Stearoyl-CoA desaturases sustain cholinergic excitation and copulatory robustness in metabolically aging C. elegansmales.

Regulated metabolism is required for behaviors as adults age. To understand how lipid usage affects motor coordination, we studied male Caenorhabditis elegans copulation as a model of energy-intensive behavior. Copulation performance drops after 48 h of adulthood. We found that 12-24 h before behavioral decline, males prioritize exploring and copulation behavior over feeding, suggesting that catabolizing stored metabolites, such as lipids, occurs during this period. Because fat-6/7-encoded stearoyl-CoA desaturases are essential for converting the ingested fatty acids to lipid storage, we examined the copulation behavior and neural calcium transients of fat-6(lf); fat-7(lf) mutants. In wild-type males, intestinal and epithelial fat-6/7 expression increases during the first 48 h of adulthood. The fat-6(lf); fat-7(lf) behavioral and metabolic defects indicate that in aging wild-type males, the increased expression of stearoyl-CoA desaturases in the epidermis may indirectly modulate the levels of EAG-family K+ channels in the reproductive cholinergic neurons and muscles.

Succinate Dehydrogenase-Regulated Phosphoenolpyruvate Carboxykinase Sustains Copulation Fitness in Aging C. elegans Males.

Dysregulated metabolism accelerates reduced decision-making and locomotor ability during aging. To identify mechanisms for delaying behavioral decline, we investigated how C. elegans males sustain their copulatory behavior during early to mid-adulthood. We found that in mid-aged males, gluco-/glyceroneogenesis, promoted by phosphoenolpyruvate carboxykinase (PEPCK), sustains competitive reproductive behavior. C. elegans' PEPCK paralogs, pck-1 and pck-2, increase in expression during the first 2 days of adulthood. Insufficient PEPCK expression correlates with reduced egl-2-encoded ether-a-go-go K+ channel expression and premature hyper-excitability of copulatory circuits. For copulation, pck-1 is required in neurons, whereas pck-2 is required in the epidermis. However, PCK-2 is more essential, because we found that epidermal PCK-2 likely supplements the copulation circuitry with fuel. We identified the subunit A of succinate dehydrogenase SDHA-1 as a potent modulator of PEPCK expression. We postulate that during mid-adulthood, reduction in mitochondrial physiology signals the upregulation of cytosolic PEPCK to sustain the male's energy demands.

CRF-like receptor SEB-3 in sex-common interneurons potentiates stress handling and reproductive drive in C. elegans.

Environmental conditions can modulate innate behaviours. Although male Caenorhabditis elegans copulation can be perturbed in the presence of stress, the mechanisms underlying its decision to sustain copulation are unclear. Here we describe a mating interference assay, which quantifies the persistence of male C. elegans copulation in noxious blue light. We show that between copulations, the male escapes from blue light illumination at intensities over 370 µW mm(-2). This response is attenuated in mutants with constitutive activation of the corticotropin-releasing factor receptor family homologue SEB-3. We show that activation of this receptor causes sex-common glutamatergic lumbar ganglion interneurons (LUA) to potentiate downstream male-specific reproduction circuits, allowing copulatory behaviours to partially override the light-induced escape responses in the male. SEB-3 activation in LUA also potentiates copulation during mild starvation. We suggest that SEB-3 activation allows C. elegans to acclimate to the environment and thus continue to execute innate behaviours even under non-optimal conditions.

Comparative Metabolomic Profiling Reveals That Dysregulated Glycolysis Stemming from Lack of Salvage NAD+ Biosynthesis Impairs Reproductive Development in Caenorhabditis elegans.

Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD(+) consumers to resynthesize NAD(+), resulting in a reduction in global NAD(+) bioavailability. We manipulate NAD(+) levels to demonstrate that a minor deficit in NAD(+) availability is incompatible with a normal pace of gonad development. The NAD(+) deficit compromises NAD(+) consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal widespread metabolic perturbations, and using complementary pharmacological and genetic approaches, we demonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD(+) biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD(+) salvage biosynthesis for the purposes of inhibiting tumor growth.