Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

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Homeostatic synaptic plasticity (HSP) regulates synaptic strength in response to changing neuronal firing patterns. This form of plasticity is defined by neurons’ ability to sense and over time integrate their level of firing activity, and to actively maintain it within a defined range. For instance, a compensatory increase in synaptic strength occurs when neuronal activity is chronically attenuated. However, the underpinning cellular mechanisms of this fundamental neural process remain poorly understood. We previously found that during activity deprivation, HSP leads to an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor function as well as a shift in subunit composition from Ca2+-impermeable GluA2-containing AMPA receptors to Ca2+-permeable GluA2-lacking AMPA receptors not only at synapses, but also at extrasynaptic sites. Neurons therefore appear to be actively enhancing Ca2+ entry, possibly as a compensatory mechanism in response to a prolonged Ca2+ deficit. To test whether the homeostatic response may, at least in part, be mediated by internal Ca2+ stores, we depleted endoplasmic reticulum (ER) Ca2+ stores by using the Sarco/endoplasmic reticulum Ca2+ ATPases (SERCA) pump blocker cyclopiazonic acid (CPA) for a prolonged period. Interestingly, we have found that prolonged Ca2+-store depletion leads not only to an increase in synaptic strength per se, but also a cell-wide increase in synaptic Ca2+-permeable GluA2-lacking AMPARs. This increase in Ca2+ influx following periods of inactivity is conceptually highly reminiscent of a store-operated response, whereby cells re-establish their calcium levels following Ca2+ store depletion using cell surface Ca2+ channels. Our results suggest that neurons use synaptic receptors as means to regulate store Ca2+ levels, thus significantly expanding our understanding of the repertoire used by neurons to modulate cellular excitability.

6-hydroxydopa (6-OHDOPA) was synthesized with the expectation that it would be able to cross the blood-brain barrier to be enzymatically decarboxylated to 6-hydroxydopamine (6-OHDA), the newly discovered neurotoxin for noradrenergic and dopaminergic neurons. In part, 6-OHDOPA fulfilled these criteria. When administered experimentally to rodents, 6-OHDOPA destroyed peripheral sympathetic noradrenergic nerves and did exert neurotoxicity to noradrenergic nerves in brain—in large part, from its conversion to 6-OHDA. However, the efficacy of 6-OHDOPA was less than that of 6-OHDA; also, 6-OHDOPA was relatively selective for noradrenergic neurons; near-lethal doses of 6-OHDOPA were required to damage dopaminergic nerves; and ultimately, 6-OHDOPA was found to be an agonist at AMPA receptors, thus accounting for more non-specificity. Nevertheless, 6-OHDOPA was found to be a particularly valuable tool in uncovering processes and mechanisms associated with noradrenergic nerve regeneration and sprouting, particularly when administered to perinatal rodents. Also, 6-OHDOPA was a good tool for selective mapping of noradrenergic nerve tracts in brain, since dopaminergic tracts were unaffected and did not interfere with the histofluorescent methodology used for this purpose in the early 1970s. As an experimental research tool, 6-OHDOPA was valuable in a short time-window, but its utility is largely limited because of newer research technologies that provide better means today for nerve tract mapping, and for experimental approaches engaged toward study of processes and mechanisms attending nerve regeneration. AMPA actions of 6-OHDOPA have not been extensively studied, so this avenue may enliven use of 6-OHDOPA in the future.

Despite the fact that more men are diagnosed with substance use disorder, women escalate their drug consumption faster, exhibit higher craving during withdrawal, and have poorer treatment outcomes. Furthermore, as our cultural expectations of men and women have changed, there has been an increase in drug use in women and this increase is likely to persist. Preclinically, female rodents show stronger behavioral responses to drugs of abuse during initiation, escalation, and reinstatement of drug seeking. These behavioral differences are accompanied by alterations in structural plasticity within the mesocorticolimbic reward system. However, little is known about what functional sex differences exist in glutamate transmission in these circuits. The goal of these experiments was to determine functional sex differences in reward circuitry that may underlie behavioral sex differences in substance use disorder. We found heightened glutamate transmission in both the medial prefrontal cortex and nucleus accumbens in females compared to males. These findings corresponded with the nucleus accumbens being less plastic in females. We then investigated the role of PKMζ, a glutamatergic AMPA receptor trafficking protein, in plasticity and opioid-taking. We found PKMζ plays a role in synaptic plasticity within the nucleus accumbens and it works to blunt oxycodone-taking and motivation in a dose-dependent manner. Taken together these findings suggest there are functional sex differences at many levels within the reward system and gaining a better understanding of these differences could provide insight into improved treatments for substance use disorder. / Psychology

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Los suelos de la Región Semiárida Central Argentina (RSCA) son una fuente importante de emisión de PM10 a la atmósfera, las cuales se relacionan con efectos adversos en la salud humana y diversos efectos en el ambiente. Los procesos que generan la emisión de PM10 del suelo incluyen la erosión eólica, las actividades de labranzas y el tránsito por caminos sin pavimentar. La capacidad de emisión de material particulado emitido por diferentes fuentes, así como la composición química del mismo son dos aspectos que interesan conocer. En las últimas décadas el uso de herbicidas, principalmente el glifosato [C3H8NO5P], ha aumentado drásticamente en los suelos agrícolas de Argentina. De igual manera ocurrió con el consumo de fertilizantes, los cuales puede aportar diferentes contenidos de metales traza al suelo. El glifosato y su principal metabolito, el AMPA [CH6NO3P], tienden a adsorberse en la capa superior del suelo expuesta a la erosión. Los caminos sin pavimentar a pesar de no recibir aplicaciones en forma directa pueden estar expuestos a estos agroquímicos por diferentes procesos como la deriva, el agua de lluvia o la deposición de material transportado por el viento. La capacidad de emisión de los suelos de la RSCA bajo distintos manejos y la composición química del PM10 emitido son aspectos poco conocidos. Es por esto que el objetivo de esta tesis fue evaluar la emisión y caracterizar químicamente el material respirable emitido por suelos de la RSCA. Para ello se determinó la emisión potencial de PM10 (eficiencia de emisión, EE) de suelos agrícolas de diferentes texturas con dos metodologías: 1) utilizando el suelo tamizado por 2 mm (EE PM10), 2) utilizando las emisiones potenciales de las fracciones de agregados (EEfa) y su proporción en el suelo (EE2 PM10). Para caracterizar químicamente el PM10, se midió la concentración de glifosato y AMPA en el PM10 emitido por suelos bajo diferentes manejos (agrícola, agrícola - ganadero y ganadero) y el contenido de Cu, Ni, Mn, Fe (total y disponible), glifosato y AMPA en suelos agrícolas y caminos rurales sin pavimentar aledaños. En los suelos agrícolas se aplicaron herbicidas frecuentemente (al menos tres aplicaciones al año) y fertilizantes, en suelos agrícolas - ganaderos el uso de herbicidas fue menos frecuente (menos de una aplicación al año) y en suelos ganaderos no se aplicaron agroquímicos al menos en los últimos 20 años. Los resultados mostraron que la eficiencia de emisión de PM10 calculada con ambas metodologías se correlacionaron positivamente, aunque la EE PM10 fue el doble de la EE2 PM10. La EE PM10 aumentó con el contenido de arena y limo y disminuyó con el aumento en el contenido de arcilla y MO del suelo. La EEfa disminuyó con el aumento en el tamaño de la fracción de agregados, siendo la fracción <0,42 mm la de mayor EE y la fracción >19,2 mm la de menor EE. Este análisis mostró que la fracción <0,42 mm representa más del 80 % de la EE2 PM10 del suelo. Los análisis químicos mostraron que los porcentajes de detección y concentración de glifosato y AMPA fueron en suelos agrícolas> suelos agrícolas - ganaderos> suelos ganaderos. La detección de glifosato y AMPA en los suelos ganaderos sugiere que estos compuestos ingresaron desde otras áreas por distintos mecanismos como la deriva, a través del agua de lluvia o por la deposición de sedimentos transportados por el viento. Las concentraciones de glifosato y AMPA encontradas en el PM10 fueron mayores a las encontradas en el suelo. Esto indica que ambos compuestos se acumulan en el material respirable emitido por suelos, lo cual pone de manifiesto el potencial riesgo para la salud y el ambiente. En todos los manejos analizados y caminos rurales el contenido de AMPA en el suelo y en el PM10 fue mayor que el contenido de glifosato. El análisis de las emisiones actuales de PM10 mostró que la cantidad de glifosato transportado en el PM10 movilizado por la erosión eólica de una hectárea de camino rural sin pavimentar fue entre 497 y 956 veces mayor que en suelos agrícolas. Mientras que, la cantidad de AMPA transportado en el PM10 emitido por caminos rurales fue entre 27 y 381 veces mayor que la emitida por suelos agrícolas. Las concentraciones de Cu, Ni, Mn, Fe y Fe disponible fueron mayores en el PM10 que en el suelo. Los contenidos de los elementos analizados en el PM10 emitido por caminos rurales fueron mayores o similares a los presentes en el PM10 emitido por los suelos agrícolas. Los resultados de esta tesis ponen de manifiesto la importancia de los caminos rurales como fuente de emisión de PM10 y transporte de sustancia contaminantes a la atmósfera y otros destinos. Los suelos productivos bajo distintos manejos son una fuente menor de emisión por unidad de superficie respecto de los caminos. Las condiciones de manejo actuales de los suelos productivos mantienen a los mismos con alta cobertura evitando la erosión eólica y la emisión de PM10. Sin embargo, estos suelos tienen un alto potencial de emitir PM10 y así transportar sustancias contaminantes. Este resultado advierte sobre las posibles consecuencias en el caso de que ocurran cambios en el uso de la tierra hacia sistemas de manejo donde el suelo presente menor cobertura vegetal. / The soils of Central Semiarid Región of Argentina (CSRA) are an important source of PM10 emissions into the atmosphere, which are related to adverse effects on human health and various effects on the environment. The processes that generate the emission of PM10 from the soil include wind erosion, tillage activities and traffic on unpaved roads. The emission capacity of particulate material emitted by different sources, as well as its chemical composition are two aspects that are interesting to know. In the last decades the use of herbicides, mainly glyphosate [C3H8NO5P], has increased dramatically in the agricultural soils of Argentina. In the same way it happened with the consumption of fertilizers, which can contribute different contents of trace metals to the soil. Glyphosate and its main metabolite, AMPA [CH6NO3P], tends to be adsorbed in the upper layer of soil exposed to erosion. Unpaved roads, despite not receiving direct applications, can be exposed to these agrochemicals by different processes such as drift, rainwater or the deposition of material carried by the wind. The emission capacity of the soils of the CSRA under different management and the chemical composition of the PM10 emitted are little known aspects. This is why the objective of this thesis was to evaluate the emission and chemically characterize the respirable material emitted by the CSRA soils. For this, the potential emission of PM10 from agricultural soils of different textures was determined using two methodologies: from the soil sieved by 2 mm (EE PM10) and from the potential emissions of the aggregate fractions (EEfa) by their proportion in the soil (EE2 PM10). To chemically characterize the PM10, the concentration of glyphosate and AMPA in the PM10 emitted by soils under different management (agricultural, agricultural - livestock and livestock) and the content of Cu, Ni, Mn, Fe (total and available), glyphosate and AMPA on agricultural soils and surrounding unpaved rural roads were measured. In agricultural soils, herbicides were frequently applied (at least three applications per year) and fertilizers, in agricultural soils - livestock the use of herbicides was less frequent (less than one application per year) and in livestock soils, agrochemicals were not applied at least in the last 20 years. The results showed that the PM10 emission efficiency calculated with both methodologies were positively correlated, although the PM10 EE was double that of the PM10 EE2. The EE PM10 increased with the content of sand and silt and decreased with the increase in the content of clay and OM of the soil. The EEfa decreased with the increase in the size of the aggregate fraction, being the fraction <0,42 mm the one with the highest EE and the fraction >19,2 mm the one with the lowest EE. This analysis showed that the fraction <0,42 mm represents more than 80 % to EE2 PM10 from the soil. The chemical analyzes showed that the percentages of detection and concentration of glyphosate and AMPA were in agricultural soils> agricultural soils - livestock> livestock soils. The detection of glyphosate and AMPA in livestock soils suggests that these compounds entered from other areas by different mechanisms such as drift, through rainwater or by the deposition of sediments carried by the wind. Glyphosate and AMPA concentrations found in PM10 were higher than those found in soil. This indicates that both compounds accumulate in the respirable dust emitted by soils, showing the potential risk to health and the environment. In all the management analysed and rural roads, the AMPA content in the soil and in PM10 was higher than the glyphosate content. Analysis of actual PM10 emissions showed that the amount of glyphosate transported in PM10 mobilized by wind erosion of one hectare of unpaved rural road was between 497 and 956 times higher than in agricultural soils. While, the amount of AMPA transported in PM10 emitted by rural roads was between 27 and 381 times greater than that emitted by agricultural soils. The concentrations of Cu, Ni, Mn, Fe and available Fe were higher in PM10 than in soil. The contents of the elements analyzed in the PM10 emitted by rural roads were higher or similar to those present in the PM10 emitted by agricultural soils. The results of this thesis showed the importance of rural roads as a source of PM10 emission and transport of polluting substances to the atmosphere and other destinations. Productive soils under different management are a minor source of emissions per unit area compared to roads. The actual management conditions of productive soils maintain them with high coverage, avoiding wind erosion and the emission of PM10. However, these soils have a high potential to emit PM10 and thus transport pollutants. This result warns of the possible consequences in the event that changes in land use occur towards management systems where the soil has less coverage.