Early Presymptomatic and Long-Term Changes of Rest Activity Cycles and Cognitive Behavior in a MPTP-Monkey Model of Parkinson's Disease

It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms.Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested.Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits

Réseaux anatomiques fonctions et dysfonctions frontales chez le primate non-humain (vers une approche en recherche préclinique)

La compréhension des mécanismes du traitement de l information a bénéficié de l'essor des techniques d'exploration structurelle et fonctionnelle des aires corticales. Des fonctions spécifiques sont associées à des aires spécifiques du cerveau, définies par leur cytoarchitecture, connectivité et propriétés électrophysiologiques; cependant c'est de l'activité globale des différents réseaux corticaux spécialisés que les processus sensoriels et cognitifs sont supposés émerger. Partant de la connectivite neuronale d'une aire frontale visuelle chez le singe nous verrons que nos descriptions d une organisation hiérarchique du système visuel constituent une véritable base conceptuelle pour la compréhension des relations structure-fonction du cerveau. Dans ce contexte, j'ai initié une étude des fonctions frontales chez le primate non-humain et leurs dépendances au système dopaminergique. Grâce au développement d enregistrements chroniques permettant de caractériser et suivre à long terme des marqueurs neurophysiologiques émis lors d une tâche cognitive, j ai pu montrer l altération des marqueurs aux cours d apprentissages et tester leur dépendance au système dopaminergique. Cette étude a permis de valider l approche pour la caractérisation fonctionnelle des troubles cognitifs précoces chez le modèle singe de la maladie de Parkinson (traitement avec de faibles doses de MPTP). En utilisant ce modèle j'ai ainsi pu (i) décrire finement l'évolution de troubles moteurs et non-moteurs caractéristiques de la maladie, (ii) confirmer que les altérations cognitives et circadiennes précèdent l'entrée en phase symptomatique, et (iii) mettre en place un programme d étude sur le suivi longitudinal des marqueurs physiologiques frontaux en phase pré symptomatique et après thérapie cellulaire. Les perspectives de cette thèse sont ainsi de permettre l'évaluation de la réparation de réseaux neuronaux dans un modèle primate préclinique, et de montrer la faisabilité de l exploitation des cellules ES en thérapie cellulaire dans le cadre des maladies neurodégénératives. Une grande diversité de pathologies neurologiques devrait bénéficier de la mise en oeuvre de thérapies de remplacement cellulaire basée sur la différenciation neuronale des cellules souches embryonnairesUnderstanding information processing mechanisms benefited from the expansion of structural and functional exploration techniques of cortical areas. Specific functions have been associated to specific brain areas defined in terms of cytoarchitecture, connectivity and electrophysiological properties; however, sensorial and cognitive processes are supposed to emerge from global activity arising from different cortical networks. From neuronal connectivity pattern of a visual frontal area in monkey we will see that our descriptions of visual system hierarchical organisation constitute a real conceptual framework for the understanding of brain structure-function relationships. In this context, I initiated a study of frontal functions in non-human primate and their dependencies to dopaminergic system. The development of chronic recordings allowing characterization and long-term follow-up of neurophysiological markers produced during a cognitive task, led me show the existence of alterations during learning stages and dependency to dopaminergic system. This study permitted the validation of this approach for functional characterization of early cognitive troubles in a monkey model of Parkinson's Disease (chronic low-doses mptp treatment). Using this model I could (i) describe precisely evolution of motor and non-motor troubles characteristic of the disease, (ii) confirm that cognitive and circadian alterations predate the entry in symptomatic state and (iii) set up a study program on the longitudinal follow-up of frontal physiological markers in pre-symptomatic phase and after cellular therapy. Perspectives of this thesis are hence directed toward the evaluation of neuronal networks repair in a preclinical primate model and to demonstrate applicability of ES cells exploitation for cellular therapy in neurodegenerative diseases. A large diversity of neurological pathologies should benefit from cellular therapy based on neural differentiation of embryonic stem cellsLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Expectations, gains, and losses in the anterior cingulate cortex.: Expectation, gains, and losses in ACC

International audienceThe anterior cingulate cortex (ACC) participates in evaluating actions and outcomes. Little is known on how action-reward values are processed in ACC and if the context in which actions are performed influences this processing. In the present article, we report ACC unit activity of monkeys performing two tasks. The first task tested whether the encoding of reward values is co ntext dependent-that is, dependent on the size of theother rewards that are available in the current block of trials. The second task tested whether unexpected events signaling a change in reward are represented. We show that the context created by a block design (i.e., the context of possible alternative rewards) influences the encoding of reward values, even if no decision or choice is required. ACC activity encodes the relative and not absolute expected reward values. Moreover, cingulate activitysignals and evaluates when reward expectations are violated by unexpected stimuli, indicating reward gains or losses

Cortical Hierarchy, Dual Counterstream Architecture and The Importance of Top-Down Generative Networks

International audienceHierarchy is a major organizational principle of the cortex and underscores modern computational theories of cortical function. The local microcircuit amplifies long-distance inter-areal input, which show distance-dependent changes in their laminar profiles. Statistical modeling of these changes in laminar profiles demonstrates that inputs from multiple hierarchical levels to their target areas show remarkable consistency, allowing the construction of a cortical hierarchy based on a principle of hierarchical distance. The statistical modeling that is applied to structure can also be applied to laminar differences in the oscillatory coherence between areas thereby determining a functional hierarchy of the cortex. Close examination of the anatomy of inter-areal connectivity reveals a dual counterstream architecture with well-defined distance-dependent feedback and feedforward pathways in both the supra- and infragranular layers, suggesting a multiplicity of feedback pathways with well-defined functional properties. These findings are consistent with feedback connections providing a generative network involved in a wide range of cognitive functions. A dynamical model constrained by connectivity data sheds insight into the experimentally observed signatures of frequency-dependent Granger causality for feedforward versus feedback signaling. Concerted experiments capitalizing on recent technical advances and combining tract-tracing, high-resolution fMRI, optogenetics and mathematical modeling hold the promise of a much improved understanding of lamina-constrained mechanisms of neural computation and cognition. However, because inter-areal interactions involve cortical layers that have been the target of important evolutionary changes in the primate lineage, these investigations will need to include human and non-human primate comparisons

Human Brain Project Partnering Projects Meeting: Status Quo and Outlook

International audienceAs the European Flagship Human Brain Project (HBP) ends in September 2023, a meeting dedicated to the Partnering Projects (PPs), a collective of independent research groups that partnered with the HBP, was held on September 4–7, 2022. The purpose of this meeting was to allow these groups to present their results, reflect on their collaboration with the HBP and discuss future interactions with the European Research Infrastructure (RI) EBRAINS that has emerged from the HBP. In this report, we share the tour-de-force that the Partnering Projects that were present in the meeting have made in furthering knowledge concerning various aspects of Brain Research with the HBP. We describe briefly major achievements of the HBP Partnering Projects in terms of a systems-level understanding of the functional architecture of the brain and its possible emulation in artificial systems. We then recapitulate open discussions with EBRAINS representatives about the evolution of EBRAINS as a sustainable Research Infrastructure for the Partnering Projects after the HBP, and also for the wider scientific community

Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss

Hierarchical order in the cortex.

Strong regularities of early visual areas interconnections led to the suggestion that rostral directed connections are feedforward (FF) pathways channelling information from lower to higher order areas, while caudal directed connections constitute feedback (FB) pathways (Rockland and Pandya, 1979). Analysis of these pathways in primate enabled the identification of a hierarchical organization (Felleman and Van Essen, 1991), providing a major conceptual framework for understanding structure-function relationships of the cortex. Because previous description of cortical topology have been restricted to binary connectivity leading to strong indeterminacy (Hilgetag et al., 1996), we re-examined network description of cortex structure by making retrograde tracer injections in areas spanning all cortical lobes. We used quantitative tools to estimate hierarchical distance and relative weights of connections (Barone et al., 2000, Vezoli et al., 2004) and used computational modeling analysis to analyse the underlying hierarchical structure of cortical networks. Comparing weighted and unweighted analyses, we demonstrated a significant hierarchical tendency in the pattern of laminar relations between cortical areas. Further, we evidenced a highly parallel system with high degree of reciprocity and found that rare pairs of areas are reciprocally connected by FF connections, constituting unexpected descending paths (Crick and Koch, 1998) in an otherwise surprisingly hierarchical system of cortical areas