Sub-region specific contribution of the ventral hippocampus to drug context-induced reinstatement of cocaine-seeking behavior in rats

The ventral hippocampus (VH) plays critical roles in cue-induced and cocaine-primed reinstatement of cocaine seeking (Rogers and See, 2007). Subregions of the VH make distinct projections to elements of the brain relapse circuitry that mediate drug context-induced reinstatement. Thus, the VH may also critically contribute to this form of cocaine seeking in a subregion-specific manner. Accordingly, this study evaluated the hypothesis that functional inactivation of the ventral hippocampus proper (VHp) – but not of the dentate gyrus (DG) – impairs cocaine seeking elicited by re-exposure to a drug-paired environmental context. Rats were trained to lever press for un-signaled intravenous cocaine infusions (0.15 mg/infusion) in a distinct environmental context (cocaine-paired context) followed by extinction training in a distinctly different context (extinction context). Subsequently, cocaine-seeking behavior (i.e., non-reinforced active lever responding) was assessed in either the previously cocaine-paired context or the extinction context. Rats received bilateral microinfusions of the gamma-aminobutyric acid (GABA) agonist cocktail, baclofen+muscimol (BM: 1.0/.01mM), or vehicle into the VHp, DG, or the posterior dorsal hippocampus (pDH; extra-VH control) immediately before each test session. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished cocaine-seeking behavior following vehicle pretreatment. BM pretreatment administered into the VHp, but not the DG or pDH, significantly attenuated drug context-induced cocaine seeking. These results indicate that the VH contributes to drug context-induced cocaine seeking in a subregion-specific manner, with the functional integrity of the VHp being necessary for memory or motivational aspects of drug-paired environmental stimuli that sustain stimulus control over goal-directed behavior

Resistivity due to low-symmetrical defects in metals

The impurity resistivity, also known as the residual resistivity, is calculated ab initio using multiple-scattering theory. The mean-free path is calculated by solving the Boltzmann equation iteratively. The resistivity due to low-symmetrical defects, such as an impurity-vacancy pair, is calculated for the FCC host metals Al and Ag and the BCC transition metal V. Commonly, 1/f noise is attributed to the motion of such defects in a diffusion process.Comment: 24 pages in REVTEX-preprint format, 10 Postscript figures. Phys. Rev. B, vol. 57 (1998), accepted for publicatio

Theory for the electromigration wind force in dilute alloys

A multiple scattering formulation for the electromigration wind force on atoms in dilute alloys is developed. The theory describes electromigration via a vacancy mechanism. The method is used to calculate the wind valence for electromigration in various host metals having a close-packed lattice structure, namely aluminum, the noble metals copper, silver and gold and the $4d$ transition metals. The self-electromigration results for aluminum and the noble metals compare well with experimental data. For the $4d$ metals small wind valences are found, which make these metals attractive candidates for the experimental study of the direct valence.Comment: 18 pages LaTeX, epsfig, 8 figures. to appear in Phys. Rev. B 56 of 15/11/199

A Dual-loop Model Predictive Voltage Control/Sliding-mode Current Control for Voltage Source Inverter Operation in Smart Microgrids

The design of a robust controller for the voltage source inverter is essential for reliable operation of distributed energy resources in future smart microgrids. The design problem is challenging in the case of autonomous operation subsequent to an islanding situation. In this article, a dual-loop controller is proposed for voltage source inverter control. The outer loop is designed for microgrid voltage and frequency regulation based on the model predictive control strategy. This outer loop generates reference inverter currents for the inner loop. The inner loop is designed using a sliding-mode control strategy, and it generates the pulse-width modulation voltage commands to regulate the inverter currents. A standard space vector algorithm is used to realize the pulse-width modulation voltage commands. Performance evaluation of the proposed controller is carried out for different loading scenarios. It is shown that the proposed dual-loop controller provides the specified performance characteristics of an islanded microgrid with different loading conditions.http://www.tandfonline.com/loi/uemp20hb201

Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats

Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of cocaine-seeking behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced cocaine-seeking behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced cocaine-seeking behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of cocaine-seeking behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior

Dorsal hippocampal regulation of memory reconsolidation processes that facilitate drug context-induced cocaine-seeking behavior in rats

Exposure to a cocaine-paired context increases the propensity for relapse in cocaine users and prompts cocaine-seeking behavior in rats. According to the reconsolidation hypothesis, upon context re-exposure, established cocaine-related associations are retrieved and can become labile. These associations must undergo reconsolidation into long-term memory to effect enduring stimulus control. The dorsal hippocampus (DH), dorsolateral caudate-putamen, and dorsomedial prefrontal cortex are critical for the expression of context-induced cocaine seeking, and these brain regions may also play a role in the reconsolidation of cocaine-related memories that promote this behavior. To test this hypothesis, rats were trained to press a lever for un-signaled cocaine infusions (0.2 mg/infusion, IV) in a distinct environmental context (cocaine-paired context), followed by extinction training in a different context (extinction context). Rats were then re-exposed to the cocaine-paired context for 15 min in order to reactivate cocaine-related memories or received comparable exposure to a novel unpaired context. Immediately thereafter, rats received bilateral microinfusions of the protein synthesis inhibitor anisomycin, the sodium channel blocker tetrodotoxin, or vehicle into one of the above brain regions. After additional extinction training in the extinction context, reinstatement of cocaine-seeking behavior (i.e., non-reinforced lever presses) was assessed in the cocaine-paired context. Tetrodotoxin, but not anisomycin, administered into the DH inhibited drug context-induced cocaine-seeking behavior in a memory reactivation-dependent manner. Other manipulations failed to alter this behavior. These findings suggest that the DH facilitates the reconsolidation of associative memories that maintain context-induced cocaine-seeking behavior, but it is not the site of anisomycin-sensitive memory re-stabilization per se

Unintended consequences of patient online access to health records: a qualitative study in UK primary care

Background: Health systems around the world are seeking to harness digital tools to promote patient autonomy and increase the efficiency of care. One example of this policy in England is online patient access to full medical records in primary care. Since April 2019, all NHS England patients have had the right to access their full medical record prospectively, and full record access has been the “default position” since April 2020. / Aim: To identify and understand the unintended consequences of online patient access their medical record. / Design and Setting: Qualitative interview study in 10 general practices in South West and North West England. / Method: Semi-structured individual interviews with 13 patients and 16 general practice staff with experience of patient online access to health records. / Results: Online access generated unintended consequences that negatively impacted patients’ understanding of their health care, for example patients discovering surprising information or information that was difficult to interpret. Online access impacted GPs’ documentation practices, such as when GPs pre-emptively attempted to minimise potential misunderstandings to aid patient understanding of their health care, in other cases, negatively impacting the quality of the records and patient safety when GPs avoided documenting their speculations or concerns. Contrary to assumptions that practice workload would be reduced, online access introduced extra work, such as managing and monitoring access and taking measures to prevent possible harm to patients. / Conclusion: The unintended consequences described by both staff and patients show that to achieve the intended consequences set out in NHS policy additional work is necessary to prepare records for sharing and prepare patients about what to expect. It is crucial that practices are adequately supported and resourced to manage the unintended consequences of online access now that it is the default position

Enhancing discovery of genetic variants for posttraumatic stress disorder through integration of quantitative phenotypes and trauma exposure information

Background Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

BACKGROUND: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. PRESENTATION OF THE HYPOTHESIS: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. TESTING THE HYPOTHESIS: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments