To Do or Not to Do: Dopamine, Affordability and the Economics of Opportunity

Five years ago, we introduced the thrift hypothesis of dopamine (DA), suggesting that the primary role of DA in adaptive behavior is regulating behavioral energy expenditure to match the prevailing economic conditions of the environment. Here we elaborate that hypothesis with several new ideas. First, we introduce the concept of affordability, suggesting that costs must necessarily be evaluated with respect to the availability of resources to the organism, which computes a value not only for the potential reward opportunity, but also the value of resources expended. Placing both costs and benefits within the context of the larger economy in which the animal is functioning requires consideration of the different timescales against which to compute resource availability, or average reward rate. Appropriate windows of computation for tracking resources requires corresponding neural substrates that operate on these different timescales. In discussing temporal patterns of DA signaling, we focus on a neglected form of DA plasticity and adaptation, changes in the physical substrate of the DA system itself, such as up- and down-regulation of receptors or release probability. We argue that changes in the DA substrate itself fundamentally alter its computational function, which we propose mediates adaptations to longer temporal horizons and economic conditions. In developing our hypothesis, we focus on DA D2 receptors (D2R), arguing that D2R implements a form of “cost control” in response to the environmental economy, serving as the “brain’s comptroller”. We propose that the balance between the direct and indirect pathway, regulated by relative expression of D1 and D2 DA receptors, implements affordability. Finally, as we review data, we discuss limitations in current approaches that impede fully investigating the proposed hypothesis and highlight alternative, more semi-naturalistic strategies more conducive to neuroeconomic investigations on the role of DA in adaptive behavior

High Fructose Corn Syrup Induces Metabolic Dysregulation and Altered Dopamine Signaling in the Absence of Obesity

The contribution of high fructose corn syrup (HFCS) to metabolic disorder and obesity, independent of high fat, energy-rich diets, is controversial. While high-fat diets are widely accepted as a rodent model of diet-induced obesity (DIO) and metabolic disorder, the value of HFCS alone as a rodent model of DIO is unclear. Impaired dopamine function is associated with obesity and high fat diet, but the effect of HFCS on the dopamine system has not been investigated. The objective of this study was to test the effect of HFCS on weight gain, glucose regulation, and evoked dopamine release using fast-scan cyclic voltammetry. Mice (C57BL/6) received either water or 10% HFCS solution in combination with ad libitum chow for 15 weeks. HFCS consumption with chow diet did not induce weight gain compared to water, chow-only controls but did induce glucose dysregulation and reduced evoked dopamine release in the dorsolateral striatum. These data show that HFCS can contribute to metabolic disorder and altered dopamine function independent of weight gain and high-fat diets

Natural Striatal Signaling Dynamics During Food Approach

Reduced dopamine (DA) signaling has been hypothesized to induce compulsive overeating in obesity. However, DA signaling facilitates food pursuit by acting on direct and indirect pathways. This disparity between why individuals compulsively overeat despite decreased DA and satiety signals is unclear. Characterizing how DA and direct/indirect pathways respond to satiation may elucidate how satiety signals become overwritten in obesity. The food\u27s palatability may underlie this, which is putatively thought to override the satiety hormones since it directly increases DA signaling, resulting in the increased appetitive drive. We determined the pattern of dopamine and pathway-specific medium spiny neuron (MSN) activity across satiation. We used fiber photometry with a red-shifted fluorescent dopamine sensor (RdLight1) and a Cre recombinase-dependent, green calcium indicator. Both fluorescent sensors were injected into mice expressing dopamine D1 receptor (D1-Cre) or adenosine A2a receptor (Adora-Cre) (markers of direct MSNs and indirect MSNs, respectively). This straightforward approach allows for the simultaneous recordings of both DA and pathway-specific MSN activity across satiation. We measured satiation and satiety using a free-feeding paradigm. This paradigm is designed so that mice directly control their eating patterns. We confirmed that DA and MSN activity changes as a result of satiation by altering hunger and satiation via fasting and pharmacologically activating satiation areas. These studies directly measure changes in DA and d/iMSN activity from when mice are hungry to when mice become sated. We predicted that a reduced food approach would correlate with reduced DA release and dMSN activity during satiation. Also, we assessed the extent to which food\u27s palatability overrides satiety in real-time. Using the same preparation, we examined the effects of food palatability, standard grain vs. high-fat, high sugar (HFHS) pellets, on diminishing satiation across one week. We found that repeated exposure to highly palatable foods did not delay satiation but did correlate with DA release changes. Our findings may expand our understanding on two levels: First, uncovering the dynamic changes in striatal signaling under satiation, and second, improving our understanding of the effect of palatable foods on food consumption and satiation

To Do or Not to Do: Dopamine, Affordability and the Economics of Opportunity

Five years ago, we introduced the thrift hypothesis of dopamine (DA), suggesting that the primary role of DA in adaptive behavior is regulating behavioral energy expenditure to match the prevailing economic conditions of the environment. Here we elaborate that hypothesis with several new ideas. First, we introduce the concept of affordability, suggesting that costs must necessarily be evaluated with respect to the availability of resources to the organism, which computes a value not only for the potential reward opportunity, but also the value of resources expended. Placing both costs and benefits within the context of the larger economy in which the animal is functioning requires consideration of the different timescales against which to compute resource availability, or average reward rate. Appropriate windows of computation for tracking resources requires corresponding neural substrates that operate on these different timescales. In discussing temporal patterns of DA signaling, we focus on a neglected form of DA plasticity and adaptation, changes in the physical substrate of the DA system itself, such as up- and down-regulation of receptors or release probability. We argue that changes in the DA substrate itself fundamentally alter its computational function, which we propose mediates adaptations to longer temporal horizons and economic conditions. In developing our hypothesis, we focus on DA D2 receptors (D2R), arguing that D2R implements a form of “cost control” in response to the environmental economy, serving as the “brain’s comptroller”. We propose that the balance between the direct and indirect pathway, regulated by relative expression of D1 and D2 DA receptors, implements affordability. Finally, as we review data, we discuss limitations in current approaches that impede fully investigating the proposed hypothesis and highlight alternative, more semi-naturalistic strategies more conducive to neuroeconomic investigations on the role of DA in adaptive behavior

To Do or Not to Do: Dopamine, Affordability and the Economics of Opportunity

Five years ago, we introduced the thrift hypothesis of dopamine (DA), suggesting that the primary role of DA in adaptive behavior is regulating behavioral energy expenditure to match the prevailing economic conditions of the environment. Here we elaborate that hypothesis with several new ideas. First, we introduce the concept of affordability, suggesting that costs must necessarily be evaluated with respect to the availability of resources to the organism, which computes a value not only for the potential reward opportunity, but also the value of resources expended. Placing both costs and benefits within the context of the larger economy in which the animal is functioning requires consideration of the different timescales against which to compute resource availability, or average reward rate. Appropriate windows of computation for tracking resources requires corresponding neural substrates that operate on these different timescales. In discussing temporal patterns of DA signaling, we focus on a neglected form of DA plasticity and adaptation, changes in the physical substrate of the DA system itself, such as up- and down-regulation of receptors or release probability. We argue that changes in the DA substrate itself fundamentally alter its computational function, which we propose mediates adaptations to longer temporal horizons and economic conditions. In developing our hypothesis, we focus on DA D2 receptors (D2R), arguing that D2R implements a form of “cost control” in response to the environmental economy, serving as the “brain’s comptroller”. We propose that the balance between the direct and indirect pathway, regulated by relative expression of D1 and D2 DA receptors, implements affordability. Finally, as we review data, we discuss limitations in current approaches that impede fully investigating the proposed hypothesis and highlight alternative, more semi-naturalistic strategies more conducive to neuroeconomic investigations on the role of DA in adaptive behavior

Fig 2A HFCS_colorplot data

data files for Fig 2A color plot for HFCS grou

2_20 Hz_traces.csv

current data at 20Hz for control and HFCS group

Rscript_Fig2B_traces.txt

R script generating traces in Fig 2

Fig 2C-G data

Fig 2C-G data:<div><br></div><div>summary data (panels D-G)</div><div>voltammagram (panel C)</div><div>text file: explanation of column labels in summary data</div

Fig 1 data

datasets for Fig 1:<div>1. body weights across experiment</div><div>2. glucose challenge</div><div>3. area under the curve for glucose challenge</div><div>4. water vs. HFCS consumption (by cage)</div><div><br></div