Dynamic functional connectivity in the static connectome of Caenorhabditis elegans

Abstract

A hallmark of adaptive behavior is the ability to flexibly respond to sensory cues. To understand how neural circuits implement this flexibility, it is critical to resolve how a static anatomical connectome can be modulated such that functional connectivity in the network can be dynamically regulated. Here, we review recent work in the roundworm Caenorhabditis elegans on this topic. EM studies have mapped anatomical connectomes of many C. elegans animals, highlighting the level of stereotypy in the anatomical network. Brain-wide calcium imaging and studies of specified neural circuits have uncovered striking flexibility in the functional coupling of neurons. The coupling between neurons is controlled by neuromodulators that act over long timescales. This gives rise to persistent behavioral states that animals switch between, allowing them to generate adaptive behavioral responses across environmental conditions. Thus, the dynamic coupling of neurons enables multiple behavioral states to be encoded in a physically stereotyped connectome.

Figure 1:. A physically invariant network with dynamic activity.

A. Sensory circuit at 3 different developmental stages. Circles represent neurons, while lines represent chemical synapses. Only chemical synapses were mapped in Witvliet et al. B. Heatmap of neuronal activity measured by NLS-GCaMP5k fluorescence. Image is reproduced from Kato et al. C. A large fraction of neuronal activity from B represents the motor program. Most dynamics lie along a manifold in the first 3 principal components from PCA dimension reduction of neuronal activity (left panel). Manifold is colored according to the motor phase (right panel). Images are reproduced from Kato et al. D. Interneuron circuit. Certain neurons like AVB and RIB strongly correlate with forward behavior while neurons like AVA and RIM strongly correlate with reversal behavior. However, other interneurons like AIA, AIB, AIY and AIZ transiently correlate with motor state.

Figure 2:. Sensory and neuromodulatory context influence interneuron correlation with motor program

A. The path global neuronal dynamics take through PCA-reduced space is strongly influenced by sensory context. Each colored volume represents the average phase trajectory of whole-brain neuronal activity during sensory stimulation with 2-3 pentanedione (purple), 2-butanone (orange), or NaCl (yellow). Image is reproduced from Yemini et al. B. Neuronal activity correlates poorly with chemical and electrical synapse connectivity. Image is reproduced from Yemini et al. C. The AIB interneuron exhibits activity that correlates with sensory-induced activity from AWC, and/or reverse motor activity mediated by synaptic input from RIM. D. The AIY interneuron exhibits activity that correlates with sensory-induced activity from AFD, and/or forward motor activity mediated by neuromodulatory inhibition from RIM. E. AIA drives dwelling in the presence of food and the absence of odor gradients. Its activity is tightly coupled to the serotonergic neuron NSM which inhibits AIY and other MOD-1 expressing neurons. However, in the presence of odor gradients while on food, AIA drives roaming behavior. In this context, AIA activity is tightly coupled to forward interneuron activity. F. AIA activity is strongly influenced by both sensory and food context. Under well-fed conditions, AWC activity does not correlate with warming gradients, and in turn does not inhibit AIA activity via glutamate. Under starved conditions, AWC is sensitized to warm gradients via INS-1 signaling from the gut. Increased AWC activity silences AIA, which in turn decreases forward drive.

Figure 3:. Neural Circuits for Behavioral State Control in C. elegans

A. The RIS interneuron acts as a command neuron to control developmentally timed sleep, whereas the ALA interneuron controls stress-induced sleep. Each releases distinct neuropeptides that have causal roles in inhibiting the main C. elegans motor programs and thereby inducing sleep. B. Mutual inhibition between the neurons that produce the opposing 5-HT and PDF neuromodulators underlies bi-stable switching between roaming and dwelling behavioral states. Food ingestion activates the serotonergic system to increase dwelling, while both neuromodulatory systems receive feedforward inputs from the chemosensory system. C. Chemosensory and mechanosensory cues are detected by different sets of sensory neurons that feed into a reorientation circuit. Immediately after food removal, the sensory neurons are spontaneously active and strongly coupled to the reorientation circuit. As animal continue to explore without successfully finding food, sensory neurons display reduced activity and reduced coupling to the reorientation circuit.