17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors

Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared with males, an effect tied to elevated estrogen phases of the ovarian hormone cycle. Although estrogens can enhance drug-seeking behavior, they do not directly induce reinstatement on their own. To model this phenomenon, we tested whether an estrogen could augment drug-seeking behavior in response to an ordinarily subthreshold reinstatement trigger. Following cocaine self-administration and extinction, female rats were ovariectomized to isolate estrogen effects on reinstatement. Although neither peak proestrus levels of the primary estrogen 17β-estradiol (E2; 10 μg/kg, i.p., 1-h pretreatment) nor a subthreshold cocaine dose (1.25 mg/kg, i.p.) alone were sufficient to reinstate drug-seeking behavior, pretreatment with E2 potentiated reinstatement to the ordinarily subthreshold cocaine dose. Furthermore, E2 microinfusions revealed that E2 (5 μg/0.3 μl, 15-min pretreatment) acts directly within the prelimbic prefrontal cortex (PrL-PFC) to potentiate reinstatement. As E2 has been implicated in endocannabinoid mobilization, which can disinhibit PrL-PFC projection neurons, we investigated whether cannabinoid type-1 receptor (CB1R) activation is necessary for E2 to potentiate reinstatement. The CB1R antagonist AM251 (1 or 3 mg/kg, i.p., 30-min pretreatment) administered prior to E2 and cocaine suppressed reinstatement in a dose-dependent manner. Finally, PrL-PFC AM251 microinfusions (300 ng/side, 15-min pretreatment) also suppressed E2-potentiated reinstatement. Together, these results suggest that E2 can augment reactivity to an ordinarily subthreshold relapse trigger in a PrL-PFC CB1R activation-dependent manner

The Role of Brain-synthesized E2 in Hippocampal Learning and Memory Consolidation in Female Mice

The potent estrogen 17beta-Estradiol (E2) plays a critical role in neuroprotection, serving as an important trophic factor for neurons in the hippocampus, basal forebrain, and prefrontal cortex (Brinton, 2001). In the hippocampus, E2 promotes neurogenesis (Tanapat et al., 1999, Prange-Kiel et al., 2006), protects against cell death after ischemic injury (Garcia-Segura et al., 2001, Zhao and Brinton, 2007), and helps maintain spine morphology crucial for synaptic connectivity and memory (Woolley et al., 1990; Gould et al., 1990, Woolley and McEwen, 1992, Li et al., 2004). However, the mechanisms through which E2 promotes synaptic plasticity and enhances memory function are largely unknown. It has been principally assumed that E2\u27s effects on memory are due to E2 synthesized from the ovaries, which are the primary endogenous source of E2 in pre-menopausal females. However, E2 is also synthesized locally in the adult brain of a variety of species, where it regulates synaptic plasticity and can be synthesized in response to behavioral experiences (Prange-Kiel et al., 2003, Kretz et al., 2004, Remage-Healey et al., 2008, Azcoitia et al., 2011). Although de novo E2 may be a critical regulator of memory, very little is known about the functional role of local E2 synthesis in brain regions important for cognition, or the potential mental health implications of a reduction in local E2 synthesis (e.g., during menopause or in neurodegenerative disease). Therefore, the present study examined the role of locally synthesized estrogens in hippocampal memory consolidation. Three studies were used to determine if 1) hippocampal E2 synthesis is necessary for the consolidation of hippocampus-dependent object recognition and spatial memories, 2) experience-induced changes occur in hippocampal E2 levels after behavioral training, and 3) local E2 synthesis contributes to the memory-enhancing effects of exogenous E2. To block hippocampal E2 synthesis, we bilaterally infused into the DH an inhibitor of aromatase, the enzyme that synthesizes E2 from testosterone. We first found that blocking E2 synthesis in the DH during consolidation impaired both object recognition and spatial memory consolidation. We next found that local E2 levels are acutely increased in the DH after object training. This increase in E2 is blocked by DH infusion of an aromatase inhibitor at a dose that impairs memory consolidation in vivo. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory, suggesting that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory consolidation. Combined, these data demonstrate for the first time in mammals that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation

The Role of Hippocampal and Medial Prefrontal Interactions in the Estrogenic Regulation of Memory

Dendritic spine plasticity is thought to be essential for the formation and storage of memories. The sex-steroid hormone 17-estradiol (E2) increases dendritic spine density in 2 brain regions necessary for memory formation, the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC), but the mechanisms through which it does so remain largely unknown. Further, the extent to which these brain regions interact to mediate E2’s effects on memory is also unclear. Recently, we found that infusion of E2 directly into the DH also increases dendritic spine density in the DH and mPFC, and that these effects depend upon rapid activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) cell-signaling pathways in the DH (Tuscher et al., 2016). These intriguing findings highlighted a previously unexplored interaction between the DH and mPFC that may have important implications for understanding how E2 regulates memory. As such, these data led us to question what the role of the mPFC is during object memory formation, and whether interactions between the DH and mPFC are necessary for the E2-induced memory enhancements we have previously observed in our object memory tasks (Fernandez et al., 2008, Boulware et al., 2013, Fortress et al., 2013). Therefore the overall goal of the dissertation was to examine the role of the DH and mPFC in object memory consolidation both in the presence and absence of exogenous E2 infusions, and to examine how E2 regulates spine density changes in these regions, which may ultimately strengthen the synaptic connections involved in the formation of such memories. To this end, we first utilized inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to inactivate the DH, the mPFC, or both brain regions simultaneously immediately after novel object training to assess the role of each of these regions individually and in combination during object memory consolidation. Next, we asked whether E2 can act directly in the mPFC to enhance object memory consolidation and increase spine density in the mPFC and DH. Finally, we combined DREADD-mediated inhibition of the mPFC with direct infusion of E2 into the DH to examine whether DH-mPFC interactions are necessary for the beneficial mnemonic effects of DH infused E2. Our results collectively suggest that individual and simultaneous activation of both the DH and mPFC is required for the successful consolidation of object recognition and spatial memories. We also found that infusion of E2 directly into the mPFC increases mPFC apical spine density and facilitates object memory consolidation. Finally, we demonstrate that activation of the mPFC is necessary for the memory-enhancing effects of DH-infused E2. Together, these studies provide critical insight into how the DH and mPFC work in concert to facilitate E2-mediated memory enhancement in female mice. Further, this work will enable future studies investigating circuit and cellular-level questions regarding how E2 mediates cognition across the lifespan

Evaluation of Flood Losses to Buildings: Effect of Room Dimensions

Currently, the use of loss curves is largely limited, since they are usually based only on a few selected parameters. As a result, the amount of estimated losses may not fully correspond to the real costs of restoring the building to its original condition. The aim of the presented research is to determine whether the factor of room dimensions has a significant effect on the amount of unit flood loss on a building. It has been found that this effect may have a significant impact on the evaluation of flood loss on the level of a single room using loss curves. Therefore, it is concluded that this issue should be examined further to establish its significance on the level of whole buildings in order to increase the accuracy of flood loss evaluations carried out by insurance companies

Researches on direct injection in internal-combustion engines

These researches present a solution for reducing the fatigue of the Diesel engine by permitting the preservation of its components and, at the same time, raising its specific horsepower to a par with that of carburetor engines, while maintaining for the Diesel engine its perogative of burning heavy fuel under optimum economical conditions. The feeding of Diesel engines by injection pumps actuated by engine compression achieves the required high speeds of injection readily and permits rigorous control of the combustible charge introduced into each cylinder and of the peak pressure in the resultant cycle

Evaluation of Flood Losses to Buildings: Effect of Room Dimensions

Currently, the use of loss curves is largely limited, since they are usually based only on a few selected parameters. As a result, the amount of estimated losses may not fully correspond to the real costs of restoring the building to its original condition. The aim of the presented research is to determine whether the factor of room dimensions has a significant effect on the amount of unit flood loss on a building. It has been found that this effect may have a significant impact on the evaluation of flood loss on the level of a single room using loss curves. Therefore, it is concluded that this issue should be examined further to establish its significance on the level of whole buildings in order to increase the accuracy of flood loss evaluations carried out by insurance companies

The Impact of the World Economic Crysis on Building Industry in the Czech Republic

Tato diplomová práce se zabývá vlivem světové ekonomické krize na stavebnictví v České republice. Popisuje vznik, průběh a dopady novodobé světové ekonomické krize na světovou ekonomiku. Zároveň porovnává první ekonomickou krizi v 30. letech se součastnou probíhající krizí. Dále se blíže zaměřuje na dopady krize na stavební sektor v České republice a popisuje jeho vývoj v období krize. Cílem práce bylo zachycení vývoje a popsání důsledků, který tento vývoj zapříčinil a najít vhodná opatření pro nový rozvoj.This diploma thesis deals with the influence of global economic crisis on building industry in the Czech Republic. It describes origins, course and impacts of contemporary world economic crisis on global economy. It compares the first economic crisis in the 1930s with current crisis as well. This paper is also focused on the impacts of the crisis on the building industry in the Czech Republic and depicts its evolution in time of the crisis. The goal of the thesis was to capture the evolution, describe the impacts of this evolution and find some appropriate measures for a new development.