Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants

Abstract

Defects in insulin signaling have been reported in schizophrenia and major depressive disorder, which also share certain negative symptoms such as avolition, anhedonia, and apathy. These symptoms reflect diminished motivational states, which have been modeled in rodents as increased immobility in the forced swimming test. We have discovered that loss-of-function mutations in the insulin receptor (daf-2) and syntaxin (unc-64) genes in Caenorhabditis elegans, brief food deprivation, and exposure to DMSO produce immobility and avolition in non-dauer adults. The animals remain responsive to external stimuli; however, they fail to forage and will remain in place for >12 days or until they die. Their immobility can be prevented with drugs used to treat depression and schizophrenia and that reduce immobility in the forced swimming test. This includes amitriptyline, amoxapine, clozapine, and olanzapine, but not benzodiazepines and haloperidol. Recovery experiments confirm that immobility is induced and maintained by excessive signaling via serotonergic and muscarinic cholinergic pathways. The immobility response described here represents a potential protophenotype for avolition/anhedonia in man. This work may provide clues about why there is a significant increase in depression in patients with diabetes and suggest new therapeutic pathways for disorders featuring diminished motivation as a prominent symptom.

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

“…Recently, a protophenotype for diminished motivation has been reported in C. elegans [30]. Mutant animals with temperature-sensitive loss of function in insulin/IGF-1 signaling (IIS) via the insulin receptor ( daf-2 ) become immobile when they experience acute food deprivation in the presence of low concentrations (0.8-1%) of DMSO.…”

“…The main treatment for catatonia - benzodiazepines - failed to correct immobility, whereas antidepressants and certain second-generation antipsychotic drugs stimulated normal foraging [30]. Based on the pharmacology and the genetics of the response, this C. elegans protophenotype was considered more relevant for diminished motivation underlying the anhedonia and avolition characteristic of depressive states or negative symptoms.…”

“…The potential downstream targets in neurons that mediate changes in motivation include various ion channels, transporters, and neurotransmitter receptors. Ultimately, IIS affects release and actions of major neurotransmitters such as serotonin and acetylcholine, which were implicated in studies of motivation in C. elegans [30]. …”

“…Moreover, these drugs show selectivity in their actions. For example, antidepressants correct immobility in C. elegans , whereas benzodiazepines do not [30]. Therefore, immobility may be more relevant as a model for depression than for catatonia or anxiety disorders.…”

Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

“…For example, apathy is considered a hallmark symptom of DM1 (121). In an animal model, induced loss of function of insulin receptor signaling leads to a state of reduced motivation, thought to be translatable to a condition of apathy in humans (122). In addition, brain insulin resistance may lead to cognitive deficits, especially visuospatial and verbal memory deficits (119).…”