Cognitive enhancing effects of voluntary exercise, caloric restriction and environmental enrichment: A role for adult hippocampal neurogenesis and pattern separation?

Several behavioural interventions, such as physical exercise, dietary restriction, and enriched environments are associated with both improved cognition and increased adult hippocampal neurogenesis. Whether the learning and memory improvements associated with these interventions are causally dependent on the upregulated neurogenesis has not yet been conclusively determined. However, with the accumulating evidence of a role for adult-born hippocampal neurons in spatial pattern separation, it is possible that the improvements in learning and memory result, at least in part, from an improvement in pattern separation. The following review focuses on three major behavioural manipulations associated with cognitive enhancement: voluntary exercise, caloric restriction, and environmental enrichment (including learning), and how increased neurogenesis may contribute to the enhancement by improving pattern separation.The authors would like to acknowledge financial contribution from the following funding sources: the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008, of which resources are composed of a European Federation of Pharmaceutical Industries and Associations in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013); The Wellcome Trust/Medical Research Council (089703/Z/09/Z) and the Biotechnology and Biological Sciences Research Council (grant BB/G019002/1). C.A.O. received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 603016. B.A.K. was supported by Gates Cambridge.This is the author accepted manuscript. The final version is available from Elsevier at http://www.sciencedirect.com/science/article/pii/S235215461500087X

Time-order-errors and duration ranges in the episodic Temporal generalization task

Fil: Mikulan, Ezequiel P. Laboratory of Experimental Psychology and Neuroscience (LPEN), Institute of Cognitive and Translational Neuroscience (INCYT), INECO Foundation, Favaloro University, Buenos Aires, Argentina. National Scientific and Technical Research Council (CONICET), Buenos Aires, ArgentinaFil: Bruzzone, Manuel. Laboratory of Experimental Psychology and Neuroscience (LPEN), Institute of Cognitive and Translational Neuroscience (INCYT), INECO Foundation, Favaloro University, Buenos Aires, ArgentinaFil: Laboratory of Experimental Psychology and Neuroscience (LPEN), Institute of Cognitive and Translational Neuroscience (INCYT), INECO Foundation, Favaloro University, Buenos Aires, ArgentinaFil: Sigman, Mariano. Universidad Torcuato Di Tella, Escuela de Negocios, Laboratorio de Neurociencia, Buenos Aires, ArgentinaFil: Bekinschtein, Tristan A. Consciousness and Cognition Lab, Department of Psychology, University of Cambridge, Cambridge, UKFil: García, Adolfo.Laboratory of Experimental Psychology and Neuroscience (LPEN), Institute of Cognitive and Translational Neuroscience (INCYT), INECO Foundation, Favaloro University, Buenos Aires, Argentina. National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. Faculty of Education, National University of Cuyo (UNCuyo), Mendoza, ArgentinaFil: Sedeño, Lucas. Laboratory of Experimental Psychology and Neuroscience (LPEN), Institute of Cognitive and Translational Neuroscience (INCYT), INECO Foundation, Favaloro University, Buenos Aires, Argentina. National Scientific and Technical Research Council (CONICET), Buenos Aires, ArgentinaFil: Ibáñez, Agustín. Laboratory of Experimental Psychology and Neuroscience (LPEN), Institute of Cognitive and Translational Neuroscience (INCYT), INECO Foundation, Favaloro University, Buenos Aires, Argentina. National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. Universidad Autónoma del Caribe, Barranquilla, Colombia. Center for Social and Cognitive Neuroscience (CSCN), School of Psychology, Universidad Adolfo Ibañez, Santiago de Chile, Chile. Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australi

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Contains fulltext : 169681.pdf (publisher's version ) (Open Access)Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/- heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/- knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/- and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/- mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/- mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/- mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability

Ritmos biológicos y uso del tiempo en una comunidad mapuche aislada

Este proyecto persigue establecer la influencia de factores ambientales y culturales sobre los patrones temporales de poblaciones humanas. Estudiamos la comunidad mapuche de Milaín Currical (Neuquén) en distintas estaciones, registrando el ciclo diario sueño-vigilia y otros parámetros relacionados con cambios cíclicos en el comportamiento y la fisiología de los habitantes. El objetivo es lograr una explicación englobadora del uso del tiempo en poblaciones bajo distintas condiciones ambientales. Asimismo, se registró la variación estacional en los procesos migratorios y en variables epidemiológicas. Las variables ambientales (fotoperíodo, temperatura, lluvias) exhibieron ciclos anuales de gran amplitud. La comunidad presenta variaciones estacionales con claras diferencias entre verano e invierno, incluyendo cambios de horario de sus actividades y del ciclo sueño-vigilia, que correlacionan con variaciones ambientales. Las consultas médicas tuvieron un pico hacia el final del invierno. La comunidad realiza una migración anual entre las tierras de veranada y de invernada, que puede ser correlacionada con las variables ambientales, en particular el fotoperíodo. El estudio de comunidades sujetas a cambios temporales profundos en el ambiente (sin sincronizadores artificiales) ofrece un excelente modelo para la investigación del sistema cronobiológico humano.Asociación de Antropología Biológica de la República Argentin

Ritmos biológicos y uso del tiempo en una comunidad mapuche aislada

Este proyecto persigue establecer la influencia de factores ambientales y culturales sobre los patrones temporales de poblaciones humanas. Estudiamos la comunidad mapuche de Milaín Currical (Neuquén) en distintas estaciones, registrando el ciclo diario sueño-vigilia y otros parámetros relacionados con cambios cíclicos en el comportamiento y la fisiología de los habitantes. El objetivo es lograr una explicación englobadora del uso del tiempo en poblaciones bajo distintas condiciones ambientales. Asimismo, se registró la variación estacional en los procesos migratorios y en variables epidemiológicas. Las variables ambientales (fotoperíodo, temperatura, lluvias) exhibieron ciclos anuales de gran amplitud. La comunidad presenta variaciones estacionales con claras diferencias entre verano e invierno, incluyendo cambios de horario de sus actividades y del ciclo sueño-vigilia, que correlacionan con variaciones ambientales. Las consultas médicas tuvieron un pico hacia el final del invierno. La comunidad realiza una migración anual entre las tierras de veranada y de invernada, que puede ser correlacionada con las variables ambientales, en particular el fotoperíodo. El estudio de comunidades sujetas a cambios temporales profundos en el ambiente (sin sincronizadores artificiales) ofrece un excelente modelo para la investigación del sistema cronobiológico humano.Asociación de Antropología Biológica de la República Argentin

Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor.

Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01), suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods

Dopamine in the dorsal hippocampus impairs the late-consolidation of cocaine-associated memory

Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.Fil: Kramar, Cecilia Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Chefer, Vladimir I.. National Institutes of Health; Estados UnidosFil: Wise, Roy A.. National Institutes of Health; Estados UnidosFil: Medina, Jorge Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Barbano, María Flavia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Detecting Awareness in the Vegetative State: Electroencephalographic Evidence for Attempted Movements to Command

Patients in the Vegetative State (VS) do not produce overt motor behavior to command and are therefore considered to be unaware of themselves and of their environments. However, we recently showed that high-density electroencephalography (EEG) can be used to detect covert command-following in some VS patients. Due to its portability and inexpensiveness, EEG assessments of awareness have the potential to contribute to a standard clinical protocol, thus improving diagnostic accuracy. However, this technique requires refinement and optimization if it is to be used widely as a clinical tool. We asked a patient who had been repeatedly diagnosed as VS for 12-years to try to move his left and right hands, between periods of rest, while EEG was recorded from four scalp electrodes. We identified appropriate and statistically reliable modulations of sensorimotor beta rhythms following commands to try to move, which could be significantly classified at a single-trial level. These reliable effects indicate that the patient attempted to follow the commands, and was therefore aware, but was unable to execute an overtly discernable action. The cognitive demands of this novel task are lower than those used previously and, crucially, allow for awareness to be determined on the basis of a 20-minute EEG recording made with only four electrodes. This approach makes EEG assessments of awareness clinically viable, and therefore has potential for inclusion in a standard assessment of awareness in the VS

Up-regulation of brain-derived neurotrophic factor in primary afferent pathway regulates colon-to-bladder cross-sensitization in rat

Background In humans, inflammation of either the urinary bladder or the distal colon often results in sensory cross-sensitization between these organs. Limited information is known about the mechanisms underlying this clinical syndrome. Studies with animal models have demonstrated that activation of primary afferent pathways may have a role in mediating viscero-visceral cross-organ sensitization. Methods Colonic inflammation was induced by a single dose of tri-nitrobenzene sulfonic acid (TNBS) instilled intracolonically. The histology of the colon and the urinary bladder was examined by hematoxylin and eosin (H&E) stain. The protein expression of transient receptor potential (TRP) ion channel of the vanilloid type 1 (TRPV1) and brain-derived neurotrophic factor (BDNF) were examined by immunohistochemistry and/or western blot. The inter-micturition intervals and the quantity of urine voided were obtained from analysis of cystometrograms. Results At 3 days post TNBS treatment, the protein level of TRPV1 was increased by 2-fold (p \u3c 0.05) in the inflamed distal colon when examined with western blot. TRPV1 was mainly expressed in the axonal terminals in submucosal area of the distal colon, and was co-localized with the neural marker PGP9.5. In sensory neurons in the dorsal root ganglia (DRG), BDNF expression was augmented by colonic inflammation examined in the L1 DRG, and was expressed in TRPV1 positive neurons. The elevated level of BDNF in L1 DRG by colonic inflammation was blunted by prolonged pre-treatment of the animals with the neurotoxin resiniferatoxin (RTX). Colonic inflammation did not alter either the morphology of the urinary bladder or the expression level of TRPV1 in this viscus. However, colonic inflammation decreased the inter-micturition intervals and decreased the quantities of urine voided. The increased bladder activity by colonic inflammation was attenuated by prolonged intraluminal treatment with RTX or treatment with intrathecal BDNF neutralizing antibody. Conclusion Acute colonic inflammation increases bladder activity without affecting bladder morphology. Primary afferent-mediated BDNF up-regulation in the sensory neurons regulates, at least in part, the bladder activity during colonic inflammation

The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway

Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures