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

Dopaminergic systems create reward seeking despite adverse consequences

Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking1. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking2,3, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals

Dopaminergic systems create reward seeking despite adverse consequences

Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking1. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking2,3, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals

Integration of Parallel Opposing Memories Underlies Memory Extinction.

Accurately predicting an outcome requires that animals learn supporting and conflicting evidence from sequential experience. In mammals and invertebrates, learned fear responses can be suppressed by experiencing predictive cues without punishment, a process called memory extinction. Here, we show that extinction of aversive memories in Drosophila requires specific dopaminergic neurons, which indicate that omission of punishment is remembered as a positive experience. Functional imaging revealed co-existence of intracellular calcium traces in different places in the mushroom body output neuron network for both the original aversive memory and a new appetitive extinction memory. Light and ultrastructural anatomy are consistent with parallel competing memories being combined within mushroom body output neurons that direct avoidance. Indeed, extinction-evoked plasticity in a pair of these neurons neutralizes the potentiated odor response imposed in the network by aversive learning. Therefore, flies track the accuracy of learned expectations by accumulating and integrating memories of conflicting events.S.W. was funded by a Wellcome Principal Research Fellowship (200846/Z/16/Z), by the Gatsby Charitable Foundation (GAT3237), and by the Bettencourt-Schueller Foundation. J.F. was supported by the DFG (FE 1563/1-1). G.S.X.E.J. was funded by Medical Research Council. D.D.B. funded by HHMI. G.S.X.E.J., D.D.B., and S.W. were funded by a Wellcome Collaborative Award (203261/Z/16/Z)

Reporting whole-body vibration intervention studies: Recommendations of the International Society of Musculoskeletal and Neuronal Interactions

Whole-body vibration (WBV) is receiving increasing interest as a therapeutic modality to improve neuromuscular performance or to increase bone mass or density. In order to help improve the quality of reports about WBV treatment studies, the International Society of Musculoskeletal and Neuronal Interactions (ISMNI) invited experts in the field to provide suggestions on how the intervention should be described in such reports. The recommendations are presented here

Reinstatement in honeybees is context-dependent

During extinction animals experience that the previously learned association between a conditioned stimulus (CS) and an unconditioned stimulus (US) no longer holds true. Accordingly, the conditioned response (CR) to the CS decreases. This decrease of the CR can be reversed by presentation of the US alone following extinction, a phenomenon termed reinstatement. Reinstatement and two additional phenomena, spontaneous recovery and renewal, indicate that the original CS–US association is not lost through extinction but can be reactivated through different processes. In honeybees (Apis mellifera), spontaneous recovery, i.e., the time-dependent return of the CR, has been demonstrated, suggesting that also in these insects the original CS–US association is not lost during extinction. To support this notion, we ask whether honeybees show reinstatement after extinction. In vertebrates reinstatement is context-dependent, so we examined whether the same holds true for honeybees. We demonstrate reinstatement in restrained honeybees and show that reinstatement is context-dependent. Furthermore, we show that an alteration of the color of light illuminating the experimental setup suffices to indicate a contextual change. We conclude that in honeybees the initially formed CS–US memory is not lost after extinction. Rather, honeybees might learn about the context during extinction. This enables them to adequately retrieve one of the two opposing memories about the CS that have been formed after extinction.7 page(s

Re-evaluation of learned information in Drosophila.

Animals constantly assess the reliability of learned information to optimize their behaviour. On retrieval, consolidated long-term memory can be neutralized by extinction if the learned prediction was inaccurate. Alternatively, retrieved memory can be maintained, following a period of reconsolidation during which it is labile. Although extinction and reconsolidation provide opportunities to alleviate problematic human memories, we lack a detailed mechanistic understanding of memory updating. Here we identify neural operations underpinning the re-evaluation of memory in Drosophila. Reactivation of reward-reinforced olfactory memory can lead to either extinction or reconsolidation, depending on prediction accuracy. Each process recruits activity in specific parts of the mushroom body output network and distinct subsets of reinforcing dopaminergic neurons. Memory extinction requires output neurons with dendrites in the α and α' lobes of the mushroom body, which drive negatively reinforcing dopaminergic neurons that innervate neighbouring zones. The aversive valence of these new extinction memories neutralizes previously learned odour preference. Memory reconsolidation requires the γ2α'1 mushroom body output neurons. This pathway recruits negatively reinforcing dopaminergic neurons innervating the same compartment and re-engages positively reinforcing dopaminergic neurons to reconsolidate the original reward memory. These data establish that recurrent and hierarchical connectivity between mushroom body output neurons and dopaminergic neurons enables memory re-evaluation driven by reward-prediction error

Short- and long-term memories formed upon backward conditioning in honeybees (Apis mellifera)

In classical conditioning, the temporal sequence of stimulus presentations is critical for the association between the conditioned stimulus (CS) and the unconditioned stimulus (US). In forward conditioning, the CS precedes the US and is learned as a predictor for the US. Thus it acquires properties to elicit a behavioral response, defined as excitatory properties. In backward conditioning, the US precedes the CS. The CS might be learned as a predictor for the cessation of the US acquiring inhibitory properties that inhibit a behavioral response. Interestingly, behavior after backward conditioning is controlled by both excitatory and inhibitory properties of the CS, but the underlying mechanisms determining which of these opposing properties control behavior upon retrieval is poorly understood. We performed conditioning experiments in the honeybee (Apis mellifera) to investigate the CS properties that control behavior at different time points after backward conditioning. The CS properties, as characterized by the retardation or enhancement of subsequent acquisition, were examined 30 min and 24 h after backward conditioning. We found that 30 min after backward conditioning, the CS acquired an inhibitory property during backward conditioning depending on the intertrial interval, the number of trials, and the odor used as the CS. One day after backward conditioning, we observed significant retardation of acquisition. In addition, we demonstrated an enhanced, generalized odor response in the backward conditioned group compared to untreated animals. These results indicate that two long-lasting opposing memories have been formed in parallel: one about the excitatory properties of the CS and one about the inhibitory properties of the CS.9 page(s