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

Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics.

Recent studies have indicated that the serotonin receptor subtype 7 (5-HT7R) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life. Here we show that pharmacological stimulation of 5-HT7R using a highly selective agonist, LP-211, enhances neurite outgrowth in neuronal primary cultures from the cortex, hippocampus and striatal complex of embryonic mouse brain, through multiple signal transduction pathways. All these signaling systems, involving mTOR, the Rho GTPase Cdc42, Cdk5, and ERK, are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth. Indeed, our data indicate that neurite elongation stimulated by 5-HT7R is modulated by drugs affecting actin polymerization. In addition, we show, by 2D Western blot analyses, that treatment of neuronal cultures with LP-211 alters the expression profile of cofilin, an actin binding protein involved in microfilaments dynamics. Furthermore, by using microfluidic chambers that physically separate axons from the soma and dendrites, we demonstrate that agonist-dependent activation of 5-HT7R stimulates axonal elongation. Our results identify for the first time several signal transduction pathways, activated by stimulation of 5-HT7R, that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation. Therefore, the activation of 5-HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development

High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status

Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case-control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/negative, FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46-0.95], p\u2009=\u20090.0281), PFS (HR 0.65 [95% CI 0.48-0.89]; p\u2009=\u20090.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p\u2009=\u20090.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of\u2009 65\u20091 somatic DDR gene mutation was 20% and 24.5% (p\u2009=\u20090.6684) in FHC-high vs. FHC-low/negative, with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p\u2009=\u20090.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted

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

Information content of dendritic spines after motor learning

Dendritic spines, small protrusions emerging from the dendrites of most excitatory synapses in the mammalian brain, are highly dynamic structures and their shape and number is continuously modulated by memory formation and other adaptive changes of the brain. In this study, using a behavioral paradigm of motor learning, we applied the non-linear analysis of dendritic spines to study spine complexity along dendrites of cortical and subcortical neural systems, such as the basal ganglia, that sustain important motor learning processes. We show that, after learning, the spine organization has greater complexity, as indexed by the maximum Lyapunov exponent (LyE). The positive value of the exponent demonstrates that the system is chaotic, while recurrence plots show that the system is not simply composed by random noise, but displays quasi-periodic behavior. The increase in the maximum LyE and in the system entropy after learning was confirmed by the modification of the reconstructed trajectories in phase-space. Our results suggest that the remodeling of spines, as a result of a chaotic and non-random dynamical process along dendrites, may be a general feature associated with the structural plasticity underlying processes such as long-term memory maintenance. Furthermore, this work indicates that the non-linear method is a very useful tool to allow the detection of subtle stimulus-induced changes in dendritic spine dynamics, giving a key contribution to the study of the relationship between structure and function of spines

Rod–Coil Block Copolymer: Fullerene Blend Water-Processable Nanoparticles: How Molecular Structure Addresses Morphology and Efficiency in NP-OPVs

The use of water-processable nanoparticles (WPNPs) is an emerging strategy for the processing of organic semiconducting materials into aqueous medium, dramatically reducing the use of chlorinated solvents and enabling the control of the nanomorphology in OPV active layers. We studied amphiphilic rod-coil block copolymers (BCPs) with a different chemical structure and length of the hydrophilic coil blocks. Using the BCPs blended with a fullerene acceptor material, we fabricated NP-OPV devices with a sustainable approach. The goal of this work is to clarify how the morphology of the nanodomains of the two active materials is addressed by the hydrophilic coil molecular structures, and in turn how the design of the materials affects the device performances. Exploiting a peculiar application of TEM, EFTEM microscopy on WPNPs, with the contribution of AFM and spectroscopic techniques, we correlate the coil structure with the device performances, demonstrating the pivotal influence of the chemical design over material properties. BCP5, bearing a coil block of five repeating units of 4-vinilpyridine (4VP), leads to working devices with efficiency comparable to the solution-processed ones for the multiple PCBM-rich cores morphology displayed by the blend WPNPs. Otherwise, BCP2 and BCP15, with 2 and 15 repeating units of 4VP, respectively, show a single large PCBM-rich core; the insertion of styrene units into the coil block of BCP100 is detrimental for the device efficiency, even if it produces an intermixed structure