Adult hippocampal neurogenesis impairment at preplaque stage in a transgenic rat model of Alzheimer like amyloid pathology

The contribution of adult hippocampal neurogenesis (AHN) impairment on cognitive decline in early Alzheimer disease (AD) remains poorly understood. This can be ascribed to the technical difficulties to measure AHN in postmortem brains and patients. Furthermore, most animal models of AD exhibit an aggressive neuropathology at early age and harbor gene mutations and express transgenes that disrupts AHN by pathways not directly involved in AD pathology. To overcome some of these limitations, we studied AHN at preplaque stage (6 month old) in hemizygous (Tg+/-) and homozygous (Tg+/+) McGill-R-Thy1-APP transgenic rats. This model exhibits a much less aggressive neuropathology that nevertheless is associated with a marked cognitive impairment from early age. Our results revealed that Tg+/+ rats showed a reduced number of PCNA+ cells, DCX+ immature neurons and BrdU+/NeuN+ colabed neurons in dorsal and ventral dentate gyrus. Moreover, dendritic arborization was less developed. AHN was not impaired in Tg+/- rats, although dendritic arborization was slightly decreased. On the other hand, both hemizygous and homozygous rats exhibited spatial memory impairments in the Morris water maze. These results suggest that 1) AHN is dysregulated from the preplaque stage in homozygous rats, 2) AHN impairment is dependent on APP transgene copy numbers since hemizygous rats did not show it, 3) Dysregulation of AHN is not directly associated with spatial memory impairments since hemizygous rats exhibited spared neurogenesis despite showing spatial memory deficits. Funding: International Society for Neurochemistry CAEN Grant and Andalucia TECH-ICE (PG), and PICT-2015-0285 (LM).Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Dalmasso, María Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Prestia, Federico Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Cuello, Augusto Claudio. McGill University; CanadáFil: Santín Nuñez, Luis Javier. Universidad de Málaga; EspañaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaThe International Society for Neurochemistry and the American Society for Neurochemistry MeetingMontrealCanadáInternational Society for NeurochemistryAmerican Society for Neurochemistr

Pharmacogenetic inhibition of the infralimbic cortex promotes reinstatement of cocaine-context memories in mice.

Funding: PID2020-113806RB-I00, 08-2021-AREA3, B1-2020_06, FPU20/00908, PRE2018-085673, PREDOC_01094, POSTDOC_ 21_00222. II Plan Propio de Investigación, Transferencia y Divulgación Científica de la UMA.Relapse is one of the main problems concerning treatment of cocaine use disorder. It have been suggested that the infralimbic cortex (IL), a division of the medial prefrontal cortex, is involved in extinction and reinstatement of associative memories, including those involving drugs. However, more selective strategies are needed to elucidate the involvement of IL in the long-term maintenance of drug-related maladaptive behaviours. Here, we employed pharmacogenetics to assess the causal role of IL in the reinstatement of a cocaine-induced conditioned place preference (CPP). For this purpose, adult C57BL/6J mice received bilateral intra-IL microinjections of an adeno-associated viral (AAV) vector containing the hM4Di designed receptor (AAV5-CaMKII-hM4Di-mCherry; AAV-hM4Di, n=11) or a control vector (AAV5-CaMKII-mCherry; AAV-control, n=9) prior receiving training in the cocaine-induced CPP model. After habituation, animals received compartment-paired conditioning by increasing doses of cocaine (2-16 mg/kg/day, i.p.) and were tested for cocaine-CPP, after which they were subjected to forced CPP extinction and then re-tested for cocaine-CPP. On day 37 after AAV infusion, mice received Clozapine N-oxide (CNO, 5 mg/kg, i.p.) and 30 min later were tested for cocaine-primed (7.5 mg/kg, i.p.) CPP reinstatement. Ninety minutes after, animals were perfused, and brains dissected. Our results indicated that both groups acquired and subsequently extinguished cocaine-CPP. However, only the AAV-hM4Di group showed a significant preference for the cocaine-paired compartment during the CPP reinstatement test. Immunofluorescence analyses of c-Fos expression in IL revealed a decrease of ~60% in mCherry+/c-Fos+ co-labelling in the AAV-hM4Di group, suggesting reduced IL neural activity during CPP reinstatement. Therefore, our data suggests that the IL plays a causal role in relapse to cocaine-related maladaptive behaviours, highlighting its importance as a potential therapeutic target.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Hyperactivity induced by the dopamine D2/D3 receptor agonist quinpirole is attenuated by inhibitors of endocannabinoid degradation in mice

The present study was designed to investigate the effect of pharmacological inhibition of endocannabinoid degradation on behavioural actions of the dopamine D2/D3 receptor agonist quinpirole in male C57Bl/6J mice. In addition, we studied the effects of endocannabinoid degradation inhibition on both cocaine-induced psychomotor activation and behavioural sensitization. We analysed the effects of inhibition of the two main endocannabinoid degradation enzymes: fatty acid amide hydrolase (FAAH), using inhibitor URB597 (1 mg/kg); monoacylglycerol lipase (MAGL), using inhibitor URB602 (10 mg/kg). Administration of quinpirole (1 mg/kg) caused a temporal biphasic response characterized by a first phase of immobility (0–50 min), followed by enhanced locomotion (next 70 min) that was associated with the introduction of stereotyped behaviours (stereotyped jumping and rearing). Pretreatment with both endocannabinoid degradation inhibitors did not affect the hypoactivity actions of quinpirole. However, this pretreatment resulted in a marked decrease in quinpirole-induced locomotion and stereotyped behaviours. Administration of FAAH or MAGL inhibitors did not attenuate the acute effects of cocaine. Furthermore, these inhibitors did not impair the acquisition of cocaine-induced behavioural sensitization or the expression of cocaine-induced conditioned locomotion. Only MAGL inhibition attenuated the expression of an already acquired cocaine-induced behavioural sensitization. These results suggest that pharmacological inhibition of endocannabinoid degradation might exert a negative feedback on D2/D3 receptor-mediated hyperactivity. This finding might be relevant for therapeutic approaches for either psychomotor disorders (dyskinesia, corea) or disorganized behaviours associated with dopamine-mediated hyperactivity.Fil: Luque Rojas, María Jesús. Fundación IMABIS; EspañaFil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); ArgentinaFil: Suarez, Juan . Fundación IMABIS; EspañaFil: Araos, Pedro. Fundación IMABIS; EspañaFil: Santín Nuñez, Luis Javier. Universidad de Malaga; EspañaFil: Rodríguez de Fonseca, Fernando. Fundación IMABIS; EspañaFil: Blanco Calvo, Eduardo. Fundación IMABIS; España. Universidad de Malaga; Españ

Environmental enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice

Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic-like behaviour and alleviated cognitive impairment in spatial memory in the cocaine-abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine-treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction.This study was funded by the following grants: PSI2015-73,156-JIN to E.C-O. and PSI2017-82604R to L.J.S. (MINECO-AEI cofounded by FEDER), PID2020-114374RB-I00 (funded by MCIN/AEI/10.13039/501100011033) to E.C-O., PID2020-113806RB-I00 to L.J.S. (MICINN) and University of Malaga (B4: ‘Ayudas para Proyectos Puente’ to E. C–O). Authors M. C. M-P., P. T. and S. G-R. hold predoctoral grants from the Spanish Ministry of Science, Innovation and Universities (FPU17/00276 to M. C. M-P.; FPU18/00069 to P. T and FPU18/00941 to S. G-R.). The authors acknowledge the IBIMA's common research support structure of animal experimentation and behaviour (“Centro de Experimentación y Conducta Animal”; University of Malaga) and their staff for their valuable assistance during the behavioural experiments and maintenance of the mice and to Belén García and Carmen Hernández for their help with the confocal microscopy at the Cajal Institute // Funding for open access charge: Universidad de Málaga/CBUA

The infralimbic cortex and the hippocampal CA1-Subiculum are functionally involved in the extinction of cocaine-context associationes in mice.

Funding: PID2020-113806RB-I00, 08-2021-AREA3, B1-2020_06, PREDOC_01094, PRE2018-085673, FPU20/00908, POSTDOC_ 21_00222. II Plan Propio de Investigación, Transferencia y Divulgación Científica de la Universidad de Málaga.Cocaine abuse is a health and social problem worldwide. Treatment seeking for cocaine use disorder is on the rise, and relapse prevention remains as a primary goal. Interventions based on extinction of cocaine-related associative memories are promising but so far have not been successful. In this sense, further research is needed to elucidate the neurobiological substrates of extinction learning. Here, we aimed to study the neural circuitry involved in extinction of cocaine-context associations in the Conditioned Place Preference (CPP) model. Adult C57BL/6J mice received habituation to the CPP apparatus followed by conditioning with increasing doses of cocaine (2, 4, 8 and 16 mg/kg/day). After testing for CPP acquisition, a group of mice was submitted to four sessions of forced extinction (CPP+EXT, n = 9) while another group was maintained at home-cage (CPP+ACQ, n = 6). Then, both conditions were retested for cocaine-CPP. Ninety minutes later, animals were perfused, and brains collected. Next, we analysed by immunohistochemistry the expression of c-Fos in a variety of addiction-related structures including the medial prefrontal cortex (prelimbic, infralimbic), the striatum (nucleus accumbens, caudate-putamen), the basolateral amygdala and the hippocampus. Our results indicated that both groups acquired cocaine-CPP, but only the CPP+EXT condition ceased to show preference for the cocaine-paired compartment during the CPP retest. Importantly, the CPP+EXT mice showed increased c-Fos expression in the infralimbic cortex (IL), and the hippocampal CA1-subiculum during the CPP retest, with no changes in the other brain areas examined. Multivariate analyses revealed a relationship between IL and CA1-subiculum activity and CPP extinction. This suggest that such structures are functionally involved in retrieval of extinction memory for cocaine-context associations, thus standing out as potential therapeutic targets.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Palmitoylethanolamide attenuates cocaine-induced behavioral sensitization and conditioned place preference in mice

Cocaine addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and drug-taking behaviors. Previous studies have demonstrated that cocaine, as well as other drugs of abuse, alters the levels of lipid-based signaling molecules, such as N-acylethanolamines (NAEs). Moreover, brain levels of NAEs have shown sensitivity to cocaine self-administration and extinction training in rodents. Given this background, the aim of this study was to investigate the effects of repeated or acute administration of palmitoylethanolamide (PEA), an endogenous NAE, on psychomotor sensitization and cocaine-induced contextual conditioning. To this end, the potential ability of repeated PEA administration (1 or 10 mg/kg, i.p.) to modulate the acquisition of cocaine-induced behavioral sensitization (BS) and conditioned place preference (CPP) was assessed in male C57BL/6J mice. In addition, the expression of cocaine-induced BS and CPP following acute PEA administration were also studied. Results showed that repeated administration of both doses of PEA were able to block the acquisition of cocaine-induced BS. Furthermore, acute administration of both doses of PEA was able to abolish the expression of BS, while the highest dose also abolished the expression of cocaine-induced CPP. Taken together, these results indicate that exogenous administration of PEA attenuated psychomotor sensitization, while the effect of PEA in cocaine-induced CPP depended on whether PEA was administered repeatedly or acutely. These findings could be relevant to understand the role that NAEs play in processes underlying the development and maintenance of cocaine addiction.Fil: Zambrana Infantes, Emma. Universidad de Málaga; EspañaFil: Rosell del Valle, Cristina. Universidad de Málaga; EspañaFil: Ladrón de Guevara Miranda, David. Universidad de Málaga; EspañaFil: Galeano, Pablo. Universidad de Málaga; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Castilla Ortega, Estela. Hospital Regional Universitario de Málaga; EspañaFil: Rodríguez De Fonseca, Fernando. Hospital Regional Universitario de Málaga; EspañaFil: Blanco, Eduardo. Universidad de Lleida; EspañaFil: Santín, Luis Javier. Universidad de Málaga; Españ

Sequential treadmill exercise and cognitive training synergistically increase adult hippocampal neurogenesis in mice

Combining physical and cognitive training has been suggested to promote further benefits on brain and cognition, which could include synergistic improvement of hippocampal neuroplasticity. In this paper, we investigated whether treadmill exercise followed by a working memory training in the water maze increase adult hippocampal neurogenesis to a greater extent than either treatment alone. Our results revealed that ten days of scheduled running enhance cell proliferation/survival in the short-term as well as performance in the water maze. Moreover, exercised mice that received working memory training displayed more surviving dentate granule cells compared to those untreated or subjected to only one of the treatments. According to these findings, we suggest that combining physical and cognitive stimulation yield synergic effects on adult hippocampal neurogenesis by extending the pool of newly-born cells and subsequently favouring their survival. Future research could take advantage from this non-invasive, multimodal approach to achieve substantial and longer-lasting enhancement in adult hippocampal neurogenesis, which might be relevant for improving cognition in healthy or neurologically impaired conditions.This study received financial support from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación, AEI), which was cofounded by the European Regional Development Fund (AEI/FEDER, UE; PSI2017-82604R to L.J.S.); by the Spanish Ministry of Science and Innovation (PID2020-113806RB-I00 to L.J.S); by the Biomedical Research Institute of Málaga (IBIMA; 08-2021-AREA3 to D.L.G.M) and by the University of Málaga (B1-2020_06 to D.L.G-M). Funding for Open Access charge: Universidad de Málaga/CBU

The combination of Galanin (1-15) and Escitalopram decrease the alcohol selfadministration in rats through the functional network ventral tegmental area – dorsal raphe.

Alcohol Use Disorder AUD is a highly prevalent, and most AUD patients suffer comorbidity with depression. To investigate the effect of GAL(1-15) on ESCmediated effect in depression-alcoholism comorbidity, we used the alcohol self-administration test. In addition, to study the circuits involved, we analyzed the immuno of C-Fos in several nuclei implicated in reward-seeking behaviour and we assessed the brain circuits using principal component analysis (PCA) to understand brain functional organization. Male Sprague-Dawley rats received three intraperitoneal injections of ESC(2.5mg/Kg) 23, 5 and 1h and icv injection of GAL(1-15)(0.3nmol) 15' before the alcohol self-administration test. The brain was removed 90' after the icv injection toanalyzed C-Fos in several nuclei involved in depression and AUD: dorsal raphe (DR), rostromedial tegmental nucleus (RMTg), lateral habenula (LHb), medial habenula (mHb), ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (CPF). ANOVA followed by Fisher´s least significant di"erence test was used. In the alcohol self-administration test, the combination of GAL(1-15)(0,3nmol) and ESC(2,5mg/Kg) decreased the number of alcohol reinforcements and the number of active lever. GAL(1-15)+ESC coadministration significantly decreased C-Fos expression in the VTA compared with control group but no significative effects were observed in the rest of the nuclei. However, PCA analysis revealed three independent factor representing the functional brain modules. The main factor was DR, VTA and RMTg. The results indicate a functional network involved in GAL(1-15)+ESC alcohol self-administration effects. It opens up the possibility to use GAL(1-15)+ESC as a novel strategy in AUD comorbidity with depression.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat