The mammalian neocortex is an exquisite, highly organized brain structure composed of hundreds of subpopulations of neurons and glia, precisely connected to enable motor control, sensory perception, information integration, and planning. Unique molecular, structural, and anatomical neuronal properties underlie diverse functionality, endowing much of the neocortex’s complex processing power. Neocortical size correlates with information processing capacity, suggesting that increased neuronal number and diversity begets increased sophistication. One excitatory projection neuron type, callosal projection neurons (CPN), has disproportionately expanded with cortical size increase. CPN directly connect homotypic regions of the two neocortical hemispheres by sending axons via the largest white matter fiber tract in the brain, the corpus callosum (CC), allowing quick relay, integration, and comparison of information. In humans, the CC contains over 300,000 axons, CPN have been centrally implicated in autism spectrum disorders, and absence or surgical disruption of CPN connectivity in humans is associated with defects in abstract reasoning, problem solving, and generalization. Therefore, CPN are critical to complex brain functions, and their diversity likely contributes to these roles. Work presented in this dissertation addresses molecular controls over CPN development, specifically genes that are expressed by, and function in, particular subpopulations of CPN. While much progress has been made in identifying molecular controls over neocortical arealization, lamination, and broad subtype specification, CPN diversity has remained largely unaddressed. Therefore, this work begins by identifying genes more highly expressed in CPN than other closely related projection neuron populations, and uncovers molecular diversity within CPN. From this molecular diversity, functional analysis of three candidate molecular controls over CPN subtype diversity follows. Cited2 acts broadly in neocortical progenitor development and postnatally in refining somatosensory CPN identity. Caveolin1 identifies a population of CPN with dual axonal projections. Tmtc4 is mutated in human CC disease and can function in CPN axonal development. These analyses of CPN molecular diversity in mouse then expand to an investigation of which molecular subpopulations are conserved, expanded, or uncommon between rodent and primate, allowing both for comparative evolutionary theories of CPN function, and indicating which CPN populations critical for human brain function can be best studied in rodent models.

Luman (CREB3, LZIP) is a basic leucine zipper transcription factor involved in regulation of the unfolded protein response (UPR), dendritic cell maturation, and cell migration. But despite reported expression in primary sensory neurons, little is known about its role in the nervous system. Luman mRNA from rat sensory neurons was amplified and its coding sequence was determined. The rat Luman cDNA contains a full-length open reading frame encoding 387 amino acids, and the recombinant protein generated from this clone activated transcription from UPR elements. Quantitative RT-PCR revealed rat Luman transcripts in a variety of rat tissues with the highest levels in nervous system tissue. In situ hybridization confirmed the findings and demonstrated that the Luman mRNA hybridization signal localizes to neurons and satellite glial cells in dorsal root ganglia (DRG), the cytoplasm of hepatocytes in liver, and the hippocampal pyramidal cell layers in CA1 and CA3 and the granular cell layer of the dentate gyrus. Luman protein localizes with axonal endoplasmic reticulum (ER) components along the axon length within the sciatic nerve and is activated by sciatic nerve injury. Adult sensory axons also contain Luman mRNA which is translated within the axon and transported to the cell body via the importin-mediated retrograde transport system in response to nerve injury. Further, creation of an N-terminal, C-terminal dual fluorescence-tagged Luman adenoviral construct allowed visualization of the cleavage and retrograde translocation of the N-terminal portion of Luman to the nucleus in real time in vivo and in vitro. Neuronal or subcellular axonal knockdown of Luman significantly impaired the intrinsic ability of injury-conditioned, but not naïve, sensory neurons to extend the regeneration-associated elongating form of neurites. Sciatic nerve crush injury also induced activation of the UPR in axotomized DRGs, including genes linked to cholesterol biosynthesis. Knockdown of Luman decreased the activation of UPR and cholesterol biosynthesis, and axotomy-inducted increases in neurite outgrowth, which could be largely rescued with either mild UPR inducer treatment or cholesterol supplementation. Together these findings provide novel insights linking remote injury-associated axonal ER responses to the regenerative growth capacity of adult sensory neurons via axonal activation and synthesis of Luman and reveal a role for the UPR in regulation of axotomy-induced neurite outgrowth that is critically dependent on Luman.

The growth of a neuronal dendritic tree depends on the neuron’s internal state and the environment within which it is situated. Different types of neuron develop dendritic trees with specific characteristics, such as the average number of terminal branches and the average length of terminal and intermediate segments. A key aspect of the growth process is the construction of the microtubule cytoskeleton within the dendritic tree. Neurite elongation requires assembly of microtubules from free tubulin at the growth cone. The stability of microtubule bundles is an important factor in determining how likely it is for a growth cone to split to form new daughter branches. Microtubule assembly rates and bundle stability are controlled by microtubule-associated proteins, principally MAP2 in dendrites. Extending previous work (Hely et al, J. Theor. Biol. 210:375-384, 2001) I have developed a mathematical model of neurite outgrowth in which elongation and branching rates are determined by the phosphorylation state of MAP2 at the tips of each terminal branch. Tubulin and MAP2 are produced in the cell body and transported along the neurite by a combination of diffusion and active transport. Microtubule (dis)assembly at neurite tips is a function of tubulin concentration. The rate of assembly depends on the amount of unphosphorylated MAP2 bound to the microtubules and linking them together. Phosphorylation of MAP2 destroys its linking capability and destabilises the microtubule bundles. Each terminal has a probability of branching that depends on the phosphorylation of MAP2 which, in turn, is a function of calcium concentration. Results from this model show that changes in the (de)phosphorylation rates of MAP2 affect the topology of the final dendritic tree. Higher phosphorylation promotes branching and results in trees with many short terminal branches and relatively long intermediate segments. Reducing phosphorylation promotes elongation and inhibits branching.

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In a world dominated by temporal order, memory capable of processing, encoding and subsequently recalling ordered information is very important. Over the decades this memory, known as serial memory, has been extensively studied, and its effects are well known. Many models have also been developed, and while these models are able to reproduce the behavioural effects observed in human recall studies, they are not always implementable in a biologically plausible manner. This thesis presents the Ordinal Serial Encoding model, a model inspired by biology and designed with a broader view of general cognitive architectures in mind. This model has the advantage of simplicity, and we show how neuro-plausibility can be achieved by employing the principles of the Neural Engineering Framework in the model’s design. Additionally, we demonstrate that not only is the model able to closely mirror human performance in various recall tasks, but the behaviour of the model is itself a consequence of the underlying neural architecture.

The present diploma work investigates visualization of multidimensional data using multilayer neuron networks. The research comprised artificial neuron network (SAMANN) for non – linear projection, and visualization of multidimensional space data to smaller measurement space. The SAMANN network is trained by error backpropagation algorithm, that is, a multilayer perceptron is trained by using gradient descent rule for minimization of accumulated square error. Programme language helped creating a language for SAMANN network realization. Practical researches were carried out, that is, plane visualization of specific data sets complex (vectors). Dependence of visualization accuracy on number of iterations, training speed parameter and number of neurons in hidden layers was established. The following software was used for the work: Microsoft Visual Studio 6.00 C++ (for realization of SAMANN network) and Microsoft Excel 2002 (for visualization of the created programme).

Normal intestinal functions are coordinated by enteric neurons within the enteric nervous system (ENS). In the embryonic and neonatal gut, enteric neuron survival is dependent on the expression of glial cell line-derived neurotrophic factor (GDNF) from its targets of innervation - the intestinal smooth muscle cells (ISMC). In the inflamed adult intestine, enteric neuron loss is immediately followed by ISMC proliferation, resulting in severe disruption of normal intestinal functions. Although GDNF can support the survival of postnatal enteric neurons, whether adult ISMC can secrete GDNF and support neuron survival is unclear. Results from qPCR analysis showed that freshly isolated adult ISMC have acquired the ability to express GDNF at the onset of proliferation, in vitro. Western blot analysis indicates that GDNF continues to be upregulated in ISMC at Passage 2 (P2), but its expression is decreased after long periods of proliferation at Passage 10 (P10). A neuron survival bioassay suggests that GDNF expression is correlated with enteric neuron survival. Results showed that P2 ISMC or conditioned media (CM) - but not P10 ISMC and CM, significantly increased enteric neuron survival. In subsequent experiments, the RET tyrosine kinase inhibitor vandetanib was used to block GDNF receptor-ligand interactions, and anti-GDNF neutralizing antibody was used to sequester soluble GDNF within the culture media. Both methods were successful at decreasing myenteric neuron survival. Furthermore, abolishing GDNF expression in P2 ISMC with GDNF siRNA also resulted in a decreased myenteric neuron survival. The above observations suggest that ISMC-derived GDNF is important in supporting myenteric neuron survival in vitro. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2012-09-28 09:43:23.968