The Role of Striatal Neuropeptides on Glutamate and Methamphetamine-Induced Neurotoxicity in the Murine Brain
Author:
Lauriaselle Afanador
Year of Dissertation:
2012
Dopamine-glutamate interaction in the actions of typical antipsychotic drugs
Year of Dissertation:
2009
Typical antipsychotic drugs (APD) are currently the most effective psychoactive agents for the treatment of schizophrenia. Studies suggest that besides their conventional action of blocking dopamine (DA) D2 receptors, these drugs also interact with glutamatergic N-methyl-D-aspartate (NMDA) receptors. In addition, blockade of DA D2 receptors is believed to result in DA cell depolarization block (DB) and movement disorders (catalepsy) in animals. Since it has been hypothesized that drug's antipsychotic potency may be predicted by its ability to produce DB and catalepsy, using CD rats in behavioral, microdialysis and receptor binding studies we investigated whether typical APD induce DB and catalepsy though action on the dopaminergic system, glutamatergic system, or through the interaction between the two systems. Focus of this project was on striatum (STR) and frontal cortex (FC), two brain regions implicated in the DA-glutamate interplay. Our behavioral results show that haloperidol, a potent APD and postsynaptic DA D2 receptor blocker is a strong catalepsy inducer. Receptor binding study showed that chronic administration of this drug caused a decrease in maximal binding at the NMDA receptors in STR and FC but no significant changes in the DA D2 receptor densities were seen in the two brain areas. In contrast, metoclopramide, another DA D2 receptor blocker but not an APD, within the therapeutic doses (5 mg/kg-10 mg/kg) did not produce catalepsy in experimental animals. The maximal binding parameters for DA D2 and NMDA receptors in STR and FC after repeated administration of metoclopramide were significantly elevated as compared to haloperidol. However, when animals were pre-treated with metoclopramide (10 mg/kg) it sensitized the brain to haloperidol and enhanced catalepsy. Additionally, our receptor binding studies showed that psychotomimetic agents, PCP and ketamine that cause schizophrenia-like symptoms have several-fold higher binding affinity at NMDA receptors as compared to DA D2 receptors, indicating that pharmacological effect of these drugs may be mainly mediated by blockade of NMDA receptors. Finally, studying the neurochemical mechanism for DA cell DB we saw a decrease in striatal DA release after chronic cocaine treatment compared to controls. In a series of follow-up experiments we compared the effect of low dose (0.5 mg/kg) haloperidol and high dose (3.0 mg/kg) haloperidol by acute injection to the chronic cocaine treated rats and to the control animals. Low dose haloperidol significantly increased straital DA release compared to respective controls, while the high dose haloperidol significantly reduced it compared to the low dose. On the other hand, high dose haloperidol drastically increased striatal DA release in chronic cocaine-treated rats compared to controls. These results suggest that the mechanism for catalepsy is based on the concurrent DA D2 receptor antagonism and activation of glutamatergic NMDA transmission. Similarly, the mechanism for DA cell DB is mediated through blockade of dopaminergic D2 receptors and stimulation of NMDA receptors. Thus, catalepsy as well as antipsychotic activity appears to be mediated through modifications of dopaminergic and glutamatergic transmissions.
Biodiversity and Ethnography of Tea Management Systems in Yunnan, China
Year of Dissertation:
2011
This study investigates biodiversity and cultural practices associated with tea (Camellia sinensis (L.) O. Kuntze; Theaceae) management systems in Yunnan Province of southwestern China. Surveys were conducted in smallholder communities of six sociolinguistic groups (Akha, Bulang, Han, Hmong, Lahu, and Yao) that manage tea resources in forests, agro-forests, mixed crop fields, and terrace gardens. Interviews were carried out between 2006 - 2010 to identify the influence of socio-economic and policy variables on tea production and consumption patterns. Ecological plot sampling and ethnobotanical inventories were employed to characterize the composition, structure, and uses of tea management systems. Tea leaf samples were randomly selected within each plot for: (1) video morphometrics to measure six shape and size attributes, (2) high performance liquid chromatography (HPLC) to quantify nine catechin and methylxanthine compounds and, (3) amplified fragment length polymorphisms (AFLP) molecular marker analysis to assess genetic diversity. Results indicate a relationship between the perceived value of a commodity and a change of management practices, ecological knowledge, and land use. Findings demonstrate how variable management practices result in the loss, conservation, or enhancement of plant species richness and genetic diversity, and how smallholders variably benefit from diversity in their agro-ecosystems. Plant species richness was found in the order agro-forest edge > forest > agro-forest > mixed crop field > terrace gardens. Statistically significant variation was found in morphological, phytochemical, and genetic characters between the different types of tea management systems. Morphological diversity was found in the order agro-forest > mixed crop field > forest > terrace gardens, whereas genetic diversity was found in the order mixed crop field > agro-forest > forest > terrace gardens. HPLC data show that tea samples from agro-forests and mixed crop fields had greater mean Total Catechin Content (TCC) and mean Total Methylxanthine Content (TMC) compared to forests and terrace gardens. Results further demonstrate that management, processing, and preparation methods are related to the phytochemical profile, anti-oxidant activity, and flavor of tea. This study provides useful baseline data to examine long-term change linked to expanded market integration and an engagement of ecosystem ecology with anthropology.
MAG does not Require NgR1, PirB or Sialic Acid Binding to Inhibit Neurite Outgrowth
Year of Dissertation:
2011
The Role of Gangliosides, NgR1, NgR2 and PirB Receptors in MAG Inhibition of Neurite Outgrowth
Neural Effects of Exposure to the Environmental Chemical, Bisphenol A, During Development
Year of Dissertation:
2010
Exposure to Bisphenol A (BPA), an environmental chemical, has been linked to changes in physiology, neural development, and behavior. The focus of this study was to determine the effects of BPA exposure, during a short developmental window, on physiology, activity, anxiety, cognition, and neurochemistry. In prenatal study, dams were administered 100 mcg/kg/day orally, from gestational day 16 to parturition. Postnatal study pups received subcutaneous injection of 60 or 100 mcg/kg BPA from postnatal day 0 to 6. All pups were weighed, examined for evidence of vaginal opening, and, at adulthood, performed behavioral tasks measuring locomotor activity, anxiety, and visual and spatial memory. Brain monoamines were measured using high performance liquid chromatography in the postnatal group. Prenatal BPA contributed to low juvenile body weight in both sexes and adult overweight in male subjects. Hyperactivity and memory deficits were observed in both sexes of BPA treated subjects. Postnatal 100 mcg/kg BPA females experienced delayed vaginal opening, less anxiety behavior in elevated plus maze, and spatial memory impairments. BPA treated subjects of both sexes had increased norepinephrine and dopamine turnover in basolateral amygdala and hippocampus, areas which are implicated in anxiety and cognition, respectively. The data suggests that BPA exposure during perinatal life causes disruptions in physiology, behavior, memory and neurochemistry that persist to adulthood. In addition, postnatal effects of BPA may be mediated by alterations in central monoaminergic function.
The Vocal Behaviors of Captive North American River Otters (Lontra canadensis) Individual differences and shared repertoires
Year of Dissertation:
2011
The current information on the vocal repertoire of the North American River Otter is very limited. To date there have been no direct studies conducted on their repertories. In this study, I examined the vocal behavior of 12 captive river otters. The discriminant function analysis suggests that river otters have 4 distinct call types with 7 sub-call types and one call the whistle is unique to one group of pups. The results of the Kruskal-Wallis comparing acoustical structures shows strong evidence for the presence of individuality with some individuals showing greater differences in comparison to the others. I also examined the differences in sexes and age groups, and the results show that unique calls are present, and there are significant differences across groups when comparing acoustical structures. Finally, I examined the uses of vocalizations, and the results show a positive correlation between the duration, max frequency, and max power of the call and the arousal state of the individual producing the call. Specific call types also showed tendencies to be produced when the individual was in a particular interaction (asocial or social) and when in a particular arousal state.
The Ecology of the Woodlands of Central Park, New York City
Year of Dissertation:
2012
A quantitative ecological inventory was conducted in the 54.6-hectare (ha) urban woodlands of Central Park, New York City. Fifteen sites were selected and woody stems greater than or equal to one centimeter (cm) diameter were surveyed using the point-centered quarter transect method. Total area surveyed was 1.091 hectares. The survey tallied 1,271 stems from 82 species in 31 families and 50 genera. Stem diameters ranged from 1 cm to 218 cm. In terms of ecological dominance, Prunus serotina Ehrh. was the dominant taxon followed by Quercus rubra L. The largest trees were Quercus rubra, Prunus serotina, Morus alba L., Phellodendron amurense Rupr., Platanus occidentalis L., Liriodendron tulipifera L., Quercus palustris Münchh., Ulmus americana L., and Styphnolobium japonicum (L.) Schott, ranging in diameter from 100 cm to 218 cm. Lower diameter at breast height (DBH) quartile stem sizes were dominated by Acer platanoides L., Prunus serotina, Celtis occidentalis L. and Q. palustris.
The diet and foraging ecology of gray seals, Halichoerus grypus, in United States waters
Year of Dissertation:
2009
Once extinct in U.S. waters, there are now more than 7,000 gray seals (Halichoerus grypus) that breed and forage in the waters of Maine and Massachusetts. This is the first long-term study of the diet and foraging behavior of this species in its U.S. range. I used hard parts in 305 seal scats and 49 stomachs, and fatty acid profiles in 45 seal blubber cores, to 1) reconstruct the diet of gray seals in U.S. waters, and 2) investigate regional, temporal, and intraspecific variation in the diet. I compared species in the diet with those most abundant in the seals' range, as measured by bottom trawl surveys. I analyzed the tracks of 6 satellite-tagged seals, and asked which prey species were most abundant in areas where foraging activity occurred. I recovered a total of 3,798 otoliths, and 7,005 prey individuals from 34 prey taxa. Sand lance (Ammodytes spp.) dominated the diet by weight (53.3% of total) and number (66.3% of total). Sand lance, winter flounder (Pseudopleuronectes americanus), red/white hake (Urophycis spp.) and Atlantic cod (Gadus morhua) together made up 82% of the diet by weight. Cod comprised 6.4% of the diet by weight, although this varied seasonally. Fatty acid profiles were best able to classify seals by age (young-of-the-year pups vs. yearlings, Wilks-Lambda = 0.27, F25,19 = 2.07, p <0.054), suggesting that diet differences were most pronounced between these two groups. Consistent 2:1 ratios of 22:6n3 and 20:5n3 fatty acids occurred in seal blubber (10.12/5.00 = 2.02). These ratios are similar to those in smooth skate (Malacoraja senta, 20.87/10.02 = 2.08) and alewife (Alosa pseudoharengus, 15.04/7.48 = 2.01), indicating that these species were important in the diet. Seals consumed abundant species, and tracked interannual trends in sand lance abundance, but the diet could not be predicted from prey availability alone. Satellite telemetry of seals revealed area restricted search behavior and central place foraging activity in areas with high abundance of sand lance and winter flounder, and these taxa comprised over 72% of the diet estimated from scats.
Neuromodulatory and cytoprotective roles of zinc in the vertebrate retina
Year of Dissertation:
2013
There is increasing evidence that the role of Zn2+ in the central nervous system is more complex and widespread than originally thought. Chelatable Zn2+ is co-localized with glutamate in the terminals of mossy fiber hippocampal and first order retinal neurons. The co-release of Zn2+ with glutamate in a stimulation-dependent manner has been shown in the hippocampus and the distal retina, while the electrophysiological effects of photoreceptor-released Zn2+ suggest a neuromodulatory role at the first visual synapse. This dissertation examines the neuromodulatory and cytoprotective roles of zinc in the vertebrate retina.
Population Genetics of Canine Heartworm (Dirofilaria immitis)
Year of Dissertation:
2011
Dirofilaria immitis, canine heartworm, is a filarial nematode that may have genetic features that favor the development of drug resistance, including rapid rates of mutation, large population sizes, and high levels of gene flow. This parasite is currently treated with macrocyclic lactone anthelminthics, and while it has not yet shown evidence for evolving resistance to these chemotherapeutic compounds, resistance has evolved in related filarial nematodes infecting ruminants and humans. Heartworm samples from domestic dogs and coyotes were obtained via donations from veterinarians and researchers across the United States. I isolated and characterized 11 microsatellite loci for canine heartworm. Using the observed distribution of alleles, I determined the amount of genetic variability and quantified the partitioning of genetic variance. In conjunction with microsatellite data, specific mitochondrial (cox1) and Wolbachia (wsp and ftsZ) loci were used to genotype a subset of host taxa. Results indicate a lack of mitochondrial diversity and maximum likelihood trees show no discernable geographic patterning on a continental scale. This is not unexpected in a Wolbachia-infected organism like D. immitis as this bacterium has been shown to purge mitochondrial diversity in numerous model systems. After establishing baseline genetic parameters, a model of population dynamics was created to answer questions about the potential spread of drug resistance alleles. In the absence of selection, gene flow between subpopulations drives the dispersal of drug resistance alleles. Fixation time is directly proportional to selection pressure. When resistance alleles arise in a source population they spread more rapidly than if they arise in a sequestered population.