Congruent and Incongruent Corticospinal Activations at the Level of Multiple Effectors

Motor resonance is defined as the subliminal activation of the motor system while observing actions performed by others. However, resonating with another person's actions is not always an appropriate response: In real life, people do not just imitate but rather respond in a suitable fashion. A growing body of neurophysiologic studies has demonstrated that motor resonance can be overridden by complementary motor responses (such as preparing a precision grip on a small object when seeing an open hand in sign of request). In this study, we investigated the relationship between congruent and incongruent corticospinal activations at the level of multiple effectors. The modulation of MEPs evoked by single-pulse TMS over the motor cortex was assessed in upper and lower limb muscles of participants observing a soccer player performing a penalty kick straight in their direction. Study results revealed a double dissociation: Seeing the soccer player kicking the ball triggered a motor resonance in the observer's lower limb, whereas the upper limb response afforded by the object was overridden. On the other hand, seeing the ball approaching the observers elicited a complementary motor activation in upper limbs while motor resonance in lower limbs disappeared. Control conditions showing lateral kicks, mimicked kicks, and a ball in penalty area were also included to test the motor coding of object affordances. Results point to a modulation of motor responses in different limbs over the course of action and in function of their relevance in different contexts. We contend that ecologically valid paradigms are nowadays needed to shed light on the motor system functioning in complex forms of interaction

The serotonin receptor 7 and the structural plasticity of brain circuits

Serotonin (5-hydroxytryptamine, 5-HT) modulates numerous physiological processes in the nervous system. Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R) in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration

Enhancement of Dopaminergic Differentiation in Proliferating Midbrain Neuroblasts by Sonic Hedgehog and Ascorbic Acid

We analyzed the molecular mechanisms involved in the acquisition and maturation of dopaminergic (DA) neurons generated in vitro from rat ventral mesencephalon (MES) cells in the presence of mitogens or specific signaling molecules. The addition of basic fibroblast growth factor (bFGF) to MES cells in serum-free medium stimulates the proliferation of neuroblasts but delays DA differentiation. Recombinant Sonic hedgehog (SHH) protein increases up to three fold the number of tyrosine hydroxylase (TH)-positive cells and their differentiation, an effect abolished by anti-SHH antibodies. The expanded cultures are rich in nestin-positive neurons, glial cells are rare, all TH+ neurons are DA, and all DA and GABAergic markers analyzed are expressed. Adding ascorbic acid to bFGF/SHH-treated cultures resulted in a further five- to seven-fold enhancement of viable DA neurons. This experimental system also provides a powerful tool to generate DA neurons from single embryos. Our strategy provides an enriched source of MES DA neurons that are useful for analyzing molecular mechanisms controlling their function and for experimental regenerative approaches in DA dysfunction

Toll-like receptor-4 is involved in hepatic fibrogenesis in the course of non-alcoholic fatty liver disease

Toll-like receptor-4 (TLR4) is actively involved in liver in the response to injury from a variety of etiologies. Recently TLR4 expression by hepatic progenitor cells (HPC) and biliary epithelial cells has been associated to the progression of liver damage in chronic HCV-related hepatitis (1). HPC compartment activation in ductular reaction (DR) is a feature of progressive disease also in non-alcoholic fatty liver disease (NAFLD) (2). We aimed to investigate the association among TLR4 expression, HPC compartment activation and histopathologic features of fibrotic disease progression in NAFLD. Seventy-four patients who had undergone liver biopsy were included and immunohistochemistry for TLR4 was performed on hepatic tissue samples. CK-7 was used to evaluate HPC, bile ducts (BD)/ductules of DR and intermediate hepatocytes; α-smooth muscle actin was used to quantify the activation of hepatic stellate cells (HSC) and of portal/septal myofibroblasts (MF). HPC in BD/DR were responsible for the highest TLR4 intensity of staining. TLR4-positive HPC and BD/ DR correlated with fibrosis (p<0.01 and p<0.05), activity of MF (p<0.001 and p<0.05) and HSC (p<0.001 and p<0.001), portal and interface chronic inflammation (p<0.01 and p=0.01). The present study indicates the activation of the TLR4 expressing HPC compartment as important determinant of the progressive liver damage in NAFLD. TLR4 stimulation could represent one of the mechanisms directly linking the activation of HPC to inflammation and fibrosis in NAFLD

Portal and interface chronic inflammation are associated with the progenitor cell compartment activation during NAFLD

Background and aim: During nonalcoholic fatty liver disease (NAFLD), portal and interface chronic inflammation (PCI and ICI) are strongly associated with fibrosis by activation of hepatic stellate cell (HSC)s (Brunt et al., 2009; Vespasiani-Gentilucci et al., 2014). However, the determinants of PCI and ICI observed in NAFLD remain to be elucidated. Since portal and periportal ductular reaction is related to disease progression, we aimed to investigate if PCI and ICI are associated with hepatic progenitor cell (HPC) compartment activation. Methods: Fifty-two NAFLD patients were studied. NAFLD activity score, fibrosis, PCI and ICI were histologically evaluated. HPCs, intermediate hepatobiliary cells and bile ductules/interlobular bile ducts were evaluated by immunohistochemistry for CK-7, CK-19 and EpCAM. HSC and myofibroblast (MF) activity were determined by immunohistochemistry for α-SMA. Results: PCI and ICI strongly correlated with HPC compartment activation and with the activity of MFs (p≤0.001). Lobular inflammation, ballooning and HPC compartment activation were all associated with both PCI (p<0.01) and ICI (p<0.05) by univariate analysis. In the multivariate models, HPC compartment activation was independently associated with PCI and ICI (OR 4.4, 1.7-11.5; OR 3.4, 1.5-7.9, respectively). Conclusions: During NAFLD, PCI and ICI are strongly associated with HPC compartment activation and this association is likely one determinant subtending the strong association between PCI/ICI and fibrosis

Design, stereoselective synthesis, configurational stability and biological activity of 7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide

Chiral 5-arylbenzothiadiazine derivatives have recently attracted particular attention because they exhibit an interesting pharmacological activity as AMPA receptor (AMPAr) positive modulators. However, investigations on their configurational stability suggest a rapid enantiomerization in physiological conditions. In order to enhance configurational stability, preserving AMPAr activity, we have designed the novel compound (R,S)-7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide bearing a pyrrolo moiety coupled with the 5-(furan-3-yl) substituent on benzothiadiazine core. A stereoselective synthesis was projected to obtain single enantiomer of the latter compound. Absolute configuration was assigned by X-ray crystal structure. Patch clamp experiments evaluating the activity of single enantiomers as AMPAr positive allosteric modulator showed that R stereoisomer is the active component. Molecular modeling studies were performed to explain biological results. An on-column stopped-flow bidimensional recycling HPLC procedure was applied to obtain on a large scale the active enantiomer with enantiomeric enrichment starting from the racemic mixture of the compound

Reelin expression in liver and pancreas and its correlation with liver fibrosis

Reelin is an extracellular glycoprotein secreted by a variety of cell types in both embryonic and adult tissue and plays a critical role during brain development (1,2). Reelin is up-regulated in experimental liver cirrhosis of rats in hepatic stellate cell(HSC)s, the cell type mainly implicated in liver fibrogenesis, supporting that reelin is involved in the pathogenesis of liver fibrosis (3). Pancreatic stellate cell(PSC)s share similar morphology and function to HSCs, in pancreatic fibrosis setting (4). Currently, the role of reelin in human liver and pancreas is still unclear. We investigated reelin expression in different stages of chronic liver disease in 81 liver biopsies of HCV affected patients and in pancreatic tissue near to tumoral lesions. The expression of Reelin, HSC markers (CRBP1, alpha-SMA) and Dab1, a Reelin adaptor protein, was investigated by immunohistochemistry and immunofluorescence. Reelin protein was expressed by HSCs and a strong correlation was found between Reelin expression and liver fibrosis stage (

The hepatic expression of GH/IGF1 axis components is impaired with fibrosis progression in patients with HCV-related chronic hepatitis

Background and aim: Resistance to the action of growth hormone (GH), characterized by low serum levels of insulin-like growth factor-1 (IGF1) in the face of high concentrations of GH, frequently complicates cirrhosis (Assy et al., 2008). Physiologically, the activation of GH receptor (GHR) determines phosphorylation of signal transducer and activator of transcription (STAT)-5 and the consequent induction of IGF-1 expression. The suppressor of cytokine signalling (SOCS)-3 negatively regulates this intracellular cascade. Since, to date, the hepatic expression of the GH/IGF1 axis components has been studied mainly in animal models (Blaas L et al., 2010), we aimed to evaluate their expression in the liver of patients with HCV-related chronic hepatitis. Methods: Fifty HCV patients were studied and liver samples were histologically re-evaluated for grading and staging. The expression of GH/IGF1 axis components was assessed by immunohistochemistry. Results: At the hepatocyte level, IGF-1 and phospho-STAT5 showed a negative correlation with fibrosis stage, while SOCS3 a positive one (p<0,05 for all). Furthermore, the hepatocyte expression of IGF1 was negatively correlated with its expression by hepatic stellate cells (p<0,05). Conclusions: IGF1 expression by hepatocytes was reduced with fibrosis progression, probably due to the impairment of GHR intracellular cascade. The inverse correlation between IGF1 expressed by hepatocytes and hepatic stellate cells suggests specific roles for IGF-I produced by different hepatic cells

Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

The development of midbrain dopaminergic (DA) neurons requires a fine temporal and spatial regulation of a very specific gene expression program. Here, we report that during mouse brain development, the microRNA (miR-) 204/211 is present at a high level in a subset of DA precursors expressing the transcription factor Lmx1a, an early determinant for DA-commitment, but not in more mature neurons expressing Th or Pitx3. By combining different in vitro model systems of DA differentiation, we show that the levels of Lmx1a influence the expression of miR-204/211. Using published transcriptomic data, we found a significant enrichment of miR-204/211 target genes in midbrain dopaminergic neurons where Lmx1a was selectively deleted at embryonic stages. We further demonstrated that miR-204/211 controls the timing of the DA differentiation by directly downregulating the expression of Nurr1, a late DA differentiation master gene. Thus, our data indicate the Lmx1a-miR-204/211-Nurr1 axis as a key component in the cascade of events that ultimately lead to mature midbrain dopaminergic neurons differentiation and point to miR-204/211 as the molecular switch regulating the timing of Nurr1 expression

Comparison of gene expression profile in embryonic mesencephalon and neuronal primary cultures

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