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The simultaneous use of Arch and Mac enabled inhibition of two different neuronal subpopulations, depending on the illuminating lights used. Light-sensitive probes expressed in C. However, promoter-driven single cell expression of optogenetic protein is challenging to achieve due to the lack of single cell-specific promoter and instead proteins are diversely expressed, eliciting robust behavioral responses upon whole-field illumination Husson et al.
Although it may be useful for inspecting a novel optogenetic protein, optical manipulation of individual neurons needs to be accomplished in order to obtain insights into individual contribution by single neurons in functional connectivity. To this aim, new methods have been adapted in C. Table 1. Cell-specific optogenetic applications in C. Mainly adapted approach to specifically deliver light-sensitive opsins to individual neurons of C. The recombinase-dependent gene expression is driven by a set of two promoters, a first promoter driving the expression of opsin conjugated with a fluorophore along with or without a bicistronic fluorescent reporter and a second promoter driving the expression of Cre or FLP recombinase.
In the first promoter-containing construct, a transcription termination sequence flanked by recombinase recognition sequences, loxP or FRT that are recognized by Cre or FLP recombinase is enclosed in front of opsin. The Cre or FLP recombinase-mediated recombination of loxP or FRT sites excised the stop sequence and allows conditional expression of opsin only in the target cell where both promoters are active Husson et al.
Further effort to isolate exclusive expression of the light-sensitive proteins in a single cell Ezcurra et al. Figure 2. Restricted expression of light-sensitive opsin mediated by Cre or FLP recombinases. Promoter 1-containing construct is designed to drive expression of opsin with a fluorescent reporter. Promoter 2 drives expression of Cre or FLP recombinase. Conditional expression of opsin is mediated by the Cre or FLP recombinases by removing a transcription termination sequence flanked by loxP or FRT only in target cell where the both promoters are active.
Instead of using genetically generated system and whole-field illumination, spatiotemporally patterned illumination of neurons expressing light-sensitive optogenetic proteins in immobilized C. Improvement in microscopic analysis and optogenetic illumination system allowed manipulation of neural activity in a freely behaving C. A modified three-panel liquid crystal display 3-LCD projector for simultaneous multicolor illumination and a motorized X-Y stage for keeping the unrestrained worm centered in the camera's field of view with a standard inverted epifluorescence microscope were systemized Stirman et al.
Spatial regulation of optical illumination is controlled either by estimating the coordinates of targeted cells using the machine-vision algorithms Leifer et al.
Both systems have been instrumental in defining neural coding of several behaviors in C. Another report using the Colbert system equipped with the DMD investigated an experience-dependent salt chemotaxis circuit. Optogenetic manipulation of neuronal activity of the ASER sensory neuron expressing ChR2 was shown to be connected to positive and negative chemotaxis in response to salt concentrations, indicating that ASER sensory neuron encodes the perception of salt concentration and the memory of the chemotactic set point in a chemotaxis circuit of C.
Furthermore, multispectral illumination Stirman et al. Emerging studies have successfully facilitated multimodal optogenetic manipulation on C. As genetically encoded fluorescent proteins have been rapidly developed for the past decades since the GFP was introduced in the field, it is also expected that the number of optogenetic tools will rapidly increase to likely provide optogenetic proteins with different spectral properties Zhang et al.
During such processes, it is confidently predicted that C. Together with the improvement of fluorescent and optogenetic tools, continuous development in C. In addition to the monitoring and controlling of existing neuronal circuits via optogenetic applications and advanced microscopy systems as described in this review, it is very plausible to develop the ways to actively manipulate neural circuits for instance by inserting new connections or removing existing connections, resulting in the reprogramming of neural circuits.
Indeed, a recent study on artificial modifications of neural circuits was reported in C. Conversely, laser ablation method can be used to remove existing connection Sulston and White, ; Bargmann et al. Such artificial modification of neural circuits not only help understand fundamental functions of neuronal connectivity underlying complex behavior but could also be applied to disease brain circuits with the purpose of therapeutics at the circuit level.
All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The work in M. Ackermann, F. Presynaptic active zones in invertebrates and vertebrates. EMBO Rep. Akins, M. Cell-cell interactions in synaptogenesis. Bargmann, C.
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In the prefrontal cortex, peak levels of synapses occur sometime during the first year of life. This part of the brain is used for a variety of complex behaviors, including planning and personality. During the second year of life, the number of synapses drops dramatically. Synaptic pruning happens very quickly between ages 2 and During this time, about 50 percent of the extra synapses are eliminated.
In the visual cortex, pruning continues until about 6 years of age. Synaptic pruning continues through adolescence, but not as fast as before. The total number of synapses begins to stabilize.
While researchers once thought the brain only pruned synapses until early adolescence, recent advancements have discovered a second pruning period during late adolescence. According to newer research, synaptic pruning actually continues into early adulthood and stops sometime in the late 20s.
Research that looks at the relationship between synaptic pruning and schizophrenia is still in the early stages. For example, when researchers looked at images of the brains of people with mental disorders, such as schizophrenia, they found that people with mental disorders had fewer synapses in the prefrontal region compared to the brains of people without mental disorders. Then, a large study analyzed post-mortem brain tissue and DNA from more than , people and found that people with schizophrenia have a specific gene variant that may be associated with an acceleration of the process of synaptic pruning.
More research is needed to confirm the hypothesis that abnormal synaptic pruning contributes to schizophrenia. While this is still a long way off, synaptic pruning may represent an interesting target for treatments for people with mental disorders. To test this hypothesis, researchers looked at brain tissue of 13 children and adolescents with and without autism who passed away between ages 2 and The scientists found that the brains of the adolescents with autism had a lot more synapses than the brains of neurotypical adolescents.
Young children in both groups had roughly the same number of synapses. This suggests that the condition may occur during the pruning process.
This research only shows a difference in synapses, but not whether this difference might be a cause or an effect of autism, or just an association. Necessary methodology that allows detection of synapse formation under low light and long period would greatly facilitate the studies of the dynamics of synaptic assembly.
Ultrastructural analysis of synapses in young larvae would also be very informative. Special thanks to M. Nonet, R. Weimer, J-L. Bessereau, D. Hall, for communicating unpublished results.
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