Enhancing adult hippocampal neurogenesis with lysophosphatidic acid: a proposal for erasing cocaine contextual memory

Stimulating adult hippocampal neurogenesis (AHN) has been uncovered as a promising approach in the manipulation of retrograde memories. This work aims to study whether increasing AHN with lysophosphatidic acid (LPA, an endogenous lysophospholipid with proneurogenic actions) promotes the forgetting of previously established cocaine-contextual associations. C57BL/6J mice previously trained in a cocaine-induced conditioned place preference (CPP) paradigm were submitted to 23 days of withdrawal, during which they received repeated intracerebroventricular infusions of LPA, ki16425 (a selective LPA1/3 receptors antagonist), or vehicle solution. Then, CPP maintenance was assessed, and the causal role of AHN in this process was evaluated using a mediation analysis. In a complementary experiment, wild-type and LPA1-null mice were acutely infused with LPA or ki16425 to determine the involvement of the LPA1 receptor in the in vivo proneurogenic actions of LPA. The chronic LPA treatment significantly weakened the long-term retention of a previously acquired cocaine-CPP memory, an effect clearly mediated by a LPA-induced increase in the number of adult-born dentate granule cells. In contrast, the ki16425-treated mice displayed aberrant responses of initially decreased CPP retention that progressively increased CPP across the extinction sessions, in absence of effects on AHN. The histological studies suggested that the proneurogenic actions of LPA were related to the enhancement of cell proliferation and critically depended on the LPA1 receptor function. Our results suggest that the LPA/LPA1-pathway acts as a potent in vivo modulator of AHN, and highlight the usefulness of a post-learning increase of adult-born hippocampal neurons as a strategy to promote the forgetting of cocaine-context associations.Plan Propio de Investigación y Transferencia. Campus de Excelencia Internacional Andalucía Tech. Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), co‐funded by the European Research Development Fund (AEI/FEDER, UE) (PSI2013‐44901‐P and PSI2017‐82604‐R to L.J.S. and PSI2015‐73156‐JIN to E.C.O.); by the National System of Health‐Instituto de Salud Carlos III, which is co‐funded by AEI/FEDER, UE (Red de Trastornos Adictivos; RD16/0017/0001 to F.R.d.F.); and by the Andalusian R&D&I Programme, Regional Ministry of Economy and Knowledge (PAIDI CTS643 to G.E.T.). D.L.G.M. hold a FPU grant from the Spanish Ministry of Education, Culture and Sports (FPU13/04819 ). F.R.d.F. and G.E.T. are supported by Nicolas Monardes Programme, from the Andalusian Regional Ministry of Health. E.C.O. holds a ‘Jóvenes Investigadores’ grant (code: PSI2015‐73156‐JIN) from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), which is co‐funded by the AEI/FEDER, UE

Persistent drug-associated memories coexist with hippocampal-dependent cognitive decline and altered adult hippocampal neurogenesis in mice withdrawn from cocaine.

Aims: Using a new animal model (‘chronic’ cocaine-induced conditioned place preference –CPP- paradigm), this work studied whether the long-term maintenance of cocaine-associated memories was concomitant to cognitive impairment and adult hippocampal neurogenesis (AHN) alterations. Methods: Male c57BL/6J mice were submitted to a CPP task treated either with cocaine (20 mg/kg/day) or saline for 14 days (n=10 per group). Bromodeoxyuridine (BrdU) was administered to label the new hippocampal neurons generated one week after the last cocaine dose. After 28 drug-free days, mice were assessed for the CPP memory and on a battery of emotional and cognitive behavioral tests. After completion of behavior, brains were collected for AHN analysis. Results: In mice treated with cocaine, preference for the cocaine-paired compartment (CPP memory) persisted over time. In addition, the cocaine-withdrawn mice overall displayed normal emotional behavior but they showed hippocampal-dependent cognitive impairment for novelty recognition (object and place) and spatial (reference and working) memory. The number of BrdU+ cells was unaffected, suggesting that cocaine withdrawal did not impair basal AHN. However, the cocaine-withdrawn mice excessively increased the number immature hippocampal neurons (doublecortin+) after behavioral training, in direct correlation with their cognitive performance, probably as a result of effortful learning. Conclusions: The CPP memory induced by cocaine remains unaltered after a prolonged period of abstinence, accompanied by defective acquisition of new learnings. Since the doublecortin+ neurons correlated with better cognitive performance in the cocaine-withdrawn mice, strategies that increase AHN could alleviate neurocognitive deficits induced by cocaine.Plan Propio Universidad de Málaga Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Catalunya després de la batalla d'Almansa: els desastres de la guerra contra la població civil (1707-1711)

--This article describes the military operations for the occupation of Catalonia by the Bour bon armies between 1707 and 1711, that is, between the battle of Almansa and the last Allied offensive over Madrid. Evidence from the main Spanish archives (AGS, AHN, BN) shows that, besides seasonal fighting between both contende, the Bourbon military staff carried out a deliberate policy of violence against civil population, aiming at the demoralization and defeatism among the inhabitants of rural areas, as a means to accelerate the surrender of Catalonia.Este trabajo describe las operaciones de ocupación de Cataluña por parte de los ejércitos borbónicos entre 1707 y 1711, es decir, entre la batalla de Almansa y la última ofensiva aliada sobre Madrid. La documentación procedente de los grandes archivos estatales (AGS, AHN, BN) pone al descubierto que al margen de los combates estacionales entre ambos contendientes, el estado mayor borbónico practicó una política de violencia deli berada contra la población civil, con la manifiesta intención de fomentar la desmoraliza ción y el derrotismo entre los habitantes de las zonas rurales, a fin de acelerar la rendición de Cataluña

Influence of neurogenic improvement strategies on extinction and reinstatement of cocaine-induced conditioned place preference

AIMS: Modulation of adult hippocampal neurogenesis (AHN) has been shown to influence the maintenance of drug-context associations. We aimed to study whether the enhancement of AHN by using a water maze spatial learning task (WM), solely or under conditions of neurogenesis stimulation (forced treadmill exercise), could facilitate extinction and prevent primed reinstatement of cocaine-context associations. METHODS: Adult male C57BL/6J mice (N=37) were trained in the Conditioned Place Preference (CPP) paradigm with ascending doses of cocaine (2, 4, 8, 16 mg/kg/d) and subsequently received bromodeoxyuridine (BrdU) injections to label newborn neurons. Then, experimental groups were submitted to 12 days of scheduled exercise and/or 8 days of spatial training in the WM. Sedentary and/or untrained groups stayed undisturbed in their home cages. When BrdU+ cells reached maturation (~6 weeks-old), all mice were tested for CPP memory retrieval. Finally, animals were submitted to forced CPP extinction and tested for CPP extinction and cocaine-primed reinstatement. RESULTS: Animals submitted either to the scheduled exercise protocol, training in the WM or both strategies combined, required fewer sessions to extinct cocaine-CPP associations than control animals. Furthermore, animals submitted to both environmental strategies showed a reduced reinstatement when compared to sedentary animals. These effects are partially related to the functional integration of the newborn neurons in the hippocampus. CONCLUSIONS: Both environmental strategies, alone and combined, can reduce the long-term persistence of cocaine-context associations, being AHN associated with these beneficial effects.PSI2017-82604; PRE2018-085673; 08-2021-AREA3; B1-2020_06;Posdoc_21_00222; Posdoctoral_a32. I Plan Propio de la Universidad de Málaga. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

A note on constrained degree reduction of polynomials in Bernstein–Bézier form over simplex domain

AbstractIn the paper [H.S. Kim, Y.J. Ahn, Constrained degree reduction of polynomials in Bernstein–Bézier form over simplex domain, J. Comput. Appl. Math. 216 (2008) 14–19], Kim and Ahn proved that the best constrained degree reduction of a polynomial over d-dimensional simplex domain in L2-norm equals the best approximation of weighted Euclidean norm of the Bernstein–Bézier coefficients of the given polynomial. In this paper, we presented a counterexample to show that the approximating polynomial of lower degree to a polynomial is virtually non-existent when d≥2. Furthermore, we provide an assumption to guarantee the existence of solution for the constrained degree reduction

Soil and water pollution in a banana production region in tropical Mexico

The effects of abundant Mancozeb (Mn, Zn— bisdithiocarbamate) applications (2.5 kg ha-1week-1 for 10 years) on soil and surface-, subsurface- and groundwater pollution were monitored in a banana production region of tropical Mexico. In soils, severe manganese accumulation was observed, wheras the main metabolite ethylenethiourea was near the detection limit. Surface and subsurface water was highly polluted with ethylenethiourea, the main metabolite of Mancozeb (22.5 and 4.3 lg L-1, respectively), but not with manganese. In deep ground water, no ethylenethiourea was detected. The level of pollution in the region presents a worrisome risk for aquatic life and for human health

Anonymity and Information Hiding in Multiagent Systems

We provide a framework for reasoning about information-hiding requirements in multiagent systems and for reasoning about anonymity in particular. Our framework employs the modal logic of knowledge within the context of the runs and systems framework, much in the spirit of our earlier work on secrecy [Halpern and O'Neill 2002]. We give several definitions of anonymity with respect to agents, actions, and observers in multiagent systems, and we relate our definitions of anonymity to other definitions of information hiding, such as secrecy. We also give probabilistic definitions of anonymity that are able to quantify an observer s uncertainty about the state of the system. Finally, we relate our definitions of anonymity to other formalizations of anonymity and information hiding, including definitions of anonymity in the process algebra CSP and definitions of information hiding using function views.Comment: Replacement. 36 pages. Full version of CSFW '03 paper, submitted to JCS. Made substantial changes to Section 6; added references throughou

Effects of sequential exposure to physical exercise and cognitive training on hippocampal neurogenesis in mice

AIMS: Physical exercise and cognitive training hippocampal dependent tasks are known to enhance adult hippocampal neurogenesis (AHN). Here we aimed to evaluate the effect of either a moderate-intensity exercise protocol, a working memory task and the combination of both treatments on mice AHN. METHODS: Adult male C57BL6/J mice (N=34) were submitted to a scheduled treadmill exercise protocol for 12 days (EX-groups) or remained at home cage (SED-groups). 24 hours later, animals either were perfused or trained in a spatial learning task in the Water Maze (WM groups) for 8 days while control groups remained at home cage (CAGE groups). Bromodeoxyuridine (BrdU) was injected at the beginning of every experimental procedure to label hippocampal cells that proliferated during the initial exercise sessions. RESULTS: Mice submitted to scheduled exercise showed an increased number of BrdU+ and PCNA+ dentate granule cells (DGCs) in the short but not in the long-term when compared to sedentary groups. Conversely, training in the WM solely reduced the amount of BrdU+ and PCNA+ DGCs compared to CAGE group. However, animals submitted to scheduled exercise and WM training showed increased proliferation/survival of DGCs in the long-term compared to all other groups. CONCLUSIONS: Our data suggests that the combination of moderate-intensity exercise with spatial training has a powerful neurogenic effect in the DG, being a valuable non-pharmacological strategy for the treatment of neurodegenerative diseases associated with impaired AHN. Funding: PSI2017-82604; PRE2018-085673; FPU20/00908; 08-2021-AREA3; B1-2020_06; Posdoc_21_00222; Posdoctoral_a32. I Plan Propio de Investigación, Transferencia y Divulgación Científica de la Universidad de Málaga.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech