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Drug discovery for psychiatric conditions is stagnating. Behavioral changes could be used as a primary phenotypic screen for new drug candidates, if enough useful data can be generated from behavioral models. Could machine learning be the answer to extracting the data we need?

The amount of time already spent on a task influences human choice about whether to continue. This dedicated time, known as the “sunk cost,” reduces the likelihood of giving up the pursuit of a reward, even when there is no indication of likely success. Sweis et al. show that this sensitivity to time invested occurs similarly in mice, rats, and humans (see the Perspective by Brosnan). All three display a resistance to giving up their pursuit of a reward in a foraging context, but only after they have made the decision to pursue the reward. Science , this issue p. 178 ; see also p. 124 Mice, rats, and humans show similar sensitivity to time invested when making foraging decisions. Sunk costs are irrecoverable investments that should not influence decisions, because decisions should be made on the basis of expected future consequences. Both human and nonhuman animals can show sensitivity to sunk costs, but reports from across species are inconsistent. In a temporal context, a sensitivity to sunk costs arises when an individual resists ending an activity, even if it seems unproductive, because of the time already invested. In two parallel foraging tasks that we designed, we found that mice, rats, and humans show similar sensitivities to sunk costs in their decision-making. Unexpectedly, sensitivity to time invested accrued only after an initial decision had been made. These findings suggest that sensitivity to temporal sunk costs lies in a vulnerability distinct from deliberation processes and that this distinction is present across species.

Regret can be defined as the subjective experience of recognizing that one has made a mistake and that a better alternative could have been selected. The experience of regret is thought to carry negative utility. This typically takes two distinct forms: augmenting immediate postregret valuations to make up for losses, and augmenting long-term changes in decision-making strategies to avoid future instances of regret altogether. While the short-term changes in valuation have been studied in human psychology, economics, neuroscience, and even recently in nonhuman-primate and rodent neurophysiology, the latter long-term process has received far less attention, with no reports of regret avoidance in nonhuman decision-making paradigms. We trained 31 mice in a novel variant of the Restaurant Row economic decision-making task, in which mice make decisions of whether to spend time from a limited budget to achieve food rewards of varying costs (delays). Importantly, we tested mice longitudinally for 70 consecutive days, during which the task provided their only source of food. Thus, decision strategies were interdependent across both trials and days. We separated principal commitment decisions from secondary reevaluation decisions across space and time and found evidence for regret-like behaviors following change-of-mind decisions that corrected prior economically disadvantageous choices. Immediately following change-of-mind events, subsequent decisions appeared to make up for lost effort by altering willingness to wait, decision speed, and pellet consumption speed, consistent with past reports of regret in rodents. As mice were exposed to an increasingly reward-scarce environment, we found they adapted and refined distinct economic decision-making strategies over the course of weeks to maximize reinforcement rate. However, we also found that even without changes in reinforcement rate, mice transitioned from an early strategy rooted in foraging to a strategy rooted in deliberation and planning that prevented future regret-inducing change-of-mind episodes from occurring. These data suggest that mice are learning to avoid future regret, independent of and separate from reinforcement rate maximization.

Neuroeconomic theories propose changes in decision making drive relapse in recovering drug addicts, resulting in continued drug use despite stated wishes not to. Such conflict is thought to arise from multiple valuation systems dependent on separable neural components, yet many neurobiology of addiction studies employ only simple tests of value. Here, we tested in mice how prolonged abstinence from different drugs affects behavior in a neuroeconomic foraging task that reveals multiple tests of value. Abstinence from repeated cocaine and morphine disrupts separable decision-making processes. Cocaine alters deliberation-like behavior prior to choosing a preferred though economically unfavorable offer, while morphine disrupts re-evaluations after rapid initial decisions. These findings suggest that different drugs have long-lasting effects precipitating distinct decision-making vulnerabilities. Our approach can guide future refinement of decision-making behavioral paradigms and highlights how grossly similar behavioral maladaptations may mask multiple underlying, parallel, and dissociable processes that treatments for addiction could potentially target. Neuroeconomic theories suggest that conflict during decision, such as exhibited by relapsing drug addicts who continue drug use despite stated wishes not to, might arise from separable processes in decision making. Here the authors test mice in a foraging task designed to separate these processes and find that mice show alterations in separable components of decision conflict following abstinence from cocaine versus morphine.

Background Hyperglycemia is common in extremely low gestational age newborns (ELGAN) and is associated with increased mortality and morbidity, including abnormal neurodevelopment. Hippocampus-mediated cognitive deficits are common in this population, but the specific effects of hyperglycemia on the developing hippocampus are not known. Methods The objective of this study was to determine the acute and long-term effects of hyperglycemia on the developing hippocampus in neonatal rats using a streptozotocin (STZ)-induced model of hyperglycemia. STZ was injected on postnatal day (P) 2, and littermates in the control group were injected with an equivalent volume of citrate buffer. The acute effects of hyperglycemia on markers of oxidative stress, inflammatory cytokines, microglial activation, and reactive astrocytosis in the hippocampus were determined in the brain tissue collected on P6. The long-term effects on hippocampus-mediated behavior and hippocampal dendrite structure were determined on P90. Results On P6, the transcript and protein expression of markers of oxidative stress and inflammatory cytokines, including the CXCL10/CXCR3 pathway, were upregulated in the hyperglycemia group. Histological evaluation revealed microglial activation and astrocytosis. The long-term assessment on P90 demonstrated abnormal performance in Barnes maze neurobehavioral testing and altered dendrite structure in the hippocampus of formerly hyperglycemic rats. Conclusions Neonatal hyperglycemia induces CXCL10/CXCR3 signaling, microglial activation, and astrocytosis in the rat hippocampus and alters long-term synaptogenesis and behavior. These results may explain the hippocampus-specific cognitive deficits common in ELGAN who experience neonatal hyperglycemia.

Objectives The use of topical corticosteroids to manage postoperative sinonasal symptoms after endoscopic skull base surgery (ESBS) has not been well studied. We quantified long‐term impact of postoperative steroid irrigations (SIs) on quality of life of patients after ESBS. Methods Retrospective review of patients at the University of Pennsylvania undergoing ESBS from 2010 to 2019. Data on patient demographics and postoperative treatment with nasal saline irrigation twice daily with and without dissolved steroids (mometasone or budesonide) was collected. Preoperative, and 1‐, 3‐, 6‐, 12‐, 18‐, and 24‐month postoperative Sino‐Nasal Outcome Test (SNOT‐22) scores were assessed. Results A total of 727 patients were assessed (53.4% males), with 479 patients in the no SI group and 248 patients in the SI group. Preoperative SNOT‐22 scores did not differ significantly (P = 0.19). 1‐, 3‐, 6‐, 12‐, 18‐, and 24‐month post‐op SNOT‐22 scores did not significantly differ between groups. However, mometasone irrigations resulted in significantly lower postoperative 2‐year SNOT‐22 scores compared to budesonide (P < 0.01) and saline (P = 0.03). Conclusions Though corticosteroid irrigations are routine in managing inflammatory sinus disease, their role in postoperative management after ESBS for tumors is unclear. Our findings suggest that mometasone irrigation may be effective at improving postoperative quality of life in patients after ESBS.

The nucleus accumbens shell (NAcSh) is critically important for reward valuations, yet it remains unclear how valuation information is integrated in this region to drive behaviour during reinforcement learning. Using an optogenetic spatial self-stimulation task in mice, here we show that contingent activation of different excitatory inputs to the NAcSh change expression of different reward-related behaviours. Our data indicate that medial prefrontal inputs support place preference via repeated actions, ventral hippocampal inputs consistently promote place preferences, basolateral amygdala inputs produce modest place preferences but as a byproduct of increased sensitivity to time investments, and paraventricular inputs reduce place preferences yet do not produce full avoidance behaviour. These findings suggest that each excitatory input provides distinct information to the NAcSh, and we propose that this reflects the reinforcement of different credit assignment functions. Our finding of a quadruple dissociation of NAcSh input-specific behaviours provides insights into how types of information carried by distinct inputs to the NAcSh could be integrated to help drive reinforcement learning and situationally appropriate behavioural responses. An optogenetic, spatial self-stimulation task in mice reveals how information carried by distinct inputs to the nucleus accumbens shell is potentially integrated to drive behavioural responses.

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. A neuroeconomic approach to characterize decision-making behavior reveals alterations in distinct valuation algorithms in a mouse model of diabetes, shedding light on the interaction between metabolic disorders, energy balance, and cognitive heuristics.

Sunk cost sensitivity describes escalating decision commitment with increased spent resources. On neuroeconomic foraging tasks, mice, rats, and humans show similar escalations from sunk costs while quitting an ongoing countdown to reward. In a new analysis taken across computationally parallel foraging tasks across species and laboratories, we find that these behaviors primarily occur on choices that are economically inconsistent with the subject’s other choices, and that they reflect not only the time spent, but also the time remaining, suggesting that these are change-of-mind re-evaluation processes. Using a recently proposed change-of-mind drift-diffusion model, we find that the sunk cost sensitivity in this model arises from decision-processes that directly take into account the time spent (costs sunk). Applying these new insights to experimental data, we find that sensitivity to sunk costs during re-evaluation decisions depends on the information provided to the subject about the time spent and the time remaining. Computationally parallel ‘change-of-mind’ tasks in mice, rats and humans are analysed and demonstrate that sensitivity to sunk costs during re-evaluation depends on the awareness of time spent and remaining.

The nucleus accumbens shell (NAcSh) is involved in reward valuation. Excitatory projections from infralimbic cortex (IL) to NAcSh undergo synaptic remodeling in rodent models of addiction and enable the extinction of disadvantageous behaviors. However, how the strength of synaptic transmission of the IL–NAcSh circuit affects decision-making information processing and reward valuation remains unknown, particularly because these processes can conflict within a given trial and particularly given recent data suggesting that decisions arise from separable information-processing algorithms. The approach of many neuromodulation studies is to disrupt information flow during on-going behaviors; however, this limits the interpretation of endogenous encoding of computational processes. Furthermore, many studies are limited by the use of simple behavioral tests of value which are unable to dissociate neurally distinct decision-making algorithms. We optogenetically altered the strength of synaptic transmission between glutamatergic IL–NAcSh projections in mice trained on a neuroeconomic task capable of separating multiple valuation processes. We found that induction of long-term depression in these synapses produced lasting changes in foraging processes without disrupting deliberative processes. Mice displayed inflated reevaluations to stay when deciding whether to abandon continued reward-seeking investments but displayed no changes during initial commitment decisions. We also developed an ensemble-level measure of circuit-specific plasticity that revealed individual differences in foraging valuation tendencies. Our results demonstrate that alterations in projection-specific synaptic strength between the IL and the NAcSh are capable of augmenting self-control economic valuations within a particular decision-making modality and suggest that the valuation mechanisms for these multiple decision-making modalities arise from different circuits.