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Increased longevity is often associated with age-related conditions. The most common neurodegenerative disorders in the older population are Alzheimer's disease (AD) and Parkinson's disease (PD), associated with progressive neuronal loss leading to functional and cognitive impairments. Although symptomatic treatments are available, there is currently no cure for these conditions. Gut dysbiosis has been involved in the pathogenesis of AD and PD, thus interventions targeting the "gut-brain axis" could potentially prevent or delay these pathologies. Recent evidence suggests that the skeletal muscle and the gut microbiota can affect each other via the "gut-muscle axis". Importantly, cognitive functions in AD and PD patients significantly benefit from physical activity. In this review, we aim to provide a comprehensive picture of the crosstalk between the brain, the skeletal muscle and the gut microbiota, introducing the concept of "gut-muscle-brain axis". Moreover, we discuss human and animal studies exploring the modulatory role of exercise and probiotics on cognition in AD and PD. Collectively, the findings presented here support the potential benefits of physical activity and probiotic supplementation in AD and PD. Further studies will be needed to develop targeted and multimodal strategies, including lifestyle changes, to prevent or delay the course of these pathologies. • Dysbiosis has been implicated in neurodegenerative disorders. • Physical exercise can promote microbiota diversity and taxonomic shifts towards anti-inflammatory bacterial species. • Gut microbiota can affect the muscle physiology by increasing aminoacids availability and by releasing SCFAs. • Probiotic supplementation and physical exercise may ameliorate cognitive dysfunctions in AD and PD. • Both nutritional factors and exercise may have converging effects on brain functions via a "gut-muscle-brain axis". [ABSTRACT FROM AUTHOR]

Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. [ABSTRACT FROM AUTHOR]

Here we discuss the role of diverse environmental manipulations affecting cognition with special regard to psychiatric conditions. We present evidence supporting a direct causal correlation between the valence of the environmental stimulation and some psychopathological traits and how the environment influences brain structure and function with special regard to oxidative stress and mitochondrial activity. Increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called "mitochondrial allostatic load". This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. In this review we discuss the role of diverse environmental manipulations to affect cognition with special regard to psychiatric conditions. How the environment influences brain structure and function, and the interactions between rearing conditions, oxidative stress and mitochondrial activity are fundamental questions that are still poorly understood. As will be discussed, increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called "mitochondrial allostatic load". This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. The brain requires considerable mitochondrial reserve not only to sustain basal neuronal needs but also to provide increasing energy demands during stress. Consistently with these high energetic requirements, it is reasonable to hypothesise that the brain is particularly vulnerable to mitochondrial defects. Thus, even subtle metabolic alterations might have a substantial impact on cognitive functions. Over the last decade, several experimental evidence supported the hypothesis that a suboptimal mitochondrial function, which could be of genetic origin or acquired following adverse life events, is a key vulnerability factor for stress-related psychopathologies. Chronic psychological stress is a major promoter of anxiety as well as of oxidative damage, as shown in several studies. Recent evidence from mouse models harbouring mutations in mitochondrial genes demonstrated the role of mitochondria in modulating the response to acute psychological stress. However, it has yet to be determined whether mitochondrial dysfunctions are the cause or the consequence of anxiety. In this review, we discuss how adverse psychosocial environments can impact mitochondrial bioenergetics at the molecular level and we gather evidence from several studies linking energy metabolism and stress resilience/vulnerability. Moreover, we review recent findings supporting that metabolic dysfunction can underlie deficits in complex social behaviours. As will be discussed, aberrations in mitochondrial functionality have been found in the nucleus accumbens of highly anxious mice and mediate low social competitiveness. In addition, alterations in sociability can be reversed by enhancing mitochondrial functions. Recent evidence also demonstrated that a specific mutation in mitochondrial DNA, previously linked to autism spectrum disorder, produces autistic endophenotypes in mice by altering respiration chain and reactive oxygen species (ROS) production. Finally, we discuss a "Negative Enrichment" model that can explain some of the psychopathological conditions relevant to humans. Evidence of a direct causal correlation of valence of environmental stimulation and psychopathological traits will be presented, and possible molecular mechanisms that focus on oxidative stress. Collectively, the findings described here have been achieved with a wide set of behavioural and cognitive tasks with translational validity. Thus, they will be useful for future work aimed to elucidate the fine metabolic alterations in psychopathologies and devise novel approaches targeting mitochondria to alleviate these conditions. • Diverse environmental manipulations can affect cognition with special regard to psychiatric conditions. • Alterations in cellular homeostasis are thought to predispose to disease by triggering the so-called "mitochondrial allostatic load". • Metabolic dysfunction can underlie complex social behaviours. • Brain mitochondria are considered crucial mediators of allostasis. • The brain requires considerable mitochondrial reserve to sustain basal neuronal needs to support neuronal plasticity during stress. • Suboptimal mitochondrial functionis a key vulnerability factor for stress-related psychopathologies. [ABSTRACT FROM AUTHOR]

Background and Purpose: Regulator of G‐protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance for l‐Dopa‐induced dyskinesia. Experimental Approach HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small‐molecule NOP agonist AT‐403, using D1‐stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with either N/OFQ or AT‐403 in the presence of the experimental RGS4 chemical probe, CCG‐203920, and D1‐stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG‐203920 was co‐administered with AT‐403 and l‐Dopa to 6‐hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. Key Results: RGS4 expression reduced NOFQ and AT‐403 potency and efficacy in HEK293T cells. CCG‐203920 increased N/OFQ potency in primary rat striatal neurons and potentiated AT‐403 response in mouse striatal slices. CCG‐203920 enhanced AT‐403‐mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor‐improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by l‐Dopa. l‐Dopa acutely up‐regulated RGS4 in the lesioned striatum. Conclusions and Implications: RGS4 physiologically inhibits NOP receptor signalling. CCG‐203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 up‐regulation occurring during dyskinesia expression. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is a genetic condition characterized by congenital heart defects, short stature and characteristic facial features. We here present the case of a girl with moderate learning disabilities, delayed language development, craniofacial features and skin anomalies reminiscent of NS. After a mutation screening of the known NS genes PTPN11, SOS1, RAF1, KRAS, GRB2, BRAF and SHOC2 we found the heterozygous c.755T>C variant in SOS1 causing the p.I252T amino-acid substitution, which was considered possibly pathogenetic by bioinformatic predictions. The same variant was present in the proband's mother, displaying some NS features, and maternal grandfather showing no NS traits, but also by a healthy subject in 1000 genomes project database without phenotype informations. The functional analysis revealed that SOS1 c.755C activated the RAS-ERK intracellular pathway, whereas no effects on RAC-JNK cascade have been detected. After a comparison between the sequence of SOS1 cDNA from peripheral blood and SOS1 genomic DNA, we showed for the first time a differential allelic expression of the SOS1 gene in healthy individuals, thus occurring as a physiologic condition. Interestingly, we found that the mutated allele C was 50% more expressed than the wild-type allele T in all familial carriers. The comparable amount of SOS1 mRNA between mutated individuals and the controls indicates that the variant does not affect SOS1 expression. The present study provides a first evidence of allelic imbalance of SOS1 and pinpoints this condition as a possible mechanism underlying a different penetrance of some SOS1-mutated alleles in unrelated carriers. [ABSTRACT FROM AUTHOR]

Background and Purpose: We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression.Experimental Approach: Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6-hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated.Key Results: AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT-403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo.Conclusions and Implications: NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo. [ABSTRACT FROM AUTHOR]

Background Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson’s disease and in l -3,4-dihydroxyphenylalanine ( l -DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson’s disease. Methods Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. Results We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. Conclusions These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA. [ABSTRACT FROM AUTHOR]

the present study we investigated whether the neuropeptide nociceptin/orphanin FQ (N/OFQ), previously implicated in the pathogenesis of Parkinson's disease, also affects L-DOPA-induced dyskinesia. In striatal slices of naive rodents, N/OFQ (0.1-1 μM) prevented the increase of ERK phosphorylation and the loss of depotentiation of synaptic plasticity induced by the Dl receptor agonist SKF38393 in spiny neurons. In vivo, exogenous N/OFQ (0.03-1 nmol, i.c.v.) or a synthetic N/OFQ receptor agonist given systemically (0.01-1 mg/Kg) attenuated dyskinesias expression in 6-hydroxydopamine hemilesioned rats primed with L-DOPA, without causing primary hypoloco-motive effects. Conversely, N/OFQ receptor antagonists worsened dyskinesia expression. In vivo microdialysis revealed that N/OFQ prevented dyskinesias simultaneously with its neurochemical correlates such as the surge of nigral GABA and glutamate, and the reduction of thalamic GABA. Regional microinjections revealed that N/OFQ attenuated dyskinesias more potently and effectively when microinjected in striatum than substantia nigra (SN) reticulata, whereas N/OFQ receptor antagonists were ineffective in striatum but worsened dyskinesias when given in SN. Quantitative autoradiography showed an increase in N/OFQ receptor binding in striatum and a reduction in SN of both unprimed and dyskinetic 6-hydroxydopamine rats, consistent with opposite adaptive changes of N/OFQ transmission. Finally, the N/OFQ receptor synthetic agonist also reduced dyskinesia expression in l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine-treated dyskinetic macaques without affecting the global parkinsonian score. We conclude that N/OFQ receptor agonists may represent a novel strategy to counteract L-DOPA-induced dyskinesias. Their action is possibly mediated by upregulated striatal N/OFQ receptors opposing the Dl receptor-mediated overactivation of the striatonigral direct pathway. [ABSTRACT FROM AUTHOR]