Intracellular Mechanisms Associated with Cocaine Induced Conditioned Place Preference

The aim of this dissertation was to investigate the intracellular responses associated with the acquisition and expression of cocaine-context associations. ERK (extracellular regulated kinase), CREB (cAMP responsive element binding protein), FosB and deltaFosB proteins were of particular interest due to their involvement in cocaine reward and in synaptic plasticity underlying learning and memory. We used the conditioned place preference (CPP) paradigm, which employs a Pavlovian conditioning procedure to establish an association between a drug-paired environment and the drug\u27s rewarding effects, to study the role of these signaling pathways in cocaine-context associations. N-methyl-D-aspartate receptor (NMDAR) antagonism prior to cocaine administration during conditioning blocked the acquisition of cocaine CPP and reduced Nucleus Accumbens (NAc) phosphorylated-ERK (pERK) levels following the CPP test (drug-free). NAc pERK levels increased after re-exposure to the cocaine-paired environment regardless of CPP expression. Conversely, Caudate Putamen (CPu) pERK and FosB protein levels only increased after CPP expression and re-exposure to the cocaine chamber. These results suggest that NAc ERK phosphorylation may be involved with retrieving the contextual information of a cocaine-association, without the expression of the behavior. Finally, we investigated whether ERK/CREB intracellular responses underlying cocaine environmental associations are sexually dimorphic. Following CPP expression, cocaine treated rats showed increased NAc pERK and pCREB and CPudeltaFosB levels. Cocaine females had a larger increase in CPu deltaFosB levels than cocaine males; partly due to lower protein levels in saline female rats when compared to saline males. CPP scores were positively correlated to NAc pERK and CPu FosB protein levels, suggesting that similar to males, the ERK/CREB intracellular pathway undergoes cocaine induced neuroplasticity in female rats. However, there seem to be intrinsic sexual dimorphisms that may contribute to responses expressed after cocaine-CPP. Taken together, the different patterns of intracellular responses in the NAc and CPu likely indicate region specific roles for pERK/pCREB/FosB signaling in the acquisition and retrieval of cocaine-context associations. These results will aid in the advancement of general knowledge about the molecular formation and retrieval of cocaine-associated memories that can be used in the future when designing treatments for cocaine addiction that target both prevention and relapse

Dorsal-CA1 hippocampal neuronal ensembles encode nicotine-reward contextual associations

Natural and drug rewards increase the motivational valence of stimuli in the environment that, through Pavlovian learning mechanisms, become conditioned stimuli that directly motivate behavior in the absence of the original unconditioned stimulus. While the hippocampus has received extensive attention for its role in learning and memory processes, less is known regarding its role in drug-reward associations. We used in vivo Ca2+ imaging in freely moving mice during the formation of nicotine preference behavior to examine the role of the dorsal-CA1 region of the hippocampus in encoding contextual reward-seeking behavior. We show the development of specific neuronal ensembles whose activity encodes nicotine-reward contextual memories and that are necessary for the expression of place preference. Our findings increase our understanding of CA1 hippocampal function in general and as it relates to reward processing by identifying a critical role for CA1 neuronal ensembles in nicotine place preference

Stress-induced reinstatement of nicotine preference requires dynorphin/kappa opioid activity in the basolateral amygdala

UNLABELLED: The dynorphin (DYN)/kappa-opioid receptor (KOR) system plays a conserved role in stress-induced reinstatement of drug seeking for prototypical substances of abuse. Due to nicotine\u27s high propensity for stress-induced relapse, we hypothesized that stress would induce reinstatement of nicotine seeking-like behavior in a KOR-dependent manner. Using a conditioned place preference (CPP) reinstatement procedure in mice, we show that both foot-shock stress and the pharmacological stressor yohimbine (2 mg/kg, i.p.) induce reinstatement of nicotine CPP in a norbinaltorphimine (norBNI, a KOR antagonist)-sensitive manner, indicating that KOR activity is necessary for stress-induced nicotine CPP reinstatement. After reinstatement testing, we visualized robust c-fos expression in the basolateral amygdala (BLA), which was reduced in mice pretreated with norBNI. We then used several distinct but complementary approaches of locally disrupting BLA KOR activity to assess the role of KORs and KOR-coupled intracellular signaling cascades on reinstatement of nicotine CPP. norBNI injected locally into the BLA prevented yohimbine-induced nicotine CPP reinstatement without affecting CPP acquisition. Similarly, selective deletion of BLA KORs in KOR conditional knock-out mice prevented foot-shock-induced CPP reinstatement. Together, these findings strongly implicate BLA KORs in stress-induced nicotine seeking-like behavior. In addition, we found that chemogenetic activation of Gαi signaling within CaMKIIα BLA neurons was sufficient to induce nicotine CPP reinstatement, identifying an anatomically specific intracellular mechanism by which stress leads to reinstatement. Considered together, our findings suggest that activation of the DYN/KOR system and Gαi signaling within the BLA is both necessary and sufficient to produce reinstatement of nicotine preference. SIGNIFICANCE STATEMENT: Considering the major impact of nicotine use on human health, understanding the mechanisms by which stress triggers reinstatement of drug-seeking behaviors is particularly pertinent to nicotine. The dynorphin (DYN)/kappa-opioid receptor (KOR) system has been implicated in stress-induced reinstatement of drug seeking for other commonly abused drugs. However, the specific role, brain region, and mechanisms that this system plays in reinstatement of nicotine seeking has not been characterized. Here, we report region-specific engagement of the DYN/KOR system and subsequent activation of inhibitory (Gi-linked) intracellular signaling pathways within the basolateral amygdala during stress-induced reinstatement of nicotine preference. We show that the DYN/KOR system is necessary to produce this behavioral state. This work may provide novel insight for the development of therapeutic approaches to prevent stress-related nicotine relapse

A Semiconductor Nanowire-Based Superconducting Qubit

We introduce a hybrid qubit based on a semiconductor nanowire with an epitaxially grown superconductor layer. Josephson energy of the transmon-like device ("gatemon") is controlled by an electrostatic gate that depletes carriers in a semiconducting weak link region. Strong coupling to an on-chip microwave cavity and coherent qubit control via gate voltage pulses is demonstrated, yielding reasonably long relaxation times (0.8 {\mu}s) and dephasing times (1 {\mu}s), exceeding gate operation times by two orders of magnitude, in these first-generation devices. Because qubit control relies on voltages rather than fluxes, dissipation in resistive control lines is reduced, screening reduces crosstalk, and the absence of flux control allows operation in a magnetic field, relevant for topological quantum information

Parity lifetime of bound states in a proximitized semiconductor nanowire

Quasiparticle excitations can compromise the performance of superconducting devices, causing high frequency dissipation, decoherence in Josephson qubits, and braiding errors in proposed Majorana-based topological quantum computers. Quasiparticle dynamics have been studied in detail in metallic superconductors but remain relatively unexplored in semiconductor-superconductor structures, which are now being intensely pursued in the context of topological superconductivity. To this end, we introduce a new physical system comprised of a gate-confined semiconductor nanowire with an epitaxially grown superconductor layer, yielding an isolated, proximitized nanowire segment. We identify Andreev-like bound states in the semiconductor via bias spectroscopy, determine the characteristic temperatures and magnetic fields for quasiparticle excitations, and extract a parity lifetime (poisoning time) of the bound state in the semiconductor exceeding 10 ms.Comment: text and supplementary information combine

A large community outbreak of waterborne giardiasis- delayed detection in a non-endemic urban area

BACKGROUND: Giardia is not endemic in Norway, and more than 90% of reported cases acquire the infection abroad. In late October 2004, an increase in laboratory confirmed cases of giardiasis was reported in the city of Bergen. An investigation was started to determine the source and extent of the outbreak in order to implement control measures. METHODS: Cases were identified through the laboratory conducting giardia diagnostics in the area. All laboratory-confirmed cases were mapped based on address of residence, and attack rates and relative risks were calculated for each water supply zone. A case control study was conducted among people living in the central area of Bergen using age- and sex matched controls randomly selected from the population register. RESULTS: The outbreak investigation showed that the outbreak started in late August and peaked in early October. A total of 1300 laboratory-confirmed cases were reported. Data from the Norwegian Prescription Database gave an estimate of 2500 cases treated for giardiasis probably linked to the outbreak. There was a predominance of women aged 20–29 years, with few children or elderly. The risk of infection for persons receiving water from the water supply serving Bergen city centre was significantly higher than for those receiving water from other supplies. Leaking sewage pipes combined with insufficient water treatment was the likely cause of the outbreak. CONCLUSION: Late detection contributed to the large public health impact of this outbreak. Passive surveillance of laboratory-confirmed cases is not sufficient for timely detection of outbreaks with non-endemic infections

Structural properties of hard disks in a narrow tube

Positional ordering of a two-dimensional fluid of hard disks is examined in such narrow tubes where only the nearest-neighbor interactions take place. Using the exact transfer-matrix method the transverse and longitudinal pressure components and the correlation function are determined numerically. Fluid-solid phase transition does not occur even in the widest tube, where the method just loses its exactness, but the appearance of the dramatic change in the equation of state and the longitudinal correlation function shows that the system undergoes a structural change from a fluid to a solid-like order. The pressure components show that the collisions are dominantly longitudinal at low densities, while they are transverse in the vicinity of close packing density. The transverse correlation function shows that the size of solid-like domains grows exponentially with increasing pressure and the correlation length diverges at close packing. It is managed to find an analytically solvable model by expanding the contact distance up to first order. The approximate model, which corresponds to the system of hard parallel rhombuses, behaves very similarly to the system of hard disks.Comment: Acceped in Journal of Statistical Mechanics: Theory and Experimen

Anisotropic Pair Correlations and Structure Factors of Confined Hard-Sphere Fluids: An Experimental and Theoretical Study

We address the fundamental question: how are pair correlations and structure factors of hard-sphere fluids affected by confinement between hard planar walls at close distance? For this purpose, we combine x-ray scattering from colloid-filled nanofluidic channel arrays and first-principles inhomogeneous liquid-state theory within the anisotropic Percus-Yevick approximation. The experimental and theoretical data are in remarkable agreement at the pair-correlation level, providing the first quantitative experimental verification of the theoretically predicted confinement-induced anisotropy of the pair-correlation functions for the fluid. The description of confined fluids at this level provides, in the general case, important insights into the mechanisms of particle-particle interactions in dense fluids under confinement

Decreased neuroinflammation correlates to higher vagus nerve activity fluctuations in near-term ovine fetuses: a case for the afferent cholinergic anti-inflammatory pathway?

Motor Nucleus of Vagus---Location. Methods supplementary material: Neuroanatomical approach to locating vagal motor nucleus in fetal sheep brain (PDF 1716 kb

Sequential Monte Carlo multiple testing

Motivation: In molecular biology, as in many other scientific fields, the scale of analyses is ever increasing. Often, complex Monte Carlo simulation is required, sometimes within a large-scale multiple testing setting. The resulting computational costs may be prohibitively high