Biology subjects

Setlow, B.

Publications and source records attributed to Setlow, B..

15 recordsLinked to original sources

bioRxiv2026

Ventral tegmental area dopamine neuron activity mediates multi-valent outcomes during decision making under risk of punishment

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 StatementDopamine 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.

neuroscience↗

bioRxiv2026

Effects of Chronic Cannabis Smoke Exposure on Inflammatory Markers in Periphery and Brain in Young and Aged Mice

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. HIGHLIGHTSO_LIAged C57BL/6 mice have elevated cytokines levels, especially in the hippocampus C_LIO_LICannabis smoke exposure produces age-dependent changes in cytokine levels in hippocampus C_LIO_LIIn HPC, cannabis smoke exposure attenuated age-related increases in IL-13 and Dkk1 C_LI

neuroscience↗

bioRxiv2025

A novel cost-benefit decision-making task involving cued punishment; effects of sex and psychostimulant administration

Chronic substance use is associated with alterations in multiple forms of cost-benefit decision making, which may prolong and exacerbate continued use. Cues that predict reward can cause substantial shifts in a variety of reward-directed behavior, including decision making. In contrast, how decision making is modulated by cues predictive of punishment is much less well understood. To begin to address these issues, male and female Long-Evans rats were tested in a novel decision-making task in which they chose between a small, "safe" reward and a large reward that was punished by a mild footshock when it was preceded by a probabilistically delivered cue prior to the choice. Rats of both sexes were sensitive to the cue, preferring the large reward in the absence of the cue but the small reward in the presence of the cue. Acute systemic amphetamine reduced choice of the large reward and diminished the efficacy of the cue in guiding choice behavior. Chronic cocaine led to divergent patterns of cue insensitivity in males and females; males increased choice of the large reward on cued trials, whereas females increased avoidance of the large reward on uncued trials. Similar to acute amphetamine, acute systemic administration of the D2/3 dopamine receptor agonist bromocriptine reduced preference for the large reward across all groups. These findings highlight the contributions of punishment cues to decision making, as well as the importance of sex as a biological variable in investigating cognitive alterations caused by chronic substance use.

neuroscience↗

bioRxiv2025

Optogenetic inhibition reveals distinct contributions of medial prefrontal cortex to intertemporal choice in young and aged rats

The ability to choose adaptively between rewards differing in magnitude and delay (intertemporal choice) is critical for numerous life outcomes. Compared to younger adults, older adults tend to exhibit greater preference for large, delayed over small, immediate rewards (i.e., less delay discounting), which could lead to missed opportunities to obtain resources necessary for quality of life. Intertemporal choice is mediated by the prefrontal cortex, but how this is impacted by advanced age is not well understood. We used optogenetic inactivation to investigate contributions of medial prefrontal cortex (mPFC) during distinct components of an intertemporal choice task in young and aged rats. mPFC inactivation during deliberation (during decisions between small, immediate vs. large, delayed rewards) increased preference for large, delayed rewards in both age groups. In contrast, inactivation during delays prior to large reward delivery increased preference for large, delayed rewards only in aged rats. Choices were unaffected by inactivation during other task phases. Results suggest that mPFC integrates information regarding anticipated outcomes into the decision process across the whole lifespan, but that only in aging is mPFC critical for consolidating information regarding reward delays into the decision structure in order to modulate choice behavior.

neuroscience↗

bioRxiv2025

Cannabidiol Reduces Oxycodone Self-Administration While Preserving Its Analgesic Efficacy in a Rat Model of Neuropathic Pain

Prescription opioid misuse is a significant public health concern among individuals with chronic pain. Treating severe pain often requires high doses of opioids, increasing the risk of developing an opioid use disorder. Cannabidiol (CBD) is a non-psychoactive component of cannabis that has shown therapeutic potential without abuse liability. This study investigated the effects of CBD on oxycodone self-administration and hyperalgesia in an animal model of chronic neuropathic pain. Adult male rats were trained to self-administer intravenous oxycodone (0.06 mg/kg/infusion). Subsequently, they underwent chronic constriction injury (CCI) of the sciatic nerve or received sham surgery. Paw withdrawal latency was measured using the Hargreaves test as an indicator of thermal pain sensitivity. CBD (0, 1, 3, and 10 mg/kg, IP) was administered before the self-administration sessions, and pain testing was conducted afterward. The rats acquired oxycodone self-administration, as indicated by more active than inactive lever presses. CCI surgery decreased the paw withdrawal latency, confirming the induction of neuropathic pain. CCI alone did not affect oxycodone self-administration, suggesting that neuropathic pain does not affect opioid intake. Treatment with CBD reduced oxycodone self-administration in both the sham and CCI rats. Oxycodone self-administration in the CCI rats reversed the CCI-induced decrease in paw withdrawal latency. However, CBD did not affect the antinociceptive effect of oxycodone in CCI rats. Taken together, these findings demonstrate that CBD reduces oxycodone self-administration without affecting the antinociceptive effects of oxycodone in neuropathic pain. This study supports the potential of CBD to reduce opioid use and misuse, regardless of pain status.

pharmacology and toxicology↗

bioRxiv2025

Muscarinic type 1 receptor activated effectors in principal neurons of the rat basolateral amygdala

The basolateral amygdala (BLA) plays a crucial role in context-specific learning and memory by integrating valence-specific stimuli with internal physiological states. Cholinergic signaling systems modulate neural excitability to influence information processing in the BLA. Muscarinic acetylcholine receptors (mAChRs) are of particular interest because aberrant mAChR signaling in BLA circuits is associated with neuropsychiatric disorders, cognitive impairment, substance use, and age-related cognitive decline. This study evaluates mAChR activation in BLA principal neurons (PNs) in juvenile rat brain slices using whole-cell patch-clamp recordings. We found that bath application of carbachol (CCh,) produces a pirenzepine sensitive excitatory response in BLA PNs voltage clamped near the resting potential, which depends on an underlying biphasic change in membrane resistance, indicating an involvement of multiple effectors. More specifically, we observed that CCh excites BLA PNs by inhibiting the afterhyperpolarization (AHP), by reducing a steady state inhibitory current, and by promoting an afterdepolarization (ADP). We further identify and characterize a CCh-induced and calcium-activated non-selective cation current (ICAN) that underlies the ADP in voltage clamp. Overall, our findings provide new insights into specific effectors modulated by activation of pirenzepine sensitive mAChRs expressed by BLA PNs. We also reveal new details about the time-and voltage-dependence of current carried by the CCh - activated ICAN like current in BLA PNs, and highlight its ability to promote a suprathreshold ADP capable of generating sustained firing after a brief excitatory stimulus. Improved understanding of these effectors will provide potentially valuable new insights on the wide range of mechanisms through which cholinergic system dysfunction can lead to impaired executive function.

neuroscience↗

bioRxiv2024

Cannabis smoke and oral Δ9THC enhance working memory in aged but not young adult subjects

With increased legalization of recreational and medical cannabis, use of this drug is growing rapidly among older adults. As cannabis use can impair cognition in young adults, it is critically important to understand how consumption interacts with the cognitive profile of aged individuals, who are already at increased risk of decline. The current study was designed to determine how cannabis influences multiple forms of cognition in young adult and aged rats of both sexes when delivered via two translationally-relevant routes of administration. Acute exposure to cannabis smoke enhanced prefrontal cortex-dependent working memory accuracy in aged males, but impaired accuracy in aged females, while having no effects in young adults of either sex. In contrast, the same cannabis smoke exposure regimen had minimal effects on a hippocampus-dependent trial-unique non-matching to location mnemonic task, irrespective of age or sex. In a second set of experiments, chronic oral consumption of {Delta}9-tetrahydrocannabinol ({Delta}9THC) enhanced working memory in aged rats of both sexes, while having no effects in young adults. In contrast, the same oral {Delta}9THC regimen did not affect spatial learning and memory in either age group. Minimal age differences were observed in {Delta}9THC pharmacokinetics with either route of administration. Together, these results show that cannabis and {Delta}9THC can attenuate working memory impairments that emerge in aging. While these enhancing effects do not extend to hippocampus-dependent cognition, cannabis does not appear to exacerbate age-associated impairments in this cognitive domain.

neuroscience↗

bioRxiv2024

Effects of systemic oxytocin receptor activation and blockade on risky decision making in female and male rats

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.

neuroscience↗

bioRxiv2023

Effects of Reproductive Experience on Cost-Benefit Decision Making in Females and Males

Almost all individuals undergo reproductive and/or parenting experience at some point in their lives, and pregnancy and childbirth in particular are associated with alterations in the prevalence of several psychiatric disorders. Research in rodents shows that maternal experience affects spatial learning and other aspects of hippocampal function. In contrast, there has been little work in animal models concerning how reproductive experience affects cost-benefit decision making, despite the relevance of this aspect of cognition for psychiatric disorders. To begin to address this issue, reproductively experienced (RE) and reproductively naive (RN) female and male Long-Evans rats were tested across multiple tasks that assess different forms of cost-benefit decision making. In a risky decision-making task, in which rats chose between a small, safe food reward and a large food reward accompanied by variable probabilities of punishment, RE and RN males did not differ, whereas RE females chose the large risky reward significantly more frequently than RN females (greater risk taking). In an intertemporal choice task, in which rats chose between a small, immediate food reward and a large food reward delivered after a variable delay period, RE males chose the large reward more frequently than RN males, whereas RE females chose the large reward less frequently than RN females. Together, these results show distinct effects of reproductive experience on different forms of cost-benefit decision making in rats of both sexes, and highlight reproductive status as a variable that could influence aspects of cognition relevant for psychiatric disorders.

animal behavior and cognition↗

bioRxiv2023

Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward

Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. Primary cilia are microtubule-based organelles that project from the surface of nearly all mammalian cells, including neurons. They function as signaling hubs and are enriched with a diverse array of GPCRs, including several known to be associated with motivation and drug-related behaviors; however, our understanding of how cilia regulate neuronal function and behavior is still limited. The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in male and female mice. Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons exhibited greater locomotor sensitization to cocaine compared to wild-type littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 & 30mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to wild-type littermates. Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell-and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.

neuroscience↗

bioRxiv2023

Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA[->]NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA[->]NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.

neuroscience↗

bioRxiv2021

Oxycodone decreases anxiety-like behavior in the elevated plus-maze test in male and female rats

The prescription opioid oxycodone is widely used for the treatment of pain in humans. Oxycodone misuse is more common among people with an anxiety disorder than those without one. Therefore, oxycodone might be misused for its anxiolytic properties. We investigated if oxycodone affects anxiety-like behavior in adult male and female rats. The rats were treated with oxycodone (0.178, 0.32, 0.56, or 1 mg/kg), and anxiety-like behavior was investigated in the elevated plus-maze test. Immediately after the elevated plus-maze test, a small open field test was conducted to determine the effects of oxycodone on locomotor activity. In the elevated plus-maze test, oxycodone increased the percentage of time spent on the open arms, the percentage of open arm entries, time on the open arms, open arm entries, and the distance traveled. The males treated with vehicle had a lower percentage of open arm entries than the females treated with vehicle, and oxycodone treatment led to a greater increase in the percentage of open arm entries in the males than females. Furthermore, the females spent more time on the open arms, made more open arm entries, spent less time in the closed arms, and traveled a greater distance than the males. In the small open field test, treatment with oxycodone did not affect locomotor activity or rearing. Sex differences were observed; the females traveled a greater distance and displayed more rearing than the males. In conclusion, oxycodone decreases anxiety-like behavior in rats, and oxycodone has a greater anxiolytic-like effect in males than females.

pharmacology and toxicology↗

bioRxiv2020

Neuron-specific cilia loss alters locomotor responses to amphetamine.

The neural mechanisms that underlie responses to drugs of abuse are complex, and impacted by a number of neuromodulatory peptides. Within the past ten years it has been discovered that several of the receptors for neuromodulators are enriched in the primary cilia of neurons. Primary cilia are microtubule-based organelles that project from the surface of nearly all mammalian cells, including neurons. Despite what we know about cilia, our understanding of how cilia regulate neuronal function and behavior is still limited. The primary objective of this study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to amphetamine. To test the consequences of cilia loss on amphetamine-induced locomotor activity we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. Cilia loss had no effect on baseline locomotion in either mouse strain. Both female and male mice lacking cilia on dopaminergic neurons showed significantly reduced responses to acute administration of 3.0 mg/kg amphetamine compared to wildtype mice. In contrast, changes in the locomotor response to amphetamine in mice lacking cilia on GAD2-GABAergic neurons were primarily driven by reductions in locomotor activity in males. Following repeated amphetamine administration (1.0 mg/kg/day over 5 days), mice lacking cilia on GAD2-GABAergic neurons exhibited enhanced sensitization of the locomotor stimulant response to the drug, whereas mice lacking cilia on dopaminergic neurons did not differ from their wildtype controls. These results indicate that cilia play neuron-specific roles in both acute and neuroplastic responses to psychostimulant drugs of abuse.

neuroscience↗

bioRxiv2019

Aging alters the role of basolateral amygdala in intertemporal choice

Aging is associated with an increased ability to delay gratification. Moreover, even when matched for performance, young and aged subjects recruit distinct brain circuitry to complete complex cognitive tasks. Experiments herein used an optogenetic approach to test whether altered recruitment of the basolateral amygdala (BLA), a brain region implicated in valuation of reward-cost contingencies, contributes to age-dependent changes in intertemporal decision making. BLA inactivation while rats deliberated prior to choices between options that yielded either small, immediate or large, delayed rewards rendered both young and aged rats less impulsive. In contrast, BLA inactivation after choices were made (during evaluation of choice outcomes) rendered young rats more impulsive but had no effect in aged rats. These data define multiple, temporally-discrete roles for BLA circuits in intertemporal decision making and implicate altered recruitment of BLA in the elevated preference for delayed rewards that is characteristic of advanced age. Impact StatementBasolateral amygdala (BLA) performs multiple, temporally-discrete functions during intertemporal decision making. Differential engagement of BLA contributes to the enhanced ability to delay gratification that is characteristic of advanced ages.

neuroscience↗

bioRxiv2017

Optogenetic inhibition reveals distinct roles for basolateral amygdala activity at discrete timepoints during risky decision making

Decision making is a multifaceted process, consisting of several distinct phases that likely require different cognitive operations. Previous work showed that the basolateral amygdala (BLA) is a critical substrate for decision making involving risk of punishment; however, it is unclear how the BLA is recruited at different stages of the decision process. To this end, the current study used optogenetics to inhibit the BLA during specific task phases in a model of risky decision making (Risky Decision-making Task; RDT) in which rats choose between a small, \"safe\" reward and a large reward accompanied by varying probabilities of footshock punishment. Rats received intra-BLA microinjections of viral vectors carrying either halorhodopsin (eNpHR3.0-mCherry) or mCherry alone (control) followed by optic fiber implants and were trained in the RDT. Laser stimulation during the task occurred during either intertrial interval, deliberation, or reward outcome phases, the latter of which was further divided into the three possible outcomes (small, safe; large, unpunished; large, punished). Inhibition of the BLA selectively during the deliberation phase decreased choice of the large, risky outcome (decreased risky choice). In contrast, BLA inhibition selectively during delivery of the large, punished outcome increased risky choice. Inhibition had no effect during the other phases, nor did it affect performance in control rats. Collectively, these data indicate that the BLA can either inhibit or promote choice of risky options, depending on the phase of the decision process in which it is active.\n\nSignificance StatementTo date, most behavioral neuroscience research on neural mechanisms of decision making has employed techniques that preclude assessment of distinct phases of the decision process. Here we show that optogenetic inhibition of the basolateral amygdala (BLA) has opposite effects on choice behavior in a rat model of risky decision making depending on the phase in which inhibition occurs. BLA inhibition during a period of deliberation between small, safe and large, risky outcomes decreased risky choice. In contrast, BLA inhibition during receipt of the large, punished outcome increased risky choice. These findings highlight the importance of temporally targeted approaches to understand neural substrates underlying complex cognitive processes. More importantly, they reveal novel information about dynamic BLA modulation of risky choice.

neuroscience↗