Genetically Encoded Photocatalysis Enables Spatially Restricted Optochemical Modulation of Neurons in Live Mice.

Light provides high temporal precision for neuronal modulations. Small molecules are advantageous for neuronal modulation due to their structural diversity, allowing them to suit versatile targets. However, current optochemical methods release uncaged small molecules with uniform concentrations in the irradiation area, which lack spatial specificity as counterpart optogenetic methods from genetic encoding for photosensitive proteins. Photocatalysis provides spatial specificity by generating reactive species in the proximity of photocatalysts. However, current photocatalytic methods use antibody-tagged heavy-metal photocatalysts for spatial specificity, which are unsuitable for neuronal applications. Here, we report a genetically encoded metal-free photocatalysis method for the optochemical modulation of neurons via deboronative hydroxylation. The genetically encoded photocatalysts generate doxorubicin, a mitochondrial uncoupler, and baclofen by uncaging stable organoboronate precursors. The mitochondria, nucleus, membrane, cytosol, and ER-targeted drug delivery are achieved by this method. The distinct signaling pathway dissection in a single projection is enabled by the dual optogenetic and optochemical control of synaptic transmission. The itching signaling pathway is investigated by photocatalytic uncaging under live-mice skin for the first time by visible light irradiation. The cell-type-specific release of baclofen reveals the GABABR activation on NaV1.8-expressing nociceptor terminals instead of pan peripheral sensory neurons for itch alleviation in live mice.

Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory.

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

miR-208a in Cardiac Hypertrophy and Remodeling.

Various stresses, including pressure overload and myocardial stretch, can trigger cardiac remodeling and result in heart diseases. The disorders are associated with high risk of morbidity and mortality and are among the major health problems in the world. MicroRNAs, a class of ~22nt-long small non-coding RNAs, have been found to participate in regulating heart development and function. One of them, miR-208a, a cardiac-specific microRNA, plays key role(s) in modulating gene expression in the heart, and is involved in a broad array of processes in cardiac pathogenesis. Genetic deletion or pharmacological inhibition of miR-208a in rodents attenuated stress-induced cardiac hypertrophy and remodeling. Transgenic expression of miR-208a in the heart was sufficient to cause hypertrophic growth of cardiomyocytes. miR-208a is also a key regulator of cardiac conduction system, either deletion or transgenic expression of miR-208a disturbed heart electrophysiology and could induce arrhythmias. In addition, miR-208a appeared to assist in regulating the expression of fast- and slow-twitch myofiber genes in the heart. Notably, this heart-specific miRNA could also modulate the "endocrine" function of cardiac muscle and govern the systemic energy homeostasis in the whole body. Despite of the critical roles, the underlying regulatory networks involving miR-208a are still elusive. Here, we summarize the progress made in understanding the function and mechanisms of this important miRNA in the heart, and propose several topics to be resolved as well as the hypothetical answers. We speculate that miR-208a may play diverse and even opposite roles by being involved in distinct molecular networks depending on the contexts. A deeper understanding of the precise mechanisms of its action under the conditions of cardiac homeostasis and diseases is needed. The clinical implications of miR-208a are also discussed.