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Environmental and Genetic Regulation of Motivated Behavior

Research Summary

L. René García studies how hardwired behaviors can be influenced by environmental factors, using C. elegans male mating behavior as a model system.

My lab focuses on understanding how in different conditions, an animal's neural muscular circuitry modifies the intensity of goal-oriented behaviors. For simple animals, innate behaviors are directed toward satiating a physiological need, such as acquiring water and nutrition, migrating toward an optimal temperature clime, resting, and reproduction. These activities can be generalized as motivated behaviors, and the intensity of performance can be described as the behavioral drive. The drive's magnitude depends on how a neural muscular circuit's excitability threshold responds to various stimuli strengths. In turn, these thresholds are adjusted by the animal's physiological state.

Caenorhabditis elegans male mating behavior has features that allow dissection of a complex goal-oriented behavior. The adult male contains 89 gender-specific neurons and 41 gender-specific muscles that regulate sex. Their electrical and chemical connectivities are known and have been experimentally correlated with specific motor outputs used in mating. Under optimal conditions, a male moves toward a hermaphrodite. After his sensory-laden tail contacts his mate, he ceases forward locomotion, presses his body against her, and crawls backwards, scanning for her vulva. The hermaphrodite is not receptive to mating and will attempt to dislodge him. Contact between the vulva and his cloacal sensilla signals the male to attempt breaching the vulval slit with his copulatory spicules. When the male inserts his spicules, his body seizes and he ejaculates into his mate. Afterwards, he withdraws his spicules and sluggishly crawls away; after 10 minutes, he will mate again (Figure 1).

My group is interested in determining how overlapping and unique mechanisms function in response to the animal's physiological state to modify circuits used for sexual reproduction. The condition that strongly affects sex drive is the male's nutritional state. The behaviors of the well-fed male focus on sex. In contrast, the sex drive of a food-restricted male is decreased, and his behaviors are directed toward food acquisition. By studying the circuitry that controls spicule insertion and ejaculation—behaviors that are simple to assay—we deciphered how excitable cells in the mating circuits hypo- or hyperpolarize in response to nutritional changes.

One question we are addressing concerns how mating circuit outputs are reduced when the male is food-stressed. If the male is removed from diffusible and volatile food-related chemicals, the AWC head sensory neurons increase in activity. This increase results in the secretion of signals from downstream neurons. The daf-2-encoded insulin-like receptor tyrosine kinase, located in the male genital circuits, likely responds to some of these humoral signals and functions genetically upstream of the plc-3-encoded phospholipase C gamma,unc-43-encoded calcium-activated CaMKII kinase, and the egl-2-encoded voltage-gated EAG K+ channel. We found that physical interactions between CaMKII and the EAG K+ channel act in conjunction with the unc-103-encoded ERG voltage-gated K+ channel and the slo-1-encoded Ca2+ sensitive voltage-gated Big Current K+channel to hyperpolarize the male genital muscles, making them less responsive to stimulation under food-stressful conditions (Figure 2).

We are also interested in determining which molecules involved in regulating mating drive are genetically plastic to allow reproduction in suboptimal nutritional environments. If a male enters a suboptimal food environment, his sex drive remains suppressed until he encounters an ideal food source. We have identified genetic loci that, when mutated, will expand the range of nutrient environments acceptable for male mating. A chemically defined axenic media can suboptimally maintain C. elegans growth; however, larval developmental rate is retarded, the adult animals have a starved appearance, and the males display no sex drive. We isolated EMS mutations that accelerate larval development in this suboptimal media; however, the adult mutants still appear starved. One of these mutations disrupts a channel-like membrane protein encoded by tmc-1. The TMC-1 protein is homologous to a conserved class of membrane proteins implicated in mammalian cochlea hair cell function. In the axenic media, the mutation affects a few cholinergic head neurons and indirectly promotes the expression of glycolytic catabolic enzymes. Interestingly, unlike the wild type, the starved-appearing mutant males will copulate in the axenic media. This observation indicates that there is overlap between mechanisms that couple developmental rate with nutritional assimilation and mechanisms that control the excitability thresholds of mating circuits (Figure 3).

Figure 5: Changes in neural muscular activities...

An additional question of interest relates to how circuits, normally involved with environmental sensing of noxious stimuli, are attenuated while the male is engaged in mating. We use high-intensity blue light to irritate the copulating male. When he is not copulating, blue-light exposure induces an avoidance response; however, while he is scanning for the vulva or attempting to insert his spicules, he is more light tolerant. We found that mating-mediated blue-light tolerance is promoted by the stimulatory corticotropin-releasing factor (CRF)-like GPCR SEB-3. In mammals, the CRF ligand is released upon stress, presumably as a coping mechanism. In C. elegansmales, its counterpart facilitates behavioral drive states. A seb-3 constitutive activated allele promotes higher behavioral tolerance to blue-light stress, whereas males containing a null allele will terminate mating upon light exposure. The stimulatory SEB-3 receptor is broadly expressed in gender common neurons in the male head and ventral cord, indicating that signaling from this receptor enhances outputs from some of these cells to override the avoidance signals from the head ASJ, AWB, ASK, and ASH photoreceptor cells (Figure 4).

Finally, we are interested in how satiation of mating temporally reduces sex drive. The male will tenaciously attempt to copulate until the hermaphrodite dislodges him or he ejaculates, which is the satiation step of mating. In vivo calcium-imaging experiments of behaving males indicate that during ejaculation, the activity levels of multiple sensory-motor neurons involved in different steps of mating immediately decrease and remain low, even after the mated male leaves the hermaphrodite. In contrast, the tissues that display dynamic calcium transients throughout ejaculation are the myo-epithelial gonadal vas deferens and the intestines. We are investigating whether these two tissues are the source of diffusible satiation signals that globally reduce the excitability of multiple mating circuits and define the refractory period between copulation attempts (Figure 5).

As of November 13, 2012

Scientist Profile

Investigator
Texas A&M University
Genetics, Neuroscience