Regulation of PDF Receptor signaling controlling daily locomotor rhythms in Drosophila

G protein-coupled receptors (GPCRs) trigger second messenger signaling cascades following activation by cognate ligands. GPCR signaling ceases following receptor desensitization or uncoupling from G proteins. Each day and in conjunction with ambient daylight conditions, neuropeptide PDF regulates the phase and amplitude of locomotor activity rhythms in Drosophila through its receptor, a Family B GPCR. Its time of action – when it starts signaling and when it stops – must change every day to following changing day lengths. We studied the process by which PDF Receptor (PDFR) signaling turns off in vivo, by modifying as many as half of the 28 potential sites of phosphorylation in its C terminal tail. We report that many such sites are conserved evolutionarily, and that in general their conversion to a non-phosphorylatable residue (alanine) creates a specific behavioral syndrome opposite to loss of function phenotypes previously described for pdfr. Such “gain of function” pdfr phenotypes include increases in the amplitudes of both Morning and Evening behavioral peaks as well as multi-hour delays of their phases. Such effects were most clearly associated with a few specific serine residues, and were seen following alanine-conversion of as few as one or two residues. The behavioral phenotypes produced by these PDFR sequence variants are not a consequence of changes to the pharmacological properties or of changes in their surface expression, as measured in vitro. We conclude that the mechanisms underlying termination of PDFR signaling are complex and central to an understanding of how this critical neuropeptide modulates daily rhythmic behavior.

Movement is governed by rotational population dynamics in spinal motor networks

Although the nervous system is elegantly orchestrating movements, the underlying neural principles remain unclear. Since flexor- and extensor-muscles alternate during movements like walking, it is often assumed that the responsible neural circuitry is similarly alternating in opposition. Here, we present ensemble recordings of neurons in the lumbar spinal cord that indicate that, rather than alternation, the population is performing a "rotation" in neural space, i.e. the neural activity is cycling through all phases continuously during the rhythmic behavior. The radius of rotation correlates with the intended muscle force. Since existing models of spinal motor control offer an inadequate explanation of rotation, we propose a new theory of neural generation of movement from which this and other unresolved issues, such as speed regulation, force control, and multi-functionalism, are conveniently explained.

Movement is governed by rotational population dynamics in spinal motor networks

ABSTRACTAlthough the nervous system is elegantly orchestrating movements, the underlying neural principles remain unclear. Since flexor- and extensor-muscles alternate during movements like walking, it is often assumed that the responsible neural circuitry is similarly alternating in opposition. Here, we present ensemble-recordings of neurons in the lumbar spinal cord that indicate that, rather than alternation, the population is performing a “rotation” in neural space, i.e. the neural activity is cycling through all phases continuously during the rhythmic behavior. The radius of rotation correlates with the intended muscle force. Since existing models of spinal motor control offer an inadequate explanation of rotation, we propose a new theory of neural generation of movement from which this and other unresolved issues, such as speed regulation, force control, and multi-functionalism, are conveniently explained.

Presynaptic coupling by electrical synapses coordinates a rhythmic behavior by synchronizing the activities of a neuron pair

Electrical synapses are specialized structures that mediate the flow of electrical currents between neurons and have well known roles in synchronizing the activities of neuronal populations, both by mediating the current transfer from more active to less active neurons and by shunting currents from active neurons to their less active neighbors. However, how these positive and negative functions of electrical synapses are coordinated to shape rhythmic synaptic outputs and behavior is not well understood. Here, using a combination of genetics, behavioral analysis, and live calcium imaging in Caenorhabditis elegans, we show that electrical synapses formed by the gap junction protein INX-1/innexin couple the presynaptic terminals of a pair of motor neurons (AVL and DVB) to synchronize their activation in response to a pacemaker signal. Live calcium imaging reveals that inx-1/innexin mutations lead to asynchronous activation of AVL and DVB, due, in part, to loss of AVL-mediated activation of DVB by the pacemaker. In addition, loss of inx-1 leads to the ectopic activation of DVB at inappropriate times during the cycle through the activation of the L-type voltage-gated calcium channel EGL-19. We propose that electrical synapses between AVL and DVB presynaptic terminals function to ensure the precise and robust execution of a specific step in a rhythmic behavior by both synchronizing the activities of presynaptic terminals in response to pacemaker signaling and by inhibiting their activation in between cycles when pacemaker signaling is low.

Rhythmic abilities in humans and non-human animals: A review and recommendations from a methodological perspective

Rhythmic behavior is ubiquitous in both human and non-human animals, but it is unclear whether the cognitive mechanisms underlying the specific rhythmic behaviors observed in different species are related. Lab experiments combined with highly controlled stimuli and tasks can be very effective in probing the cognitive architecture underlying rhythmic abilities. Rhythmic abilities have been examined in the lab with explicit and implicit perception tasks, and with production tasks, such as sensorimotor synchronization, with stimuli ranging from isochronous sequences of artificial sounds to human music. Here, we provide an overview of experimental findings on rhythmic abilities in human and non-human animals, while critically considering the wide variety of paradigms used. We identify several gaps in what is known about rhythmic abilities. Many bird species have been tested on rhythm perception, but research on rhythm production abilities in the same birds is lacking. In contrast, research in mammals has primarily focused on rhythm production rather than perception. Many experiments also do not differentiate between possible components of rhythmic abilities, such as processing of single temporal intervals, rhythmic patterns, a regular beat, or hierarchical metrical structures. For future research, we suggest a careful choice of paradigm to aid cross-species comparisons, and a critical consideration of the multifaceted abilities that underlie rhythmic behavior.

Temporally and spatially partitioned neuropeptide release from individual clock neurons

Neuropeptides control rhythmic behaviors, but the timing and location of their release within circuits is unknown. Here, imaging in the brain shows that synaptic neuropeptide release by Drosophila clock neurons is diurnal, peaking at times of day that were not anticipated by prior electrical and Ca2+ data. Furthermore, hours before peak synaptic neuropeptide release, neuropeptide release occurs at the soma, a neuronal compartment that has not been implicated in peptidergic transmission. The timing disparity between release at the soma and terminals results from independent and compartmentalized mechanisms for daily rhythmic release: consistent with conventional electrical activity–triggered synaptic transmission, terminals require Ca2+ influx, while somatic neuropeptide release is triggered by the biochemical signal IP3. Upon disrupting the somatic mechanism, the rhythm of terminal release and locomotor activity period are unaffected, but the number of flies with rhythmic behavior and sleep–wake balance are reduced. These results support the conclusion that somatic neuropeptide release controls specific features of clock neuron–dependent behaviors. Thus, compartment-specific mechanisms within individual clock neurons produce temporally and spatially partitioned neuropeptide release to expand the peptidergic connectome underlying daily rhythmic behaviors.

Drosophila acquires seconds-scale rhythmic behavior

Detection of the temporal structure of stimuli is crucial for prediction. While perception of interval timing is relevant for immediate behavioral adaptations, it has been scarcely investigated, especially in invertebrates. Here we examined if the fruit fly, Drosophila melanogaster, can acquire rhythmic behavior in the range of seconds. To this end, we developed a novel temporal conditioning paradigm utilizing repeated electric shocks. Combined automatic behavioral annotation and time-frequency analysis revealed that behavioral rhythms continued after cessation of the shocks. Furthermore, we found that aging impaired interval timing. This study thus not only demonstrated the ability of insects to acquire behavioral rhythms of a few seconds, but highlighted a life-course decline of temporal coordination, that is common also in mammals.

Integration of Circadian Clock Information in the Drosophila Circadian Neuronal Network

Circadian clocks are biochemical time-keeping machines that synchronize animal behavior and physiology with planetary rhythms. In Drosophila, the core components of the clock comprise a transcription/translation feedback loop and are expressed in seven neuronal clusters in the brain. Although it is increasingly evident that the clocks in each of the neuronal clusters are regulated differently, how these clocks communicate with each other across the circadian neuronal network is less clear. Here, we review the latest evidence that describes the physical connectivity of the circadian neuronal network . Using small ventral lateral neurons as a starting point, we summarize how one clock may communicate with another, highlighting the signaling pathways that are both upstream and downstream of these clocks. We propose that additional efforts are required to understand how temporal information generated in each circadian neuron is integrated across a neuronal circuit to regulate rhythmic behavior.

On the Multimodal Path to Language: The Relationship Between Rhythmic Movements and Deictic Gestures at the End of the First Year

The aim of this study is to analyze the relationship between rhythmic movements and deictic gestures at the end of the first year of life, and to focus on their unimodal or multimodal character. We hypothesize that multimodal rhythmic movement performed with an object in the hand can facilitate the transition to the first deictic gestures. Twenty-three children were observed at 9 and 12 months of age in a naturalistic play situation with their mother or father. Results showed that rhythmic movements with objects in the hand are a frequent behavior in children's repertoires. Rhythmic behaviors tend to decrease from 9 to 12 months, specifically when they are unimodal. Multimodal rhythmic behavior production at 9 months is positively related with proximal deictic gestures 3 months later. Multimodal rhythmic movements are not directly related to distal deictic gestures, but are indirectly related via proximal deictic gestures. These results highlight the relevance of multimodal behaviors in the transition to the use of early gestures, and can be considered as a transitional phenomenon between the instrumental action and early communicative gestures.