Barry Setlow

Dopamine contributes to reward-related decision making, but its contributions to decision contexts that include explicit punishment are less well understood. To elucidate the role of ventral tegmental area (VTA) dopamine neurons in decision making under risk of punishment, we used fiber photometry to record activity in these neurons during a decision-making task in which rats choose between a small, “safe” reward and a large reward associated with varying probabilities of explicit punishment. Dopamine neuron activity exhibited phasic increases during risky “Wins” (reward without punishment) and phasic decreases during risky “Losses” (reward plus punishment), each of which scaled with punishment probability and intensity. Further analyses revealed that this outcome-evoked activity predicted choices on subsequent trials. To determine whether VTA dopamine neuron activity plays a causal role in these risk-based decisions, we used optogenetics to selectively inhibit these neurons during risky Wins and Losses. Inhibition of VTA dopamine neurons during Wins selectively reduced the frequency of risky choices after a Win, whereas inhibition during Losses selectively reduced the frequency of risky choices after a Loss. These data reveal that VTA dopamine neuron activity during outcome receipt is causally related to subsequent decision-making behavior. In addition, the fact that the effects of inhibition on choice behavior were specific to the outcome with which the inhibition was paired suggests that VTA dopamine neuron activity contributes to updating after Wins and Losses independently. Significance Statement: Dopamine is implicated in movement, motivation, and learning, and has been strongly linked with substance use and risk-seeking behavior. Despite these associations, it is unclear how the activity of dopamine neurons influences decision making under risk of punishment. To elucidate this, we recorded from ventral tegmental area (VTA) dopamine neurons and found that their activity at the population level integrates reward alongside the probability and intensity of punishment experienced during risky outcomes. Further, inhibition of VTA dopamine neuron activity during risky outcomes decreased risk-seeking behavior in an outcome-specific manner. Our findings align with models suggesting that VTA dopamine neurons signal prediction errors, and provide insight into the role of these neurons in adaptive decision making.

BACKGROUND: The biological basis for the male-biased prevalence of many neurodevelopmental disorders remains poorly understood. We found that preconception exposure of male rats to sevoflurane induces persistent dysregulation of stress and inflammatory signaling, while their offspring, almost exclusively males, develop neurobehavioral abnormalities. These effects in both generations are prevented by paternal pretreatment with either the Na ⁺ /K ⁺ /2Cl ⁻ cotransporter inhibitor bumetanide or the glucocorticoid receptor antagonist RU486. Using offspring from the same treatment groups, we tested the hypothesis that dysregulation of male-specific, sex hormone–dependent brain masculinization processes during the perinatal critical period contributes to the observed male-biased abnormalities. METHODS: Sprague-Dawley F0 males were exposed to 2.1% sevoflurane for 3 hours on postnatal days (P) 56, 58, and 60. Subsets received bumetanide or RU486 30 minutes before each exposure. On P90, F0 males were mated to generate F1 offspring. On P0–P1, F1 males of sevoflurane-exposed sires received the androgen receptor (AR) antagonist flutamide, the estradiol (E2) synthesis inhibitor formestane, the estrogen receptor α (ERα) antagonist 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP), or the estrogen receptor β (ERβ) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) (n = 18/group). Sex steroid concentrations and hippocampal mRNA expression of enzymes and receptors involved in brain masculinization were measured in P0 F1 males from control sires (F1M_C), sevoflurane-exposed sires (F1M_S), or sires pretreated with bumetanide (F1M_BS) or RU486 (F1M_RS) (n = 6–8/group). Behavioral and stress-responsivity outcomes were assessed in adulthood. RESULTS: Compared with F1M_C, P0 F1M_S exhibited increased hippocampal testosterone (mean ± standard error of the mean [SEM]: 1.979 ± 0.527 vs 0.524 ± 0.122 ng/mg; P = .008) and E2 levels (10.997 ± 3.756 vs 2.793 ± 0.719 ng/mg; P = .027). Hippocampal mRNA expression of the testosterone-synthesizing enzyme 17β-hydroxysteroid dehydrogenase (1.629 ± 0.135 vs 1.000 ± 0.066; P = .001) and the E2-synthesizing enzyme aromatase (1.617 ± 0.093 vs 1.000 ± 0.070; P = .001) was also increased. In contrast, serum testosterone levels and hippocampal Ar , Erα , and Erβ mRNA expression were unchanged. F1M_BS and F1M_RS did not differ from F1M_C in any of these measures. Perinatal flutamide treatment reduced stress and neuroinflammatory markers and improved sociability, anxiety-like behavior, sensorimotor gating, and spatial memory in adulthood. Formestane normalized inflammatory and behavioral abnormalities; MPP improved sociability and spatial memory; and PHTPP improved spatial memory only. CONCLUSIONS: These findings suggest that male-specific neurodevelopmental abnormalities following paternal preconception sevoflurane exposure arise from stress- and inflammation-programmed increases in brain-derived testosterone during the critical brain masculinization period, involving both AR and E2 signaling.

Aging is associated with chronic low-grade inflammation, which is thought to contribute to both cognitive decline and various neurodegenerative diseases. Cannabinoids are reported to reduce levels of inflammatory markers; however, these effects have not been thoroughly assessed in aged subjects. To address this gap, we evaluated effects of chronic cannabis smoke exposure on peripheral and brain inflammatory markers in young and aged mice. Young adult (4 months old) and aged (22 months old) C57Bl/6J mice were exposed to smoke from burning either cannabis (5.5 - 6.2% THC) or placebo (0% THC) cigarettes daily for 30 consecutive days. Following exposure sessions, both blood and brain tissue from the prefrontal cortex (PFC) and hippocampus (HPC) were collected and analyzed for multiple markers of inflammation. Overall, the patterns of inflammatory markers varied across the three tissue types. Both comparisons of individual cytokines and global cytokine profiles revealed that aging caused modest increases in cytokine levels in serum and PFC, with little influence of cannabis exposure. In contrast, HPC samples had stronger age effects, with numerous cytokines elevated in aged mice compared to young. Cannabis also interacted with age in the HPC such that smoke exposure tended to increase cytokine levels in young mice but decrease them in aged mice. These findings point to general age-related increases in brain inflammatory markers in this mouse strain, but cannabis effects were largely restricted to the HPC, where smoke exposure produced age-dependent changes in cytokine profiles. HIGHLIGHTS: Aged C57BL/6 mice have elevated cytokines levels, especially in the hippocampus Cannabis smoke exposure produces age-dependent changes in cytokine levels in hippocampus In HPC, cannabis smoke exposure attenuated age-related increases in IL-13 and Dkk1

There are few cognitive functions more essential than decision making, as better decisions improve our chances of survival. Cost–benefit decisions as they apply to most scenarios in the developed world can range from relatively mundane to reasonably important; however, particularly risky choices such as speeding on our way to work or consuming suspicious foods can pose a genuine risk of significant harm or illness. How is it that our brains learn and evaluate these risks and rewards to arrive at decisions? Additionally, what drives some of us to continue despite, or avoid because of, potential adverse consequences? This review explores neural mechanisms underlying cost–benefit decision making, focusing on paradigms used in human and particularly rodent studies to model decision making under the risk of explicit punishments, such as pain, discomfort, or loss. The review focuses on several key brain regions (the prefrontal cortex, basolateral amygdala, and striatum), and their roles in the assessment of rewards, punishments (or risk thereof), and motivated behaviors. It also discusses pertinent literature on the role of dopamine arising from the ventral tegmental area, as a neuromodulator critical for learning and reinforcement in the context of risky decision making.This article is categorized under: Neuroscience > Behavior Economics > Individual Decision‐Making Psychology > Reasoning and Decision Making

The neuropeptide oxytocin is traditionally known for its roles in parturition, lactation, and social behavior. Other data, however, show that oxytocin can modulate behaviors outside of these contexts, including drug self-administration and some aspects of cost-benefit decision making. Here we used a pharmacological approach to investigate the contributions of oxytocin signaling to decision making under risk of explicit punishment. Female and male Long-Evans rats were trained on a risky decision-making task in which they chose between a small, "safe" food reward and a large, "risky" food reward that was accompanied by varying probabilities of mild footshock. Once stable choice behavior emerged, rats were tested in the task following acute intraperitoneal injections of oxytocin or the oxytocin receptor antagonist L-368,899. Oxytocin dose-dependently reduced preference for the large, risky reward only in females, whereas L-368,899 dose-dependently reduced preference for the large, risky reward in both sexes. Control experiments showed that these effects could not be accounted for by drug-induced alterations in preference for the large reward or shock sensitivity. Together, these results reveal partially sex-dependent effects of oxytocin signaling on risky decision making in rats. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Purpose: To estimate incidence rates of suicidal ideation and behavior following treatment initiation with gabapentinoids or dopamine agonists (DAs) in patients with newly diagnosed early‐onset idiopathic restless legs syndrome (RLS) and to examine suicidal behavior risk, comparing between those receiving gabapentinoids and DAs.Methods: A new user retrospective cohort study using MarketScan claims data from 2012 to 2019 was conducted. Exposures were monotherapy gabapentinoids or DAs initiated within 60 days of new RLS diagnosis. Three varying outcome measures of suicidality were examined and incidence rates were calculated for each. A log‐binomial regression model the estimated relative risk (RR) of the outcomes with gabapentinoids. Propensity score weighting adjusted for baseline covariates, including age, substance use disorders, hyperlipidemia, antipsychotic use, hypnotic/sedative use, and mood stabilizer use, which were most imbalanced before weighting.Results: The cohort included 6672 patients, with 4986 (74.7%) initiating a DA and 1686 (25.3%) initiating a gabapentinoid. Incidence rates for all outcome measures were higher in the gabapentinoid group (suicidality: 21.6 vs. 10.7 per 1000 person‐years; suicidality with self‐harm: 23.0 vs. 11.1 per 1000 person‐years; overdose‐ and suicide‐related events: 30.0 vs. 15.5 person‐years). Associated risk of suicidality (adjusted RR, 1.27 [95% CI, 0.86–1.88]); suicidality with self‐harm (adjusted RR, 1.30 [95% CI, 0.89–1.90]); or overdose‐ and suicide‐related events (adjusted RR, 1.30 [95% CI, 0.93–1.80]) was not significant with gabapentinoids.Conclusions: Incidence rates for suicidal ideation and behavior were higher among the gabapentinoid group, although increased risk was not detected after adjustment. A possible signal cannot be ruled out given limitations of the data and rarity of the outcome.

The neuropeptide oxytocin is traditionally known for its roles in parturition, lactation, and social behavior. Other data, however, show that oxytocin can modulate behaviors outside of these contexts, including drug self-administration and some aspects of cost-benefit decision making. Here we used a pharmacological approach to investigate the contributions of oxytocin signaling to decision making under risk of explicit punishment. Female and male Long-Evans rats were trained on a risky decision-making task in which they chose between a small, “safe” food reward and a large, “risky” food reward that was accompanied by varying probabilities of mild footshock. Once stable choice behavior emerged, rats were tested in the task following acute intraperitoneal injections of oxytocin or the oxytocin receptor antagonist L-368,899. Neither drug affected task performance in males. In females, however, both oxytocin and L-368,899 caused a dose-dependent reduction in preference for large risky reward. Control experiments showed that these effects could not be accounted for by alterations in food motivation or shock sensitivity. Together, these results reveal a sex-dependent effect of oxytocin signaling on risky decision making in rats.