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Paoli, E.

Publications and source records attributed to Paoli, E..

5 recordsLinked to original sources

A zebrafish circuit for behavioral credit assignment

Improving behavioral performance relies on the ability to associate decisions with their positive and negative outcomes. Although neurons that associate actions with their consequences have been identified across multiple brain regions, the circuit-level mechanisms underlying this integration remain poorly understood. Here, using an operant thermoregulatory assay, we show that larval zebrafish maintain a short-term memory of action-outcome associations and that the dorsal habenula-interpeduncular nucleus (dHb-IPN) pathway is necessary for this process. Consistently, a population of intermediate IPN neurons encodes actions only when they lead to a thermal reward, suggesting a major role in establishing short-term associations and influencing subsequent decisions. We then combine circuit mapping and axon imaging to show that actions and reward signals are conveyed by GABAergic prepontine and glutamatergic dHb neurons, respectively. Finally, the integration between motor and sensory streams relies on presynaptic GABAB receptor-mediated modulation of dHb axon terminals by prepontine neurons. These results link a crucial computation for adaptive behavior to a specific circuit mechanism.

neuroscience↗

Multimodal synapse analysis reveals restricted integration of transplanted neurons remodeled by TREM2

Neuron transplantation offers a promising approach for circuit restoration after injury, but depends crucially on adequate synaptic integration. Yet, our knowledge of the effects of the host injury environment on transplanted neuron (tN) network integration remains limited. Here, we used a stab wound injury model to examine how tN synapses mature and integrate using multimodal read-outs. Morphological, ultrastructural and functional electrophysiological analysis of tN synapses indicated that tN integration and functional maturation are partially stunted. Spatial transcriptomics revealed persistent inflammatory signatures at the transplant site including Trem2 upregulation. Strikingly, in an environment devoid of TREM2, synaptic integration as well as functional maturation of tNs, including action potential maturation and spontaneous firing, were almost fully rescued. Spatial transcriptomics further showed reduced inflammatory pathways and improved maturation of tNs in Trem2-/- brains. This study highlights the importance of tackling chronic inflammation for adequate tN integration.

neuroscience↗

Selection and characterization of DNA aptamers targeting the surface borrelial protein CspZ with high-throughput cross-over SELEX

Lyme borreliosis (LB) is the most prevalent tick-borne illness, with an estimated 700 000 cases annually in the United States and Europe. LB diagnosis based on two-tiered serology remains controversial due to its indirect nature and low sensitivity during the early stage of the disease. Aptamers are single-stranded DNA or RNA oligonucleotides that exhibit high selectivity and specificity for their target due to their unique three-dimensional structure. By applying cross-over-SELEX process, an enrichment of DNA oligonucleotide sequences against a surface protein of Borrelia, named CspZ, has been performed and monitored using absorbance at 260 nm, melting curves and NGS analyses. Beyond sequence enrichment, oligonucleotides binding to CspZ were observed during the selection rounds by Dot Blot and beads assays. Thirteen unique and highly redundant oligonucleotide sequences have been further characterized using multiple approaches such as Dot Blot, BioLayer Interferometry and Surface Plasmon Resonance. The selected aptamers showed KD values from tens of nanomolar to the micromolar range by BLI and SPR. Two aptamers, characterized by flow cytometry and epifluorescence microscopy, were able to specifically recognize Borrelia burgdorferi sensu stricto. This novel strategy holds promise for the development of an improved diagnosis assay. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/632687v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@3a2697org.highwire.dtl.DTLVardef@1bba993org.highwire.dtl.DTLVardef@17a0a60org.highwire.dtl.DTLVardef@13f4a4f_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIDNA aptamers were selected by cross-over SELEX. C_LIO_LIAptamers KDs ranged from tens of nanomolar to the micromolar range. C_LIO_LIAptamer characterization was performed by Dot Blot, beads assay, BLI, and SPR. C_LIO_LIInteraction with Borrelia was tested by flow cytometry and epifluorescence microscopy. C_LIO_LIAptamers bind to both the recombinant and borrelial surface CspZ protein. C_LI

biochemistry↗

The Preoptic Area and Dorsal Habenula Jointly Support Homeostatic Navigation in Larval Zebrafish

Animals must maintain physiological processes within an optimal temperature range despite changes in their environment. While the preoptic area of the hypothalamus (PoA) acts as a thermostat in mammals through autonomic and behavioral adaptations, its role in temperature regulation of animals lacking internal homeostatic mechanisms is not known. Through novel behavioral assays, wholebrain functional imaging and neural ablations, we show that larval zebrafish achieve thermoregulation through movement and a neural network connecting the PoA to brain areas enabling spatial navigation. PoA drives reorientation when thermal conditions are worsening and conveys this information for instructing future motor actions to the navigation-controlling habenula (Hb) - interpeduncular nucleus (IPN) circuit. These results suggest a conserved function of the PoA in thermoregulation acting through species- specific neural networks. We propose that homeostatic navigation arose from an ancient chemotaxis navigation circuit that was subsequently extended to serve in other sensory modalities.

neuroscience↗

Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity against Hepatitis B Virus

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify replication inhibitors. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) an ester prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as an increased H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS-5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious from the in vitro model. Here we discuss potential reasons for the disconnect between in vitro and in vivo efficacy, which highlight the translational difficulties of epigenetic targets for viral diseases.

pharmacology and toxicology↗