Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity-dependent structural remodelling that has been proposed to be a cellular basis of learning and memory. How structural remodelling supports synaptic plasticity, such as long-term potentiation, and whether such plasticity is input-specific at the level of the individual spine has remained unknown. We investigated the structural basis of long-term potentiation using two-photon photolysis of caged glutamate at single spines of hippocampal CA1 pyramidal neurons. Here we show that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid and selective enlargement of stimulated spines that is transient in large mushroom spines but persistent in small spines. Spine enlargement is associated with an increase in AMPA-receptor-mediated currents at the stimulated synapse and is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our results thus indicate that spines individually follow Hebb's postulate for learning. They further suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long-term memory.

Structural basis of long-term potentiation in single dendritic spines

mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

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mRNA vaccines — a new era in vaccinology

Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiological characterization of opsins from over 100 species of alga. Chrimson's excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable experiments in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.

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Independent optical excitation of distinct neural populations

Microbial engineering often requires fine control over protein expression--for example, to connect genetic circuits or control flux through a metabolic pathway. To circumvent the need for trial and error optimization, we developed a predictive method for designing synthetic ribosome binding sites, enabling a rational control over the protein expression level. Experimental validation of >100 predictions in Escherichia coli showed that the method is accurate to within a factor of 2.3 over a range of 100,000-fold. The design method also correctly predicted that reusing identical ribosome binding site sequences in different genetic contexts can result in different protein expression levels. We demonstrate the method's utility by rationally optimizing protein expression to connect a genetic sensor to a synthetic circuit. The proposed forward engineering approach should accelerate the construction and systematic optimization of large genetic systems.

Automated design of synthetic ribosome binding sites to control protein expression

Despite their name, synonymous mutations have significant consequences for cellular processes in all taxa. As a result, an understanding of codon bias is central to fields as diverse as molecular evolution and biotechnology. Although recent advances in sequencing and synthetic biology have helped to resolve longstanding questions about codon bias, they have also uncovered striking patterns that suggest new hypotheses about protein synthesis. Ongoing work to quantify the dynamics of initiation and elongation is as important for understanding natural synonymous variation as it is for designing transgenes in applied contexts.

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Synonymous but not the same: the causes and consequences of codon bias.

Coding-Sequence Determinants of Gene Expression in Escherichia coli

The fly Drosophila melanogaster can discriminate and remember visual landmarks. It analyses selected parts of its visual environment according to a small number of pattern parameters such as size, colour or contour orientation, and stores particular parameter values. Like humans, flies recognize patterns independently of the retinal position during acquisition of the pattern (translation invariance). Here we show that the central-most part of the fly brain, the fan-shaped body, contains parts of a network mediating visual pattern recognition. We have identified short-term memory traces of two pattern parameters—elevation in the panorama and contour orientation. These can be localized to two groups of neurons extending branches as parallel, horizontal strata in the fan-shaped body. The central location of this memory store is well suited to mediate translational invariance. Like humans, Drosophila fruit flies recognize and remember visual landmarks, and they recognize patterns (such as vertical or oblique bars) independently of where they are projected on the retina at first encounter. In an experiment using genetic manipulation and a fruit-fly flight simulator, the nerve cells required for these feats of visual memory have been identified for the first time in an insect. Two groups of about 20 neurons are found in two narrow strata in the ‘fan-shaped body’, the largest component of the central complex that is characteristic of the arthropod brain. The main role of the central complex was thought to be to integrate information in the two brain hemispheres; this new study is the first to attribute well defined behavioural functions to this brain region.

Distinct memory traces for two visual features in the Drosophila brain

The world is permanently changing. Laboratory experiments on learning and memory normally minimize this feature of reality, keeping all conditions except the conditioned and unconditioned stimuli as constant as possible1. In the real world, however, animals need to extract from the universe of sensory signals the actual predictors of salient events by separating them from non-predictive stimuli (context2). In principle, this can be achieved ifonly those sensory inputs that resemble the reinforcer in theirtemporal structure are taken as predictors. Here we study visual learning in the fly Drosophila melanogaster, using a flight simulator3,4, and show that memory retrieval is, indeed, partially context-independent. Moreover, we show that the mushroom bodies, which are required for olfactory5,6,7 but not visual or tactile learning8, effectively support context generalization. In visual learning in Drosophila, it appears that a facilitating effect of context cues for memory retrieval is the default state, whereas making recall context-independent requires additional processing.

Context generalization in Drosophila visual learning requires the mushroom bodies

Vision in Drosophila

In theDrosophila mutantoptomotorblindH31 (ombH31), previously isolated for its defects in the optomotor turning response, the visual giant neurons of the lobula plate are missing or significantly reduced. In particular, fibres homologous to the H-and V-cells ofCalliphora as well as two fibres (M-cells) in the middle plane of the plate are affected.

Reinhard Wolf

Papers

Coding-Sequence Determinants of Gene Expression in Escherichia coli

Distinct memory traces for two visual features in the Drosophila brain

Context generalization in Drosophila visual learning requires the mushroom bodies

Vision in Drosophila

Optomotor-blindH31—aDrosophila mutant of the lobula plate giant neurons