Activity of D1/2 Receptor Expressing Neurons in the Nucleus Accumbens Regulates Running, Locomotion, and Food Intake

While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The NAc is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have distinct functions in regulating reward behavior and require further examination. The goal of the present study is to investigate how activation and inhibition of D1 and D2 neurons in the NAc influences behaviors related to energy intake and expenditure. Specific manipulation of D1 vs D2 neurons was done in both low expenditure and high expenditure (wheel running) conditions to assess behavioral effects in these different states. Direct control of neural activity was achieved using a DREADD (Designer Receptors Exclusively Activated by Designer Drugs) strategy. Activation of NAc D1 neurons increased food intake, wheel running and locomotor activity. In contrast, activation of D2 neurons in the NAc reduced running and locomotion while D2 neuron inhibition had opposite effects. These results highlight the importance of considering both intake and expenditure in the analysis of D1 and D2 neuronal manipulations. Moreover, the behavioral outcomes from D1 NAc neuronal manipulations depend upon the activity state of the animals (wheel running vs non-running). The data support and complement the hypothesis of specific NAc dopamine pathways facilitating energy expenditure and suggest a potential strategy for human weight control

Neuromodulation for motor recovery in stroke patients

Programa de Doctorado en NeurocienciasStroke is a leading cause of disability worldwide. Seeking new therapeutic options is mandatory for improving existing motor rehabilitation techniques to obtain a better motor recovery. Stroke patients undergo some spontaneous degree of functional recovery; this process may occur even beyond the resolution of acute changes and could be due to the reorganization of remaining neural circuits. This reorganization falls into the concept of plasticity that could be defined as any enduring change in cortical properties. Plasticity is continuously modified by experience and learning and seems to be enhanced after brain lesions. In the last decades, plasticity of human brain after a lesion has been studied in vivo by means of non invasive brain stimulation (NIBS): neurophysiologic and biologic substrate of plasticity should provide a rational basis for tailoring specific strategies for therapeutic intervention for stroke recovery. Functional neuroimaging studies have demonstrated that recovered motor function in the paretic hand of chronic stroke patients relies predominantly on reorganized activity within motor areas of the affected hemisphere. Furthermore, changes in gamma-aminobutyric acid (GABA)-ergic activity in perilesional cortex after stroke seem to have a central role in recovery. It can be hypothesized that shaping reorganization in the adjacent intact cortex, and contralateral healthy hemisphere could facilitate functional recovery of the brain after stroke. NIBS can modulate cerebral cortex excitability not invasively and seem to be a promising tool for driving plasticity in damaged brain. The changes induced by NIBS are related to long-term changes in synaptic transmission analogue to long-term potentiation (LTP) and long-term depression (LTD) seen in the hippocampus after repeated activation. Several recent studies demonstrated that induction of LTP-like effects (by facilitatory rTMS and tDCS) in the stroke hemisphere and LTD-like effects (by inhibitory rTMS and tDCS) in healthy hemisphere can enhance the effects of motor rehabilitation after stroke, following the ¿rivalry¿ model theory. Nonetheless, the effects were limited and variable. On the other hand, it was recently demonstrated that rTMS could improve learning via a different mechanism that involves the phenomenon of ¿homeostatic¿ plasticity: a protocol capable of inducing LTD-like effects strongly facilitates motor learning while protocols inducing LTP-like effects have a less pronounced and short-lived facilitatory effect on learning. In the context of stroke this would predict that, contrary to usual practice that uses facilitatory protocols on the affected hemisphere, an inhibitory rTMS protocol (that induces LTD-like effects) over the stroke hemisphere would lead to better relearning in stroke patients through mechanisms of homeostatic metaplasticity. In sum, non-invasive brain stimulation techniques offer the opportunity to evaluate the stroke-induced change in motor cortex functionality and to modify the intra-cortical networks to promote recovery. To this aim, in a group of acute stroke patients we explored intracortical excitability of both hemisphere and looked for a possible correlation with motor recovery. Subsequently, in a different study, we tested whether the contemporary application of an excitatory neuromodulation over the affected hemisphere and an inhibitory neuromodulation over the unaffected hemisphere (following the idea of the rivalry theory) in the sub-acute phase of a stroke could enhance motor recovery. Furthermore we also tested, in a different group of patients, if the application of an inhibitory neuromodulation over the affected hemisphere, in chronic stroke patients could improve motor functionality by means of homeostatic metaplasticity. We found that the acute stroke-induced reduction of intracortical inhibition, indexed by short latency afferent inhibition (SAI), positively correlated with motor improvement at 6 months after stroke. Nevertheless, when a contemporary inhibition of the excitability of healthy hemisphere and a facilitation of the affected hemisphere were induced by means of bilateral tDCS (delivered for 40 minutes daily for 5 consecutive days) during the acute phase after a stroke, a significantly reduction of inter-hemispheric imbalance between affected and unaffected hemispheres was found without any significant change in hand motor function. At last, when an inhibitory plasticity was induced in the affected hemisphere (to achieve any metaplastic change to promote re-learning of motor function) in chronic stroke patients by means of cTBS (1 daily session for 2 weeks), a short lasting improvement in hand motor function was seen. Our studies demonstrated that NIBS, by means of repetitive TMS or tDCS, could be considered a safe procedure to apply in stroke patients both in the acute and chronic phases. On the other hand, we demonstrated that NIBS are able to change motor cortex excitability in stroke patients toward an inter-hemispheric re-balance when applied to increase stroke hemisphere excitability (or decrease unaffected hemisphere excitability) Furthermore, although larger and multi-centric studies are warranted to draw stronger conclusions, the induction of metaplasticity in the affected hemisphere by means of inhibitory protocols could be considered as a useful and promising tool to restore learning and improve motor function also years after a stroke.Universidad Pablo de Olavide de Sevilla. Departamento de Fisiología, Anatomía y Biología CelularPostprin

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.Peer reviewedPublisher PD

Effect of wheat cultivar mixtures on populations of Puccinia striiformis races

This study quantified the frequency of simple versus complex races of Puccinia striiformis Westend. in mixtures of wheat cultivars possessing different race-specific resistance genes. A simple race of a pathogen can infect only one component, and a complex race of the pathogen can infect two or more components of an intraspecific plant mixture. The treatments were designed so that the race that was complex changed depending on the host mixture, thus enabling us to observe the influence of pathogen complexity in different host genetic backgrounds. Six cultivar mixtures and one pure stand of winter wheat were inoculated with three races of P. striiformis (CDL 27, CDL 29, and CDL 41) at two locations for two seasons. Potted plants of three winter wheat cultivars (Paha, Tres, and Tyee) that were each susceptible to one of the three races of the pathogen were used to sample the pathogen during the field epidemics. Disease incidence on the differential cultivars was used to calculate the proportion of the three races in each treatment. The specific cultivars included in the mixtures influenced the frequencies of the three races. Increasing the number of virulent races in a mixture reduced the frequency of the complex race relative to the other two races. When two of the races (races 29 and 41) were complex on the same mixture, location had an effect on which of the races was more frequent. When race 29 was the complex race in the mixture, it was more frequent than when race 41 was the complex race. The results suggest that environmental interactions, genetic background of the pathogen race, host composition, and interaction among pathogen races may be as important in determining race frequencies in mixtures as is stabilizing selection sensu Vanderplank (1968)

A revised diet matrix to improve the parameterization of a West Florida Shelf Ecopath model for understanding harmful algal bloom impacts

Harmful algal blooms (HABs) are a growing concern in the West Florida Shelf (WFS) region. An Ecopath with Ecosim (EwE) model of the WFS explicitly simulating HABs was previously developed to illuminate the potential impacts of blooms of the dinoflagellate Karenia brevis (colloquially referred to as “red tides”) on the WFS ecosystem. However, the diet matrix of the Ecopath component of this EwE model (referred to as “WFS-HAB Ecopath”) was based largely on sparse, cursory information and not on local survey data. Here, we revise the diet matrix of the WFS-HAB Ecopath model using predictions of a robust statistical model that incorporates local survey data and employs the Dirichlet distribution and maximum likelihood estimation. The relative impacts of both the revised diet matrix and red tide mortality scenarios on model structure are explored by comparing four alternative WFS-HAB Ecopath models: (i) the base model; (ii) a model employing the revised diet matrix; (iii) a model with elevated red tide mortality; and (iv) a model with both the revised diet matrix and elevated red tide mortality. Incorporating the revised diet matrix into the WFS-HAB Ecopath model had a relatively large impact on ecosystem structure (i.e., trophic organization, mortality rates, trophic interaction strengths, and omnivory). Elevated red tide mortality had virtually no impact on ecosystem structure aside from altering the contribution of fishing, natural, and red tide mortalities to the total mortality of functional groups; however, elevated red tide mortality might have meaningful implications in dynamic simulations, which should be explored in future studies. Collectively, results showed that incorporating the revised diet matrix into WFS-HAB Ecopath, which revealed a number of new predator-prey linkages, led to a more complex and interconnected food web. Specifically, prey items were generally consumed by a broader variety of predators, which contrasts with the base WFS-HAB Ecopath model where many prey, particularly juvenile fishes, were subjected to exceedingly high predation mortality rates from specific predators. The incorporation of the revised diet matrix into the WFS-HAB Ecopath model discussed herein is a fundamental step towards increasing the realism of trophic interactions in the model, which is particularly important as these trophic interactions define starting conditions for dynamic simulations.publishedVersio

Porphyrin Containing Polymersomes with Enhanced ROS Generation Efficiency: in vitro evaluation

Abstract Porphyrins are molecules possessing unique photophysical properties making them suitable for application in photodynamic therapy. The incorporation of porphyrins into natural or synthetic nano-assemblies such as polymersomes is a strategy to improve and prolong their therapeutic capacities and to overcome their limitations as therapeutic and diagnostic agents. Here, 5,10,15,20-tetrakis(1-(6-ethoxy-6-oxohexyl)-4-pyridin-1-io)-21H,23H-porphyrin tetrabromide porphyrin is inserted into polymersomes in order to demonstrate that the encapsulation enhances its ability to generate highly reactive singlet oxygen (1O2) upon irradiation in vitro. The photoactivation of the free and polymersome-encapsulated porphyrin is evaluated by electron spin resonance and cell viability assays on three different mammalian cell lines. The results indicate that by encapsulating the porphyrin, a controlled ROS delivery within the cells is achieved, at the same time avoiding side effects such as dark toxicity, non-specific porphyrin release and over time decreased activity in vitro. This work focuses on showing a not-toxic model system for modern therapeutic nanomedicine, which works under mild irradiation and dosage conditions

Erk1/2 Mediates Leptin Receptor Signaling in the Ventral Tegmental Area

Leptin acts on the ventral tegmental area (VTA) to modulate neuronal function and feeding behavior in rats and mice. To identify the intracellular effectors of the leptin receptor (Lepr), downstream signal transduction events were assessed for regulation by direct leptin infusion. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and phosphorylated extracellular signal-regulated kinase-1 and -2 (pERK1/2) were increased in the VTA while phospho-AKT (pAKT) was unaffected. Pretreatment of brain slices with the mitogen-activated protein kinase kinase -1 and -2 (MEK1/2) inhibitor U0126 blocked the leptin-mediated decrease in firing frequency of VTA dopamine neurons. The anorexigenic effects of VTA-administered leptin were also blocked by pretreatment with U0126, which effectively blocked phosphorylation of ERK1/2 but not STAT3. These data demonstrate that pERK1/2 may have a critical role in mediating both the electrophysiogical and behavioral effects of leptin receptor signaling in the VTA

Early poststroke clinically significant fatigue predicts functional independence: a prospective longitudinal study

BackgroundPoststroke fatigue is a prevalent issue among stroke survivors, significantly impeding functional recovery and diminishing their quality of life.AimThis prospective cohort study aims to investigate the association between poststroke fatigue and the extent of functional recovery in survivors of ischemic and hemorrhagic strokes. Additionally, it seeks to delineate the temporal progression of poststroke fatigue in these two stroke subtypes.MethodsWe assessed a cohort of 79 patients recovering from acute ischemic or hemorrhagic strokes. Poststroke fatigue was quantified using the Fatigue Severity Scale (FSS) and the Numeric Rating Scale (NRSfatigue). Patients’ condition was evaluated using the National Institute of Health Stroke Scale (NIHSS), and functional independence levels were determined using the Barthel Index for Activities of Daily Living (BIADL) and the Modified Rankin Scale (MRS). Depressive mood and pain were measured using the Beck Depression Inventory (BDI) and the Numeric Rating Scale for pain (NRSpain), respectively.ResultsOur primary findings indicate that the early manifestation of clinically significant fatigue (CSF) is predictive of a poorer trajectory in functional independence levels during recovery. Furthermore, we observed differing patterns of fatigue progression between ischemic and hemorrhagic strokes. Fatigue tends to ameliorate over time in hemorrhagic stroke cases, paralleling functional recovery, while it remains stable over time in ischemic stroke cases.ConclusionOur results underscore the detrimental impact of early poststroke fatigue on long-term outcomes. Furthermore, they highlight the imperative of managing poststroke fatigue, particularly during the subacute phase of stroke recovery

A Feasible Methodological Approach to Estimate the Burden of Autism Spectrum Disorder: Results from the EPI-ASD Study in the Province of Lecce (Southern Italy)

Diagnoses of Autism Spectrum Disorder (ASD) have rapidly increased globally. However, the lack of comprehensive epidemiological surveys and surveillance systems, able to provide official data at a national or European level is one of the main issues in the monitoring of this condition. The present study aimed to estimate the prevalence of ASD in children and adolescents aged 3-18 years old living in the province of Lecce (Southern Italy) through official data provided by the Local Health Authority of Lecce (ASL/LE) up to 31 October 2020, and compare it with school-based data concerning the number of students needing support for ASD. Based on data provided by the ASL/LE, in 2020 there were 509 cases of ASD among children and adolescents aged 3-18 years old, corresponding to a prevalence of 0.46%. A total of 408 (80.2%) were boys and 101 (19.8%) were girls. In relation to their age, 155 ASD cases (0.90%) were diagnosed in the 3-5 age group, while 222 (0.55%) in the 6-11 age group and 132 (0.25%) in the 12-18 age group. Prevalence of ASD assessed by school-based dataset was underestimated in the 3-5 age group, while the 6-11 and 12-18 age groups were consistent with the official data provided by the ASL/LE

Fatigue in multiple sclerosis: general and perceived fatigue does not depend on corticospinal tract dysfunction.

Background: Multiple sclerosis (MS) is an autoimmune disorder of the CNS in which inflammation, demyelination, and axonal damage of the central nervous system coexist. Fatigue is one of the most disabling symptoms in MS and little is known about the neurophysiological mechanisms involved. Methods: To give more mechanistic insight of fatigue in MS, we studied a cohort of 17 MS patients and a group of 16 age-matched healthy controls. Baseline Fatigue Severity Scales and Fatigue Rating were obtained from both groups to check the level of fatigue and to perform statistical correlations with fatigue-induced neurophysiologic changes. To induce fatigue we used a handgrip task. During the fatiguing task, we evaluated fatigue state (using a dynamometer) and after the task we evaluated the Borg Rating of Perceived Exertion Scale. Transcranial magnetic stimulation and peripheral electric stimulation were used to assess corticospinal tract and peripheral system functions before and after the task. Results: Clinically significant fatigue and central motor conduction time were greater in patients than in controls, while motor cortex excitability was decreased and maximal handgrip strength reduced in patients. Interestingly, fatigue state was positively correlated to perceived fatigue in controls but not in patients. Furthermore, in the presence of similar fatigue state over time, controls showed a significant fatigue-related reduction in motor evoked potential (a putative marker of central fatigue) whereas this effect was not seen in patients. Conclusions: in MS patients the pathogenesis of fatigue seems not driven by the mechanisms directly related to corticospinal function (that characterize fatigue in controls) but seems probably due to other “central abnormalities” upstream to primary motor cortex.post-print1473 K