Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by ...the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington's disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin's gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington's disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington's disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington's disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington's disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington's disease.
Chronic Levodopa therapy, the gold-standard treatment for Parkinson's Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulation ...has been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulation induces LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving LID mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effects of cerebellar stimulation. Moreover, cerebellar stimulation reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide motor network, and may be valuable for LID treatment.
•Hebbian protocols induce bidirectional plasticity (LTP and LTD) in the striatum.•Multiple pathways interact to induce activity-dependent STDP in the striatum.•Recent studies link goal-directed and ...procedural learning with striatal plasticity.•Solving the distal reward problem with eligibility traces and striatal plasticity.
The striatum, the main input nucleus of the basal ganglia, controls goal-directed behavior and procedural learning. Striatal projection neurons integrate glutamatergic inputs from cortex and thalamus together with neuromodulatory systems, and are subjected to plasticity. Striatal projection neurons exhibit bidirectional plasticity (LTP and LTD) when exposed to Hebbian paradigms. Importantly, correlative and even causal links between procedural learning and striatal plasticity have recently been shown. This short review summarizes the current view on striatal plasticity (with a focus on spike-timing-dependent plasticity), recent studies aiming at bridging in vivo skill acquisition and striatal plasticity, the temporal credit-assignment problem, and the gaps that remain to be filled.
In response to the COVID-19 pandemic, the World Health Organization established a number of key recommendations such as educational activities especially within primary care practices (PCPs) which ...are a key component of this strategy. This paper aims to examine the educational activities of PCPs during COVID-19 pandemic and to identify the factors associated with these practices across 38 countries.
A "Patient Education (PE)" score was created based on responses to six items from the self-reported questionnaire among PCPs (n = 3638) compiled by the PRICOV-19 study. Statistical analyses were performed on 3638 cases, with PCPs with missing PE score values were excluded.
The PE score features a mean of 2.55 (SD = 0.68) and a median of 2.50 (2.16 - 3.00), with a maximum of 4.00, and varies quite widely between countries. Among all PCPs characteristics, these factors significantly increase the PE score: the payment system type (with a capitation payment system or another system compared to the fee for service), the perception of average PCP with patients with chronic conditions and the perception of adequate governmental support.
The model presented in this article is still incomplete and requires further investigation to identify other configuration elements favorable to educational activities. However, the results already highlight certain levers that will enable the development of this educational approach appropriate to primary care.
Rosemary (Rosmarinus officinalis L.) is a perennial herb with an intensive aromatic flavor. Its most important chemical constituents are essential oils (e.g., 1,8-cineole and camphor) and ...antioxidants (e.g., carnosic acid and rosmarinic acid). The common methods to extract the essential oil of rosemary are steam or hydro distillation. The aim of this work is to investigate the residual antioxidants after hydro distillation, especially rosmarinic acid and carnosic acid. For this purpose, the hydro distillation water residues were analyzed by HPLC-UV. Moreover, the influence of the extraction duration on the concentration of the antioxidants was investigated. Also, the residual amount of these compounds in the leaves was examined. The total antioxidant activity of the extracts and of the pure compounds was determined by DPPH assays. It is shown that after 2.5 h of hydro distillation the amount of rosmarinic acid and the antioxidant activity in the water residue reaches a maximum value. In addition, the yield and the quality of the essential oil were investigated to draw a comparison between steam and hydro distillations of Moroccan rosemary leaves.
Le romarin (Rosmarinus officinalis L.) est une plante aromatique pérenne. Ses composants chimiques principaux sont les huiles essentielles (par exemple de 1,8-cineol, de camphre) et les antioxydants (par exemple l'acide carnosique, l'acide rosmarinique). Les méthodes traditionnelles pour extraire l'huile essentielle de romarin sont la distillation par entraînement à la vapeur et l'hydrodistillation. L'objectif de ce travail est l'étude des antioxydants résiduels après l'hydrodistillation, en particulier de l'acide rosmarinique et carnosique. Pour atteindre cet objectif, l'eau résiduelle de l'hydrodistillation a été analysée par HPLC-UV. De plus, l'influence de la durée d'extraction sur la concentration des antioxydants a été étudiée. La quantité résiduelle de ces composants dans les feuilles a également été examinée. L'activité antioxydant totale de ces extraits et celle des composants purs a été déterminée en utilisant le DPPH comme molécule test. Il a été montré que la quantité d'acide rosmarinique et l'activité antioxydant de l'eau résiduelle atteignent une valeur maximale après 2,5 h d'hydrodistillation. Le rendement et la qualité de l'huile essentielle ont également été étudiés pour comparer la distillation par entraînement à la vapeur et l'hydrodistillation des feuilles de romarin marocain.
Abstract
The striatum integrates inputs from the cortex and thalamus, which display concomitant or sequential activity. The striatum assists in forming memory, with acquisition of the behavioral ...repertoire being associated with corticostriatal (CS) plasticity. The literature has mainly focused on that CS plasticity, and little remains known about thalamostriatal (TS) plasticity rules or CS and TS plasticity interactions. We undertook here the study of these plasticity rules. We found bidirectional Hebbian and anti-Hebbian spike-timing-dependent plasticity (STDP) at the thalamic and cortical inputs, respectively, which were driving concurrent changes at the striatal synapses. Moreover, TS- and CS-STDP induced heterosynaptic plasticity. We developed a calcium-based mathematical model of the coupled TS and CS plasticity, and simulations predict complex changes in the CS and TS plasticity maps depending on the precise cortex–thalamus–striatum engram. These predictions were experimentally validated using triplet-based STDP stimulations, which revealed the significant remodeling of the CS-STDP map upon TS activity, which is notably the induction of the LTD areas in the CS-STDP for specific timing regimes. TS-STDP exerts a greater influence on CS plasticity than CS-STDP on TS plasticity. These findings highlight the major impact of precise timing in cortical and thalamic activity for the memory engram of striatal synapses.
The striatum mediates two learning modalities: goal-directed behavior in dorsomedial (DMS) and habits in dorsolateral (DLS) striata. The synaptic bases of these learnings are still elusive. Indeed, ...while ample research has described DLS plasticity, little remains known about DMS plasticity and its involvement in procedural learning. Here, we find symmetric and asymmetric anti-Hebbian spike-timing-dependent plasticity (STDP) in DMS and DLS, respectively, with opposite plasticity dominance upon increasing corticostriatal activity. During motor-skill learning, plasticity is engaged in DMS and striatonigral DLS neurons only during early learning stages, whereas striatopallidal DLS neurons are mobilized only during late phases. With a mathematical modeling approach, we find that symmetric anti-Hebbian STDP favors memory flexibility, while asymmetric anti-Hebbian STDP favors memory maintenance, consistent with memory processes at play in procedural learning.
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•Opposite plasticity in DMS and DLS dominate with increased corticostriatal activity•DMS expresses symmetric and DLS asymmetric anti-Hebbian corticostriatal STDP•Distinct anti-Hebbian STDP theoretically favors memory flexibility or maintenance•Early versus late phase of motor skill learning involves region- and input-specific STDP
Perez et al. show that medium spiny neurons in the dorsal striatum exhibit opposite forms of plasticity, which are region (dorsolateral versus dorsomedial)- and input (stritonigral versus striatopallidal)-specific and that reflect memory flexibility or memory maintenance, consistent with memory processes at play in procedural learning.
Tensions are generated by the inevitable presence of dogs accompanying humans in cities. Built-up outdoor areas, spaces that are “in between” the home and dog parks, are widely frequented by dogs and ...their owners. The present case study, performed in Lyon (France), is the first to provide a description of these dyads in areas that vary according to terrain, district, dog legislation and use in three areas: a busy street where dogs are allowed and a park and a square where dogs are forbidden. Dog-owner profiles were identified. They adjusted their presence differently across areas and according to anthropogenic and ecological pressures, such as day of the week, time of day, weather, frequentation, and legislation. They mutually adapted their behaviors. Interactions between dogs or owners and other social agents were few; dogs primarily sniffed and urinated. There was little barking, no aggression, minor impact on the environment, and, despite instances of dogs appropriating forbidden areas and dogs off their leashes, the dogs seemed to go virtually unnoticed. The study shows how the need for more-than-human areas is evident in outdoor built-up areas (for instance, the results on types of interaction and activity across areas, absence of a leash, and appropriation of forbidden areas) as well as how the cultural and natural aspects of dogs play out. The results suggest that dog regulations should be adjusted in outdoor built-up areas and that dog parks should be developed.
Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which ...nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, post-prandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TGs directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior.
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•Dopamine receptor type 2 (DRD2)-expressing neurons respond to dietary triglycerides (TGs)•Dietary TGs modulate dopamine-dependent behaviors•Lipoprotein lipase participates in the action of TGs on the reward circuit•In humans, plasma TGs influence brain responses to food
Dietary triglycerides (TGs) can gate dopamine receptor type 2 (DRD2)-expressing neurons’ activity and dopamine-dependent behaviors. These results highlight a new physiological mechanism by which nutritional inputs can directly tune reward-associated behaviors and provide a new basis by which energy-rich diets may lead to (mal)adaptations in brain circuits that underlie compulsive behavior.
Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding and weight gain. Yet the mechanisms by which ...nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional TG, a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, post-prandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TG directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior.
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