Knowledge of connectivity in the nervous system is essential to understanding its function. Here we describe connectomes for both adult sexes of the nematode Caenorhabditis elegans, an important model organism for neuroscience research. We present quantitative connectivity matrices that encompass all connections from sensory input to end-organ output across the entire animal, information that is necessary to model behaviour. Serial electron microscopy reconstructions that are based on the analysis of both new and previously published electron micrographs update previous results and include data on the male head. The nervous system differs between sexes at multiple levels. Several sex-shared neurons that function in circuits for sexual behaviour are sexually dimorphic in structure and connectivity. Inputs from sex-specific circuitry to central circuitry reveal points at which sexual and non-sexual pathways converge. In sex-shared central pathways, a substantial number of connections differ in strength between the sexes. Quantitative connectomes that include all connections serve as the basis for understanding how complex, adaptive behavior is generated.

Mutations in the unc-17 gene of the nematode Caenorhabditis elegans produce deficits in neuromuscular function. This gene was cloned and complementary DNAs were sequenced. On the basis of sequence similarity to mammalian vesicular transporters of biogenic amines and of localization to synaptic vesicles of cholinergic neurons in C. elegans, unc-17 likely encodes the vesicular transporter of acetylcholine. Mutations that eliminated all unc-17 gene function were lethal, suggesting that the acetylcholine transporter is essential. Molecular analysis of unc-17 mutations will allow the correlation of specific parts of the gene (and the protein) with observed functional defects. The mutants will also be useful for the isolation of extragenic suppressors, which could identify genes encoding proteins that interact with UNC-17.

We have identified the Caenorhabditis elegans homolog of the mammalian vesicular monoamine transporters (VMATs); it is 47% identical to human VMAT1 and 49% identical to human VMAT2. C. elegans VMAT is associated with synaptic vesicles in approximately 25 neurons, including all of the cells reported to contain dopamine and serotonin, plus a few others. When C. elegans VMAT is expressed in mammalian cells, it has serotonin and dopamine transport activity; norepinephrine, tyramine, octopamine, and histamine also have high affinity for the transporter. The pharmacological profile of C. elegans VMAT is closer to mammalian VMAT2 than VMAT1. The C. elegans VMAT gene is cat-1; cat-1 knock-outs are totally deficient for VMAT immunostaining and for dopamine-mediated sensory behaviors, yet they are viable and grow relatively well. The cat-1 mutant phenotypes can be rescued by C. elegans VMAT constructs and also (at least partially) by human VMAT1 or VMAT2 transgenes. It therefore appears that the function of amine neurotransmitters can be completely dependent on their loading into synaptic vesicles.

Drosophila melanogaster has been conditioned with shock to avoid various odors. Mutants that failed to learn this task have been isolated. Here we report tests on these mutants for more elementary types of behavioral plasticity-habituation and sensitization of a reflex. Fruit flies have taste receptors on their feet. When a starved, water-satiated fly has sucrose applied to one foot, it usually responds by extending its proboscis. In normal flies this feeding reflex shows habituation: application of sugar to one foot depresses responsiveness through the contralateral leg for at least 10 min. The reflex also shows brief sensitization: application of concentrated sucrose solution to the proboscis increases subsequent responsiveness to tarsal stimulation for 2-5 min. In three associative learning mutants, the proboscis-extension reflex is present with a normal threshold but behavioral modulation of the response is altered. The dunce, turnip, and rutabaga mutants all habituate less than normal flies. In addition, sensitization wanes unusually rapidly in dunce and rutabaga flies, lasting less than a minute in the case of dunce.Animals can modify their behavior, based on past experience, in several ways. Along with associative learning, which includes classical and operant conditioning, they show two elementary types of neurally mediated behavioral plasticity which may be considered forms of nonassociative learning. Habituation, broadly defined, is the decrease in a behavioral response on repeated presentations of the same stimulus. (If the decrease merely reflects a change in the sensory receptors it is called "adaptation.") Sensitization, on the other hand, is an increase in an animal's responsiveness after a strong or novel stimulus. Whether habituation, sensitization, and learning rely on similar neural mechanisms is currently not known. This issue has recently become important.Associative learning corresponds to "learning" used in the educational sense, and psychological research has concentrated on this phenomenon. Nevertheless, progress in understanding the underlying mechanism has been slow. The physical and chemical changes that take place when an associative memory is stored in the brain are not known.By contrast, habituation and sensitization look relatively uncomplicated and seem to be amenable to elucidation with present techniques. Recently, in fact, there has been rapid progress in this area. In particular Kandel and his colleagues (1-3) working with the mollusc Aplysia, have found that a gill-withdrawal reflex undergoes habituation and sensitization. They have been able to correlate this behavioral plasticity with changing transmission efficacy in a few parallel synapses in the central nervous system, and they have identified physiological and biochemical events that appear to underlie the synaptic changes. The general applicability of their model has not been established. It is unlikely, for example, that habituation proceeds by the same mechanism in all cases. Nevertheless, other workers (4-...

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