The formation of dendritic arbors is necessary for the proper establishment of neuronal circuits. The Drosophila transcription factor Spineless has been shown to play an important role in the control of dendritic morphogenesis, although the pathways through which it functions are not completely understood. Here, we show genetic evidence that Spineless interacts with the actin/microtubule cross linking protein Shortstop to control the dendrite arbor development of the dendritic arborization (da) sensory neurons. In addition, we have discovered a novel function for spineless as we show that spineless mutant larvae exhibit an increased sensitivity to specific odorants in the absence of morphological defects of the chemosensory organs. These data show that spineless acts in multiple cell-specific contexts to control the diversification of sensory neuron morphology and function.

Thesis (Ph. D.)--State University of New York at Binghamton, Department of Systems Science and Industrial Engineering (Biosystem concentration), 2005. / Includes bibliographical references.

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The provision of proprioceptive feedback from limb muscle to spinal motor neuron is essential for the generation of coordinated movement. Proprioceptive sensory neurons form a precise matrix of connections with motor neurons and do so in the absence of patterned activity, implying the existence of proprioceptor subtype identities that mediate selective connectivity. The developing limb has been shown to influence the pattern of connections made by proprioceptors with motor neurons, suggesting that the patterning cues distributed along its cardinal axes are capable of influencing the molecular identities of proprioceptors. In this thesis, I describe efforts to characterize the molecular diversity of proprioceptors supplying distinct muscles located at different dorsoventral and proximodistal positions within the mouse hindlimb. I demonstrate the selective expression of several genes – cdh13, vstm2b, sema5a, and crtac1 – by proprioceptors supplying defined positional domains of the limb. I proceed to determine the limb tissue source of proprioceptor patterning information by examining the expression of these genes in mice in which one of three tissues encountered by proprioceptors – the motor axon, limb mesenchyme, and target muscle – has been genetically manipulated, revealing that both mesenchyme and muscle supply cues capable of directing proprioceptor gene expression. Finally, I show that one marker of proprioceptor muscle-type identity, cdh13, mediates the formation of selective connections between proprioceptors and motor neurons, thereby establishing a molecular link between proprioceptor subtype identity and patterned central connectivity.

The common neurotrophin receptor, p75NTR, has been implicated in diverse responses of sensory neurons including a role in nociception following nerve injury, suggesting that it may serve a similar role in intact sensory neurons and their satellite glial cells (SGCs). To examine the impact of suppressing neuronal p75NTR expression on known molecular modulators/regulators of the nociceptive state namely, the sodium channels NaV1.8 and NaV1.9, the nerve growth factor receptor TrkA, the potassium channel Kir4.1, glial fibrillary acidic protein (GFAP), SGC p75NTR, connexin 43, we intrathecally infused p75NTR anti-sense oligonucleotides (AS OGN), previously shown by Obata et al. (2006) to effectively suppress p75NTR expression in intact neurons. Male, Wistar rats were divided into three groups, receiving either no treatment (non-infused), seven day intrathecal infusion of p75NTR AS OGN or sense control (SC OGN) via an osmotic pump. Serial L4 and L5 DRG sections were processed for immunohistochemistry to detect alterations in NaV1.8, NaV1.9, TrkA, Kir4.1, p75NTR, GFAP and connexin-43 protein expression. Sciatic nerve sections were also processed for immunohistochemistry to detect NaV1.8, NaV1.9, TrkA and GFAP protein expression. Infusion of p75NTR AS OGNs resulted in a significant decrease in neuronal p75NTR expression, however no significant change was observed in neuronal NaV1.8, NaV1.9 or TrkA expression relative to SC OGN treated or non-infused controls. On the contrary, SGC expression of phenotypic markers normally associated with the reactive state that is induced in these cells in response to peripheral nerve axotomy was dramatically altered. More specifically, in response to p75NTR AS OGN infusion, there was a significant increase in SGC protein expression of the cytoskeletal protein GFAP and p75NTR, along with a significant decrease in expression of the inward rectifying potassium channel Kir4.1. Preliminary data also revealed this induced reactive state in SGCs to be associated with an increase in the number of SGCs surrounding individual neurons as well as increased SGC expression of the gap junction protein, connexin 43. In conclusion, reductions in neuronal p75NTR expression and potentially reduced neurotrophin signaling lead to alterations in neuron/glial or axon/glial communication that results in induction of a reactive phenotype in the associated SGCs. With our ever increasing understanding of the role of SGCs modulating pain states, elucidation of the pathways leading to adoption of pathological phenotypes can help in the identification of novel therapeutic targets.

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Description based on contents viewed Oct. 6, 2008; title from PDF t.p. Includes bibliographical references (p. 51-52).

Thesis (Ph.D.)--Indiana University, 2006. / Title from screen (viewed on Apr. 27, 2007) Department of Pharmacology & Toxicology, Indiana University-Purdue University Indianapolis (IUPUI) Includes vita. Includes bibliographical references (leaves 181-239)

Behaving in a complex world requires flexible mapping between sensory inputs and motor outputs. One must be able to make decisions about what actions to take based on a wide variety of inputs. This presents a routing problem: brain areas involved in decision making must receive information encoded by different sensory neurons in different situations. In this thesis I investigate this routing problem using two variations of the random dot motion task which require flexible routing. In the first, a single random dot motion task appears in different locations on different trials. Recording from the lateral intraparietal area (LIP) revealed several neural features which varied with stimulus location. A second task made it possible to disentangle routing from other signals, by separating the time of routing from the onset of motion and decision making. In this second task, a visual cue indicated the location at which relevant motion would appear. After the cue was extinguished, two random dot motion patches appeared. An informative patch appeared at the cued location, and an uninformative patch appeared at another location. Comparison of these two tasks revealed three location dependent signals at motion onset: a visual signal related to surround suppression, a second suppressive signal that may set the amount of evidence required for decision making, and a 12-20 hertz oscillation in firing rate. This oscillation appears to be a signature of flexible information routing. It appears at motion onset when the motion stimulus varies in location unpredictably; it appears at cue onset when a spatial cue indicates the location information must be routed from; and it does not appear when stimulus location is fixed and flexible routing is not required. Future work on this project will eventually require tools which are not well developed for use in rhesus macaques. The final chapter describes two projects which attempt to address this problem, one through the use of optogenetics in monkeys and the other by adapting an established monkey behavioral task for use in mice.