Neuroeconomically dissociable forms of mental accounting are altered in a mouse model of diabetes - PubMed (original) (raw)

doi: 10.1038/s42003-025-07500-6.

Romain Durand-de Cuttoli 1, Zainab M Oketokoun 1, Samantha O Brown 1 2, Jillian E Haller 1 3, Adriana Méndez 1, Mohammad Jodeiri Farshbaf 1, Y Zoe Cho 1 4, Sanjana Ahmed 1 5, Sophia Leng 1 6, Jessica L Ables 7 8, Brian M Sweis 9 10

Affiliations

Neuroeconomically dissociable forms of mental accounting are altered in a mouse model of diabetes

Chinonso A Nwakama et al. Commun Biol. 2025.

Abstract

Those with diabetes mellitus are at high-risk of developing psychiatric disorders, especially mood disorders, yet the link between hyperglycemia and altered motivation has not been thoroughly explored. Here, we characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on Restaurant Row, a naturalistic neuroeconomic foraging paradigm capable of behaviorally capturing multiple decision systems known to depend on dissociable neural circuits. Mice made self-paced choices on a daily limited time-budget, accepting or rejecting reward offers based on cost (delays cued by tone pitch) and subjective value (flavors), in a closed-economy system tested across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy overprioritizing high-value rewards. These foraging behaviors were driven by impairments in multiple decision-making processes, including the ability to deliberate when engaged in conflict and cache the value of the passage of time as sunk costs. Surprisingly, diabetes-induced changes in motivation depended not only on the type of choice being made, but also on the salience of reward-scarcity in the environment. These findings suggest that complex relationships between metabolic dysfunction and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt distinct computational processes leading to comorbid psychiatric vulnerabilities.

© 2025. The Author(s).

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Fig. 1

Fig. 1. Streptozocin-induced diabetes mellitus mouse model of chronic hyperglycemia.

a Experimental timeline. Dashed box indicates time period relevant for this figure: hyperglycemia incubation. Randomly selected male C57BL/6 J mice received daily intraperitoneal injections of vehicle (VEH, Hank’s balanced saline solution, n = 20) or streptozocin (STZ, 50 mg/kg, n = 20) injections for 5 consecutive days (gray or orange tick icon). STZ is an antibiotic that ablates insulin-producing beta cells of the pancreas. Mice were allowed to incubate for 8 weeks while sampling body weights and fasting tail vein blood glucose levels (small droplet icon) weekly before sampling tail vein blood Hemoglobin A1c once (large droplet icon) and then beginning longitudinal neuroeconomic behavioral testing for an additional ~2 months. In brief, mice foraged for food rewards of varying costs across distinct economic landscapes that changed at different rates, described further in subsequent figures. b Weekly body weights. As expected, STZ-treated mice experienced an initial drop in weight before returning to a rate of weight gain similar to VEH-treated mice. c Fasting tail vein blood glucose levels. STZ treatment significantly elevated blood glucose measurements compared to VEH-treated mice. d Tail vein blood Hemoglobin A1c obtained at week 8, confirming chronic hyperglycemia in STZ-treated mice, sampled 3 days before starting behavioral testing. *Represents significant differences between VEH- and STZ-treated groups, p < 0.0001. Dots represent individual mice. Shading / error bars represent ±1 SEM.

Fig. 2

Fig. 2. STZ-treated mice are able to acquire the basic structure of the naturalistic, unconstrained, neuroeconomic foraging task Restaurant Row.

a Timeline. Dashed box indicates time period relevant for this figure: first week of behavioral testing when all costs were fixed at 1 s delays (green epoch). b Task schematic. Mice were allotted a 45 min daily budget to invest time foraging for their primary source of food in a self-paced manner. Costs to obtain rewards were in the form of delays mice would have to wait near feeder sites. Mice were required to run in a counterclockwise direction encountering offers for different flavors at each “restaurant” in serial order. Each restaurant, separated by hallways, was divided into a T-shaped “offer zone” choice point and a separate “wait zone” that housed the pellet dispenser. Upon offer zone entry from the correct heading direction, a tone sounded whose pitch indicated the delay mice would have to wait if accepting the offer by entering the wait zone. If entered, tone pitch descended in the wait zone, cuing the indicated delay. Each trial terminated if mice skipped in the offer zone, quit during the countdown in the wait zone, or earned a reward, after which animals were required to proceed to the next restaurant. This task captures dissociable motivational elements of choice deliberation, re-evaluation, and opportunity costs that depend on subjective value and the economic demand of the environment. c–g Simple behavioral metrics across the first week of testing during which all offers were 1 s only (lowest pitch, 4 kHz): c laps run in the correct direction, d inter-trial travel time between restaurants, e total rewards earned, f earnings split by flavors ranked from least to most preferred by summing each day’s end-of-session totals in each restaurant and g normalized to number of laps run (treatment x rank: F = 3.823, p < 0.01). In (c–e) right, *represents significant differences between VEH- and STZ-treated groups on day 7 (dashed box), p < 0.01, _t_-test. Dots represent individual mice. Error bars represent ±1 SEM.

Fig. 3

Fig. 3. STZ-treated mice display early satiety and within-session meal consumption patterns skewed toward most preferred flavors.

a Timeline. Dashed box indicates relevant time period for this figure: day 7. b, c Rewards earned within each 2.5 min bin across the session (b) in total earnings or (c) earnings split by flavor ranking. * in black near the VEH / STZ legend labels represents significant differences between VEH- and STZ-treated groups collapsing across time. * in black near individual time bins represents significant differences between groups at those times. Blue arrows indicate a main effect of time (e.g., satiety related changes across the session), with significance reported in blue. d Cumulative total rewards earned summed across the session. e Percentage of total session rewards earned split by flavor. f Tail vein blood glucose levels sampled immediately before and after day 7’s session. g Change in blood glucose from f post minus pre task. h Scatter plot of change in blood glucose from g against change in body weight measured immediately before and after day 7’s session. Gray dashed lines indicate 0 on both axes. Scatter plot of pre-task blood glucose from f against day 7’s end-of-session earns for i least and j most preferred flavors. Dots represent individual mice. Error bars represent ±1 SEM. Shading represents 95% confidence interval of linear fit.

Fig. 4

Fig. 4. STZ-treated mice forage differently under budget constraints as reward availability decreases but depending on the salience of change in environmental scarcity.

a Timeline. Dashed box indicates time period relevant for this figure: entire 7-week Restaurant Row paradigm. b Total rewards earned each day normalized to the average of days 5–7 earnings (termed 100%, horizontal dashed green line). Visual guidance color bars along the x-axis reflect the experimental schedules (stepwise or gradual) illustrated in the timeline in a. Vertical dashed green-yellow-red lines indicate the transition points of the stepwise schedule (or matched days of the gradual schedule) and are re-used throughout all other figures as a visual aid. Top: VEH; bottom: STZ. c Change in b at each transition point of the stepwise schedule (or matched days of the gradual schedule): d7–8 (1 s only to 1–5 s offers, green to yellow), d14–15 (1–5 s to 1–15 s offers, yellow to orange), and d21–22 (1–15 s to 1–30 s offers, orange to red). Horizontal dashed gray line indicates 0 change. d Time elapsed between subsequent earns of any flavor. e Within-session cumulative earnings summed across 2.5 min bins normalized to end-of-session earnings for each restaurant. Data collapsed across the entire 1–30 s epoch (days 22–49, red). Horizontal dashed gray line indicates 50% of each flavor’s meal consumed. Dashed square box highlights mid-session data plotted within inset figure showing ranking spread (left) and a summary difference score (right) between most minus least preferred restaurants to depict whether favorite flavors are consumed relatively sooner (+) or later (−) in the session. Horizontal black line indicates 0 difference. f Time elapsed between subsequent earns of the same flavor split by ranking following an earn in the same restaurant (ignoring intervening earns). Data collapsed across either the 1 s only (green) or 1–30 s epoch (red). Shading / error bars represent ±1 SEM.

Fig. 5

Fig. 5. STZ-treated mice develop unique decision-making policies in fundamentally distinct types of choices.

a–d Offer zone (top) and wait zone (bottom) thresholds plotted (a, c) each day across the entire Restaurant Row paradigm or (b, d) split by flavor ranking collapsed across the 1–30 s epoch. Green (offer zone) and blue (wait zone) dashed staircase represent the maximum possible threshold for stepwise (top) or gradual (bottom) schedules. e, f Offer zone and wait zone thresholds within each 2.5 min bin across the session (data collapsed from entire 1–30 s epoch). Both schedules collapsed in e depicting all VEH- (top) or STZ-treated mice (bottom). Horizontal shaded bands represent offer zone threshold of 30 (green) or wait zone threshold of 9.s-13.5 (blue), corresponding to thresholds representing a strategy that would yield the maximum amount of total food as one type of optimal strategy, should animals ignore flavors, that was previously theoretically and empirically determined. Analysis from e replotted and split by least and most preferred flavors in f for both schedules collapsed (left) or for all groups splitting flavor rankings (right). g Standard deviation of offer zone and wait zone thresholds calculated across the four flavors within each 2.5 min bin. h Standard deviation of the number of rewards earned calculated across the four flavor rankings within each 2.5 min bin. Shading in (a, c)/error bars represent ±1 SEM.

Fig. 6

Fig. 6. STZ-treated mice demonstrate diminished choice conflict when deliberating.

a Example video-tracked body centroid positions in one restaurant from a single mouse on a single day. All tracked positions in black, skip decisions in red (top), enter decisions in green (bottom), tracked from offer onset upon entering the T-shaped choice point until crossing either boundary (skip: leftward hallway entry; enter: rightward wait zone entry). High vicarious trial and error (VTE) trials capture multiple reorientation events in the offer zone. b VTE behavior across the entire Restaurant Row paradigm. c VTE behavior, first normalized to all trials on a given day for a given mouse, then collapsed across the entire 1–30 s epoch and split by flavor rankings. Horizontal dashed gray line represents z-score of 0. Shading/error bars represent ±1 SEM.

Fig. 7

Fig. 7. Only STZ-treated mice previously tested on the gradual schedule are uniquely insensitive to sunk costs.

a–c Sunk cost analysis of staying behavior in the wait zone, demonstrated using all mice. a The likelihood of staying in the wait zone and earning a reward (e.g., not quit) is plotted as a function of time left in the countdown along the x-axis and time already spent waiting orthogonally in color. Note the black 0 s time spent curve represents animals having just entered the wait zone from the offer zone. Inset vertical dashed gray line illustrates an example analysis point comparing three sunk cost conditions originating from different starting offers but matched at 10 s left. Data from a dimensioned reduced in b collapsing across time left, instead highlighting the grand mean of each time spent sunk cost condition (color and x-axis). Insets depict data from curves in a are collapsed into the observed (sunk condition) and control (0 s condition) lines. Difference between curves in b are plotted in c in order to summarize the envelope of the overall effect of time already spent on escalating the commitment of staying in the wait zone. Horizontal dashed line represents 0. d Sensitivity to sunk costs plotted across the entire Restaurant Row paradigm where the delta curve in c is plotted as vertical slices in d with time already spent along the y-axis and heatmap representing magnitude. Note no sensitivity to sunk costs until after transitioning to the 1–30 s epoch in all mice, and never in STZ-gradual mice. Delta curves collapsed across the entire 1–30 s epoch for e stepwise or f gradual schedules. Dashed gray box highlights peak differences. g Peaks from e to f for all groups. h Peaks split by flavor ranking. Shading/error bars represent ±1 SEM.

Fig. 8

Fig. 8. Restoring ad libitum access to food only affects re-evaluation decisions, differentially in VEH- vs. STZ-treated mice.

Number of laps run in the correct direction (a) and total rewards earned (b) comparing between when mice were food restricted vs. had unlimited access to regular chow in the home cage (purple outlines). c Rewards earned split by flavor rankings. Offer zone thresholds (d) and wait zone thresholds (e) split by flavor ranking. Note no change in offer zone thresholds but a bidirectional change in wait zone thresholds (VEH: decreased; STZ: increased). f Normalized vicarious trial and error (VTE) behavior split by flavor ranking and by skip vs. enter offer zone outcomes. g Sensitivity to sunk cost delta curves plotted as a function of time already spent in the wait zone. Note abolished sunk costs in both STZ-treated groups regardless of schedule, in spite of no change in offer zone thresholds and similar shifts in wait zone thresholds. Insets depict peak scores. Horizontal dashed gray line represents 0. Shading/error bars represent ±1 SEM.

Update of

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