Cannabis has been used medicinally for millennia, but the cannabinoid (CB) field exploded with the identification of its endogenous receptors and endocannabinoids (eCBs). In vitro experimentation established that eCBs alter synaptic plasticity at presynaptic nerve terminals; however, the characterization of the eCB system (ECS) in vivo remains incomplete. This study aimed to determine the mechanism of in vivo eCB-mediated hippocampal synaptic plasticity and to analyze the effects this plasticity had on spatial working memory (SWM). With in vivo recordings of field excitatory postsynaptic potentials (fEPSPs) in anesthetized mice and rats as well as pharmacological manipulation of the ECS and glutamate receptor antagonism, it was found that eCBs, both anandamide (AEA) and 2-arachnidonyl glycerol (2-AG), caused LTD at hippocampal CA3-CA1 synapses. Induction of eCB-LTD occurs via a sequential activation of cannabinoid type-1 receptor (CB1R) and NR2B-containing NMDA receptor (NR2BR) and is expressed through the endocytosis of AMPA receptors (AMPARs). Increased eCB tone also caused an impairment of SWM for over 24 hours in the Delayed Non-Match-To-Sample (DNMTS) T-maze. This study provides the first evidence that an acute administration of eCB degradative enzyme inhibitors not only produces an in vivo LTD at hippocampal CA3-CA1 synapses that requires CB1R, NR2BR, and AMPAR, but also impairs SWM, a phenomenon also caused by an acute injection of exogenous CBs.

Sigma-1 receptors (σ-1Rs) are chaperone-like proteins that are broadly distributed throughout the central nervous system and in other tissues. They have been implicated in several physiological and pathological processes, primarily by their ability to modulate certain voltage- and ligand-gated ion channels. Growing evidence suggests that σ-1Rs regulate the functions of ion channels, such as voltage-gated K+ 1.2 (Kv 1.2) and the human Ether-à-go-go-Related Gene (hERG) ion channels, by modulating their expression, trafficking, and targeting. While it is well documented that σ-1Rs enhance the function of N-methyl-D-aspartate receptors (NMDARs), the mechanisms of this enhancement remain poorly understood. Using biochemical methods, we show that 90 minutes after intraperitoneal (i.p.) injection of σ-1R agonists such as (+)-SKF 10,047 (SKF) or (+)-Pentazocine (PTZ) (2 mg/kg), there is an increase in the expression of GluN2 subunits of NMDARs and postsynaptic density protein-95 (PSD-95) in the rat hippocampus. Following activation of σ-1Rs, co-immunoprecipitation (Co-IP) experiments reveal an increased interaction between σ-1Rs and NMDAR subunits; sucrose gradient centrifugation demonstrates an increase in the protein levels of GluN2 subunits in vesicular compartment; and biotinylation shows an increase in the surface levels of GluN2A-containing NMDARs. Taken together, our results suggest σ-1Rs may enhance NMDARs function by increasing their expression, trafficking, and surface levels. This σ-1R-mediated increase in NMDAR expression and surface levels might be involved in several physiological processes such as learning and memory. Our findings also suggest that σ-1Rs could form a potential target for designing novel antipsychotics.

The respiratory system is attentive, adaptive, learns and has memory. The respiratory system remembers repeated respiratory challenges to fine tune its motor activity by modulating neuronal synaptic strength. This phenomenon, respiratory long term facilitation (LTF), functions to strengthen the ability of respiratory motor neurons to enhance contraction of breathing muscles. LTF could serve as a protective mechanism against obstructive sleep apnea, a disease characterized by the collapse of upper airways, by restoring upper airway patency. LTF can be induced through modulation of vagal afferent feedback via repeated apneas. Here, we used reverse microdialysis, electrophysiology, neuropharmacology, and histology to determine if the nucleus of the solitary tract (NTS), a brain region exclusively receiving vagal afferents, is the origin of the neural circuit responsible for apnea-induced plasticity. My work shows bilateral injection of 5% lidocaine into the NTS prevented LTF. We conclude the NTS is required for triggering apnea-induced LTF.

The respiratory system is attentive, adaptive, learns and has memory. The respiratory system remembers repeated respiratory challenges to fine tune its motor activity by modulating neuronal synaptic strength. This phenomenon, respiratory long term facilitation (LTF), functions to strengthen the ability of respiratory motor neurons to enhance contraction of breathing muscles. LTF could serve as a protective mechanism against obstructive sleep apnea, a disease characterized by the collapse of upper airways, by restoring upper airway patency. LTF can be induced through modulation of vagal afferent feedback via repeated apneas. Here, we used reverse microdialysis, electrophysiology, neuropharmacology, and histology to determine if the nucleus of the solitary tract (NTS), a brain region exclusively receiving vagal afferents, is the origin of the neural circuit responsible for apnea-induced plasticity. My work shows bilateral injection of 5% lidocaine into the NTS prevented LTF. We conclude the NTS is required for triggering apnea-induced LTF.

No description available.

Evolutionary processes in any population depend upon patterns of phenotypic variation available to selection and their underlying heritability. In this thesis, I used the filamentous red seaweed Asparagopsis armata, with particular focus on its modularity, to test several key questions underlying its growth-form evolution in heterogeneous environments. I established that experimental manipulations of light quantity and quality mimicking variation in underwater light due to shading or depth induce growthform plasticity in A. armata that may be evolutionarily significant given its variability among clones. Current patterns of plasticity displayed by A. armata appear adaptive, moreover, given that a reciprocal transplant of phenotypes between light environments found densely-branched (phalanx-like) phenotypes to have higher relative growth rates than sparsely-branched (guerrilla-like) phenotypes in well-lit patches, but lower relative growth rates than the latter in shaded patches. Using the capacity for rapid growth as a proxy for fitness, multivariate selection analyses identified environment-dependent patterns of directional selection on single traits coupled with linear and nonlinear selection on multi-trait combinations that shape growth-form variation within patches of differing light intensity, thereby reinforcing plasticity across light environments. Quantitative genetic analyses, however, suggest that the modular iteration of genes in morphogenesis may limit further growth-form evolution in A. armata populations exposed to spatial heterogeneity in light by constraining thallus responses to environment-dependent selection. Last, heritable responses to artificial selection on growth-form variation among clonal cell-lineages revealed the surprising capacity for A.armata to circumvent genetic constraints inherent to its development by adapting to environmental change in the absence of sexually-generated variance among clones.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 6 uppsatser.

Dissertation (Ph.D.)--University of South Florida, 2006. / Includes bibliographical references (leaves 126-136). Also available online.

Thesis (Ph. D.)--Ohio State University, 2008. / Title from first page of PDF file. Includes bibliographical references (p. 132-138).

Thesis (Ph.D.)--Brigham Young University. Dept. of Mechanical Engineering, 2008. / Includes bibliographical references (p. 167-172).