Delineation of functional synaptic connections is fundamental to understanding sensory processing. Olfactory signals are synaptically processed initially in the olfactory bulb (OB) where neural circuits are formed among inhibitory interneurons and the output neurons mitral cells (MCs) and tufted cells (TCs). TCs function in parallel with but differently from MCs and are further classified into multiple subpopulations based on their anatomic and functional heterogeneities. Here, we combined optogenetics with electrophysiology to characterize the synaptic transmission from a subpopulation of TCs, which exclusively express the neuropeptide cholecystokinin (CCK), to two groups of spatially segregated GABAergic interneurons, granule cells (GCs) and glomerular interneurons in mice of both sexes with four major findings. First, CCKergic TCs receive direct input from the olfactory sensory neurons (OSNs). This monosynaptic transmission exhibits high fidelity in response to repetitive OSN input. Second, CCKergic TCs drive GCs through two functionally distinct types of monosynaptic connections: (1) dendrodendritic synapses onto GC distal dendrites via their lateral dendrites in the superficial external plexiform layer (EPL); (2) axodendritic synapses onto GC proximal dendrites via their axon collaterals or terminals in the internal plexiform layer (IPL) on both sides of each bulb. Third, CCKergic TCs monosynaptically excite two subpopulations of inhibitory glomerular interneurons via dendrodendritic synapses. Finally, sniff-like patterned activation of CCKergic TCs induces robust frequency-dependent depression of the dendrodendritic synapses but facilitation of the axodendritic synapses. These results demonstrated important roles of the CCKergic TCs in olfactory processing by orchestrating OB inhibitory activities.
Sleep problems are the most common non-motor symptoms in Parkinson's disease (PD), and are more difficult to treat than the motor symptoms. In the current study, the role of human leucine-rich repeat kinase 2 (hLRRK2), the most common genetic cause of PD, was investigated with regards to sleep problems, and the therapeutic potential of melatonin in hLRRK2‑associated sleep problems was explored in Drosophila. hLRRK2 was selectively expressed in the mushroom bodies (MBs) in Drosophila and sleep patterns were measured using the Drosophila Activity Monitoring System. MB expression of hLRRK2 resulted in sleep problems, presynaptic dysfunction as evidenced by reduced miniature excitatory postsynaptic current (mEPSC) and excitatory postsynaptic potential (EPSP) frequency, and excessive synaptic plasticity such as increased axon bouton density. Treatment with melatonin at 4 mM significantly attenuated the sleep problems and rescued the reduction in mEPSC and EPSP frequency in the hLRRK2 transgenic flies. The present study demonstrates that MB expression of hLRRK2 in flies recapitulates the clinical features of the sleep disturbances in PD, and that melatonin attenuates hLRRK2-induced sleep disorders and synaptic dysfunction, suggesting the therapeutic potential of melatonin in PD patients carrying LRRK2 mutations.
Liver fibrosis is a serious, life-threatening disease with high morbidity and mortality that result from diverse causes. Liver biopsy, considered the “gold standard” to diagnose, grade, and stage liver fibrosis, has limitations in terms of invasiveness, cost, sampling variability, inter-observer variability, and the dynamic process of fibrosis. Compelling evidence has demonstrated that all stages of fibrosis are reversible if the injury is removed. There is a clear need for safe, effective, and reliable non-invasive assessment modalities to determine liver fibrosis in order to manage it precisely in personalized medicine. However, conventional imaging methods used to assess morphological and structural changes related to liver fibrosis, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), are only useful in assessing advanced liver disease, including cirrhosis. Functional imaging techniques, including MR elastography (MRE), US elastography, and CT perfusion are useful for assessing moderate to advanced liver fibrosis. MRE is considered the most accurate noninvasive imaging technique, and US elastography is currently the most widely used noninvasive means. However, these modalities are less accurate in early-stage liver fibrosis and some factors affect the accuracy of these techniques. Molecular imaging is a target-specific imaging mechanism that has the potential to accurately diagnose early-stage liver fibrosis. We provide an overview of recent advances in molecular imaging for the diagnosis and staging of liver fibrosis which will enable clinicians to monitor the progression of disease and potentially reverse liver fibrosis. We compare the promising technologies with conventional and functional imaging and assess the utility of molecular imaging in precision and personalized clinical medicine in the early stages of liver fibrosis.
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