The relationship between physical activity, apolipoprotein e ϵ4 carriage, and brain health

Background: Neuronal hyperexcitability and hypersynchrony have been described as key features of neurophysiological dysfunctions in the Alzheimer's disease (AD) continuum. Conversely, physical activity (PA) has been associated with improved brain health and reduced AD risk. However, there is controversy regarding whether AD genetic risk (in terms of APOE ϵ4 carriage) modulates these relationships. The utilization of multiple outcome measures within one sample may strengthen our understanding of this complex phenomenon. Method: The relationship between PA and functional connectivity (FC) was examined in a sample of 107 healthy older adults using magnetoencephalography. Additionally, we explored whether ϵ4 carriage modulates this association. The correlation between FC and brain structural integrity, cognition, and mood was also investigated. Results: A relationship between higher PA and decreased FC (hyposynchrony) in the left temporal lobe was observed among all individuals (across the whole sample, in ϵ4 carriers, and in ϵ4 non-carriers), but its effects manifest differently according to genetic risk. In ϵ4 carriers, we report an association between this region-specific FC profile and preserved brain structure (greater gray matter volumes and higher integrity of white matter tracts). In this group, decreased FC also correlated with reduced anxiety levels. In ϵ4 non-carriers, this profile is associated with improved cognition (working and episodic memory). Conclusions: PA could mitigate the increase in FC (hypersynchronization) that characterizes preclinical AD, being beneficial for all individuals, especially ϵ4 carriers.This study was funded by the Spanish Ministry of Economy and Competitiveness under the Grant PSI2015-68793-C3-1-R [D601] and by the project B2017/BMD-3760 from NEUROCENTRO. Complimentary, it was supported by a predoctoral fellowship from La Caixa Foundation to JFL, a postdoctoral fellowship from the Spanish Ministry of Economy and Competitiveness to PC (FJCI-2015-26755), a grant from the Spanish Ministry of Science, Innovation and Universities to JVR (FJCI-2017-33396), and a predoctoral grant by the Spanish Ministry of Economy (BES-2016-076869) to FRT

Interventional programmes to improve cognition during healthy and pathological ageing: Cortical modulations and evidence for brain plasticity

Available online 06 March 2018A growing body of evidence suggests that healthy elderly individuals and patients with Alzheimer’s disease retain an important potential for neuroplasticity. This review summarizes studies investigating the modulation of neural activity and structural brain integrity in response to interventions involving cognitive training, physical exercise and non-invasive brain stimulation in healthy elderly and cognitively impaired subjects (including patients with mild cognitive impairment (MCI) and Alzheimer’s disease). Moreover, given the clinical relevance of neuroplasticity, we discuss how evidence for neuroplasticity can be inferred from the functional and structural brain changes observed after implementing these interventions. We emphasize that multimodal programmes, which combine several types of interventions, improve cognitive function to a greater extent than programmes that use a single interventional approach. We suggest specific methods for weighting the relative importance of cognitive training, physical exercise and non-invasive brain stimulation according to the functional and structural state of the brain of the targeted subject to maximize the cognitive improvements induced by multimodal programmes.This study was funded by the European Commission Marie-Skłodowska Curie Actions, Individual Fellowships; 655423-NIBSAD, Italian Ministry of HealthGR-2011-02349998, and Galician government (Postdoctoral Grants Plan I2C 2011-2015)

Development of an hiPSC-Cortical Neuron Long-Term Potentiation Model and its Application to Alzheimer\u27s Disease Modeling and Drug Evaluation

Alzheimer\u27s disease (AD) is commonly characterized by a loss of cognitive function due to the deterioration of neuronal synapses from the presence of senile amyloid beta-42 (Aß42) plaques. Evaluating cognitive deficits caused by Aß42 using human cortical neurons poses a challenge due to sourcing difficulties, and the use of animal models to assess drug efficacy creates biological hurdles from lack of species translatability. Recent advances in induced-pluripotent stem cell technology have enabled the development of mature, human-based cortical neuron models. The development of an hiPSC-cortical neuron differentiation protocol facilitates the exploration of disease onset and functional analysis from a patient-derived cell source, and further investigation of potential therapeutic treatments, while eliminating biological efficacy concerns. Long-term potentiation (LTP) was utilized as an in vitro correlate for memory and learning to quantify cognitive deficits in sporadic AD (SAD) and familial AD (FAD) systems and assess drug treatments for the prevention of Aß42-induced neurotoxicity. Synaptic connectivity and LTP induction through high-frequency stimulation was simulated through cortical neurons cultured on microelectrode arrays (MEAs), such that the functional activity of the neuronal population could be assessed overtime. AD therapeutic treatments were shown to block the Aß42-induced neurotoxic loss of synaptic plasticity and maintain persistent LTP in a model for SAD. Subsequently, FAD was assessed through the differentiation of patient-derived AD iPSCs, where LTP proficiency could be evaluated to relate to clinical cognitive evaluations. This study established a serum-free, in vitro human-derived iPSC-cortical neuron protocol that could be adapted to validate disease mechanisms and drug efficacy in patient-derived neural networks as a potential platform for precision medicine

Investigating the Cortical, Metabolic and Behavioral Effects of Transcranial Direct Current Stimulation in Preparation for Combined Rehabilitation

The goal of this thesis was to determine the cortical reorganization that occurs in patients with cervical spondylotic myelopathy (CSM) after surgical decompression and to implement this knowledge into a new rehabilitation strategy. Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate human behavior. Due to the novel electrode montage used, it was first pertinent that we determine how tDCS would modulate cortical, metabolic and motor behavior in healthy individuals. We observed the longitudinal functional adaptations that occur in patients with CSM using functional MRI. Enhanced excitation of supplementary motor area (SMA) was observed following surgical decompression and associated with increased function following surgery. This novel finding of enhanced excitation of motivated us to use a bihemispheric tDCS protocol, exciting bilateral motor areas to provide optimal motor enhancement. This novel tDCS electrode montage, targeting the SMA and primary motor cortex (M1) was implemented in healthy older adults to determine its effects on enhancing manual dexterity. Furthermore, to determine the frequency with which to apply tDCS, a single and tri session protocol was used. We observed a differential pattern of action with anti-phase and in-phase motor tasks during multisession tDCS. We used ultra-high field (7T) MRI to examined the metabolic changes that occur following tDCS. After the stimulation period we observed no significant metabolite modulation. A trend towards an increase in the NAA/tCr ratio, with a concomitant decrease in the absolute concentration of tCr was observed. Finally, we examined the functional connectivity before, during and after tDCS with the use of resting-state fMRI at 7T. We observed enhanced connectivity within right sensorimotor area after stimulation compared to during stimulation. This result confirmed that cortical modulations differ during versus after tDCS, signifying that optimal modulation of behaviour may be after the stimulation period. Furthermore, we observed an enhanced correlation between motor regions and the caudate, both during and after stimulation. In conclusion, we observed novel cortical adaptations in CSM patients after surgical decompression, which led us to believe that bihemispheric tDCS of M1-SMA network would result in optimal motor enhancement and warrants further investigation in CSM and other neurological disorders

Imaging Pain And Brain Plasticity: A Longitudinal Structural Imaging Study

Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation. The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain. The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits. To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4). In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings

Slow Inhibition and Inhibitory Recruitment in the Hippocampal Dentate Gyrus

L’hippocampe joue un rôle central dans la navigation spatiale, la mémoire et l’organisation spatio-temporelle des souvenirs. Ces fonctions sont maintenues par la capacité du gyrus denté (GD) de séparation des patrons d'activité neuronales. Le GD est situé à l’entrée de la formation hippocampique où il reconnaît la présence de nouveaux motifs parmi la densité de signaux afférant arrivant par la voie entorhinale (voie perforante). Le codage parcimonieux est la marque distinctive du GD. Ce type de codage est le résultat de la faible excitabilité intrinsèque des cellules granulaires (CGs) en combinaison avec une inhibition locale prédominante. En particulier, l’inhibition de type « feedforward » ou circuit inhibiteur antérograde, est engagée par la voie perforante en même temps que les CGs. Ainsi les interneurones du circuit antérograde fournissent des signaux GABAergique aux CGs de manière presque simultanée qu’elles reçoivent les signaux glutamatergiques. Cette thèse est centrée sur l’étude des interactions entre ces signaux excitateurs de la voie entorhinale et les signaux inhibiteurs provenant des interneurones résidant dans le GD et ceci dans le contexte du codage parcimonieux et le patron de décharge en rafale caractéristique des cellules granulaires. Nous avons adressé les relations entre les projections entorhinales et le réseau inhibitoire antérograde du GD en faisant des enregistrements électrophysiologiques des CG pendant que la voie perforante est stimulée de manière électrique ou optogénétique. Nous avons découvert un nouvel mécanisme d’inhibition qui apparait à délais dans les CGs suite à une stimulation dans les fréquences gamma. Ce mécanisme induit une hyperpolarisation de longue durée (HLD) et d’une amplitude prononce. Cette longue hyperpolarisation est particulièrement prolongée et dépasse la durée d’autres types d’inhibition transitoire lente décrits chez les CGs. L’induction de HLD crée une fenêtre temporaire de faible excitabilité suite à laquelle le patron de décharge des CGs et l’intégration d’autres signaux excitateurs sont altérés de manière transitoire. Nous avons donc conclu que l’activité inhibitrice antérograde joue un rôle central dans les processus de codage dans le GD. Cependant, alors qu’il existe une multitude d’études décrivant les interneurones qui font partie de ce circuit inhibiteur, la question de comment ces cellules sont recrutées par la voie entorhinale reste quelque peu explorée. Pour apprendre plus à ce sujet, nous avons enregistré des interneurones résidant iii dans la couche moléculaire du GD tout en stimulant la voie perforante de manière optogénétique. Cette méthode de stimulation nous a permis d’induire la libération de glutamate endogène des terminales entorhinales et ainsi d’observer le recrutement purement synaptique d’interneurones. De manière surprenante, les résultats de cette expérience démontrent un faible taux d’activation des interneurones, accompagné d’un tout aussi faible nombre total de potentiels d’action émis en réponse à la stimulation même à haute fréquence. Ce constat semble contre-intuitif étant donné qu’en générale on assume qu’une forte activité inhibitrice est requise pour le maintien du codage parcimonieux. Tout de même, l’analyse des patrons de décharge des interneurones qui ont été activés a fait ressortir la prééminence de trois grands types: décharge précoce, retardée ou régulière par rapport le début des pulses lumineux. Les résultats obtenus durant cette thèse mettent la lumière sur l’important conséquences fonctionnelles des interactions synaptique et polysynaptique de nature transitoire dans les réseaux neuronaux. Nous aimerions aussi souligner l’effet prononcé de l’inhibition à court terme du type prolongée sur l’excitabilité des neurones et leurs capacités d’émettre des potentiels d’action. De plus que cet effet est encore plus prononcé dans le cas de HLD dont la durée dépasse souvent la seconde et altère l’intégration d’autres signaux arrivants simultanément. Donc on croit que les effets de HLD se traduisent au niveau du réseaux neuronal du GD comme une composante cruciale pour le codage parcimonieux. En effet, ce type de codage semble être la marque distinctive de cette région étant donné que nous avons aussi observé un faible niveau d’activation chez les interneurones. Cependant, le manque d’activité accrue du réseau inhibiteur antérograde peut être compensé par le maintien d’un gradient GABAergique constant à travers le GD via l’alternance des trois modes de décharges des interneurones. En conclusion, il semble que le codage parcimonieux dans le GD peut être préservé même en absence d’activité soutenue du réseau inhibiteur antérograde et ceci grâce à des mécanismes alternatives d’inhibition prolongée à court terme.The hippocampus is implicated in spatial navigation, the generation and recall of memories, as well as their spatio-temporal organization. These functions are supported by the processes of pattern separation that occurs in the dentate gyrus (DG). Situated at the entry of the hippocampal formation, the DG is well placed to detect and sort novelty patterns amongst the high-density excitatory signals that arrive via the entorhinal cortex (EC). A hallmark of the DG is sparse encoding that is enabled by a combination of low intrinsic excitability of the principal cells and local inhibition. Feedforward inhibition (FFI) is recruited directly by the EC and simultaneously with the granule cells (GCs). Therefore, FFI provides fast GABA release and shapes input integration at the millisecond time scale. This thesis aimed to investigate the interplay of entorhinal excitatory signals with GCs and interneurons, from the FFI in the DG, in the framework of sparse encoding and GC’s characteristic burst firing. We addressed the long-range excitation – local inhibitory network interactions using electrophysiological recordings of GCs – while applying an electrical or optogenetic stimulation of the perforant path (PP) in the DG. We discovered and described a novel delayed-onset inhibitory post synaptic potential (IPSP) in GCs, following PP stimulation in the gamma frequency range. Most importantly, the IPSP was characterized by a large amplitude and prolonged decay, outlasting previously described slow inhibitory events in GCs. The long-lasting hyperpolarization (LLH) caused by the slow IPSPs generates a low excitability time window, alters the GCs firing pattern, and interferes with other stimuli that arrive simultaneously. FFI is therefore a key player in the computational processes that occurs in the DG. However, while many studies have been dedicated to the description of the various types of the interneurons from the FFI, the question of how these cells are synaptically recruited by the EC remains not entirely elucidated. We tackled this problem by recording from interneurons in the DG molecular layer during PP-specific optogenetic stimulation. Light-driven activation of the EC terminals enabled a purely synaptic recruitment of interneurons via endogenous glutamate release. We found that this method of stimulation recruits only a subset of interneurons. In addition, the total number of action potentials (AP) was surprisingly low even at high frequency stimulation. This result is counterintuitive, as strong and persistent inhibitory signals are assumed to restrict GC v activation and maintain sparseness. However, amongst the early firing interneurons, late and regular spiking patterns were clearly distinguishable. Interestingly, some interneurons expressed LLH similar to the GCs, arguing that it could be a commonly used mechanism for regulation of excitability across the hippocampal network. In summary, we show that slow inhibition can result in a prolonged hyperpolarization that significantly alters concurrent input’s integration. We believe that these interactions contribute to important computational processes such as sparse encoding. Interestingly, sparseness seems to be the hallmark of the DG, as we observed a rather low activation of the interneuron network as well. However, the alternating firing of ML-INs could compensate the lack of persistent activity by the continuous GABA release across the DG. Taken together these results offer an insight into a mechanism of feedforward inhibition serving as a sparse neural code generator in the DG

Etude expérimentale des dynamiques temporelles du comportement normal et pathologique chez le rat et la souris

155 p.Modern neuroscience highlights the need for designing sophisticated behavioral readout of internal cognitive states. From a thorough analysis of classical behavioral test, my results supports the hypothesis that sensory ypersensitivity might be the cause of other behavioural deficits, and confirm the potassium channel BKCa as a potentially relevant molecular target for the development of drug medication against Fragile X Syndrome/Autism Spectrum Disorders. I have also used an innovative device, based on pressure sensors that can non-invasively detect the slightest animal movement with unprecedented sensitivity and time resolution, during spontaneous behaviour. Analysing this signal with sophisticated computational tools, I could demonstrate the outstanding potential of this methodology for behavioural phenotyping in general, and more specifically for the investigation of pain, fear or locomotion in normal mice and models of neurodevelopmental and neurodegenerative disorders