition, these neurons encoded a positive and negative prediction error signal, signaling the difference between expected and realized outcome. Third, we explored how the brain represents decision conflict and how it adapts to prime future decisions allowing tradeoff between speed and accuracy. We found that individual neurons in the human dorsal anterior cingulate cortex encode the level of decision conflict in a dose-dependent manner. In addition, these neurons encode historical conflict information, priming the neural circuit to future trials of the same or varying conflict levels. Following selective ablation of the dorsal anterior cingulate cortex, we found this signal was selectively abolished. Lastly, we explored how the brain represents decisions under conflict and if these decisions are malleable to external intervention. We found that neurons in the human subthalamic nucleus are selectively activated and encode the upcoming decision during situations of high decision conflict. Based on the physiological findings, we then applied intermittent stimulation through the implanted deep brain stimulation electrode during the same task, to demonstrate a causal interaction between the physiology and behavior. In conclusion, we describe a set of experiments that systematically explore human decision-making processes at the single-neuronal level.

Schizophrenia and autism are debilitating illnesses thought to have developmental etiologies. Prenatal brain damage can alter brain development and cognition leading to the pathologies of both diseases. Furthermore, prenatal infections have been implicated as a risk factor for both schizophrenia and autism in large, population-based studies. Many studies have investigated the effects of prenatal infections on brain development and have established inflammatory cytokines as the most likely mediators of brain damage. While preeclampsia exposes a fetus to a similar inflammatory environment as a prenatal infection, a comprehensive review of the work connecting obstetric complications to autism and schizophrenia has not been conducted. The mechanisms explaining the induction of altered brain function after fetal neuroinflammation also requires further study in the specific context of preeclampsia, especially in regards to what factors may differentiate autism from schizophrenia in the course of disease development.

Microsaccades, the microscopic and fast gaze relocations occurring while we attempt to maintain steady fixation, cause both spatial and temporal changes in the input to the retina. Despite much progress in understanding the spatial functions of these small eye movements during the last decade, it remains unclear whether the temporal modulations resulting from microsaccades are also beneficial for vision. This dissertation describes three studies aimed at providing answers to the following fundamental questions: (1) What are the space-time characteristics of the input to the retina at the time of saccades and microsaccades? Spectral analyses of the retinal input during free-viewing of natural images show that luminance modulations resulting from saccades and microsaccades redistribute the power of an otherwise stationary stimulus in a way that contributes more temporal power than ocular drift within a range of low spatial frequencies. These results suggest a specific role for saccadic eye movements in the encoding of low spatial frequencies. (2) We measured how microsaccade transients affect human contrast sensitivity at different spatial frequencies. We showed that contrast thresholds remain highly similar in the presence and absence of microsaccades below 30'. However, an improvement in sensitivity to low spatial frequency stimuli was found for saccades with amplitudes larger than 30'. Furthermore, saccades of all amplitudes, including microsaccades, were strongly suppressed during exposure to the stimuli. (3) What are the dynamics of visual sensitivity around the time of occurrence of microsaccades? We show that sensitivity is reduced at the time of microsaccades and small saccades, similar to what previously reported for saccades. Moreover, sensitivity is not homogeneous within the fovea but decreases with increasing eccentricity. These results clarify the importance of microsaccades to vision. They show that the luminance modulations resulting from both microsaccades and saccades play an important role in representation of visual information and affect our perception in a systematic way. / 2018-12-06T00:00:00Z

The auditory system begins with the cochlea, a frequency analyzer and signal amplifier with exquisite precision. As neural information travels towards higher brain regions, the encoding becomes less faithful to the sound waveform itself and more influenced by non-sensory factors such as top-down attentional modulation, local feedback modulation, and long-term changes caused by experience. At the level of auditory cortex (ACtx), such influences exhibit at multiple scales from single neurons to cortical columns to topographic maps, and are known to be linked with critical processes such as auditory perception, learning, and memory. How the ACtx integrates a wealth of diverse inputs while supporting adaptive and reliable sound representations is an important unsolved question in auditory neuroscience. This dissertation tackles this question using the mouse as an animal model. We begin by describing a detailed functional map of receptive fields within the mouse ACtx. Focusing on the frequency tuning properties, we demonstrated a robust tonotopic organization in the core ACtx fields (A1 and AAF) across cortical layers, neural signal types, and anesthetic states, confirming the columnar organization of basic sound processing in ACtx. We then studied the bottom-up input to ACtx columns by optogenetically activating the inferior colliculus (IC), and observed feedforward neuronal activity in the frequency-matched column, which also induced clear auditory percepts in behaving mice. Next, we used optogenetics to study layer 6 corticothalamic neurons (L6CT) that project heavily to the thalamus and upper layers of ACtx. We found that L6CT activation biases sound perception towards either enhanced detection or discrimination depending on its relative timing with respect to the sound, a process that may support dynamic filtering of auditory information. Finally, we optogenetically isolated cholinergic neurons in the basal forebrain (BF) that project to ACtx and studied their involvement in columnar ACtx plasticity during associative learning. In contrast to previous notions that BF just encodes reward and punishment, we observed clear auditory responses from the cholinergic neurons, which exhibited rapid learning-induced plasticity, suggesting that BF may provide a key instructive signal to drive adaptive plasticity in ACtx.

Autism spectrum disorders (ASDs) are clinically characterized by decreased communication abilities, impaired social interaction, and the occurrence of repetitive behaviors, with high genetic heritability. Ubiquitin protein ligase E3A (UBE3A) is a gene located on human chromosome 15q11-13, a region that has been the focus of genetic studies of susceptibility to ASD AND Angelman syndrome. An increased UBE3A gene dosage and thus an elevated amount of E6AP, the protein product of UBE3A, is associated with ASD. However, the underlying cellular and molecular details remain poorly understood. Normal development of neuronal structure is critical for intercellular connectivity and overall brain function, and abnormal brain development is a commonality amongst ASDs. These studies therefore investigated the role of increased dosage of Ube3A/E6AP in dendritic arborization and synapse maturation during brain development. Increased E6AP expression in vitro led to significant reduction in dendritic arborization by thinning and fragmentation of the distal tip, along with a decrease in spine density and an increase in immature spines in hippocampal neurons. This morphological remodeling effect was mediated by the ubiquitination and subsequent degradation of the X-linked inhibitor of apoptosis protein (XIAP) by E6AP, which led to activation of caspase-3. Furthermore, activated caspases cleaved tubulin, leading to retraction of microtubules from the distal tip of dendrites, dendritic thinning and eventual disappearance. In vivo studies investigated the role of E6AP in ASD-related neuronal development in Ube3A 2X transgenic mice and found that, consistent with our in vitro studies, increased E6AP in the brain lead to decreased XIAP levels, increased active caspase-3, and enhanced tubulin cleavage in hippocampal tissue in Ube3A 2X mice. In accord, Ube3A 2X mice showed a reduction in dendritic growth and branching and spine density. This work elucidated an important role of Ube3A/E6AP in dendritic pruning and identified XIAP as a novel ubiquitination target of E6AP. These findings provide a new insight into the molecular pathways underlying neurodevelopmental defects in Ube3A/E6AP-associated ASDs. / 2018-07-09T00:00:00Z

Substance abuse disorders are heritable neuropsychiatric disorders with largely unknown genetic etiology. Distinct genetic factors likely contribute to the different stages and behaviors of addiction, including initial sensitivity to the subjective and physiological effects of drugs and physiological and psychological measures of withdrawal. Mammalian model organisms permit a comprehensive approach to gene mapping and to bridging genetic variation with neurobiological mechanisms of addiction-relevant behaviors. The focus of this dissertation is to investigate the genetic basis of the rewarding and aversive properties of opioids, utilizing a systems genetics approach that includes both forward and reverse genetics in combination with transcriptomics and bioinformatics as tools to determine the molecular mechanisms. The first aim of this research is to conduct a genetic linkage mapping study of addiction-associated traits in a reduced complexity cross of two nearly identical B6 substrains (C57BL/6J and C57BL/6NJ). Forward genetic techniques, such as quantitative trait locus (QTL) mapping was utilized to identify novel candidate genes involved in addiction-associated traits. We completed QTL mapping combined with genome-wide gene expression analyses to rapidly identify compelling candidate genes underlying addiction traits. Most notably, we identified a region on distal chromosome 1 that regulates opioid sensitivity and withdrawal. Using striatal expression QTL mapping, transcript/behavior covariance, and convergent haplotype analysis, we identified a strong positional candidate gene, Rgs7. The second aim of this research is to validate novel candidate genes and molecular mechanisms responsible for modulation of opioid reward and aversion. Using behavioral and expression QTL mapping, Csnk1e was previously identified as a candidate gene for psychostimulant sensitivity. Here, we utilized Csnk1e knockout mice to confirm the effect of Csnk1e deletion on opioid sensitivity and extend its role to opioid reward and a natural reward dependent on opioid signaling- sweetened palatable food consumption. Additionally, we have utilized striatal transcriptome analyses to identify potential molecular mechanisms, including aberrant myelination and neurodevelopment of the striatum. In summary, this dissertation research utilizes mouse forward and reverse genetics, in combination with transcriptome and bioinformatics analyses to identify the genetic and neurobiological underpinnings of addiction-associated traits.

The purpose of this study was to examine the effects of cathodal transcranial direct current stimulation (tDCS) on cortical spreading depression (CSD) in the rat cerebral cortex. CSD is a propagating wave of hyperexcitability that occurs in a number of neurological disorders characterized by excess cerebral excitability such as migraine, acute brain injury, or stroke. Since tDCS is a non-invasive method capable of inducing polarity-dependent changes in cortical excitability, we hypothesized that cathodal stimulation would prevent, attenuate, or change the characteristics of CSD. Forty Sprague-Dawley male rats were randomly divided into two stimulation condition groups: sham tDCS and cathodal tDCS. In both experimental groups, CSD was induced by applying potassium chloride onto cortical surface. Electroencephalogram (EEG) data was recorded during each experiment and subjected to analysis. CSD incidence was compared between the sham and cathodal tDCS group. We observed that significantly fewer CSD events were exhibited during cathodal tDCS relative to sham stimulation. Evaluation of CSD wave characteristics between experimental groups revealed no differences in propagation velocity, amplitude, or waveform of CSD, nor in the presence of neuronal silencing. The results of this study lend support for the use of cathodal tDCS as an effective method for reducing cortical excitability and provides the groundwork for future study of the mechanisms of tDCS and its treatment targets in neurological disorders whose symptoms are created or exacerbated by CSD.