The Alzheimer's disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons.

Bridging Integrator 1 (BIN1) is the second most important Alzheimer's disease (AD) risk gene, but its physiological roles in neurons and its contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role in the regulation of calcium homeostasis, electrical activity, and gene expression of glutamatergic neurons. Using single-cell RNA-sequencing on cerebral organoids generated from isogenic BIN1 wild type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), we show that BIN1 is mainly expressed by oligodendrocytes and glutamatergic neurons, like in the human brain. Both BIN1 HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1 cell-autonomously regulates gene expression in glutamatergic neurons by using a novel protocol to generate pure culture of hiPSC-derived induced neurons (hiNs). Using this system, we also show that BIN1 plays a key role in the regulation of neuronal calcium transients and electrical activity via its interaction with the L-type voltage-gated calcium channel Cav1.2. BIN1 KO hiNs show reduced activity-dependent internalization and higher Cav1.2 expression compared to WT hiNs. Pharmacological blocking of this channel with clinically relevant doses of nifedipine, a calcium channel blocker, partly rescues electrical and gene expression alterations in BIN1 KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1 KO hiNs that affect biological processes related to calcium homeostasis are also present in glutamatergic neurons of the human brain at late stages of AD pathology. Together, these findings suggest that BIN1-dependent alterations in neuronal properties could contribute to AD pathophysiology and that treatment with low doses of clinically approved calcium blockers should be considered as an option to slow disease-onset and progression.

Zika virus infection histories in brain development.

An outbreak of births of microcephalic patients in Brazil motivated multiple studies on this incident. The data left no doubt that infection by Zika virus (ZIKV) was the cause, and that this virus promotes reduction in neuron numbers and neuronal death. Analysis of patients' characteristics revealed additional aspects of the pathology alongside the decrease in neuronal number. Here, we review the data from human, molecular, cell and animal model studies attempting to build the natural history of ZIKV in the embryonic central nervous system (CNS). We discuss how identifying the timing of infection and the pathways through which ZIKV may infect and spread through the CNS can help explain the diversity of phenotypes found in congenital ZIKV syndrome (CZVS). We suggest that intraneuronal viral transport is the primary mechanism of ZIKV spread in the embryonic brain and is responsible for most cases of CZVS. According to this hypothesis, the viral transport through the blood-brain barrier and cerebrospinal fluid is responsible for more severe pathologies in which ZIKV-induced malformations occur along the entire anteroposterior CNS axis.

Pericardial Effusion and Cardiac Tamponade: Etiology and Evolution in the Contemporary Era

Abstract Background: Pericardial effusion is a relatively common finding and can progress to cardiac tamponade; etiological diagnosis is important for guiding treatment decisions. With advances in medicine and improvement in the social context, the most frequent etiological causes have changed. Objectives: To evaluate the clinical and laboratory characteristics, etiology, and clinical course of patients with pericardial effusion and cardiac tamponade. Materials and methods: Patients with pericardial effusion classified as small (< 10 mm), moderate (between 10-20 mm), or severe (> 20 mm) were included. Data from the clinical history, physical examination, laboratory tests, and complementary tests were evaluated in patients with pericardial effusion and cardiac tamponade. The significance level was set at 5%. Results: A total of 254 patients with a mean age of 53.09 ± 17.9 years were evaluated, 51.2% of whom were female. A total of 40.4% had significant pericardial effusion (> 20 mm). Pericardial tamponade occurred in 44.1% of patients. Among pericardial effusion patients without tamponade, the most frequent etiologies were: idiopathic (44.4%) and postsurgical (17.6%), while among those with tamponade, the most frequent etiologies were postsurgical (21.4%) and postprocedural (19.6%). The mean follow-up time was 2.2 years. Mortality was 42% and 23.2 in those with and without tamponade, respectively (p=0.001). Conclusions: There is an etiological difference between pericardial effusion patients with and without cardiac tamponade. An idiopathic etiology is more common among those without tamponade, while postinterventional/postsurgical is more common among those with tamponade. The tamponade group had a higher mortality rate.

Hippocampus-retrosplenial cortex interaction is increased during phasic REM and contributes to memory consolidation.

Hippocampal (HPC) theta oscillation during post-training rapid eye movement (REM) sleep supports spatial learning. Theta also modulates neuronal and oscillatory activity in the retrosplenial cortex (RSC) during REM sleep. To investigate the relevance of theta-driven interaction between these two regions to memory consolidation, we computed the Granger causality within theta range on electrophysiological data recorded in freely behaving rats during REM sleep, both before and after contextual fear conditioning. We found a training-induced modulation of causality between HPC and RSC that was correlated with memory retrieval 24 h later. Retrieval was proportional to the change in the relative influence RSC exerted upon HPC theta oscillation. Importantly, causality peaked during theta acceleration, in synchrony with phasic REM sleep. Altogether, these results support a role for phasic REM sleep in hippocampo-cortical memory consolidation and suggest that causality modulation between RSC and HPC during REM sleep plays a functional role in that phenomenon.

Two decades of research towards a potential first anti-epileptic drug.

The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10-20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.

Is REM sleep a paradoxical state?: Different neurons are activated in the cingulate cortices and the claustrum during wakefulness and paradoxical sleep hypersomnia.

Michel Jouvet proposed in 1959 that REM sleep is a paradoxical state since it was characterized by the association of a cortical activation similar to wakefulness (W) with muscle atonia. Recently, we showed using cFos as a marker of activity that cortical activation during paradoxical sleep (PS) was limited to a few limbic cortical structures in contrast to W during which all cortices were strongly activated. However, we were not able to demonstrate whether the same neurons are activated during PS and W and to rule out that the activation observed was not linked with stress induced by the flowerpot method of PS deprivation. In the present study, we answered to these two questions by combining tdTomato and cFos immunostaining in the innovative TRAP2 transgenic mice exposed one week apart to two periods of W (W-W mice), PS rebound (PSR-PSR) or a period of W followed by a period of PSR (W-PSR mice). Using such method, we showed that different neurons are activated during W and PSR in the anterior cingulate (ACA) and rostral and caudal retrosplenial (rRSP and cRSP) cortices as well as the claustrum (CLA) previously shown to contain a large number of activated neurons after PSR. Further, the distribution of the neurons during PSR in the rRSP and cRSP was limited to the superficial layers while it was widespread across all layers during W. Our results clearly show at the cellular level that PS and W are two completely different states in term of neocortical activation.

Disentangling chemical and electrical effects of status epilepticus-induced dentate gyrus abnormalities.

In rodents, status epilepticus (SE) triggered by chemoconvulsants can differently affect the proliferation and fate of adult-born dentate granule cells (DGCs). It is unknown whether abnormal neurogenesis results from intracellular signaling associated with drug-receptor interaction, paroxysmal activity, or both. To test the contribution of these factors, we systematically compared the effects of kainic acid (KA)- and pilocarpine (PL)-induced SE on the morphology and localization of DGCs generated before or after SE in the ipsi- and contralateral hippocampi of mice. Hippocampal insult was induced by unilateral intrahippocampal (ihpc) administration of KA or PL. We employed conditional doublecortin-dependent expression of the green fluorescent protein (GFP) to label adult-born cells committed to neuronal lineage either one month before (mature DGCs) or seven days after (immature DGCs) SE. Unilateral ihpc administration of KA and PL led to bilateral epileptiform discharges and focal and generalized behavioral seizures. However, drastic granule cell layer (GCL) dispersion occurred only in the ipsilateral side of KA injection, but not in PL-treated animals. Granule cell layer dispersion was accompanied by a significant reduction in neurogenesis after SE in the ipsilateral side of KA-treated animals, while neurogenesis increased in the contralateral side of KA-treated animals and both hippocampi of PL-treated animals. The ratio of ectopic neurons in the ipsilateral hippocampus was higher among immature as compared to mature neurons in the KA model (32.8% vs. 10.0%, respectively), while the occurrence of ectopic neurons in PL-treated animals was lower than 3% among both mature and immature DGCs. Collectively, our results suggest that KA- and PL-induced SE leads to distinct cellular alterations in mature and immature DGCs. We also show different local and secondary effects of KA or PL in the histological organization of the adult DG, suggesting that these unique epilepsy models may be complementary to our understanding of the disease. NEWroscience 2018.

Evidence of Progenitor Cell Lineage Rerouting in the Adult Mouse Hippocampus After Status Epilepticus.

Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that 3 days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus (DG) co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Unilateral intrahippocampal administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) triggered epileptiform discharges and led to a significant increase in the number of GFP+ cells in both ipsi and contralateral DG. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. We also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, suggesting that some Dcx-progenitors could regress to a multipotent stage. The boosted neurogenesis and astrogliogenesis observed in the Dcx-lineage following chemoconvulsants administration correlated, respectively, with preservation or degeneration of the parvalbuminergic plexus in the DG. Increased inflammatory response, by contrast, was observed both in the DG showing increased neurogenesis or astrogliogenesis. Altogether, our data support the view that cell lineage progression in the adult hippocampus is not unidirectional and could be modulated by local network activity and GABA-mediated signaling.

Association between brain morphology and electrophysiological features in Congenital Zika Virus Syndrome: A cross-sectional, observational study.

BACKGROUND: Intrauterine infection with the Zika virus (ZIKV) has been connected to severe brain malformations, microcephaly, and abnormal electrophysiological activity. METHODS: We describe the interictal electroencephalographic (EEG) recordings of 47 children born with ZIKV-derived microcephaly. EEGs were recorded in the first year of life and correlated with brain morphology. In 31 subjects, we tested the association between computed tomography (CT) findings and interictal epileptiform discharges (IED). In eighteen, CTs were used for correlating volumetric measurements of the brainstem, cerebellum, and prosencephalon with the rate of IED. FINDINGS: Twenty-nine out of 47 (62%) subjects were diagnosed as having epilepsy. Those subjects presented epileptiform discharges, including unilateral interictal spikes (26/29, 90%), bilateral synchronous and asynchronous interictal spikes (21/29, 72%), and hypsarrhythmia (12/29, 41%). Interestingly, 58% of subjects with clinical epilepsy were born with rhombencephalon malformations, while none of the subjects without epilepsy showed macroscopic abnormalities in this region. The presence of rhombencephalon malformation was associated with epilepsy (odds ratio of 34; 95% CI: 2 - 654). Also, the presence of IED was associated with smaller brain volumes. Age-corrected total brain volume was inversely correlated with the rate of IED during sleep. Finally, 11 of 44 (25%) subjects presented sleep spindles. We observed an odds ratio of 0·25 (95% CI: 0·06 - 1·04) for having sleep spindles given the IED presence. INTERPRETATION: The findings suggest that certain CT imaging features are associated with an increased likelihood of developing epilepsy, including higher rates of IED and impaired development of sleep spindles, in the first year of life of CZVS subjects. FUNDING: This work was supported by the Brazilian Federal Government through a postdoctoral fellowship for EBS (Talented Youth, Science without Borders), an undergraduate scholarship for AJR (Institutional Program of Science Initiation Scholarships, Federal University of Rio Grande do Norte, Brazil), by International Centre for Genetic Engineering and Biotechnology (CRP/BRA18-05_EC) and by CAPES (Grant number 440893/2016-0), and CNPq (Grant number 88881.130729/2016-01).

Levetiracetam Reduced the Basal Excitability of the Dentate Gyrus without Restoring Impaired Synaptic Plasticity in Rats with Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE), the most common type of focal epilepsy, affects learning and memory; these effects are thought to emerge from changes in synaptic plasticity. Levetiracetam (LEV) is a widely used antiepileptic drug that is also associated with the reversal of cognitive dysfunction. The long-lasting effect of LEV treatment and its participation in synaptic plasticity have not been explored in early chronic epilepsy. Therefore, through the measurement of evoked field potentials, this study aimed to comprehensively identify the alterations in the excitability and the short-term (depression/facilitation) and long-term synaptic plasticity (long-term potentiation, LTP) of the dentate gyrus of the hippocampus in a lithium-pilocarpine rat model of TLE, as well as their possible restoration by LEV (1 week; 300 mg/kg/day). TLE increased the population spike (PS) amplitude (input/output curve); interestingly, LEV treatment partially reduced this hyperexcitability. Furthermore, TLE augmented synaptic depression, suppressed paired-pulse facilitation, and reduced PS-LTP; however, LEV did not alleviate such alterations. Conversely, the excitatory postsynaptic potential (EPSP)-LTP of TLE rats was comparable to that of control rats and was decreased by LEV. LEV caused a long-lasting attenuation of basal hyperexcitability but did not restore impaired synaptic plasticity in the early chronic phase of TLE.

The GCN2 inhibitor IMPACT contributes to diet-induced obesity and body temperature control.

IMPACT, a highly conserved protein, is an inhibitor of the eIF2α kinase GCN2. In mammals, it is preferentially expressed in neurons. Knock-down of IMPACT expression in neuronal cells increases basal GCN2 activation and eIF2α phosphorylation and decreases translation initiation. In the mouse brain, IMPACT is particularly abundant in the hypothalamus. Here we describe that the lack of IMPACT in mice affects hypothalamic functions. Impact-/- mice (Imp-KO) are viable and have no apparent major phenotypic defect. The hypothalamus in these animals shows increased levels of eIF2α phosphorylation, as expected from the described role of IMPACT in inhibiting GCN2 and from its abundance in this brain region. When fed a normal chow, animals lacking IMPACT weight slightly less than wild-type mice. When fed a high-fat diet, Imp-KO animals gain substantially less weight due to lower food intake when compared to wild-type mice. STAT3 signaling was depressed in Imp-KO animals even though leptin levels were identical to the wild-type mice. This finding supports the observation that Imp-KO mice have defective thermoregulation upon fasting. This phenotype was partially dependent on GCN2, whereas the lean phenotype was independent of GCN2. Taken together, our results indicate that IMPACT contributes to GCN2-dependent and -independent mechanisms involved in the regulation of autonomic functions in response to energy availability.

Identification of Hypsarrhythmia in Children with Microcephaly Infected by Zika Virus.

Hypsarrhythmia is an electroencephalographic pattern specific to some epileptic syndromes that affect children under one year of age. The identification of this pattern, in some cases, causes disagreements between experts, which is worrisome since an inaccurate diagnosis can bring complications to the infant. Despite the difficulties in visually identifying hypsarrhythmia, options of computerized assistance are scarce. Aiming to collaborate with the recognition of this electropathological pattern, we propose in this paper a mathematical index that can help electroencephalography experts to identify hypsarrhythmia. We performed hypothesis tests that indicated significant differences in the groups under analysis, where the p-values were found to be extremely small.

Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation.

Once viewed as a passive physiological state, sleep is a heterogeneous and complex sequence of brain states with essential effects on synaptic plasticity and neuronal functioning. Rapid-eye-movement (REM) sleep has been shown to promote calcium-dependent plasticity in principal neurons of the cerebral cortex, both during memory consolidation in adults and during post-natal development. This article reviews the plasticity mechanisms triggered by REM sleep, with a focus on the emerging role of kinases and immediate-early genes for the progressive corticalization of hippocampus-dependent memories. The body of evidence suggests that memory corticalization triggered by REM sleep is a systemic phenomenon with cellular and molecular causes.

Electrophysiological Evidence That the Retrosplenial Cortex Displays a Strong and Specific Activation Phased with Hippocampal Theta during Paradoxical (REM) Sleep.

It is widely accepted that cortical neurons are similarly more activated during waking and paradoxical sleep (PS; aka REM) than during slow-wave sleep (SWS). However, we recently reported using Fos labeling that only a few limbic cortical structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) contain a large number of neurons activated during PS hypersomnia. Our aim in the present study was to record local field potentials and unit activity from these two structures across all vigilance states in freely moving male rats to determine whether the RSC and the ACA are electrophysiologically specifically active during basal PS episodes. We found that theta power was significantly higher during PS than during active waking (aWK) similarly in the RSC and hippocampus (HPC) but not in ACA. Phase-amplitude coupling between HPC theta and gamma oscillations strongly and specifically increased in RSC during PS compared with aWK. It did not occur in ACA. Further, 68% and 43% of the units recorded in the RSC and ACA were significantly more active during PS than during aWK and SWS, respectively. In addition, neuronal discharge of RSC but not of ACA neurons increased just after the peak of hippocampal theta wave. Our results show for the first time that RSC neurons display enhanced spiking in synchrony with theta specifically during PS. We propose that activation of RSC neurons specifically during PS may play a role in the offline consolidation of spatial memories, and in the generation of vivid perceptual scenery during dreaming.SIGNIFICANCE STATEMENT Fifty years ago, Michel Jouvet used the term paradoxical to define REM sleep because of the simultaneous occurrence of a cortical activation similar to waking accompanied by muscle atonia. However, we recently demonstrated using functional neuroanatomy that only a few limbic structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) are activated during PS. In the present study, we show for the first time that the RSC and ACA contain neurons firing more during PS than in any other state. Further, RSC neurons are firing in phase with the hippocampal theta rhythm. These data indicate that the RSC is very active during PS and could play a key role in memory consolidation taking place during this state.

Music Proficiency and Quantification of Absolute Pitch: A Large-Scale Study among Brazilian Musicians.

Absolute pitch (AP) is the ability to identify and name the pitch of a sound without external reference. Often, accuracy and speed at naming isolated musical pitches are correlated with demographic, biological, and acoustical parameters to gain insight into the genesis and evolution of this ability in specific cohorts. However, the majority of those studies were conducted in North America, Europe, or Asia. To fill this gap, here we investigated the pitch-naming performance in a large population of Brazilian conservatory musicians (N = 200). As previously shown, we found that the population performance was rather a continuum than an "all-or-none" ability. By comparing the observed distribution of correct responses to a theoretical binomial distribution, we estimated the prevalence of AP as being 18% amongst regular music students. High accuracy thresholds (e.g., 85% of correct responses) yielded a prevalence of 4%, suggesting that AP might have been underestimated in previous reports. Irrespective of the threshold used, AP prevalence was higher in musicians who started their musical practice and formal musical education early in life. Finally, we compared the performance of those music students (average proficiency group) with another group of students selected to take part in the conservatory orchestra (high proficiency group, N = 30). Interestingly, the prevalence of AP was higher in the latter in comparison to the former group. In addition, even when the response was incorrect, the mean absolute deviation from the correct response was smaller in the high proficiency group compared to the average proficiency group (Glass's Δ: 0.5). Taken together, our results show that the prevalence of AP in Brazilian students is similar to other non-tonal language populations, although this measure is highly dependent on the scoring threshold used. Despite corroborating that early involvement with musical practice and formal education can foster AP ability, the present data suggest that music proficiency may also play an important role in AP expression.

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment.

The efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120mg/kg) and valproic acid (400mg/kg) could not prevent PTZ-induced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p=0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p<0.05), which were also more frequent than in the naïve group (p<0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY- and ΔFosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

Human Brain Expansion during Evolution Is Independent of Fire Control and Cooking.

What makes humans unique? This question has fascinated scientists and philosophers for centuries and it is still a matter of intense debate. Nowadays, human brain expansion during evolution has been acknowledged to explain our empowered cognitive capabilities. The drivers for such accelerated expansion remain, however, largely unknown. In this sense, studies have suggested that the cooking of food could be a pre-requisite for the expansion of brain size in early hominins. However, this appealing hypothesis is only supported by a mathematical model suggesting that the increasing number of neurons in the brain would constrain body size among primates due to a limited amount of calories obtained from diets. Here, we show, by using a similar mathematical model, that a tradeoff between body mass and the number of brain neurons imposed by dietary constraints during hominin evolution is unlikely. Instead, the predictable number of neurons in the hominin brain varies much more in function of foraging efficiency than body mass. We also review archeological data to show that the expansion of the brain volume in the hominin lineage is described by a linear function independent of evidence of fire control, and therefore, thermal processing of food does not account for this phenomenon. Finally, we report experiments in mice showing that thermal processing of meat does not increase its caloric availability in mice. Altogether, our data indicate that cooking is neither sufficient nor necessary to explain hominin brain expansion.

Ethological Evaluation of the Effects of Social Defeat Stress in Mice: Beyond the Social Interaction Ratio.

In rodents, repeated exposure to unavoidable aggression followed by sustained sensory treat can lead to prolonged social aversion. The chronic social defeat stress model explores that phenomenon and it has been used as an animal model for human depression. However, some authors have questioned whether confounding effects may arise as the model also boosts anxiety-related behaviors. Despite its wide acceptance, most studies extract limited information from the behavior of the defeated animal. Often, the normalized occupancy around the social stimulus, the interaction zone, is taken as an index of depression. We hypothesized that this parameter is insufficient to fully characterize the behavioral consequences of this form of stress. Using an ethological approach, we showed that repeated social defeat delayed the expression of social investigation in long (10 min) sessions of social interaction. Also, the incidence of defensive behaviors, including stretched-attend posture and high speed retreats, was significantly higher in defeated mice in comparison to controls. Interestingly, a subpopulation of defeated mice showed recurrent and non-habituating stretched-attend posture and persistent flights during the entire session. Two indexes were created based on defensive behaviors to show that only recurrent flights correlates with sucrose intake. Together, the present study corroborates the idea that this model of social stress can precipitate a myriad of behaviors not readily disentangled. We propose that long sessions (>150 s) and detailed ethological evaluation during social interaction tests are necessary to provide enough information to correctly classify defeated animals in terms of resilience and susceptibility to social defeat stress.

AMPA receptors mediate passive avoidance deficits induced by sleep deprivation.

The present study addressed the effects of sleep deprivation (SD) on AMPA receptor (AMPAR) binding in brain regions associated with learning and memory, and investigated whether treatment with drugs acting on AMPAR could prevent passive avoidance deficits in sleep deprived animals. [(3)H]AMPA binding and GluR1 in situ hybridization signals were quantified in different brain regions of male Wistar rats either immediately after 96 h of sleep deprivation or after 24h of sleep recovery following 96 h of sleep deprivation. Another group of animals were sleep deprived and then treated with either the AMPAR potentiator, aniracetam (25, 50 and 100mg/kg, acute administration) or the AMPAR antagonist GYKI-52466 (5 and 10mg/kg, acute and chronic administration) before passive avoidance training. Task performance was evaluated 2h and 24h after training. A significant reduction in [(3)H]AMPA binding was found in the hippocampal formation of SD animals, while no alterations were observed in GluR1 mRNA levels. The highest dose of aniracetam (100mg/kg) reverted SD-induced impairment of passive avoidance performance in both retention tests, whereas GYKI-52466 treatment had no effect. Pharmacological enhancement of AMPAR function may revert hippocampal-dependent learning impairments produced after SD. We argue that such effects might be associated with reduced AMPAR binding in the hippocampus of sleep deprived animals.

Reduced hippocampal dentate cell proliferation and impaired spatial memory performance in aged-epileptic rats.

Increased adult neurogenesis is observed after training in hippocampal-dependent tasks and also after acutely induced status epilepticus (SE) although the specific roles of these cells are still a matter of debate. In this study, we investigated hippocampal cell proliferation and differentiation and the spatial learning performance in young or aged chronically epileptic rats. Status was induced by pilocarpine in 3 or 20-month old rats. Either 2 or 20 months later, rats were treated with bromodeoxyuridine (BrdU) and subsequently underwent to 8-day schedule of water maze (WM) tests. As expected, learning curves were faster in young than in aged animals (P < 0.001). Chronically epileptic animals exhibited impaired learning curves compared to age-matched controls. Interestingly, the duration of epilepsy (2 or 20 months) did not correlate with the memory impairment of aged-epileptic animals. The number of BrdU-positive cells was greater in young-epileptic subjects than in age-matched controls. In contrast, cell proliferation was not increased in aged-epileptic animals, irrespective of the time of SE induction. Finally, dentate cell proliferation was not related to performance in the WM. Based on the present results we conclude that even though aging and epilepsy lead to impairments in spatial learning, their effects are not additive.