Learning accurate path integration in a ring attractor model of the head direction system

Ring attractor models for angular path integration have recently received strong experimental support. To function as integrators, head-direction (HD) circuits require precisely tuned connectivity, but it is currently unknown how such tuning could be achieved. Here, we propose a network model in which a local, biologically plausible learning rule adjusts synaptic efficacies during development, guided by supervisory allothetic cues. Applied to the Drosophila HD system, the model learns to path-integrate accurately and develops a connectivity strikingly similar to the one reported in experiments. The mature network is a quasi-continuous attractor and reproduces key experiments in which optogenetic stimulation controls the internal representation of heading, and where the network remaps to integrate with different gains. Our model predicts that path integration requires supervised learning during a developmental phase. The model setting is general and also applies to architectures that lack the physical topography of a ring, like the mammalian HD system

Memory-Relevant Mushroom Body Output Synapses Are Cholinergic

Memories are stored in the fan-out fan-in neural architectures of the mammalian cerebellum and hippocampus and the insect mushroom bodies. However, whereas key plasticity occurs at glutamatergic synapses in mammals, the neurochemistry of the memory-storing mushroom body Kenyon cell output synapses is unknown. Here we demonstrate a role for acetylcholine (ACh) in Drosophila. Kenyon cells express the ACh-processing proteins ChAT and VAChT, and reducing their expression impairs learned olfactory-driven behavior. Local ACh application, or direct Kenyon cell activation, evokes activity in mushroom body output neurons (MBONs). MBON activation depends on VAChT expression in Kenyon cells and is blocked by ACh receptor antagonism. Furthermore, reducing nicotinic ACh receptor subunit expression in MBONs compromises odor-evoked activation and redirects odor-driven behavior. Lastly, peptidergic corelease enhances ACh-evoked responses in MBONs, suggesting an interaction between the fast- and slow-acting transmitters. Therefore, olfactory memories in Drosophila are likely stored as plasticity of cholinergic synapses

Maturation of active zone assembly by Drosophila Bruchpilot

Synaptic vesicles fuse at active zone (AZ) membranes where Ca2+ channels are clustered and that are typically decorated by electron-dense projections. Recently, mutants of the Drosophila melanogaster ERC/CAST family protein Bruchpilot (BRP) were shown to lack dense projections (T-bars) and to suffer from Ca2+ channel–clustering defects. In this study, we used high resolution light microscopy, electron microscopy, and intravital imaging to analyze the function of BRP in AZ assembly. Consistent with truncated BRP variants forming shortened T-bars, we identify BRP as a direct T-bar component at the AZ center with its N terminus closer to the AZ membrane than its C terminus. In contrast, Drosophila Liprin-α, another AZ-organizing protein, precedes BRP during the assembly of newly forming AZs by several hours and surrounds the AZ center in few discrete punctae. BRP seems responsible for effectively clustering Ca2+ channels beneath the T-bar density late in a protracted AZ formation process, potentially through a direct molecular interaction with intracellular Ca2+ channel domains

A Syd-1 homologue regulates pre- and postsynaptic maturation in Drosophila

A proteomics approach identifies Drosophila Syd-1 as a Bruchpilot binding partner that controls maturation on both sides of the neuromuscular junction

Drep-2 is a novel synaptic protein important for learning and memory

CIDE-N domains mediate interactions between the DNase Dff40/CAD and its inhibitor Dff45/ICAD. In this study, we report that the CIDE-N protein Drep-2 is a novel synaptic protein important for learning and behavioral adaptation. Drep-2 was found at synapses throughout the Drosophila brain and was strongly enriched at mushroom body input synapses. It was required within Kenyon cells for normal olfactory short- and intermediate-term memory. Drep-2 colocalized with metabotropic glutamate receptors (mGluRs). Chronic pharmacological stimulation of mGluRs compensated for drep-2 learning deficits, and drep-2 and mGluR learning phenotypes behaved non-additively, suggesting that Drep 2 might be involved in effective mGluR signaling. In fact, Drosophila fragile X protein mutants, shown to benefit from attenuation of mGluR signaling, profited from the elimination of drep-2. Thus, Drep-2 is a novel regulatory synaptic factor, probably intersecting with metabotropic signaling and translational regulation

Circuits that encode and guide alcohol-associated preference

A powerful feature of adaptive memory is its inherent flexibility. Alcohol and other addictive substances can remold neural circuits important for memory to reduce this flexibility. However, the mechanism through which pertinent circuits are selected and shaped remains unclear. We show that circuits required for alcohol-associated preference shift from population level dopaminergic activation to select dopamine neurons that predict behavioral choice in Drosophila melanogaster. During memory expression, subsets of dopamine neurons directly and indirectly modulate the activity of interconnected glutamatergic and cholinergic mushroom body output neurons (MBON). Transsynaptic tracing of neurons important for memory expression revealed a convergent center of memory consolidation within the mushroom body (MB) implicated in arousal, and a structure outside the MB implicated in integration of naive and learned responses. These findings provide a circuit framework through which dopamine neuronal activation shifts from reward delivery to cue onset, and provide insight into the maladaptive nature of memory

Calcium-permeable channelrhodopsins for the photocontrol of calcium signalling

Channelrhodopsins are light-gated ion channels used to control excitability of designated cells in large networks with high spatiotemporal resolution. While ChRs selective for H(+), Na(+), K(+) and anions have been discovered or engineered, Ca(+)-selective ChRs have not been reported to date. Here, we analyse ChRs and mutant derivatives with regard to their Ca(+) permeability and improve their Ca(+) affinity by targeted mutagenesis at the central selectivity filter. The engineered channels, termed CapChR1 and CapChR2 for calcium-permeable channelrhodopsins, exhibit reduced sodium and proton conductance in connection with strongly improved Ca(+) permeation at negative voltage and low extracellular Ca(+) concentrations. In cultured cells and neurons, CapChR2 reliably increases intracellular Ca(+) concentrations. Moreover, CapChR2 can robustly trigger Ca(+) signalling in hippocampal neurons. When expressed together with genetically encoded Ca(+) indicators in Drosophila melanogaster mushroom body output neurons, CapChRs mediate light-evoked Ca(+) entry in brain explants

Neuronal mechanisms underlying innate and learned olfactory processing in Drosophila

Olfaction allows animals to adapt their behavior in response to different chemical cues in their environment. How does the brain efficiently discriminate different odors to drive appropriate behavior, and how does it flexibly assign value to odors to adjust behavior according to experience? This review traces neuronal mechanisms underlying these processes in adult Drosophila melanogaster from olfactory receptors to higher brain centers. We highlight neural circuit principles like lateral inhibition, segregation and integration of olfactory channels, temporal accumulation of sensory evidence, and compartmentalized synaptic plasticity underlying associative memory