An Elegant Circuit for Balancing Risk and Reward

Summary

Animals constantly encounter conflicting cues in natural environments. To survive and thrive, they must make appropriate behavioral decisions. In this issue, Ghosh et al. (2016) identified a neural circuit underlying multisensory threat-reward decision making using an elegant C. elegans model.

Main Text

To survive the diverse and changing environment, animals must evaluate potential threats and rewards to make complex decisions. To thrive, animals also have to balance threat tolerance and the potential benefits of finding food. Understanding the circuit and molecular mechanisms that underlie a complex decision-making process is challenging in a highly complex organism with a large nervous system. Perhaps even more challenging is elucidating the mechanisms of behavioral plasticity that modulate intrinsic decision-making circuits. Thus, being able to address these issues in a simpler nervous system has the potential to uncover novel mechanisms that could guide studies in higher systems. The relatively simple and well-annotated nervous system of the nematode C. elegans has proven to be an ideal model system for deciphering the functional circuits underlying behavior. In more recent years, C. elegans sensory integration has emerged as a major focus of research. In this issue, Nitabach and colleagues report a novel top-down neural circuit underlying multimodal sensory integration and how changes in the internal state such as hunger modify this process to alter behavioral choices (Ghosh et al., 2016).

A Top-Down Circuit for Multisensory Decision Making

The investigators developed an assay to map the important events that go into the decision to cross an aversive barrier to get to the source of an attractive food-related cue (Figure 1), by modifying a paradigm previously developed by Ishihara et al. (2002). Diacetyl is a chemical found in food, and the odor is attractive to C. elegans. However, hyperosmolarity is an aversive stimulus to worms, and when surrounded by a ring of 2M fructose, worms avoid the high osmolarity and do not exit the ring (Figure 1). Therefore, worms must balance the drive for food with the threat of hyperosmolarity-induced desiccation and death.

Figure 1.

In this simple paradigm, diacetyl is detected by an olfactory neuron AWA, and fructose is perceived by a nociceptive neuron ASH (Figure 1). Sensory activities of these neurons are further processed in the interneuron layer. The authors found that the interneuron RIM plays an important role in threat-reward decision making (Figure 1). RIM functions in the locomotion circuitry, but unlike other locomotion neurons which either promote or inhibit movement in one direction, RIM has been reported to promote both forward and reverse motion (Kato et al., 2015 ; Piggott et al., 2011). Since RIM releases the neurotransmitter tyramine (Alkema et al., 2005), they tested whether tyramine is involved in threat-reward decision making by examining tdc-1 null mutant worms. tdc-1 encodes tyrosine decarboxylase, which is required for tyramine biogenesis (Alkema et al., 2005). The investigators found that tdc-1 null mutants show increased exiting, and this defect can be rescued by expressing tdc-1 gene just in RIM, suggesting that tyramine release from RIM decreases threat tolerance. To identify its downstream signaling, Nitabach and colleagues screened mutants lacking tyramine receptors and found that tyra-2 mutant worms exhibit defects in threat-reward decision making. To identify the functional site of tyra-2, Ghosh et al. (2016) performed neuron-specific rescuing experiments. Surprisingly, they found the expression of tyra-2 gene in ASH neuron can fully restore the defects in tyra-2 null mutant worms, suggesting that RIM generates a feedback tyramine signal to regulate threat-reward decision making. Calcium imaging experiments revealed that tyramine modulates ASH activity, as application of exogenous tyramine increased ASH calcium responses toward high-osmolarity fructose. In order to investigate whether the neural activity dynamics would support RIM to execute threat-reward decision making by means of “top-down” control, the authors developed a computational model of this circuit. As worms move on the assay plate, they encounter alternating levels of hyperosmolarity and diacetyl. In silico, this leads to oscillations in AWA, ASH, and RIM neural activity. With tyramine signaling intact, the activity of ASH and RIM overtakes the activity of AWA, and the worm remains inside the hyperosmotic barrier. Without tyramine, ASH and RIM activities gradually decline, and eventually the balanced activity levels permit the worm to escape from the fructose ring to approach the food odor source (Figure 1). Taken together, these results suggest that positive tyraminergic feedback from RIM to ASH forms a top-down circuit that regulates threat-reward decision making (Figure 1).

Since RIM expresses the neuropeptide PDF-2, they examined hyperosmolarity avoidance in pdf-2 null mutant worms. pdf-2 null mutants exhibited increased threat tolerance, similar to tdc-1 and tyra-2 mutants. RIM also expresses PDFR-1, the cognate receptor of the secreted neuropeptide PDF-2. To determine whether PDF signaling functions in RIM as an autocrine loop, they expressed a membrane-tethered version of PDF-2 in RIM to activate PDFR-1 and found a complete rescue of the decision balance. Thus, RIM feedback tyraminergic signaling and autocrine PDF-2 signaling together promote RIM-ASH top-down positive feedback, which decreases threat tolerance (Figure 1).

Internal State Modulates Decision Making

Another major discovery of Ghosh et al. (2016) is that the internal physiological state modulates decision-making circuit and thereby reshapes the behavioral output. They found that after 1 hr of food deprivation, worms are more likely to exit the hyperosmotic barrier, indicating that the internal physiological state modulates this decision. The authors hypothesized that food deprivation suppresses RIM activity and thus the RIM-ASH positive feedback circuit. To test this idea, they blocked the RIM-ASH feedback using tyra-2 mutation and found that tyra-2 mutant worms fail to increase exiting after 1 hr of food deprivation, suggesting that TYRA-2 positive feedback signaling is required for internal hunger state modulation of threat tolerance. The investigators suggested that the internal physiological state, including hunger, reshapes threat-reward decision making by modifying this neural circuit. Other factors have previously been reported to modulate decision making. Bendesky et al. discovered that endogenous catecholamines act on TYRA-3 in sensory neurons to modulate an exploration-exploitation decision (Bendesky et al., 2011). Feeding state is also reported to modulate ASH nociception through the interaction of dopaminergic and neuropeptide signaling pathways (Ezcurra et al., 2016). These studies indicate that circuits are not necessarily hard-wired networks, but rather the internal physiological state may endow circuits with more functional dimensionality. An interesting parallel can be drawn between these studies and those in humans and other mammals. For example, top-down circuits are involved in accurate perception and multisensory integration in mammals, suggesting that neural networks in different species employ similar circuit principles to process decision making (Manita et al., 2015).

This exciting study also raises some interesting questions. For example, with increasing lengths of food deprivation, the threat tolerance increases. As tyra-2 is mainly responsible for the regulation of short-term (1 hr) food deprivation, it would be interesting to identify other genes responsible for the regulation of longer-period food deprivation. The present study mainly focuses on the interneuron RIM. Previous work reported that the first layer interneurons AIA and AIY are also involved in a related decision-making process (i.e., diacetyl-copper choice assay), which involves the same set of sensory neurons AWA and ASH (Shinkai et al., 2011). Could these interneurons also employ top-down circuitry to integrate multisensory signaling? As ASH is a polymodal nociceptor, it would also be interesting to determine whether hunger-induced modification of the RIM-ASH feedback circuit would extend to other ASH-cued sensory behavior, such as alkaline pH avoidance and copper avoidance (Ishihara et al., 2002 ; Wang et al., 2016). The current study from Ghosh et al. (2016) presents an elegant case of harnessing the power of a simple model organism to identify fundamental neural and genetic mechanisms underlying decision making at the single neuron resolution.