Abnormal wiring of CCK⁺ basket cells disrupts spatial information coding

The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 was required for the normal integration into cortical circuits of basket cells expressing CCK and vesicular glutamate transporter 3 (VGlut3). The number of inhibitory synapses made by CCK+VGlut3+ basket cells and the inhibitory drive they exerted on pyramidal cells were reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminished the power of theta oscillations during exploratory behavior, disrupted spatial coding by place cells, and caused selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK+ basket cells in cortical networks is key to support spatial coding in the hippocampus.Supported by grants from Fundación Alicia Koplowitz and the European Research Council (ERC-2012-StG 310021) to B.R., from the European Research Council (ERC-2011-AdG 293683) to O.M., from the Spanish G293683overnment (CONSOLIDER CSD2007-00023) and Lilly Research Awards Program to B.R. and O.M, and from the French government (ANR-10-EQX-008-1 to A.M. and LabEX BRAIN ANR-10-LABX-43 to A.F. and A.M.). O.M. and B.R. are Wellcome Trust Investigators.Peer reviewe

Hippocampal-Dependent Spatial Memory in the Water Maze is Preserved in an Experimental Model of Temporal Lobe Epilepsy in Rats

Cognitive impairment is a major concern in temporal lobe epilepsy (TLE). While different experimental models have been used to characterize TLE-related cognitive deficits, little is known on whether a particular deficit is more associated with the underlying brain injuries than with the epileptic condition per se. Here, we look at the relationship between the pattern of brain damage and spatial memory deficits in two chronic models of TLE (lithium-pilocarpine, LIP and kainic acid, KA) from two different rat strains (Wistar and Sprague-Dawley) using the Morris water maze and the elevated plus maze in combination with MRI imaging and post-morten neuronal immunostaining. We found fundamental differences between LIP- and KA-treated epileptic rats regarding spatial memory deficits and anxiety. LIP-treated animals from both strains showed significant impairment in the acquisition and retention of spatial memory, and were unable to learn a cued version of the task. In contrast, KA-treated rats were differently affected. Sprague-Dawley KA-treated rats learned less efficiently than Wistar KA-treated animals, which performed similar to control rats in the acquisition and in a probe trial testing for spatial memory. Different anxiety levels and the extension of brain lesions affecting the hippocampus and the amydgala concur with spatial memory deficits observed in epileptic rats. Hence, our results suggest that hippocampal-dependent spatial memory is not necessarily affected in TLE and that comorbidity between spatial deficits and anxiety is more related with the underlying brain lesions than with the epileptic condition per se

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Spatial periodic firing in the subiculum of mice

Resumen del póster presentado en el 19th National Meeting of the Spanish Society of Neuroscience, celebrado en Lleida (España), del 3 al 5 de noviembre de 2021Spatial cognition relies on a complex circuitry in which the hippocampal formation seems to be crucial. The subiculum is a region located at the core of this circuit, it receives inputs from grid cells located in the medial entorhinal cortex (MEC) and place cells from the CA1 area of the hippocampus. It integrates input from these two relevant spatial information sources and mediates the output from the hippocampus to cortical and subcortical areas also involved in spatial coding. Despite the potential relevance of the subiculum, its role in memory and spatial coding is still poorly understood. Previous work described a very heterogeneous population of spatial neurons in the subiculum, with evidence of its role in coding the geometry of the environment and in spatial navigation in darkness. However, its role in spatial coding remains to be unveiled. With the aim of understanding further the properties of spatial coding in the subiculum, we implanted mice with microdrives mounting tetrodes and multisite electrodes aiming at the CA1 and subicular area, and recorded neuronal activity across different behavioral paradigms. Our results indicate that place cells in CA1 present higher spatial resolution and sharper firing fields than those of subicular neurons. Also, place cells in the CA1 area seem to be differentially modulated by the local field potential. Interestingly, we found pyramidal neurons in the subiculum with periodic firing, the first evidence of this type of regular firing in subicular pyramidal neurons.Peer reviewe

Stability of subicular place fields across multiple light and dark transitions

Although hippocampal CA1 place cells can be strongly modulated by visual inputs, the effect of visual modulation on place cells in other areas of the hippocampal formation, such as the subiculum, has been less extensively explored. Here, we investigated the role of visual inputs on the activity of subicular place cells by manipulating ambient light levels while freely-moving rats foraged for food. Rats were implanted with tetrodes in the dorsal subiculum and units were recorded while the animal performed a pellet-chasing task during multiple light-to-dark and dark-to-light transitions. We found that subicular place fields presented a somewhat heterogeneous response to light-dark transitions, with 45% of pyramidal units showing stable locational firing across multiple light-dark-light transitions. These data suggest that visual inputs may participate in spatial information processing by the subiculum. However, as a plurality of units was stable across light-dark transitions, we suggest that the subiculum supports, probably in association with the grid cells of the entorhinal cortex, the neurocognitive processing underlying path integration. © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.The grant sponsor were the European Commission (MSVS) Higher Education Authority Programme for Research in Third-Level Institutions (SMOM). The grant number was PRESENCCIA EU FP6-027731 and SF (Synthetic Forager) FP7- ICT-217148 to M.V.S.-V.Peer Reviewe

NMDAr blocking by MK801 produces specific oscillatory changes in the hippocampus and the prefrontal cortex impairing working memory and place cell firing

Trabajo presentado al 19th Meeting Spanish Society of Neuroscience, celebrado en Lleida del 3 al 5 de noviembre de 20231.Information processing in the brain depends on the dialog between different regions orchestrated by oscillatory activity, especially theta (4-12 Hz) and gamma rhythms (30-100Hz). Clinical and basic research has confirmed a strong relationship between cognitive impairment and distortion of these rhythms in Schizophrenia. It is hypothesized that these oscillopathies originate from alterations of the excitatoryinhibitory (E-I) balance. Therefore, unveiling the relationship between brain rhythms and cognition is crucial for understanding the cognitive manifestations of Schizophrenia. In this work, we aimed to investigate how changes in the E-I balance might reproduce rhythm and behavioral alterations. We used a mouse pharmacological model of schizophrenia, administering MK801 to adult wild-type mice, an NMDAr blocker known to alter interneuron and pyramidal activity. Mice were implanted with microdrives mounting tetrodes aimed to the dorsal hippocampus and medial prefrontal cortex (mPFC). Then brain activity was recorded while mice performed spontaneous exploration in an open field, and while testing working memory in the y-maze, after the administration of MK801 or vehicle. Our results proved that NMDAr blocking exerts differential effects in the oscillatory activity of the hippocampus and the mPFC. While in CA1 and subiculum MK801 produced an increase in gamma oscillations and a distortion of theta/gamma coupling, mPFC activity was characterized by an augmentation of theta, gamma and emergence of high frequency oscillations (HFO, 155-185 Hz). Interestingly HFO in the mPFC was strongly modulated by local theta activity. In addition, we observed an increase in CA1-mPFC coherence in the delta and alpha band, changes in locomotor behavior, defective place cell function and impaired working memory in the y-maze. We observed that CA1 theta/gamma modulation was enhanced during right alternation in the y-maze, but none of the oscillatory changes produced by MK801 could predict performance in the y-maze.Peer reviewe

Heterogeneous spatial representation by different subpopulations of neurons in the subiculum

The subiculum is a pivotal structure located in the hippocampal formation that receives inputs from grid and place cells and that mediates the output from the hippocampus to cortical and sub-cortical areas. Previous studies have demonstrated the existence of boundary vector cells (BVC) in the subiculum, as well as exceptional stability during recordings conducted in the dark, suggesting that the subiculum is involved in the coding of allocentric cues and also in path integration. In order to better understand the role of the subiculum in spatial processing and the coding of external cues, we recorded subicular units in freely moving rats while performing two experiments: the “size experiment” in which we modified the arena size, and the “barrier experiment” in which we inserted new barriers in a familiar open field thus dividing the enclosure into four comparable sub-chambers. We hypothesized that if physical boundaries were deterministic of the firing of subicular units a strong spatial replication pattern would be found in most spatially modulated units. In contrast, our results demonstrate heterogeneous space coding by different cell types: place cells, barrier-related units and BVC. We also found units characterized by narrow spike waveforms, most likely belonging to axonal recordings, that showed grid-like patterns. Our data indicate that the subiculum codes space in a flexible manner, and that it is involved in the processing of allocentric information, external cues and path integration, thus broadly supporting spatial navigation.This work was supported by the European Commission PRESENCCIA EU FP6-027731 and SF FP7-ICT-217148 (MSVS) and the Higher Education Authority Program for Research in Third-Level Institutions (Ireland) (SMOM). During part of the development of this work Stefan Schaffelhofer was supported by the Feodor-Lynen Fellowship-Germany.Peer reviewe

Basic properties of somatosensory-evoked responses in the dorsal hippocampus of the rat

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