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memories coexist with hippocampal-dependent cognitive decline and altered adult hippocampal neurogenesis in mice withdrawn from cocaine.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 In addition, the cocaine-withdrawn mice overall displayed normal emotional behavior but they showed hippocampal-dependent cognitive impairment for novelty recognition (object and place) and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 However, the cocaine-withdrawn mice excessively increased the number immature hippocampal neurons (doublecortin+) after behavioral training, in direct correlation with their cognitive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 Since the doublecortin+ neurons correlated with better cognitive performance in the cocaine-withdrawn mice, strategies that increase AHN could alleviate neurocognitive deficits induced by cocaine.Plan Propio Universidad de Málaga Universidad de Málaga.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

Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis.

Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, Trained mice reduced the number of proliferating hippocampal cells but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is an useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación) co-funded by the European Research Development Fund -AEI/FEDER, UE- (PSI2015-73156-JIN ‘Jóvenes Investigadores grant’ to E.C.O. and PSI2013-44901-P to L.J.S. and C.P.), from ‘Junta de Andalucía’ SEJ1863 to C.P. and from University of Málaga (Plan Propio 2017 – ‘Ayudas para proyectos puente’) to M.G.F. Author P.S.P. holds a ‘Juan de la Cierva-formación‘grant from the Spanish Ministry of Economy, Industry and Competitiveness (code: FJCI-2015-23925) and a ‘D.3. Estancia de investigadores de reconocido prestigio en la UMA‘ grant from the University of Málaga. Authors R.D.M.F. and D.L.G.M. hold ‘FPU’ grants from the Spanish Ministry of Education, Culture and Sports (code: FPU14-01610 and FPU13/04819, respectively). Author F.J.P. holds a ‘Miguel Servet’ grant (code: CP14/00212) from the National System of Health-Instituto de Salud Carlos-III co-funded by FEDER, UE

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