Simon d'Aquin, PhD

• Silencing of c-MafEX neurons has no impact on acute pain, while their activation induces pain
• Silencing of c-MafEX neurons in neuropathic mice reduces hypersensitivity and allodynia
• Inhibitory parvalbumin neurons silence c-MafEX neurons in naive mice
• c-MafEX neurons can directly activate deep dorsal horn projection neurons

Abstract:
Experience-dependent changes in behavior are mediated by long-term functional modifications in brain circuits. Activity-dependent plasticity of synaptic input is a major underlying cellular process. Although we have a detailed understanding of synaptic and dendritic plasticity in vitro, little is known about the functional and plastic properties of active dendrites in behaving animals. Using deep brain two-photon Ca2+ imaging, we investigated how sensory responses in amygdala… Mehr anzeigen

Abstract:
Experience-dependent changes in behavior are mediated by long-term functional modifications in brain circuits. Activity-dependent plasticity of synaptic input is a major underlying cellular process. Although we have a detailed understanding of synaptic and dendritic plasticity in vitro, little is known about the functional and plastic properties of active dendrites in behaving animals. Using deep brain two-photon Ca2+ imaging, we investigated how sensory responses in amygdala principal neurons develop upon classical fear conditioning, a form of associative learning. Fear conditioning induced differential plasticity in dendrites and somas regulated by compartment-specific inhibition. Our results indicate that learning-induced plasticity can be uncoupled between soma and dendrites, reflecting distinct synaptic and microcircuit-level mechanisms that increase the computational capacity of amygdala circuits. Weniger anzeigen

Abstract:
Learning drives behavioral adaptations necessary for survival. While plasticity of excitatory projection neurons during associative learning has been extensively studied, little is known about the contributions of local interneurons. Using fear conditioning as a model for associative learning, we found that behaviorally relevant, salient stimuli cause learning by tapping into a local microcircuit consisting of precisely connected subtypes of inhibitory interneurons. By employing… Mehr anzeigen

Abstract:
Learning drives behavioral adaptations necessary for survival. While plasticity of excitatory projection neurons during associative learning has been extensively studied, little is known about the contributions of local interneurons. Using fear conditioning as a model for associative learning, we found that behaviorally relevant, salient stimuli cause learning by tapping into a local microcircuit consisting of precisely connected subtypes of inhibitory interneurons. By employing deep-brain calcium imaging and optogenetics, we demonstrate that vasoactive intestinal peptide (VIP)-expressing interneurons in the basolateral amygdala are activated by aversive events and provide a mandatory disinhibitory signal for associative learning. Notably, VIP interneuron responses during learning are strongly modulated by expectations. Our findings indicate that VIP interneurons are a central component of a dynamic circuit motif that mediates adaptive disinhibitory gating to specifically learn about unexpected, salient events, thereby ensuring appropriate behavioral adaptations. Weniger anzeigen

Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor ​PIK-III to screen for autophagy substrates. ​PIK-III is a selective inhibitor of ​VPS34 that binds a unique hydrophobic pocket not present in related kinases such as ​PI(3)Kα. ​PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity… Mehr anzeigen

Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor ​PIK-III to screen for autophagy substrates. ​PIK-III is a selective inhibitor of ​VPS34 that binds a unique hydrophobic pocket not present in related kinases such as ​PI(3)Kα. ​PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on ​PIK-III-treated cells we identified substrates including ​NCOA4, which accumulates in ​ATG7-deficient cells and co-localizes with autolysosomes. ​NCOA4 directly binds ​ferritin heavy chain-1 (​FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, ​Ncoa4−/− mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and ​NCOA4 in the control of iron homeostasis in vivo. Weniger anzeigen