Crossing the Worm-Brain Barrier by Using <b><i>Caenorhabditis elegans</i></b> to Explore Fundamentals of Human Psychiatric Illness

Abstract

Endophenotypes and Research Domain Criteria (RDoC) represent recent efforts to deconvolute psychiatric illnesses into fundamental symptom clusters or biological markers more closely linked to genetic influences. By taking this one step farther, these biomarkers can be reduced to protophenotypes - endophenotypes conserved during evolution - with counterparts in lower organisms including Caenorhabditis elegans and Drosophila. Striking conservation in C. elegans of genes that increase the risk for mental illness bolsters the relevance of this model system for psychiatric research. Here, I review the characterization of several protophenotypes that are relevant for asociality, avolition/anhedonia, prepulse inhibition, and anorexia. Interestingly, the analogous behavioral defects in C. elegans are also corrected by psychotropic drugs used to treat the corresponding symptoms in man and/or are mediated by the same neurotransmitters. Overall, there is much we can learn about the complex human brain by studying simpler nervous systems directing evolutionarily conserved behaviors. The potential for generating important new insights from model organisms appears limitless when we begin to recognize the vestiges of evolution in ourselves.

Towards High-Throughput Chemobehavioural Phenomics in Neuropsychiatric Drug Discovery

“…C. elegans has become a popular experimental animal, and even considering there is less genetic resemblance between nematodes and humans than other vertebrate models such as zebrafish, it has contributed greatly to the understanding of pathophysiology of human diseases [36,46,66,67]. C. elegans is very attractive because many inexpensive bioassays can be rapidly performed on small, rapidly developing worms that are amenable to high-throughput screening of drugs and toxins [36,67,68,69,70,71].…”

“…In the context of neurobiology C. elegans enables studies of neuronal development, connectivity, physiology, as well as alterations in behavioural traits, modulated by both genetic factors and pharmacological intervention [67,68,69,70,71,72]. Importantly, in contrast to zebrafish, it has a very well characterized nervous system with 302 neurons (divided into 118 distinct classes in addition to 56 glial cells), 1410 neuromuscular junctions, and 6393 chemical synapses (Avila et al, 2012) [67,71,73]. The synaptic transmission in C. elegans is also evolutionary, conserved with similar pathways to mammals including cholinergic, GABAergic, glutamatergic, dopaminergic, and serotonergic signaling [73,74].…”

“…This organism is so far the only one of which we possess an entire neuronal wiring chart mapping all neurons and major synaptic connections [73,74]. Despite the sheer simplicity of nematode’s CNS, it exhibits a variety of interesting behaviours such as: different motion and gait patterns, electrotaxis, chemotaxis, thermotaxis, light avoidance, mechanotransduction, learning, memory, mating, and sleep-like behaviours [66,67,72,75]. These can be used to elucidate the functions of neuronal pathways.…”

“…These can be used to elucidate the functions of neuronal pathways. Recent reports suggests that C. elegans is an exceptional model to explore molecular foundations of addiction and other drug-induced behavioural effects [66,67,71,72,76]. The optical transparency of worms also provide ample opportunities to combine behavioural data with real-time visualization of neurons in a plethora of transgenic lines and even study neuronal excitability using live-animal calcium imaging [77].…”

“…Several recent studies demonstrated that phenotypic analysis of neurodegeneration can be modelled in worms and their applications can lead to accelerated drug discovery [78,79]. In relation to discovery of drugs for neuro-psychiatric conditions, C. elegans displays several conserved behavioural protophenotypes such as social feeding, immobility, startle suppression of pharyngeal pumping, and anorexic phenotypes [67,80,81]. Protophenotypes can be defined as precursors of higher CNS functions shared across species [82].…”