Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease

Studying animal models furthers our understanding of Parkinson’s disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson’s disease in mice

Induction de crises focales utilisant une stimulation cérébrale profonde via des champs électriques interférant temporellement

Chez les patients atteints d’épilepsie focale pharmaco-résistante, la stimulation électrique intracrânienne est utilisée lors de la localisation des zones épileptogènes et des réseaux pathologiques associés. Les tissus stimulés électriquement génèrent des oscillations de gammes bêta et gamma appelées décharges rapides qui indiquent une zone épileptogène. Cependant, il existe des limites à la stimulation intracrânienne comme l’emplacement fixe des électrodes et leur nombre implantées, laissant de nombreuses régions du cerveau inexplorées. Cette thèse présente une technique alternative qui repose exclusivement sur des électrodes de surface non pénétrante, permettant l’application de champs électriques à interférence temporelle (TI) mais aussi avec orientation réglable. Le but est de cibler le CA3 de l’hippocampe chez la souris qui évoque de manière focalisée des événements de type crise (SLE) ayant les fréquences caractéristiques des décharges rapides mais sans la nécessité des électrodes implantées. L’orientation des électrodes par rapport à celle de l’hippocampe contrôle fortement le seuil d’évocation des SLE. Une analyse dépendante de l’orientation des électrodes classiques implantées pour évoquer les SLE dans l’hippocampe est ensuite utilisée pour étayer les résultats des champs à interférence temporelle mini-invasive. Les principes de la stimulation TI à orientation réglable que l’on voit ici peuvent être ainsi applicables à un large éventail d’autres tissus et régions cérébrales excitables. Ceci permettrait de surmonter les limitations des électrodes fixes qui pénètrent dans les tissus mais aussi celles d’autres méthodes de stimulation non invasives dans l’épilepsie.In patients with focal drug-resistant epilepsy, intracranial electrical stimulation is frequently used for the seizure onset zones localization and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. In this thesis, I present and describe an alternative technique relying exclusively on non-penetrating surface electrodes, namely an orientation-tunable form of temporally-interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally-invasive temporally-interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue and overcoming several limitations of other noninvasive stimulation methods in epilepsy, such as transcranial magnetic stimulation (TMS)

The Kainic Acid Models of Temporal Lobe Epilepsy

Experimental models of epilepsy are useful to identify potential mechanisms of epileptogenesis, seizure genesis, comorbidities, and treatment efficacy. The kainic acid (KA) model is one of the most commonly used. Several modes of administration of KA exist, each producing different effects in a strain-, species-, gender-, and age-dependent manner. In this review, we discuss the advantages and limitations of the various forms of KA administration (systemic, intrahippocampal, and intranasal), as well as the histologic, electrophysiological, and behavioral outcomes in different strains and species. We attempt a personal perspective and discuss areas where work is needed. The diversity of KA models and their outcomes offers researchers a rich palette of phenotypes, which may be relevant to specific traits found in patients with temporal lobe epilepsy.Funding Agencies|Excellence Initiative of Aix-Marseille University (A*MIDEX), a French "Investissements dAvenir" programFrench National Research Agency (ANR); European Research Council under the European Unions Horizon 2020 Research and Innovation Program [716867]; Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation</p

Orientation of Temporal Interference for Non-invasive Deep Brain Stimulation in Epilepsy

In patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on non-penetrating surface electrodes, namely an orientation-tunable form of temporally interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of Pulse-width-modulation of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally invasive temporally interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue and overcoming several limitations of other non-invasive stimulation methods in epilepsy, such as transcranial magnetic stimulation (TMS).Funding Agencies|European Research Council (ERC) under the European Unions Horizon 2020 Research and Innovation ProgramEuropean Research Council (ERC) [716867]; Excellence Initiative of Aix- Marseille University-AMIDEX, a French "Investissements dAvenir" programFrench National Research Agency (ANR); Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation</p