Coordination of opposing sex-specific and core muscle groups regulates male tail posture during Caenorhabditis elegansmale mating behavior
© Whittaker and Sternberg; et al; licensee BioMed Central Ltd. 2009
Received: 09 February 2009
Accepted: 22 June 2009
Published: 22 June 2009
To survive and reproduce, animals must be able to modify their motor behavior in response to changes in the environment. We studied a complex behavior of Caenorhabditis elegans, male mating behavior, which provided a model for understanding motor behaviors at the genetic, molecular as well as circuit level. C. elegans male mating behavior consists of a series of six sub-steps: response to contact, backing, turning, vulva location, spicule insertion, and sperm transfer. The male tail contains most of the sensory structures required for mating, in addition to the copulatory structures, and thus to carry out the steps of mating behavior, the male must keep his tail in contact with the hermaphrodite. However, because the hermaphrodite does not play an active role in mating and continues moving, the male must modify his tail posture to maintain contact. We provide a better understanding of the molecular and neuro-muscular pathways that regulate male tail posture during mating.
Genetic and laser ablation analysis, in conjunction with behavioral assays were used to determine neurotransmitters, receptors, neurons and muscles required for the regulation of male tail posture. We showed that proper male tail posture is maintained by the coordinated activity of opposing muscle groups that curl the tail ventrally and dorsally. Specifically, acetylcholine regulates both ventral and dorsal curling of the male tail, partially through anthelmintic levamisole-sensitive, nicotinic receptor subunits. Male-specific muscles are required for acetylcholine-driven ventral curling of the male tail but dorsal curling requires the dorsal body wall muscles shared by males and hermaphrodites. Gamma-aminobutyric acid activity is required for both dorsal and ventral acetylcholine-induced curling of the male tail and an inhibitory gamma-aminobutyric acid receptor, UNC-49, prevents over-curling of the male tail during mating, suggesting that cross-inhibition of muscle groups helps maintain proper tail posture.
Our results demonstrated that coordination of opposing sex-specific and core muscle groups, through the activity of multiple neurotransmitters, is required for regulation of male tail posture during mating. We have provided a simple model for regulation of male tail posture that provides a foundation for studies of how genes, molecular pathways, and neural circuits contribute to sensory regulation of this motor behavior.
In addition to the neurons and muscles that the males share with hermaphrodites, ('core' neurons and muscles), each C. elegans male has an additional 89 sex-specific neurons and 41 sex-specific muscles, almost all of which are in its tail. Many of the sex-specific sensory neurons in mating behavior have known functions [3, 4]. While less is known about how male-specific and core neurons and muscles interact to regulate mating behavior, sexual dimorphism of the core nervous system does contribute to mating behavior [5–7].
Serotonin release from the male-specific CP motor neurons has been proposed to activate the SER-1 serotonin receptor in male-specific muscles, causing ventral curling of the male tail [8–10]. However, other factors are also likely to regulate ventral curling. Males lacking male-specific muscles are still able to back along, and turn around a hermaphrodite, albeit clumsily, suggesting that core muscles partially control tail posture . Likewise, males homozygous for mutations disrupting serotonin synthesis can still sometimes perform wild-type turns implying that neurotransmitters other than serotonin also act in tail curling. Finally, males lacking the CP neurons are able to turn sometimes while mating so other neurons must contribute to regulate tail posture. Meanwhile, dorsal curling of the male tail is not well understood.
Our studies showed that a balance of contraction of dorsal and ventral muscle groups maintains proper male tail posture. We showed that acetylcholine regulates both dorsal and ventral bending of the male tail, through both sex-specific and core muscle groups. Acetylcholine acts, in part, independently of serotonin to regulate ventral tail curling. Gamma-aminobutyric acid (GABA) is required for both dorsal and ventral curling of the male tail, suggesting that cross inhibition of muscle groups is important for proper regulation of tail posture. These studies provide insight into regulation of simple motor circuits and the basis of sexually dimorphic behaviors.
Increased levels of synaptic acetylcholine induce male-specific changes in tail posture
Acetylcholine regulates male tail posture via both core and sex-specific muscles
Dorsal curling in response to aldicarb, in contrast, was raised rather than lowered at later time points by the absence of male-specific muscles (Figure 4b). We therefore ablated dorsal body wall muscles in the tail region of the male and found that dorsal tail curling is eliminated in most males indicating that acetylcholine acts through these core muscles (Figure 4c). The low level of tail curling seen in some animals may be due to incomplete dorsal body wall muscle ablation. Ventral curling, in contrast, is not disrupted (Figure 4d). Thus, acetylcholine regulates male tail posture through both male-specific muscles and sexually dimorphic control of core body wall muscles.
Backing and turning phenotypes of dorsal body wall-ablated males.
Curl around hermaphrodite
Back on lateral side
Number of good turns > number of bad turns
Dorsal body wall-ablated
N = 27
N = 27
N = 24
N = 24
N = 23
P = 0.1068
N = 23
P = 0.1147
N = 20
P = 0.013
N = 20
P = 0.2125
Levamisole receptors are required for proper tail posture control
Acetylcholine can act independently of serotonin to regulate ventral tail curling
To test serotonergic CP motor neurons for function in acetylcholine-induced ventral tail curling, we examined the ability of lin-39 mutant males to respond to aldicarb. In lin-39 mutant males, CP neurons 1–4 die or are necrotic, while CP neurons 5 and 6 take on a more posterior fate, and lin-39 mutant males have a turning defect similar to that of males in which the CP neurons have been ablated [8, 32–34]. We found that ventral curling of lin-39 (n1760) mutant males in response to aldicarb was lower, but not significantly so (Figure 9b). Thus, acetylcholine largely acts downstream or in parallel to serotonin and cholinergic neurons act in parallel to the CP motor neurons to regulate ventral tail curling.
GABA is required for both dorsal and ventral curling of the male tail
To test if D-type motor neurons are required for tail curling, we examined aldicarb-induced tail curling of males homozygous mutant for unc-30, a homeodomain containing transcription factor that is required for the terminal differentiation of the D-type motor neurons . unc-30 mutant males showed a significant decrease in dorsal tail curling, indicating that acetylcholine may act in part through the D-type neurons to promote dorsal tail curling (Figure 10c). Ventral tail curling, in contrast, is largely unaffected in unc-30 mutant males suggesting that other GABAergic neurons are involved (Figure 10d).
unc-49 mutant males show a small but significant decrease in aldicarb-induced dorsal tail curling in response to aldicarb at only the 2.5 minute time point and a significant increase in ventral tail curling (Figure 10e and 10f). Thus, although acetylcholine may partly act through UNC-49 to regulate dorsal tail curling, other GABARs are involved. As we saw an increase in ventral tail curling at the 2.5 minute time point, it suggests that acetylcholine regulates dorsal tail curling, in part by inhibiting ventral muscle groups.
Mating phenotypes of unc-49(e407) mutant males.
Mutant vulva location
Improper body posture at vulva
N = 7
N = 7
N = 7
N = 7
N = 7
N = 9
P = 0.0337
N = 7
P = 0.0699
N = 7
P = 0.0699
N = 7
N = 7
P = 0.0047
Our results favor a model where serotonergic neurons act with cholinergic neurons to promote contraction of male-specific muscles and ventral tail curling. First, bathing males in the acetylcholine-esterase inhibitor aldicarb induces ventral curling of the male tail and this requires the male-specific muscles, which are necessary for efficient response and turning behavior . In addition, mutations in levamisole receptor subunits disrupt response and turning behaviors, consistent with acetylcholine regulating male tail posture during mating. We cannot rule out the possibility that due to contextual and temporal factors, there are some differences between the aldicarb assay and tail posture regulation during mating. Previous studies suggest a model where serotonin, released from the CP motor neurons, acts on the SER-1 receptor in the male-specific diagonal muscles to promote ventral curling of the male tail [8, 10]. We showed that a mutation that eliminates the CP 1–6 motor neurons does not significantly decrease aldicarb-induced ventral tail curling suggesting that there are cholinergic neurons that act, in part, in parallel to the CP motor neurons to regulate ventral tail curling. As levamisole receptor subunits are expressed in male-specific muscles, it is likely that these muscles are regulated by both acetylcholine and serotonin. It is likely that further study will reveal additional levels of complexity in cholinergic and serotonergic regulation of male tail posture. Consistent with this, our results showed that levamisole receptors are also expressed in neurons. Also, other acetylcholine receptor subunits have been shown to be expressed in neurons required for backing and/or turning behavior and there is evidence that muscarinic acetylcholine receptors regulate male tail posture [30, 39]. In egg-laying behavior, acetylcholine and serotonin act in an excitatory manner to regulate contraction of vulva muscles. However, they also act in an inhibitory manner through motor neurons to inhibit egg-laying . The sex-specific muscles and some neurons involved in egg-laying and ventral tail curling have the same precursor in males and hermaphrodites, providing an interesting model for studying development of sex-specific neural circuits on the neuronal and molecular level.
GABA activity is required to maintain proper tail posture during several steps of mating behavior. Males with mutations in the gene encoding the GABAR, UNC-49, bend their tails ventrally to too great an extent when responding to and backing along hermaphrodites. Also, males with mutations in unc-49 excessively bend their tails dorsally when spicules are inserted into the vulva, often to such an extent that males flip over and lose contact with the hermaphrodite. GABAergic regulation of male tail posture is in part regulated by acetylcholine. Males carrying a mutation that eliminates GABA synthesis, unc-25, show decreased dorsal and ventral tail curling in response to increased levels of acetylcholine. Mutations in unc-49 do not decrease dorsal tail curling to the same extent as mutations that eliminate GABA synthesis, and increase ventral tail curling at the 2.5-minute time point, suggesting other GABARs are additionally involved. There are other GABARs in the C. elegans genome, including an excitatory GABAR, exp-1 [41, 42]. Males homozygous for a mutation in unc-30, required for core GABAergic D-type neuron specification, show a decrease in aldicarb-induced dorsal tail curling. In hermaphrodites the cholinergic ventral cord motor neurons synapse on to the D-type neurons to regulate cross inhibition of body wall muscles, and thus, they are good candidates for regulation of male tail posture. However, we cannot rule out the possibility that, in males, additional neurons are specified by unc-30, and these may be required. A mutation in unc-30 does not disrupt dorsal curling as much as unc-25 mutations and does not effect ventral curling suggesting other, possibly male-specific GABAergic neurons, are required for cholinergic regulation of tail curling.
Our results have demonstrated that C. elegans male tail posture is a complex motor behavior requiring coordination of different muscle groups and involving several neurotransmitters. The relative simplicity of the C. elegans nervous system makes it possible to understand regulation of this motor behavior on both a molecular and neural circuit level. There is increasing evidence that basic circuit principles are shared between C. elegans and higher organisms and thus our studies will provide insight into control of adaptive motor behaviors in higher organisms [43, 44].
Male mating behavior is a complex behavior requiring coordinated regulation of multiple muscle groups in response to sensory input, and provides a powerful model to understand how genes and molecular pathways contribute to neural circuits that regulate motor behavior. Our results have provided insight into how the C. elegans male regulates his tail posture during mating to enable him to maintain contact with the hermaphrodite and successfully mate. We showed that proper male tail posture is maintained through a balance of activity of opposing dorsal and ventral muscle groups, and we provided a relatively simple model for neurotransmitters, receptors, neurons and muscles required for this behavior. Our results demonstrated that acetylcholine regulates both ventral and dorsal curling of the male tail. For ventral curling, acetylcholine acts partly in parallel with serotonin to regulate activity of the male-specific muscles. Acetylcholine acts in part through the nicotinic levamisole receptors, likely acting in male-specific muscles but also neurons. Acetylcholine-mediated ventral tail curling requires GABA. However, acetylcholine-induced ventral tail curling does not require the body wall muscle GABAR, UNC-49, and thus other inhibitory or excitatory GABARs are involved in promoting ventral curling of the male tail. Dorsal curling, in contrast to ventral curling, requires the core dorsal body wall muscles. Absence of these muscles results in the male over-curling his tail ventrally while backing along the hermaphrodite, which suggests that contraction of dorsal muscles may be required to counterbalance ventral tail muscles. Acetylcholine-mediated dorsal tail curling requires GABA and likely the inhibitory D-type motor neurons. However, mutations in the GABAR, UNC-49, only partially decreased acetylcholine-induced dorsal tail curling, which suggests that other GABARs are involved. Together, these results present a more detailed understanding of regulation of male tail posture during mating, and provide a basis for future studies that will yield new insights into genetic and neuronal regulation of motor behaviors.
All strains were cultured using standard methods . To increase the number of males we used a him-5(e1490) mutation in the background of the wild-type N2 strain in the following strains: unc-29(e1072), unc-38(sy576), tph-1(mg280), lin-39(n1760), unc-64(e246), and unc-30(e191). To generate males in the following strains, hermaphrodites were heat shocked at 29°C for approximately 10 hours and then the resulting male and hermaphrodite progeny were crossed to generate males: unc-63(e384), unc-25(e156), and unc-49(e407).
As there is day-to-day variation in behavioral assays, in all assays, control animals were assayed on the same day as mutant or ablated males for comparison.
Mating behavior was observed using a Wild M5A microscope at ×25 and ×50 magnification. Males were isolated from hermaphrodites as L4s and used the following day. Males were only assayed one time and then destroyed. An exception to this was that M cell-ablated and sham-ablated control males were used 16 to 32 hours after being isolated as L4s. Also, these males were assayed two times with at least a 1-hour recovery period between assays. Males were assayed for their ability to mate with partially paralyzed unc-31(e169) hermaphrodites. Response behavior was recorded as follows: the total amount of time it took males to respond to a hermaphrodite was noted (initial response). Also, the length of time males spent responding to a hermaphrodite before leaving or finding the vulva was noted (continued response). Backing behavior was assayed as follows: males were observed for their ability to back along the hermaphrodite. In addition to noting the ability to back along the hermaphrodite, it was also noted if males instead of backing along the dorsal and ventral sides of the hermaphrodite, backed along the lateral sides of the hermaphrodite. Turning behavior was assayed as follows: the number of bad turns was noted. Turns were categorized as missed, sloppy, tip, or stutter as described in Liu et al.  and Loer and Kenyon . In addition, we saw turns that were initiated before the normal turning point of the male, which we labeled 'early'. If a male executed a turn and then pulled back and executed another turn instead of continuing to back on the opposite side of the hermaphrodite, only the first turn was noted. Another turn was not counted until after the male completed a turn and continued backing on the opposite side of the hermaphrodite. Vulva location was assayed as follows: the number of times a male passed the vulva before stopping was noted. If the male passed the vulva more than one time before stopping, the male was considered mutant for that behavior.
Aldicarb was purchased from Chem. Service (Westchester, PA, USA). For assays, aldicarb was diluted from a 5 mM, or for the assays comparing males and hermaphrodites, a 25 mM, frozen stock solution. Levamisole was purchased from Sigma-Aldrich. Levamisole was diluted from a 50 mM frozen stock solution. All drugs were diluted in ddH20. L4 males were isolated the day before assays. An exception to this is M cell, dorsal body wall, and sham-ablated males, which were first assayed for mating behavior and then after a recovery period were assayed for tail curling in response to drugs. To assay males for tail curling in response to drugs, 500 μl of drug or ddH20 control solution were put in Becton Dickinson 24-well tissue culture plates. Three to six males were assayed at one time and the solution used was discarded after each assay. Males were assayed immediately, and then at 2.5-minute intervals for the first 10 minutes and then at 5-minute intervals. At each time point, males were examined for 20 seconds. Males were considered positive for each behavior if they curled their tail for >5 seconds. If both types of tail curling were seen during that period only the first response seen was recorded.
Laser ablation was done using a VSL-337 nitrogen laser and a Zeiss axioskop using standard protocols . Sham-ablated males were mounted on slides containing sodium azide and recovered at the same time as those that underwent laser ablation. The M cell was ablated in L1 stage animals and successful killing was determined by the presence of crumpled spicules. The dorsal body wall muscles were killed in L3 males.
The unc-29::dsRed construct was made by amplifying a fragment containing 1529 base pairs upstream of the start of unc-29 and having PstI sites designed at the ends of both primers. This was then first sub-cloned into the T-easy vector and then digested with PstI. The PstI fragment was then sub-cloned into the vector PSX77, containing dsRed 2 followed by the unc-54 3' UTR (courtesy of S. Xu), and injected into pha-1; him-5 males along with a pha-1 rescuing plasmid. Three stable lines were examined for expression of unc-29::dsRed and all had similar expression patterns.
All statistical tests were done using the GraphPad InStat software. Appropriate tests were chosen based on the recommendations of the program.
gamma-aminobutyric acid receptor.
We would like to thank members of the Sternberg laboratory for critical reading of this manuscript. This research was supported by the Howard Hughes Medical Institute of which PWS is an investigator. AJW was supported by NIH postdoctoral fellowship NS042497.
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