Joined the Department in 2002
- B.S., 1990, University of Texas, Austin, Microbiology.
- Ph.D., 1996, University of Texas, Austin, Microbiology.
- Postdoctoral research, California Institute of Technology.
- Howard Hughes Investigator, 2008
Genetics of Behavior and Development of C. elegans
I am interested in understanding how behavioral states are regulated at the molecular and genetic level. My lab addresses this complex question in the well-studied nematode Caenorhabditis elegans. Several physical aspects of this worm make it convenient for integrating whole organism system biology studies with genetic/molecular analysis of neurobiology and behavior. C. elegans is an anatomically simple organism; it is 1mm in size, and it contains ~ 1000 somatic cells, a third of which are neurons. The worm is also transparent, and thus every cell can be visualized by light microscopy. Behavioral mutants can be efficiently generated through standard chemical mutagenesis. In addition, gene functions involved in motivational and behavioral regulation can be determined by transgenic techniques.
My lab investigates the interplay between feeding and sex-specific mating behavior to understand how chemo/mechano-sensory and motor outputs are controlled under various physiological conditions. We study male mating by using genetics to de-construct this behavior into its fundamental sensory-motor components. We then use a combination of transgenics, pharmacology, classical genetics and laser microsurgery to understand how individual motor sub-behaviors are coordinated to produce gross behaviors during periods when the animal is food deprived, and when it is food satiated.
We focus on how food-related sensory signaling through sensory neurons and insulin growth factor-like receptor signaling regulates sensory-motor mating circuits. We have generated mutations in UNC-103/ERG K+ channels and UNC-43/CaMKII kinase that cause spontaneous firing of the mating circuitry in well-fed males. In normal males, these molecules act to attenuate neurons and muscles until proper stimulation by a mate. When ERG K+ channels and CaMKII kinase are mutated, males constitutively display mating-like behaviors that superficially resemble seizures. Depriving ERG K+ channel mutants of food can attenuate spontaneous firing of the mating circuit. This suggests that signaling pathways involved in nutritional physiology can regulate excitability of behavioral circuits.
Through multiple approaches, we determined that the chemosensory neuron AWC senses the absence of food. Under food deprivation conditions, the neuron acts with mating circuitry-expressed insulin growth factor-like receptors to stimulate calcium-regulated CaMKII kinases and EGL-2/EAG K+ channel activity. These downstream molecules then reduce the excitability of neurons and muscles, so that in ERG K+ channel mutants, they do no spontaneously display seizure behaviors; and in wild-type animals, males do not efficiently respond to mating cues. We are currently trying to understand other physiological changes that occur in the mating circuit under food deprivation conditions, and how those changes are molecularly reversed when the animal becomes food satiated.
My lab is also investigating how in food-satiated males, molecular mechanisms involved in executing motor programs are modulated, during prolonged mating attempts, to maintain behavioral persistence. Prior to ejaculation, the male must first breach his mate’s vulva with his copulatory spicules. During mating, young adult hermaphrodites are not behaviorally receptive to mating. To achieve mating success, the male uses a network of cloacal cholinergic sensory/motor neurons to maintain his position over the vulva, as he repetitively attempts to penetrate the tightly closed vulval slit. He maintains this behavior until ejaculation is accomplished. The efficacy of these sensory motor neurons to stain their output is facilitated by the GAR-3/G-protein-coupled M1/M3/M5-like muscarinic ACh receptor (mAChR). The GAR-3 receptor promotes persistence in executing behavioral programs, since males mutant in the gar-3 gene frequently cease spicule insertion attempts and move off the vulval area, if they do not immediately penetrate their mates. We are currently trying to understand how downstream effectors of GAR-3 receptor signaling integrate with nicotinic acetylcholine receptor signaling in various muscle and neuronal components of the mating circuit.
- Serrano-Saiz, E, Pereira, L, Gendrel, M, Aghayeva, U, Battacharya, A, Howell, K et al.. A Neurotransmitter Atlas of theMale Nervous System Reveals Sexually Dimorphic Neurotransmitter Usage. Genetics. 2017;206 (3):1251-1269. doi: 10.1534/genetics.117.202127. PubMed PMID:28684604 PubMed Central PMC5500128.
- Versaw, WK, Garcia, LR. Intracellular transport and compartmentation of phosphate in plants. Curr. Opin. Plant Biol. 2017;39 :25-30. doi: 10.1016/j.pbi.2017.04.015. PubMed PMID:28570954 .
- LeBoeuf, B, Garcia, LR. Male Copulation Circuitry Incorporates Sex-Shared Defecation Components To Promote Intromission and Sperm Transfer. G3 (Bethesda). 2017;7 (2):647-662. doi: 10.1534/g3.116.036756. PubMed PMID:28031243 PubMed Central PMC5295609.
- Jee, C, Goncalves, JF, LeBoeuf, B, Garcia, LR. CRF-like receptor SEB-3 in sex-common interneurons potentiates stress handling and reproductive drive in C. elegans. Nat Commun. 2016;7 :11957. doi: 10.1038/ncomms11957. PubMed PMID:27321013 PubMed Central PMC4915151.
- Rosas, PC, Nagaraja, GM, Kaur, P, Panossian, A, Wickman, G, Garcia, LR et al.. Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment. PLoS ONE. 2016;11 (3):e0149409. doi: 10.1371/journal.pone.0149409. PubMed PMID:26960140 PubMed Central PMC4784952.
- García, LR, Portman, DS. Neural circuits for sexually dimorphic and sexually divergent behaviors in Caenorhabditis elegans. Curr. Opin. Neurobiol. 2016;38 :46-52. doi: 10.1016/j.conb.2016.02.002. PubMed PMID:26929998 PubMed Central PMC4921283.
- Pereira, L, Kratsios, P, Serrano-Saiz, E, Sheftel, H, Mayo, AE, Hall, DH et al.. A cellular and regulatory map of the cholinergic nervous system of C. elegans. Elife. 2015;4 :. doi: 10.7554/eLife.12432. PubMed PMID:26705699 PubMed Central PMC4769160.
- Banerjee, S, Versaw, WK, Garcia, LR. Imaging Cellular Inorganic Phosphate in Caenorhabditis elegans Using a Genetically Encoded FRET-Based Biosensor. PLoS ONE. 2015;10 (10):e0141128. doi: 10.1371/journal.pone.0141128. PubMed PMID:26484766 PubMed Central PMC4615621.
- Correa, PA, Gruninger, T, García, LR. DOP-2 D2-Like Receptor Regulates UNC-7 Innexins to Attenuate Recurrent Sensory Motor Neurons during C. elegans Copulation. J. Neurosci. 2015;35 (27):9990-10004. doi: 10.1523/JNEUROSCI.0940-15.2015. PubMed PMID:26156999 PubMed Central PMC4495247.
- Zhang, L, Gualberto, DG, Guo, X, Correa, P, Jee, C, Garcia, LR et al.. TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment. Nat Commun. 2015;6 :6345. doi: 10.1038/ncomms7345. PubMed PMID:25695879 .