The dynamics of presynaptic transmitter release are often matched to the physiological properties and functions of the postsynaptic cell. In organisms ranging from cats to crickets, evidence suggests that retrograde signaling is essential for matching these presynaptic release properties to individual postsynaptic partners. We show that properties of facilitation and depression at the terminals of single sensory neurons (SNs) are correlated with the postsynaptic target cell in the cricket cercal sensory system. A quantal analysis applied to evoked transmitter release and demonstrates that facilitation and depression are presynaptic phenomena. Thus, single SNs are capable of making functionally distinct presynaptic terminals, simultaneously on different target cells. Furthermore, when the population of SNs contacting each target cell were sampled, all of the SNs were observed to have similar dynamic properties on a single target interneuron. This indicates that presynaptic release properties of SN terminals are specified locally, at the synapse, by an interaction with the target interneuron. A simple binomial model adequately described transmission at these synapses. We showed that the probability of release, p, varied systematically at the terminals of a single SN and is correlated with the target cell contacted. Low values of p were obtained for the contacts that facilitate at one target and higher values of p were obtained for the contacts that depressed at a second target. In addition, changes in p were primarily responsible for the dynamic changes in EPSP amplitude associated with paired pulse facilitation, depression and frequency depression. This indicates that p is regulated locally, at the synapses, by an interaction with the target cell and that this interaction influences the dynamic properties of presynaptic function. Finally, p is strongly correlated with the external calcium concentration in this system, suggesting that it reflects the activity of the calcium-dependent transmitter release mechanism. These results suggest that a retrograde signal modulates the calcium-dependent transmitter release machinery of presynaptic sensory neuron terminals, thereby matching presynaptic function to identified postsynaptic partners.

Odors from the opposite sex cause reproductive activation in prairie voles. To learn about the neural control of this response to odors, Fos immunocytochemistry was used as an anatomical marker for neural activity. Bedding soiled by conspecifics was used as an odor stimulus. Activity following exposure to odors was quantified by counting the number of Fos immunoreactive nuclei in specific brain regions. In the first experiment, the response of male and female voles to same and opposite-sex odors was compared. A factor analysis of the data revealed that fifteen brain areas could placed into four groups based on correlations of the number of Fos immunoreactive nuclei. Females responded only to male odors and in only one group, consisting of the medial amygdala (MA), medial bed nucleus of the stria terminalis (BSTM), medial preoptic area (MPA), and ventral premammillary nucleus (PMV). Males responded to male and female odors in this group. In addition, males responded to male odors in a group consisting of the basolateral and olfactory regions of the amygdala, and the lateral hypothalamus, and in a group consisting of the anterior, dorsomedial and ventromedial hypothalamus, and the anterodorsal preoptic nucleus. In the second experiment, the response of females to castrate male odors was investigated. Castrate male odors induced less of a response than intact male odors in the MA, BSTM, MPA and PMV. Only the PMV showed any response to castrate male odors. In the final experiment, the response gonadotropin releasing hormone containing (GnRH) neurons of males and females to odors from the opposite sex was studied. Opposite sex odors did not induce a change in the number of GnRH immunoreactive neurons that contained Fos. However, these odors did induce an increase in the number of GnRH immunoreactive neurons in males and a decrease in females. Together, the data presented here suggest that the MA, BSTM, MPA, and PMV may mediate reproductive activation caused by opposite sex odors. GnRH neurons may also be involved, although Fos does not increase. More experiments are needed to firmly establish a role of these brain areas in reproductive activation of prairie voles.

Secondary injury (SI) after spinal cord trauma is characterized by the multiple pathophysiological events that are set in motion by a primary mechanical insult to the spinal cord. SI produces a post-spinal cord injury (SCI) microenvironment that severely limits recovery, and results in more functional deficits. Many advances have been made to increase the scientific understanding of SI mechanisms, but there remains a lack of standardized clinical treatment to mitigate the damage caused by secondary pathophysiology. The classification of SI processes can be done based on the biological systems they take place: vascular (hemorrhagic necrosis, ischemia, edema), immune (cytokine and hormone release, residential inflammatory cells, peripheral inflammatory and immune cells), and neuronal/glial systems (excitotoxicity, mitochondrial dysfunction, ionic disturbances, overproduction of reactive oxygen and nitrogen species, cell death pathway activation, and axon degeneration). Regarding mechanisms underlying the SI processes (i.e., SI mechanisms: the biochemical events that exacerbate structural and functional losses), SCI-induced elevation of reactive oxygen and reactive nitrogen species (ROS/RNS) serve as one of the most potent triggers of neural cell and neurite death and inflammation, essentially affecting all aforementioned systems to worsen neurological dysfunction. In addition to the role in pathophysiological circumstances, ROS/RNS are also important players in mediating physiological functions (e.g., cell signaling). This feature requires that development of therapeutics for managing post-SCI ROS and RNS must specifically impede the detrimental effects of the radicals in propagating the SI scale without interfering with their physiological roles. In the context of SCI, regulation of ROS/RNS species at their homeostatic levels may serve as an effective therapeutic target for future clinical studies to mitigate neurodegeneration and neuroinflammation, and to promote a permissive environment for endogenous recovery. Based on these facts, Hydrogen Peroxide and Peroxynitrite (a representative ROS and RNS, respectively) were evaluated as SI mediators after SCI and for their potential to be targeted to develop interventions to treat SCI. Overall, the reviewed research findings suggested that oxidative damage cascades should be further studied in laboratory and clinical settings to advance understanding of SI processes of SCI for devising therapies. / 2025-02-03T00:00:00Z

The process of learning well-coordinated motor sequences is an essential aspect of human behavior. Learning to speak, play an instrument, or swing a baseball bat requires the brain to encode a very specific sequence of motor activity. It is understood at the descriptive level of analysis the environmental/experiential factors that contribute to learned motor sequences, but there is limited understanding of the neural modifications underlying such learning. This dissertation explores how auditory experience shapes the intrinsic physiology of premotor neurons during the process of learning vocal patterns. Understanding these neural modifications could help in identifying ways to improve learning and identify processes that may account for learning disabilities. The hypothesis tested in this dissertation is that learning involves plasticity of the intrinsic properties of neurons. This is tested by using in vitro patch clamp electrophysiology to study the intrinsic physiology of the premotor area HVC, a brain area responsible for the vocal timing of song in zebra finches. The first set of experiments test whether the intrinsic physiology of HVC changes over song learning and development. The results show that there are systematic changes in projection neuron physiology as juvenile finches learn to sing. Biophysical models were made to predict the changes in ion channel expression that underlie the change in physiology. Some observations included alterations in the response of HVCX neurons to hyperpolarizing current pulses, including model-predicted changes in the Ih current and the T-type Ca2+ current. Additional changes included a shift in the resting potential of HVCRA neurons. The second set of experiments tests the prediction that auditory experience drives the observed changes in intrinsic physiology. The results show that tutor-deprivation has a direct effect on the intrinsic physiology of HVC projection neurons. The results also show that limited tutor exposure can reverse the change in physiology that resulted from tutor deprivation in a dose dependent fasion. These findings suggest that vocal-motor learning involves not only the alteration of synaptic weighting between neurons, but also changes in the intrinsic physiology of the component neurons in the circuit. Consequently, models of vocal learning should account for these intrinsic changes along with changes in synaptic connectivity. More broadly, models of learning and memory should consider intrinsic plasticity of neurons as a possible contributor to how the nervous system encodes new information or novel behaviors. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2017. / October 31, 2017. / Includes bibliographical references. / Richard L. Hyson, Professor Directing Dissertation; Richard Morris, University Representative; Frank Johnson, Committee Member; Richard Bertram, Committee Member; Michael P. Kaschak, Committee Member.

No description available.

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<p>In the present research a comparison has been made of the effects of blockade of axoplasmic transport in a nerve to the hind limb of a salamander, with those of sectioning the nerve; the particular focus of attention was the peripheral fields of adjacent nerves to the same limb. The normal touch-receptive and motor fields of the spinal segmental nerves 15, 16 and 17, which innervate the hind limb, were found to be, bilaterally symmetrical. Both after section of nerve 16, or after acute treatment of it with colchicine, a drug which blocks axoplasmic transport, the adjacent nerves 15 and 17 significantly increased (P < 0.05) the size of their touch-receptive fields; increases in motor field were statistically significant only after partial denervation. However, colchicine treatment produced a blockade of the fast axoplasmic transport of catecholamines and cholinesterase, as shown by histochemical methods; presumably the axonal transport of other substances was also blocked. The colchicine also significantly reduced the number of microtubules in the treated axons. Taken as a whole, these findings are consistent with the concept that the size of peripheral nerve fields may be regulated by trophic factors which are continually supplied to the target tissues by fast axoplasmic transport. It is the reduction in the supply of these factors along sectioned nerves which is responsible for the collateral sprouting of adjacent nerves.</p> / Doctor of Philosophy (PhD)

<p>Previous analyses showed that following heterotopic transplantation of a thoracic neural tube segment into the region of the extirpated brachial neural tube in experimental (Thor-Br) chick embryos at embryonic day -2 (day -2E) the wings of hatched Thor-Br chicks are immotile. It was not known, however, if functional nerve-muscle interaction occurs during embryogenesis of Thor-Br embryos, although structural nerve-muscle connections do form in wing muscles during initial development of this experimental model. From day 8.5-9E onward, however, thoracic nerve-brachial muscle unions progressively uncouple in individual wing muscles. The present study explored the nature of initial nerve-muscle contacts and employed a well documented functional parameter, wing motility, to monitor daily the development of functional nerve-muscle interactions in wings of individual Thor-Br embryos. Control embryos were either unoperated (UC) or received a homotopic brachial neural tube transplant (Br-Br). The results demonstrated that Thor-Br embryos exhibited normal frequencies of wing movement up to day -8E; but the frequency of wing movement became greatly reduced from that of controls following this initial developmental period. The loss of wing motility in Thor-Br embryos coincided temporally with the withdrawal of intramuscular axons from individual wing muscles reported previously. Thus, foreign thoracic nerves did establish initial functional contacts with wing muscles, however, these connections were subsequently deemed inappropriate and nerve-muscle unions progressively uncoupled. To investigate factors responsible for the nerve-muscle uncoupling phenomenon observed in experimental (Thor-Br) embryos the development of heterotopically transplanted thoracic neural tubes was compared to that of neural tubes in control (Br-Br and UC) embryos. Parameters analysed include the pattern of peripheral nerve outgrowth, neural tube histogenesis, the source of motor innervation to individual wing muscles and the pattern of motoneuron death, growth and differentiation. The results showed that while the pattern of nerve outgrowth was controlled by local environmental signals, developmental events within the neural tube was governed autonomously, independent of the periphery. Thus, heterotopically transplanted thoracic neural tubes developed according to their site of origin. In addition to the heterotopic neural tube (Thor-Br) transplantation experiments a second series of surgically manipulated chick embryos (Thor-Br/som) was employed to determine if nerve-muscle incompatibility is limited to a thoracic nerve-brachial muscle combination. Experimental (Thor-Br/som) embryos were produced by transplanting thoracic somitic mesoderm into the site of extirpated brachial somites at day -2E. Daily wing motility analyses were performed to determine the extent of functional nerve-muscle interaction between in situ brachial nerves and wing muscles derived from heterotopically transplanted thoracic somitic mesoderm. The results demonstrated that functional nerve-muscle interaction did occur in wings of Thor-Br/som embryos and, in contrast to experimental (Thor-Br) embryos, wing motility was maintained in Thor-Br/som embryos throughout the developmental period analysed (day -6E through day -16E). Nerve-muscle uncoupling, therefore, dd not occur in heterotopic somitic mesoderm transplantation experiments. It was concluded that eventual nerve-muscle incompatibility observed following heterotopic neural tube (Thor-Br) transplantation is related to the rigidity of developmental processes within the spinal cord. Whereas heterotopically transplanted thoracic somitic mesoderm exhibited a high degree of plasticity and conformed to peripheral signals derived from the brachial environment, transplated thoracic neural tubes were unable to respond to environmental signals were eventually deemed inappropriate.</p> / Doctor of Philosophy (PhD)

<p>In the current investigation several biochemical techniques, including solubilization, affinity chromatography and photoaffinity labelling, were used to purify the D-1 dopamine receptor. The design and synthesis of novel analogues of the dopamine agonist ADTN (2-amino-5,6-dihydroxy-tetrahydronaphthalene) to be used as affinity and photoaffinity probes was an integral part of this investigation. Solubilization of the D-1 receptor was achieved with several detergents although cholic acid proved to be the most effective for receptor solubilization prior to affiinty chromatography. Using this procedure, yields of solubilized receptors of greater than 30% were consistently obtained. An affinity chromatography protocol utilizing an ADTN analogue covalently coupled to an affinity matrix was established for cholate-solubilized D-1 receptor. The affinity protocol developed during this investigation purified the D-1 receptor approximately 50-fold, while an average of 8% of the receptors were recovered. These results were superior to any previous literature reports of D-1 receptor purification. Several photoactive compounds were synthesized and used to crosslink D-1 receptors. One compound in particular, a photoactive derivative of the dopamine agonist ADTN, proved to be a useful ligang for this purpose. A tritiated derivative of this compound was covalently and specifically incorporated into a protein of M.W. = 79 kDa. This was the first report that the D-1 receptor had a M.W. of greater than 70 kDa was determined by affinity crosslinking. Several other investigators have subsequently confirmed this observation. Other photoactive compounds radiolabelled with ¹²⁵I were synthesized and examined for activity as D-1 and D-2 receptor probes. These compounds were not as useful as photoaffinity labels for dopamine receptors as had been originally proposed. The compounds did label and a 50 kDa protein which was determined to be neither the D-1 nor D-2 receptor. This protein (originally designated Apo-50 and later CatNAP) has very interesting properties asa it possesses binding activities with several catecholamines which are without precedent in the literature.</p> / Doctor of Philosophy (PhD)

<p>Animals with kainate- and ibotenate-induced lesions demonstrated significant nocturnal hyperactivity; however, no such effect was found in the quinolinate lesioned animals. Further, the hyperactivity in the kainate- and ibotenate-lesioned animals attenuated over prolonged testing. This study indicates that spontaneous nocturnal activity may not always be an adequate measure of striatal dysfunction. Secondly, the behavioural profile of rats with quinolinic acid-induced lesions of the medial striatum was characterized. The lesioned rats were found to be impaired in two tests of cognitive behaviour, the Morris Water Maze and the spontaneous alternation task, but were apparently unimpaired on a host of motor tests, thus strengthening the interpretation that the impairment demonstrated on the two cognitive tasks was indeed indicative of impaired visuospatial processing. The behavioural data also suggested that the lesioned animals showed impaired cognitive flexibility, and an inability to change learning strategies. Histological analysis revealed significant striatal degeneration seemingly in the absence of cortical degeneration, thus suggesting that lesions largely restricted to the medial striatum are sufficient to produce a behavioural impairment. Animals were found to be impaired in the Morris Water Maze, but were unimpaired on a number of motor tests. Histological analysis demonstrated the presence of marked cortical degeneration; interestingly, striking ventricular dilation was also present in most of these animals. The results were discussed in relation to the pathology of HD. Lastly, a morphometric study was performed on rats with chronic excitotoxin-induced striatal lesions. Degenerative changes were noted in the striatum, substantia nigra and thalamic nuclei, but no changes were found in the thalamus as a whole or the cortex. The negative cortical finding was supported by a neurochemical study of various neuropeptides in rats with chronic quinolinic acid-induced lesions of the medial striatum. (Abstract shortened by UMI.)</p> / Doctor of Philosophy (PhD)