Retinoic Acid Restores Adult Hippocampal Neurogenesis and Reverses Spatial Memory Deficit in Vitamin A Deprived Rats

A dysfunction of retinoid hippocampal signaling pathway has been involved in the appearance of affective and cognitive disorders. However, the underlying neurobiological mechanisms remain unknown. Hippocampal granule neurons are generated throughout life and are involved in emotion and memory. Here, we investigated the effects of vitamin A deficiency (VAD) on neurogenesis and memory and the ability of retinoic acid (RA) treatment to prevent VAD-induced impairments. Adult retinoid-deficient rats were generated by a vitamin A-free diet from weaning in order to allow a normal development. The effects of VAD and/or RA administration were examined on hippocampal neurogenesis, retinoid target genes such as neurotrophin receptors and spatial reference memory measured in the water maze. Long-term VAD decreased neurogenesis and led to memory deficits. More importantly, these effects were reversed by 4 weeks of RA treatment. These beneficial effects may be in part related to an up-regulation of retinoid-mediated molecular events, such as the expression of the neurotrophin receptor TrkA. We have demonstrated for the first time that the effect of vitamin A deficient diet on the level of hippoccampal neurogenesis is reversible and that RA treatment is important for the maintenance of the hippocampal plasticity and function

Correction:How the COVID-19 pandemic highlights the necessity of animal research (vol 30, pg R1014, 2020)

(Current Biology 30, R1014–R1018; September 21, 2020) As a result of an author oversight in the originally published version of this article, a number of errors were introduced in the author list and affiliations. First, the middle initials were omitted from the names of several authors. Second, the surname of Dr. van Dam was mistakenly written as “Dam.” Third, the first name of author Bernhard Englitz was misspelled as “Bernard” and the surname of author B.J.A. Pollux was misspelled as “Pullox.” Finally, Dr. Keijer's first name was abbreviated rather than written in full. These errors, as well as various errors in the author affiliations, have now been corrected online

Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats

Rationale: Stress elicits functional and structural changes in the hippocampus. Early life stress is one of the major risk factors for stress-related pathologies like depression. Patients suffering from depression show a reduced hippocampal volume, and in women, this occurs more often when depression is preceded by childhood trauma. However, the underlying mechanisms that account for a reduced hippocampal volume are unknown. Objective: We examined the effects of maternal absence on structure and function of the hippocampus in female offspring. Methods: We studied whether 24 h of maternal deprivation (MD) on postnatal day 3 altered adult neurogenesis, individual neuronal morphology and dentate gyrus (DG) structure in young adult female rats. In addition, functional alterations were addressed by studying synaptic plasticity in vitro, and spatial as well as emotional learning was tested. Results: Adult females that were subjected to MD revealed significant reductions in DG granule cell number and density. In addition, DG neurons were altered in their dendritic arrangement. No effects on the rate of adult neurogenesis were found. Furthermore, MD did not alter synaptic plasticity in vitro, neither under normal nor high-stress conditions. In addition, spatial learning and contextual fear conditioning were comparable between control and MD animals. However, MD animals showed an improved amygdala-dependent fear memory. Conclusion: Although early life stress exposure did not impair hippocampus-dependent functioning in female offspring, it irreversibly affected DG structure by reducing cell numbers. This may be relevant for the reduced hippocampal volume observed in depression and the increased vulnerability of women to develop depression

Individual Variations in Maternal Care Early in Life Correlate with Later Life Decision-Making and c-Fos Expression in Prefrontal Subregions of Rats

Early life adversity affects hypothalamus-pituitary-adrenal axis activity, alters cognitive functioning and in humans is thought to increase the vulnerability to psychopathology–e.g. depression, anxiety and schizophrenia- later in life. Here we investigated whether subtle natural variations among individual rat pups in the amount of maternal care received, i.e. differences in the amount of licking and grooming (LG), correlate with anxiety and prefrontal cortex-dependent behavior in young adulthood. Therefore, we examined the correlation between LG received during the first postnatal week and later behavior in the elevated plus maze and in decision-making processes using a rodent version of the Iowa Gambling Task (rIGT). In our cohort of male and female animals a high degree of LG correlated with less anxiety in the elevated plus maze and more advantageous choices during the last 10 trials of the rIGT. In tissue collected 2 hrs after completion of the task, the correlation between LG and c-fos expression (a marker of neuronal activity) was established in structures important for IGT performance. Negative correlations existed between rIGT performance and c-fos expression in the lateral orbitofrontal cortex, prelimbic cortex, infralimbic cortex and insular cortex. The insular cortex correlations between c-fos expression and decision-making performance depended on LG background; this was also true for the lateral orbitofrontal cortex in female rats. Dendritic complexity of insular or infralimbic pyramidal neurons did not or weakly correlate with LG background. We conclude that natural variations in maternal care received by pups may significantly contribute to later-life decision-making and activity of underlying brain structures

A preclinical perspective on the enhanced vulnerability to Alzheimer's disease after early-life stress

Stress experienced early in life (ES), in the form of childhood maltreatment, maternal neglect or trauma, enhances the risk for cognitive decline in later life. Several epidemiological studies have now shown that environmental and adult life style factors influence AD incidence or age-of-onset and early-life environmental conditions have attracted attention in this respect. There is now emerging interest in understanding whether ES impacts the risk to develop age-related neurodegenerative disorders, and their severity, such as in Alzheimer's disease (AD), which is characterized by cognitive decline and extensive (hippocampal) neuropathology. While this might be relevant for the identification of individuals at risk and preventive strategies, this topic and its possible underlying mechanisms have been poorly studied to date. In this review, we discuss the role of ES in modulating AD risk and progression, primarily from a preclinical perspective. We focus on the possible involvement of stress-related, neuro-inflammatory and metabolic factors in mediating ES-induced effects on later neuropathology and the associated impairments in neuroplasticity. The available studies suggest that the age of onset and progression of AD-related neuropathology and cognitive decline can be affected by ES, and may aggravate the progression of AD neuropathology. These relevant changes in AD pathology after ES exposure in animal models call for future clinical studies to elucidate whether stress exposure during the early-life period in humans modulates later vulnerability for AD

Mineralocorticoid Receptors Guide Spatial and Stimulus-Response Learning in Mice

Mineralocorticoid receptors guide spatial and stimulus-response learning in mice Arp, J.M.; ter Horst, J.P.F.; Kanatsou, S.; Fernández, G.; Joëls, M.; Krugers, H.J.; Oitzl, M.S. Published in: PLoS ONE DOI: 10.1371/journal.pone.0086236 Link to publication Citation for published version (APA): Arp, J. M., ter Horst, J. P., Kanatsou, S., Fernández, G., Joëls, M., Krugers, H. J., & Oitzl, M. S. (2014). Mineralocorticoid receptors guide spatial and stimulus-response learning in mice. PLoS ONE, 9(1), e86236. https://doi.org/10.1371/journal.pone.0086236 General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Abstract Adrenal corticosteroid hormones act via mineralocorticoid (MR) and glucocorticoid receptors (GR) in the brain, influencing learning and memory. MRs have been implicated in the initial behavioral response in novel situations, which includes behavioral strategies in learning tasks. Different strategies can be used to solve navigational tasks, for example hippocampus-dependent spatial or striatum-dependent stimulus-response strategies. Previous studies suggested that MRs are involved in spatial learning and induce a shift between learning strategies when animals are allowed a choice between both strategies. In the present study, we further explored the role of MRs in spatial and stimulus-response learning in two separate circular holeboard tasks using female mice with forebrain-specific MR deficiency and MR overexpression and their wildtype control littermates. In addition, we studied sex-specific effects using male and female MR-deficient mice. First, we found that MR-deficient compared to control littermates and MR-overexpressing mice display altered exploratory and searching behavior indicative of impaired acquisition of novel information. Second, female (but not male) MR-deficient mice were impaired in the spatial task, while MR-overexpressing female mice showed improved performance in the spatial task. Third, MR-deficient mice were also impaired in the stimulus-response task compared to controls and (in the case of females) MR-overexpressing mice. We conclude that MRs are important for coordinating the processing of information relevant for spatial as well as stimulus-response learning

Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity

SummaryDendritic spines are the major sites of excitatory synaptic input, and their morphological changes have been linked to learning and memory processes. Here, we report that growing microtubule plus ends decorated by the microtubule tip-tracking protein EB3 enter spines and can modulate spine morphology. We describe p140Cap/SNIP, a regulator of Src tyrosine kinase, as an EB3 interacting partner that is predominately localized to spines and enriched in the postsynaptic density. Inhibition of microtubule dynamics, or knockdown of either EB3 or p140Cap, modulates spine shape via regulation of the actin cytoskeleton. Fluorescence recovery after photobleaching revealed that EB3-binding is required for p140Cap accumulation within spines. In addition, we found that p140Cap interacts with Src substrate and F-actin-binding protein cortactin. We propose that EB3-labeled growing microtubule ends regulate the localization of p140Cap, control cortactin function, and modulate actin dynamics within dendritic spines, thus linking dynamic microtubules to spine changes and synaptic plasticity

Dynamic Microtubules Regulate Dendritic Spine Morphology and Synaptic Plasticity

Dendritic spines are the major sites of excitatory synaptic input, and their morphological changes have been linked to learning and memory processes. Here, we report that growing microtubule plus ends decorated by the microtubule tip-tracking protein EB3 enter spines and can modulate spine morphology. We describe p140Cap/SNIP, a regulator of Src tyrosine kinase, as an EB3 interacting partner that is predominately localized to spines and enriched in the postsynaptic density. Inhibition of microtubule dynamics, or knockdown of either EB3 or p140Cap, modulates spine shape via regulation of the actin cytoskeleton. Fluorescence recovery after photobleaching revealed that EB3-binding is required for p140Cap accumulation within spines. In addition, we found that p140Cap interacts with Src substrate and F-actin-binding protein cortactin. We propose that EB3-labeled growing microtubule ends regulate the localization of p140Cap, control cortactin function, and modulate actin dynamics within dendritic spines, thus linking dynamic microtubules to spine changes and synaptic plasticity