Biology subjects

Floresco, S. B.

Publications and source records attributed to Floresco, S. B..

10 recordsLinked to original sources

bioRxiv2026

A Novel Operant Conditioning Task to Assess Motivation to Exercise in Rats

Voluntary physical activity is a highly motivated behavior with important implications for physical and mental health, yet the neural and endocrine mechanisms underlying motivation to exercise remain poorly understood. In contrast, motivation for sugar/palatable foods, drugs, and sex has been extensively characterized using operant paradigms. Here, we describe a novel progressive ratio operant task to measure motivation to run, independent of running ability. Using female Long Evans rats, which exhibit robust voluntary running behavior, we validated this paradigm by applying a manipulation well known to enhance the motivation to run: calorie restriction. Calorie-restricted animals exhibited increased operant responding to gain access to a running wheel, thus demonstrating heightened motivation for exercise. More specifically, calorie-restricted rats completed more ratios, reached a higher breakpoint in the progressive ratio task, ran more, and spent more time in the operant chamber. We did not observe any effects of calorie restriction on the estrous cycle or steroids (e.g. corticosterone, testosterone) in the blood or brain. Importantly, our task dissociates the motivational drive for physical activity from the ability to perform the physical activity itself, providing a new paradigm for studying the neural and endocrine mechanisms that regulate exercise motivation.

animal behavior and cognition↗

bioRxiv2024

SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting

RationalePsychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without psychostimulant-like side effect liability. ObjectivesWe compared AMPH, MPH, and SK609 within dose ranges that display their cognitive enhancing properties in a probabilistic discounting task (PDT) of risk/reward decision making behavior to assess their potential to increase risky choice preference. MethodsRats chose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with descending probabilities across a session (100-6.25%) following administration of AMPH (0.25-1 mg/kg), MPH (2-8 mg/kg), and SK609 (4 mg/kg). ResultsAMPH and MPH increased risky choice behavior at doses previously reported to enhance cognition, whereas SK609 did not. AMPH and MPH also reduced sensitivity to non-rewarded risky choices. ConclusionsThese data highlight the combination of NE transporter blockade and selective D3 activation in pro-cognitive action without psychostimulant-like side effect liability. The absence of DA transporter blockade and non-selective dopaminergic activation are beneficial properties of SK609 that differentiates it from the traditional pro-cognitive psychostimulants.

animal behavior and cognition↗

bioRxiv2024

Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats

RationaleAdolescent cannabis use is linked to later-life changes in cognition, learning, and memory. Rodent experimental studies suggest {Delta}9-tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence. ObjectiveWe determined how 14 daily THC injections (5mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition. MethodsIn adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks--strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impacts probabilistic discounting. ResultsAdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats. ConclusionsThese studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine neurons or their projections to mPFC.

animal behavior and cognition↗

bioRxiv2024

Perturbations in Risk/Reward Decision Making and Frontal Cortical Catecholamine Regulation Induced by Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) can disrupt cognitive processes that influence risk taking behavior. Athletes, military personnel, and domestic violence victims often experience multiple mTBIs; however, little is known regarding the effects of repetitive injury (rmTBI) on risk/reward decision making or whether these outcomes are sex specific. Risk/reward decision making is mediated by the prefrontal cortex (PFC), which is composed of several sub-regions including the medial PFC (mPFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). These regions are densely innervated by catecholaminergic fibers, which modulate PFC-mediated cognitive processes. Aberrant catecholamine activity within the PFC has been documented following TBI, which may underlie TBI-induced risky behavior. Tyrosine hydroxylase (TH) and norepinephrine transporter (NET) regulate catecholamine homeostasis within the PFC; however, it has not been determined how rmTBI affects these proteins. The present study aimed to characterize the effects of rmTBI on risk/reward decision making behavior and catecholamine transmitter regulatory proteins within the PFC. Risk/reward decision making was evaluated using a probabilistic discounting task (PDT) which required rats to choose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with decreasing probabilities over a session. Rats were first trained on the PDT and then exposed to sham, single (smTBI), or a series of three closed-head control cortical impact (CH-CCI) injuries over the course of one week, followed by four weeks of PDT testing. In week 1 post-final surgery, mTBI generally enhanced preference for the larger/riskier option with these effects seemingly more prominent in females. These effects resolved by week 2 post-final surgery indicating that the effects of mTBI on choice behavior are transient. By week 4, males, but not females, exhibited increased latencies to make riskier choices following rmTBI, demonstrating a delayed effect of injury on information processing speed. A separate group of rats was used to measure changes in levels of TH and NET within the mPFC, ACC, and OFC forty-eight hours after mTBI. No injury-induced differences were observed within the mPFC or ACC. In the OFC, females exhibited dramatic increases in TH levels following smTBI, but only small increases following rmTBI. Both males and females; however, experienced reduced levels of NET following rmTBI, which may function as a compensatory response to increased extracellular levels of catecholamines. Together, these results suggest that OFC is more susceptible to catecholamine instability after rmTBI, a finding indicating that not all areas of the PFC contribute equally to the observed TBI-induced catecholamine imbalances. Overall, combining the CH-CCI model of rmTBI with the PDT proved effective in revealing time-dependent and sex-specific changes in risk/reward decision making and catecholamine regulation following repetitive mild head injuries.

animal behavior and cognition↗

bioRxiv2022

Gender and comorbidity moderate the relationship between mood disorder symptoms and effortful avoidance performance

We must often decide how much effort to exert or withhold to avoid undesirable outcomes or obtain rewards. In depression and anxiety, levels of avoidance can be excessive and reward-seeking may be reduced. Yet outstanding questions remain about the links between motivated action/inhibition and anxiety and depression levels, and whether they differ between men and women. Here we examined the relationship between anxiety and depression scores, and performance on effortful active and inhibitory avoidance (Study 1) and reward seeking (Study 2) in humans. Undergraduates and paid online workers (NAvoid = 545, NReward = 310; NFemale = 368, NMale = 450, MAge = 22.58, RangeAge = 17-62) were assessed on the Beck Depression Inventory II (BDI) and the Beck Anxiety Inventory (BAI) and performed an instructed online avoidance or reward-seeking task. Participants had to make multiple presses on active trials and withhold presses on inhibitory trials to avoid an unpleasant sound (Study 1) or obtain points towards a monetary reward (Study 2). Overall, men deployed more effort than women in both avoidance and reward-seeking, and anxiety scores were negatively associated with active reward-seeking performance based on sensitivity scores. Gender interacted with anxiety scores and inhibitory avoidance performance, such that women with higher anxiety showed worse avoidance performance. Our results illuminate effects of gender in the relationship between anxiety and depression levels and the motivation to actively and effortfully respond to obtain positive and avoid negative outcomes. Significance statementWe must often take or withhold effortful action to avoid unpleasant outcomes or obtain rewards. Depression and anxiety can impact these behaviours effectiveness, but the roles of avoidance in depression and reward-seeking in anxiety are not fully understood. Gender differences in avoidance and reward-seeking have also not been examined. We present a task in which community participants with a range of anxiety and depression levels made or withheld button presses to avoid hearing an unpleasant sound or obtain a reward. Men deployed more effort than women in avoidance, and women with higher anxiety scores had lower avoidance performance than men. We illuminate gender differences in how depressive and anxiety scores impact our ability to avoid threats and obtain rewards.

neuroscience↗

bioRxiv2021

Androgen synthesis inhibition but not gonadectomy reduces persistence during strategy set-shifting and reversal learning in male rats

Androgens regulate behavioural flexibility, which is essential to adapt to a changing environment and depends on the medial prefrontal cortex (mPFC). Testosterone (T) administration decreases behavioural flexibility. It is well known that T is produced in the gonads, but T is also produced in the mesocorticolimbic system, which modulates behavioural flexibility. It is unclear how T produced in the brain versus the gonads influences behavioural flexibility. Here, we assess the effects of the androgen synthesis inhibitor abiraterone acetate (ABI) and long-term gonadectomy (GDX) on behavioural flexibility in two paradigms. In Experiment 1, ABI independent of GDX reduced the number of trials to criterion and perseverative errors in a strategy set-shifting task. Similarly, in Experiment 2, ABI but not GDX reduced perseverative errors in a reversal learning task. In subjects from Experiment 1, we also examined tyrosine hydroxylase immunoreactivity (TH-ir), and ABI but not GDX increased TH-ir in the mPFC. Our findings suggest that neurally-produced androgens modulate behavioural flexibility via modification of dopamine signalling in the mesocorticolimbic system. These results suggest novel roles for neurosteroids and possible side effects of ABI treatment for prostate cancer.

neuroscience↗

bioRxiv2020

Ventral Pallidum GABA Neurons Mediate Motivation Underlying Risky Choice

Pursuing rewards while avoiding danger is an essential function of any nervous system. Here, we examine a new mechanism helping rats negotiate the balance between risk and reward when making high-stakes decisions. Specifically, we focus on GABA neurons within an emerging mesolimbic circuit nexus--the ventral pallidum (VP). These neurons play a distinct role from other VP neurons in simple motivated behaviors in mice, but their roles in more complex motivated behaviors is unknown. Here, we interrogate the behavioral functions of VPGABA neurons in male and female transgenic GAD1:Cre rats (and wildtype littermates), using a reversible chemogenetic inhibition approach. Employing a behavioral assay of risky decision making, and of the food-seeking and shock-avoidance components of this task, we show that engaging inhibitory Gi/o signaling specifically in VPGABA neurons suppresses motivation to pursue highly salient palatable foods, and possibly also motivation to avoid being shocked. In contrast, inhibiting these neurons did not affect seeking of low-value food, free consumption of palatable food, or unconditioned affective responses to shock. Accordingly, when rats considered whether to pursue food despite potential for shock in a risky decision-making task, inhibiting VPGABA neurons caused them to more readily select a small but safe reward over a large but dangerous one--an effect not seen in the absence of shock threat. Together, results indicate that VPGABA neurons are critical for high-stakes adaptive responding that is necessary for survival, but which may also malfunction in psychiatric disorders. Significance StatementIn a dynamic world, it is essential to implement appropriate behaviors under circumstances involving rewards, threats, or both. Here, we demonstrate a crucial role for VPGABA neurons in high-stakes motivated behavior of several types. We show that this VPGABA role in motivation impacts decision making, as inhibiting these neurons yields a conservative, risk-averse strategy not seen when the task is performed without threat of shock. These new roles for VPGABA neurons in behavior may inform future strategies for treating addiction, and other disorders of maladaptive decision making.

neuroscience↗

bioRxiv2020

Disinhibition of the orbitofrontal cortex biases goal-directed behaviour in obesity

The lateral orbitofrontal cortex (lOFC) receives sensory information about food and integrates these signals with expected outcomes to guide future actions, and thus may play a key role in a distributed network of neural circuits that regulate feeding behaviour. Here, we reveal a novel role for the lOFC in the cognitive control of behaviour in obesity. Food-seeking behaviour is biased in obesity such that in male obese mice, behaviours are less flexible to changes in the perceived value of the outcome. Obesity is associated with reduced lOFC inhibitory drive, and chemogenetic reduction in GABAergic neurotransmission in the lOFC induces obesity-like impairments in goal-directed behaviour. Conversely, pharmacological or optogenetic restoration of inhibitory neurotransmission in the lOFC of obese mice reinstates flexible behaviour. Our results indicate that obesity-induced disinhibition of the lOFC leads to a failure to update changes in the value of food with satiety, which in turn may influence how individuals make decisions in an obesogenic environment.

neuroscience↗

bioRxiv2020

Sex Differences in Risk-based Decision Making

Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17{beta}-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17{beta}-estradiol benzoate (0.3 g) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17{beta}-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias towards larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.

neuroscience↗

bioRxiv2018

Hippocampal neurogenesis promotes preference for future rewards

Adult hippocampal neurogenesis is implicated in a number of disorders where reward processes are disrupted but whether new neurons regulate specific reward behaviors remains unknown. We find that blocking neurogenesis in rats reduces activation of the ventral dentate gyrus and causes a profound aversion for delayed rewards. Delay-based decision-making restructured dendrites and spines in adult-born neurons, consistent with activity-dependent neuronal recruitment. These findings identify a novel role for neurogenesis in decisions about future rewards, which is compromised in disorders where short-sighted gains are preferred at the expense of long-term health.

neuroscience↗