Katzen, A. et al. (2017) International Worm Meeting "Subjective value guides rational foraging decisions in C. elegans."

Glimcher, P., Lockery, S., Katzen, A., Harbaugh, W.

[International Worm Meeting, 2017]

Value-based decision making - choices driven by subjective assessments of utility - is a central function of the brain and the focus of intensive study in mammals. Until now, evidence that nematodes are capable of value-based decision making has mainly been suggestive. However, economists have developed formal procedures for determining whether a consumer's decisions are based on subjective value as opposed to random or capricious impulses. We recently developed microfluidic devices that enable such tests to be performed on nematodes for the first time. The worm is held at the confluence of contiguous streams of high and low quality bacterial food leaving its head free to move. Bacteria concentrations are adjusted by the experimenter to change the relative "prices" of the two foods in terms of number of bacteria consumed per pharyngeal pump. Food concentrations can also be adjusted in tandem to increase or decrease the worm's overall consumption possibilities, i.e. "budget." Consumption is measured by counting pharyngeal pumps recorded electrically. Worms typically fed in both streams, consuming a mixture of high and low quality food that was unique for each combination of price and budget. We found that worms make globally rational choices in that they obey transitivity. That is, for all sets of food mixtures A, B, and C, if A is preferred to B, and B to C, then A is preferred to C. As transitivity is the necessary and sufficient condition for value maximization, these data provide formal evidence that C. elegans exhibits value-based decision making. Further, we found that the olfactory neuron AWC, known to be activated by the sudden absence of food, is required for intact food choice behavior. Surprisingly, however, we found that AWC is also activated by the switch from high quality food to low quality food, even when the two foods are at the same concentration (price). Thus, subjective value may be represented at the level of individual olfactory neurons. Our behavioral and neuronal data are consistent with a model in which olfactory neurons represent the subjective value of the local environment to direct behavior toward preferable mixtures of particular foods. To our knowledge, this is the first formal demonstration of value-based decision making in a genetically tractable model organism with a simple nervous system, opening the door to the discovery of conserved genes and neural circuits for rational decision making.

Katzen A et al. (2023) Elife "The nematode worm C. elegans chooses between bacterial foods as if maximizing economic utility."

Katzen A, Chung HK, Flavell SW, Harbaugh WT, Della Iacono C, Lockery SR, Glimcher P, Jackson N, Glater EE, Taylor CJ, Andreoni J, Yu SK

[Elife, 2023]

In value-based decision making, options are selected according to subjective values assigned by the individual to available goods and actions. Despite the importance of this faculty of the mind, the neural mechanisms of value assignments, and how choices are directed by them, remain obscure. To investigate this problem, we used a classic measure of utility maximization, the Generalized Axiom of Revealed Preference, to quantify internal consistency of food preferences in Caenorhabditis elegans, a nematode worm with a nervous system of only 302 neurons. Using a novel combination of microfluidics and electrophysiology, we found that C. elegans food choices fulfill the necessary and sufficient conditions for utility maximization, indicating that nematodes behave as if they maintain, and attempt to maximize, an underlying representation of subjective value. Food choices are well-fit by a utility function widely used to model human consumers. Moreover, as in many other animals, subjective values in C. elegans are learned, a process we find requires intact dopamine signaling. Differential responses of identified chemosensory neurons to foods with distinct growth potentials are amplified by prior consumption of these foods, suggesting that these neurons may be part of a value-assignment system. The demonstration of utility maximization in an organism with a very small nervous system sets a new lower bound on the computational requirements for utility maximization and offers the prospect of an essentially complete explanation of value-based decision making at single neuron resolution in this organism.

Katzen, Abraham W. et al. (2013) International Worm Meeting "Electrical recordings of naturalistic feeding behavior in a microfluidic environment."

Katzen, Abraham W., Lockery, Shawn R.

[International Worm Meeting, 2013]

Food choice - the decision of what to eat - is critical to survival and reproduction. To advance the study of food choice in C. elegans, we have devised a microfluidic device for measuring feeding behavior in single worms automatically and accurately in response to a variety of food types under naturalistic conditions. Feeding behavior in C. elegans is quantified by observing the pumping rate of the pharynx. There are currently two main methods for measuring pumping rate: manual observation of slow-motion videos of worms crawling in food, and electrical recordings, known as electropharyngeograms (EPGs). Neither method is practical for experiments requiring naturalistic feeding behavior with precise presentation of food stimuli. Manual observation is labor intensive, limited to short observation periods (~20 sec), and provides little spatiotemporal control of food presentation. EPG recordings, in which a submerged worm is sucked into a hollow recording electrode, necessarily isolate the pharynx from the environment, interfering with delivery of food to the worm. To overcome these limitations we have integrated EPG recording electrodes into an existing microfluidic device [1]. The worm is restrained with the longitudinal axis of its body aligned between two laminar fluid streams, while the head is free to move and explore either stream. The device allows the user to control the delivery, concentration, and type of food that is available to the worm in either fluid stream. Worms exhibit naturalistic feeding behavior in the microfluidic device, and stable recordings lasting 15 minutes are routine. Using this method, we are exploring the feeding response of C. elegans to familiar or novel foods of differing qualities. Additionally, we are determining the effect of food concentration on feeding latency and rate. We anticipate that this method will provide novel insights into the internal and external cues which contribute to adaptive feeding decisions. References: [1] McCormick et al. (2011) PLoS ONE 6(1):e25710.

Katzen, Abraham et al. (2021) International Worm Meeting "C. elegans chooses food exactly as if maximizing economic utility"

Della Iacono, Christina, Glimcher, Paul, Jackson, Nicholas, Harbaugh, William, Chung, Hui-Kuan, Katzen, Abraham, Lockery, Shawn

[International Worm Meeting, 2021]

The well-functioning brain makes decisions that maintain and improve the animal's welfare. These decisions are based on subjective values assigned by the chooser to available goods and actions. However, the neural mechanisms of value assignments, and choices based on them, remain obscure. To investigate this problem, we used a classic measure of utility maximization, the Generalized Axiom of Revealed Preference, to quantify internal consistency of food preferences in Caenorhabditis elegans, a nematode worm with a nervous system of only 302 neurons. Using a novel combination of microfluidics and electrophysiology, we found that C. elegans food choices fulfill the necessary and sufficient conditions for utility maximization. Moreover, as in many other animals, preferences are learned, a process we found to require intact dopamine signaling. Preferences are expressed as a modulation of the worm's normal foraging movements rather than feeding rate. Food-specific responses of identified chemosensory neurons known to direct foraging are strengthened by training, suggesting they may be part of the value-assignment system. The demonstration of utility maximization in an organism having a nervous system of only 302 neurons sets a new lower bound on the neuronal requirements for its execution, and offers the prospect of an essentially complete explanation of value-based decision making at single neuron resolution.

Katzen, Abraham et al. (2015) International Worm Meeting "Economic decision-making and neural correlates of value in C. elegans."

Harbaugh, William, Katzen, Abraham, Lockery, Shawn

[International Worm Meeting, 2015]

Investigation of the neuronal basis of economic decisions would be accelerated by establishing decision making paradigms in simple, genetically tractable organisms, such as the nematode Caenorhabditis elegans. For an organism to be a valid model of economic decision making its choice behavior must be sensitive to: (i) the difference between high and low quality goods, and (ii) the relative cost of those options.Previous work has shown that the nematode worm C. elegans quickly learns to feed on those foods (species of bacteria) that promote higher rates of growth and reproduction. Worms spend more time foraging in patches of Good bacteria (high worm growth rate) versus Mediocre bacteria (moderate growth rate) when equally abundant. Until now, however, it has not been possible to simultaneously present two food choices of different quality and cost. To that end, we have developed an electro-microfluidic device in which a semi-restrained worm forages between contiguous yet discrete fluid streams containing good and mediocre quality food. This arrangement constitutes a two-alternative forced-choice task, analogous to those used in behavioral economics. Electrodes inserted into the device monitor muscular impulses associated with individual swallowing events. Relative consumption of Good and Mediocre food is measured by counting the number of swallowing events in the respective fluid streams. The fraction of total swallowing events in Good vs Mediocre food serves as an index of food preference. Importantly, we can alter the effective prices of the two foods by adjusting the concentration of the bacteria, with price being inversely related to concentration.Here we present behavioral data delineating preference for Good vs Mediocre food across a range of relative prices. We find that worms exposed to the two species of bacteria at equal prices prefer Good bacteria, indicating that feeding preferences are normal in the device. Worms respond to price adjustments as predicted by economic theory in that increasing the relative price of a food leads to a decline in its consumption. In addition, we present calcium-imaging data from sensory neurons showing that they respond to transitions between Good and Mediocre foods, and the amplitude of calcium signal scales with relative food preference. These results show that C. elegans forages in an economic manner, and that relative value is represented at the level of the sensory neurons.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Tuck S (2011) Curr Biol "Extracellular vesicles: budding regulated by a phosphatidylethanolamine translocase."

Tuck S

[Curr Biol, 2011]

Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.