NEURONAL CELL BIOLOGY
I am a neuroscientist from the conceptual experiment design to the day to day execution of a project. Studying the function of neurons as the fundamental building block is essential for our understanding of the brain and mind. Then, we can apply this understanding to neuropathological conditions. Here, have a look at some of my work, publish, and not.
CAMKII CONTROLS NEUROMODULATION VIA NEUROPEPTIDE GENE EXPRESSION AND AXONAL TARGETING OF NEUROPEPTIDE VESICLES.
Under revision at Plos Biology
Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like BDNF. Here, we show that neuromodulator secretion is indeed reduced in mouse α- and βCaMKII-deficient (αβCaMKII DKO) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport, but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αβCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wildtype neurons produced a similar reduction. Reduced neuromodulator expression in αβCaMKII DKO neurons was restored by active βCaMKII, but not inactive βCaMKII, or αCaMKII, and by CaMKII downstream effectors that promote CREB phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to βCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.
Neuropeptides are essential signaling molecules transported and secreted by dense‐core vesicles (DCV s), but the number of DCV s available for secretion, their subcellular distribution, and release probability are unknown. Here, we quantified DCV pool sizes in three types of mammalian CNS neurons in vitro and in vivo . Super‐resolution and electron microscopy reveal a total pool of 1,400–18,000 DCV s, correlating with neurite length. Excitatory hippocampal and inhibitory striatal neurons in vitro have a similar DCV density, and thalamo‐cortical axons in vivo have a slightly higher density. Synapses contain on average two to three DCV s, at the periphery of synaptic vesicle clusters. DCV s distribute equally in axons and dendrites, but the vast majority (80%) of DCV fusion events occur at axons. The release probability of DCV s is 1–6%, depending on the stimulation. Thus, mammalian CNS neurons contain a large pool of DCV s of which only a small fraction can fuse, preferentially at axons.
Do sedatives engage natural sleep pathways? It is usually assumed that anesthetic-induced sedation and loss of righting reflex (LORR) arise by influencing the same circuitry to lesser or greater extents. For the α2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively. Selective knockdown of α2A adrenergic receptors from the LC abolished dexmedetomidine-induced LORR, but not sedation. Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation. We used TetTag pharmacogenetics in mice to functionally mark neurons activated in the preoptic hypothalamus during dexmedetomidine-induced sedation or recovery sleep. The neuronal ensembles could then be selectively reactivated. In both cases, non-rapid eye movement sleep, with the accompanying drop in body temperature, was recapitulated. Thus, α2 adrenergic receptor–induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.