Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats

Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect

Long-term effects of intermittent adolescent alcohol exposure in male and female rats

Alcohol is a serious public health concern that has a differential impact on individuals depending upon age and sex. Patterns of alcohol consumption have recently changed: heavy episodic drinking—known as binge-drinking—has become most popular among the youth. Herein, we aimed to investigate the consequences of intermittent adolescent alcohol consumption in male and female animals. Thus, Wistar rats were given free access to ethanol (20% in drinking water) or tap water for 2-h sessions during 3 days, and for an additional 4-h session on the 4th day; every week during adolescence, from postnatal day (pnd) 28–52. During this period, animals consumed a moderate amount of alcohol despite blood ethanol concentration (BEC) did not achieve binge-drinking levels. No withdrawal signs were observed: no changes were observed regarding anxiety-like responses in the elevated plus-maze or plasma corticosterone levels (pnd 53–54). In the novel object recognition (NOR) test (pnd 63), a significant deficit in recognition memory was observed in both male and female rats. Western Blot analyses resulted in an increase in the expression of synaptophysin in the frontal cortex (FC) of male and female animals, together with a decrease in the expression of the CB2R in the same brain region. In addition, adolescent alcohol induced, exclusively among females, a decrease in several markers of dopaminergic and serotonergic neurotransmission, in which epigenetic mechanisms, i.e., histone acetylation, might be involved. Taken together, further research is still needed to specifically correlate sex-specific brain and behavioral consequences of adolescent alcohol exposure

Facilitation of AMPA Receptor Synaptic Delivery as a Molecular Mechanism for Cognitive Enhancement

A small peptide from a neuronal cell adhesion molecule enhances synaptic plasticity in the hippocampus and results in improved cognitive performance in rats

CNR1 gene deletion affects the density of endomorphin-2 binding sites in the mouse brain in a hemisphere-specific manner

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are two endogenous tetrapeptides with very high affinities for the mu-opioid receptor. Until recently, the precise neuroanatomical localization of the binding sites for these peptides was unknown. However, the recent synthesis of tritiated forms of these molecules has permitted these binding sites to be analysed with a very high degree of neuroanatomical specificity. Preliminary studies demonstrated a superior binding profile for EM-2, with less non-specific binding than EM-1. As the endogenous cannabinoid and opioid systems interact at several levels, we investigated how deletion of the CNR1 gene, which encodes the cannabinoid receptor 1 (CB1R) protein, affects the brain distribution of EM-2 binding sites. Our results revealed no differences in the average density of EM-2 binding sites in CB1 receptor knockout (CB1R KO) and WT mice. However, when both hemispheres were analysed separately, we detected specific alterations in the distribution of EM-2 binding sites in the right hemisphere of CB1R KO mice. While, the density of EM-2 binding sites in CB1R KO mice was higher in the CA3 hippocampal field and in the pontine tegmental nuclei, it was lower in the superior colliculus and ventral tegmental area than in WT controls. No differences were observed in the left hemisphere for any of the regions analysed. For the first time these findings demonstrate a lateralization effect on cerebral opioid binding sites that may be mediated by the central cannabinoid system. (c) 2012 Elsevier B.V. All rights reserved

Shedding of neurexin 3 beta ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons

Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3 beta is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease.-secretase, producing secreted neurexin3 beta (sNrxn3 beta) and a single intracellular domain (Nrxn3 beta-ICD). We further completed the full characterization of the sites at which Nrxn3 beta is processed by these proteases. Supporting the physiological relevance of the Nrxn3 beta processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3 beta on the morphological development of adult newborn neurons in the mouse hippocampus. We show that sNrxn3 beta produced by the cells of the dentate gyrus increases the spine density of newborn neurons whereas sNrxn3 beta produced by the newborn neuron itself affects the number of its mossy fiber terminal extensions. These results support a pivotal role of sNrxn3 beta in plasticity and network remodeling during neuronal development

La carpeta de aprendizaje como herramienta de innovación docente: experiencia piloto en la asignatura de bioquímica

La adaptación al nuevo Espacio Europeo de Educación Superior (EEES) supone desarrollar un modelo educativo centrado en el alumno, que demanda la utilización de metodologías activas de aprendizaje, promotoras del desarrollo de competencias transversales y específicas, como parte de la formación integral del estudiante. Para satisfacer estas demandas, el equipo docente de la asignatura de Bioquímica en 1º de Odontología, ha propuesto la realización de una carpeta de aprendizaje elaborada por el estudiante, como un elemento de enseñanza-aprendizaje y evaluación. La experiencia se ha llevado a cabo en los 9 grupos de estudiantes de este grado en la Universidad Europea de Madrid (UEM) y ha consistido en una colección de evidencias realizada por el alumno, representativa de su trabajo en esta asignatura, presentada de forma individual y evaluada mediante una rúbrica que contempla el desarrollo académico y de competencias. Se ha analizado el posible impacto de la realización de esta carpeta sobre las calificaciones, así como las reflexiones y valoraciones hechas por los estudiantes en una encuesta de satisfacción. Los resultados muestran una aceptación moderada de esta herramienta por parte del estudiante. El equipo docente valora positivamente esta primera experiencia y se plantea aplicar mejoras sustanciales para el futuro.SIN FINANCIACIÓNNo data 2012UE

Unaltered cocaine self-administration in the prenatal LPS rat model of schizophrenia

Although cocaine abuse is up to three times more frequent among schizophrenic patients, it remains unclear why this should be the case and whether sex influences this relationship. Using a maternal immune activation model of schizophrenia, we tested whether animals at higher risk of developing a schizophrenia-like state are more prone to acquire cocaine self-administration behavior, and whether they show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction. Pregnant rats were injected with lipopolysaccharide on gestational day 15 and 16, and the offspring (both male and female) were tested in working memory (T-maze), social interaction and sensorimotor gating (prepulse inhibition of the acoustic startle response) paradigms. After performing these tests, the rats were subjected to cocaine self-administration regimes (0.5 mg/kg), assessing their dose-response and extinction. Male rats born to dams administered lipopolysaccharide showed impaired working memory but no alterations to their social interactions, and both male and female rats showed prepulse inhibition deficits. Moreover, similar patterns of cocaine self-administration acquisition, responsiveness to dose shifts and extinction curves were observed in both control and experimental rats. These results suggest that the higher prevalence of cocaine abuse among schizophrenic individuals is not due to a biological vulnerability directly associated to the disease and that other factors (social, educational, economic, familial, etc.) should be considered given the multifactorial nature of this illness. (C) 2016 Elsevier Inc. All rights reserved

Chronic stress in adulthood followed by intermittent stress impairs spatial memory and the survival of newborn hippocampal cells in aging animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule

In this study, we examined whether chronic stress in adulthood can exert long-term effects on spatial-cognitive abilities and on the survival of newborn hippocampal cells in aging animals. Male Wistar rats were subjected to chronic unpredictable stress at midlife (12 months old) and then reexposed each week to a stress stimulus. When evaluated in the water maze at the early stages of aging (18 months old), chronic unpredictable stress accelerated spatial-cognitive decline, an effect that was accompanied by a reduction in the survival of newborn cells and in the number of adult granular cells in the hippocampus. Interestingly, spatial-memory performance in the Morris water maze was positively correlated with the number of newborn cells that survived in the dentate gyrus: better spatial memory in the water maze was associated with more 5-bromo-2-deoxyuridine (BrdU)-labeled cells. Administration of FGL, a peptide mimetic of neural cell adhesion molecule, during the 4 weeks of continuous stress not only prevented the deleterious effects of chronic stress on spatial memory, but also reduced the survival of the newly generated hippocampal cells in aging animals. FGL treatment did not, however, prevent the decrease in the total number of granular neurons that resulted from prolonged exposure to stress. These findings suggest that the development of new drugs that mimic neural cell adhesion molecule activity might be of therapeutic relevance to treat stress-induced cognitive impairmen

Main statistical results corresponding to behavioral tests.

<p>Main significant results extracted from the three-way ANCOVA (litter was considered as a covariate factor). See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137283#sec002" target="_blank">material and methods</a> section for details.</p><p>Main statistical results corresponding to behavioral tests.</p

Expression levels in the hippocampus and frontal cortex of the mRNAs encoding insulin-like growth factor 1 (IGF1) (A), IGF1 receptor (IGF1R) (B), corticotropin-releasing hormone (CRH) (C) and leptin receptor (LepR) (D) in maternally deprived (MD) or control (Co) male and female rats treated with leptin (Lept) or vehicle (Vh) from postnatal day (PND) 9 until PND13 (n = 5–6).

<p>Post hoc test: ***p<0.005.</p