Behavioral Neuroscience

Opioid Use Disorder (OUD) remains a prominent threat to global health. Genetic background influences the susceptibility of developing OUD, although specific genetic factors remain elusive. Rodent models that differ in susceptibility to escalation and dysregulation of opioid use are valuable tools to facilitate discovery of genetic pathways. Phenotypes associated with the development of OUD were compared in seven classic inbred rat strains (M520/N, WKY/NCrl, F344/NCrl, F344/Stm, LEW/Crl, LEW/SSNHsd, LE/Stm) from the Hybrid Rat Diversity Panel (HRDP). A two-phase self-administration paradigm was utilized to assess characteristics of the acquisition of oxycodone self-administration during daily 2-h sessions, and the escalation of oxycodone use during daily 12-h sessions. Genetic background influenced the acquisition of oxycodone self-administration as indicated by differences in the initiation of responding for oxycodone during each session and different amounts of oxycodone intake. We observed that escalation of oxycodone intake between-sessions was strain dependent, and the within-session distribution of oxycodone intake was strongly influenced by strain. The M520/N strain engaged in a unique pattern of intake, characterized by rapid initiation of oxycodone responding during the acquisition phase and a significant burst-like responding during escalation. Strain-dependent sex differences were also observed in several acquisition and escalation metrics. Of interest, burst responding was more prevalent in females of the M520/N strain compared to males. Together, these data indicate that genetic background influences not only overall oxycodone intake, but specific within- and between-session metrics that capture patterns of consumption across the substance use trajectory.

Risk for opioid use disorder (OUD) is substantially heritable, yet its genetic architecture remains only partly understood. This study examined oxycodone intake in two nearly isogenic rat strains, Wistar Kyoto More Immobile (WMI) and Less Immobile (WLI), and their reciprocal female F1 offspring. The parental strains differ in depression-like behavior and substance use vulnerability, with WMI rats consuming more oxycodone than WLI controls. Voluntary consumption was measured with an operant licking self-administration protocol that delivered 60 l drug per reward. Across four experimental stages, oxycodone concentrations increased from 0.025 to 0.1 mg/ml, and session durations increased from 1 to 4 hours. Female offspring showed a parent-of-origin effect. F1 females sired by WMI fathers (WLIxWMI) displayed accelerated escalation during the transition from 1-hour to 4-hour sessions in Stage 2 and consumed more oxycodone than reciprocal WMIxWLI females across expanded-access stages. This vulnerability was associated with increased licking during the drug-unavailable timeout period. In WMI and reciprocal WMIxWLI female, consumption was regulated by the drugs subjective value, as measured by lick microstructure, during Stages 1 and 2. This relationship was absent in WLIxWMI females during Stage 2. Together, these findings suggest that paternal WMI lineage is associated with a rapid transition to high oxycodone intake and cue-directed drug seeking, and identify a parent-of-origin effect that may contribute to female vulnerability to addiction.

Emerging clinical research with psilocybin highlights the value of the psychedelic experience on successful treatment of a multitude of psychiatric disorders. While the psychedelic trip or clinical support procedures cannot be modeled in rodents, neural processes critical to meta-learning and flexible modification of previously learned strategies can be quantified during psilocybin exposure. Here we applied computational modeling and single unit recordings from medial prefrontal cortex to characterize the efect of psilocybin using a value-based probabilistic choice task. Psilocybin improved choice selection in uncertain contexts and shifted reinforcement learning rate bidirectionally, enhancing updating from rewarded, while reducing updating from unrewarded, actions. These behavioral changes coincided with selective shifts in the neural encoding of task features including enhanced neural representation of rewarded, and diminished representation of unrewarded, outcomes. Collectively these data indicate that psilocybin improves choice selection in uncertain contexts by reweighing cortical coding in a way that favors learning from positive new information over prospective actions.

RationaleAppetitive Pavlovian cues can drive maladaptive reward seeking via stimulus-reward memories. Disrupting memory reconsolidation offers a potential strategy to reduce their influence, but evidence for {beta}-adrenergic blockade with propranolol is inconsistent across behavioural paradigms, particularly relative to NMDA receptor antagonism. ObjectivesWe tested whether propranolol disrupts reconsolidation of appetitive sucrose memories in a discriminative goal-tracking paradigm, and compared its effects with those of the most commonly used NMDA receptor antagonist, MK-801. MethodsAdult Lister hooded rats underwent discriminative Pavlovian conditioning. Thirty minutes before a brief memory reminder (non-reinforced or reinforced), rats received systemic drug treatment or saline control. In study 1, MK-801 (0.1 mg/kg) was administered to male rats. In study 2, propranolol (10 mg/kg) was administered to equal numbers of male and female rats. Goal-tracking was tested drug-free at 1 and 8 days. ResultsIn study 1, MK-801 impaired subsequent discriminated responding at test. These effects were observed not only when reminder was non-reinforced as in previous successful demonstrations, but also with reinforced reminder. In study 2, Propranolol also impaired subsequent goal-tracking, regardless of reminder type, and the effects were consistent across sexes. ConclusionsPropranolol can disrupt reconsolidation of appetitive goal-tracking memories to a similar extent as MK-801 under conditions that promote memory destabilisation. These findings demonstrate that {beta}-adrenergic blockade can impair appetitive memory reconsolidation in a goal-tracking paradigm, challenging prior null findings and revitalising the potential for propranolol-based interventions in maladaptive reward-seeking behaviours.

Hormonal regulation of patch-leaving decision-making remains poorly understood. Here, young adult male and female Long-Evans rats were tested in a patch-leaving task before and after orchiectomy (ORCH), ovariectomy (OVX), or sham surgery, and were subsequently assessed in an impulsive-choice task. Patch leaving was measured under long- and short-travel conditions. Before surgery, males showed longer overstay than females during long-travel sessions, whereas no clear sex difference was detected during short-travel sessions. After surgery, orchiectomy did not produce a uniform shift in patch leaving but selectively disrupted the progressive reduction in overstay that normally emerged across repeated long-travel sessions. By contrast, ovariectomy produced weaker effects and did not reveal a comparably robust change in female patch leaving. Spatial and idle occupancy analyses showed that gonadectomy also altered within-patch behavior, with orchiectomy most strongly increasing idling-related measures in males, whereas ovariectomy more strongly redistributed female patch occupancy. Estrous stage did not significantly organize pre-surgical female overstay. Greater impulsive choice was associated with smaller post-surgical reductions in long-travel overstay in the unadjusted analysis. Together, these findings indicate that testicular hormones selectively support patch-leaving adaptation under high travel cost.

Considerable evidence suggests that the motivational control of instrumental action depends on incentive learning; i.e., on the opportunity to learn how the value of the consequences or outcome of an action, (e.g., a specific food) varies under different motivational conditions (e.g., under different degrees of hunger). The current study investigated whether learning the values of high-protein and high-carbohydrate rewards under different degrees of protein and carbohydrate appetite is also necessary for these nutrient-specific appetites to exert control over instrumental performance. Experiment 1 gave differing consummatory experience to whey protein and polycose carbohydrate outcomes under protein and carbohydrate appetite and found that, without the opportunity for incentive learning, the performance of actions earning these outcomes was insensitive to a shift in appetite. However, once the opportunity for incentive learning was provided, the rats increased their instrumental performance on a lever that earned the whey outcome relative to the polycose lever when protein hungry and on the polycose lever relative to the whey lever when carbohydrate hungry. Experiment 2 assessed how these nutrient-specific states exerted this control; whether, once learned, nutrient values were immediately controlled by nutrient appetite or whether this was based on conditional control acquired during experience with the outcomes under different nutrient appetites. We found that exposure to an outcome under a single nutrient-specific state was not sufficient to establish state-specific control. Instead, establishing the conditional control of outcome value required exposure to both the whey and polycose outcomes under both protein and carbohydrate appetites.

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.

People often must decide how long to continue waiting for rewards that will arrive at an uncertain time in the future. We propose that these persistence decisions involve weighing the benefits of continued waiting against opportunity costs of waiting, a balance that may shift over time. This framework suggests that persistence decisions share neural mechanisms with foraging decisions, which require ongoing comparisons between a current resource and possible alternatives. Dopamine and serotonin have been proposed to play opposing roles in foraging, with dopamine promoting exploration and serotonin promoting exploitation. Here we investigated their roles in persistence. In a within-subjects, double-blind, placebo-controlled study in young adults (n = 42), we examined the effects of increasing dopamine with L-dopa and increasing serotonin with escitalopram. We predicted that L-dopa would decrease persistence and escitalopram would increase it. Participants also completed patch-foraging, time perception, risk tolerance, and temporal discounting tasks to explore potential mechanisms of drug effects on persistence. Escitalopram increased persistence, after adjusting for the effects of anxiety and condition order, such that participants waited longer for rewards after taking the serotonergic drug. L-dopa did not influence persistence. In exploratory analyses controlling for age, however, L-dopa reduced persistence and increased exploration in foraging.

Decisions are often modeled as a sequential process in which evidence accumulates until it reaches a threshold, triggering a response. Studies in freely moving animals raise questions about how ongoing behavior, not just stimulus properties, shapes this process. We trained rats of both sexes on a visual detection task with three luminance levels, each associated with the same reward outcome. Rats controlled cue duration through sustained head entries into a center port, yielding a measurable index of active sampling. Females consistently sampled longer than males. Sampling durations were shorter on error than correct trials, and reaction times were longer on error trials. We used drift diffusion models to relate these behaviors to the decision process. Luminance selectively affected the rate of evidence accumulation, with drift rate increasing monotonically across low, mid, and high luminance levels. Active sampling time was associated with the decision threshold, with longer sampling predicting higher thresholds in both sexes. The relationship between sampling time and drift rate differed by sex. Females showed a negative association between sampling duration and drift rate that was absent in males. These findings suggest that cue properties and active sampling make separable contributions to the decision process. These findings suggest that cue properties and active sampling make separable contributions to decision making, with a negative association between sampling duration and drift rate evident in females but not males.

Rationale: Early life stress (ELS) is acknowledged to underlie cognitive and emotional abnormalities linked to stress-related mood disorders. ELS can lead to persistent biases in how uncertain feedback is processed to affect the flexibility of decision-making. Objectives: (1) To investigate the effects of ELS on the flexibility of rats trained on a serial probabilistic reversal learning (PRL) task involving spurious positive and negative feedback. (2) To elucidate the involvement of the stress hormone corticosterone and the noradrenergic and serotonergic systems in modulating how ELS affects PRL. Methods: Male and female rats were intermittently separated from maternal care on postnatal days five to nineteen, inclusively. As adults, the same rats were trained on a deterministic reversal learning task involving certain rewarded or non-rewarded outcomes followed by a PRL task where correct and incorrect responses were rewarded on 80% and 20% of trials, respectively. Dose-dependent effects of the beta-blocker, propranolol, selective serotonin reuptake inhibitor, citalopram and corticosterone were subsequently determined. Results: ELS resulted in an increased responsivity to feedback, specifically in males making more win-stay responses following a reward, that was associated with an increased punishment learning rate. In both control and MS rats, propranolol increased feedback sensitivity, but delayed updating following a rule switch. In contrast, neither citalopram nor corticosterone significantly affected reversal learning. Conclusions: ELS is sufficient to cause persistent changes in how feedback is processed by male rats on a reversal learning task. Activation of beta-adrenergic receptors may be necessary for updating learned associations during decision-making involving uncertain feedback.

The locus coeruleus noradrenaline (LC-NA) system is a key regulator of arousal, attention, and reward learning. Noradrenaline plays a critical role in impulse control, and recent evidence indicates the importance of noradrenaline signaling in cost-benefit decision making once choice strategies are established. However, whether the LC causally shapes the acquisition of decision strategies, and how this contribution may differ across sexes, remains unclear. We addressed these questions by chemogenetically inhibiting catecholaminergic neurons within the LC of adult tyrosine-hydroxylase Cre (TH::Cre) rats (n=69; 35 females) throughout acquisition of the cued rat gambling task (crGT), a probabilistic decision making paradigm that incorporates salient audiovisual reward-paired cues and simultaneously measures motor impulsivity. LC inhibition accelerated the development of risky choice strategies early in training in both males and females, reflected by impaired adoption of the most advantageous option and increased preference for risky options. Trial-by-trial analyses reveal that LC inhibition promoted switches in choice strategy following safe wins, while reducing switches away from risky options after both wins and losses. LC inhibition therefore seemed to encourage the repetition of actions that resulted in more uncertain outcomes. LC inhibition also selectively enhanced motor impulsivity in females, particularly early in training. These results provide causal evidence that the LC system guides the formation of optimal decisional strategies, while exerting sex-specific control over impulsive action.

Early life adversity can produce persistent changes during development that increase vulnerability to neuropsychiatric disorders. Although disruptions in reward processing are widely recognized as a hallmark of these disorders, reward is not a single construct. Distinct forms of reward including social interaction and primary rewards such as food rely on overlapping but dissociable neural circuitry and may be differentially affected by adverse experiences. Here, we used a rodent model of neonatal predator odor exposure (POE) to determine how early life threat influences motivation for social and sucrose reward in adulthood using operant procedures. Neonatal POE reduced adult motivation for a social reinforcer during an operant social self-administration task, whereas motivation for a sucrose reinforcer was unchanged. However, we did find a significant difference in sucrose self-administration with POE females pressing more for sucrose than control females. These findings demonstrate that neonatal threat does not produce a generalized deficit in motivation but rather selectively alters motivation across distinct reward domains. Together, this work identifies social reward as a particularly vulnerable behavioral domain following early life threat and provides new insight into how adverse developmental experiences shape adult reward-related behavior.

We previously reported, using in-vivo fiber photometry, that operant responding reinforced by access to a peer (social self-administration) is associated with phasic dopamine increases in nucleus accumbens (NAc) core following lever insertion (reward-availability cue) and gradual increases preceding lever-pressing. Here, we sought to replicate these findings and determine whether dopamine signals (1) generalize to responding for high-carbohydrate palatable food, (2) show opposite patterns during negative reinforcement (shock avoidance/escape), and (3) depend on whether reinforcers are experienced alone or together. We trained rats (n=11; 6 females) to lever-press for access to a same-sex peer (15 s/trial) and palatable food (45-mg pellet/trial), followed by shock avoidance/escape (0.18-0.26 mA). After training, we expressed the dopamine sensor GRAB-DA2m and implanted optic fibers into NAc core. We measured dopamine activity during sessions with either one- or three-reinforcers. During social self-administration, dopamine activity showed phasic increases following lever insertion and gradual increases preceding lever-pressing; responses were moderately greater during sessions with all three reinforcers. Palatable food self-administration showed a similar pattern, but responses were approximately twofold greater during single-reinforcer sessions. During shock avoidance/escape, dopamine activity showed phasic decreases at warning onset, lever insertion, and shock onset; responses were also greater during single-reinforcer sessions. Results suggest that NAc core dopamine signaling distinguishes positive from negative reinforcement and is modulated by reinforcer availability. Compared with single-reinforcer sessions, dopamine responses during food self-administration and shock avoidance/escape were reduced during sessions with all three reinforcers, whereas responses during social self-administration modestly increased. Significance statementNucleus accumbens (NAc) dopamine is critical for processing the valence of positive reinforcers, whereas its role in negative reinforcement is less well understood. Here, we extended our prior work on operant social self-administration to determine whether these findings generalize to food reinforcement, show the opposite pattern during operant negative reinforcement (shock avoidance/escape), and depend on whether reinforcers are experienced alone or together. Results suggest that NAc core dopamine activity differentiates positive and negative reinforcement and is modulated by the presence of other available reinforcers. Specifically, dopamine responses during food self-administration and shock avoidance/escape were reduced when all three reinforcers were available together compared with when each reinforcer was experienced alone, whereas responses during social self-administration showed the opposite pattern.

Long-term memory has been extensively documented in many animals across a range of ecological contexts. Far less is understood, however, about how long memories persist after active modification or how conflicting memories are adaptively regulated to enable flexible behaviour. Parrots are widely recognized for their high intelligence and cognitive capability, yet the study of memory has focused on only a handful of large parrot species. Here, using a binary choice symbolic system, we conducted three experiments on 28 rosy-faced lovebirds (Agapornis roseicollis) to investigate (1) memory retention of initial associative learning at intervals of two weeks, half a year, and one year; (2) reversal learning, where the rewarded and unrewarded symbols were swapped; and (3) memory retention, following reversal learning at two-week and half-year intervals. We revealed that (a) initial associative learning memory was strikingly persistent, remaining detectable after nearly 600 days; (b) reversal learning performance was comparable to that of large parrot species; and (c) while the post-reversal forgetting curve mirrored the pattern of initial learning, it exhibited a shorter retention duration and a lower retention plateau. These findings suggest that forgetting may serve as an adaptive mechanism that regulates the retrievability of conflicting information, rather than a simple erasure of memory traces. When the environment changes, the retrievability of previously functional but now maladaptive memories is suppressed, but their long-term storage is preserved for potential future use under analogous circumstances. Such dynamic regulations prevent the repetitive overwriting of information in a fluctuating environment, thereby fostering greater behavioural flexibility across dynamic scenarios.

Despite the well-established health benefits of exercise, adherence to physical activity remains low, highlighting the need to identify biological factors that regulate the initiation and persistence of exercise behavior. Here, we tested whether ovarian hormone state at the onset of voluntary wheel running (VWR) influences both immediate and long-term exercise behavior in female rats. Females that initiated VWR during proestrus (Pro) ran farther, spent more time running, and ran at higher speeds on the first day of wheel access than females initiating VWR outside of Pro. Remarkably, initiating VWR during Pro also produced persistent increases in running distance, duration, speed, and escalation across subsequent weeks, despite normal cycling through other estrous phases. In contrast, exogenous estradiol (E2) administered at VWR initiation did not alter day-1 behavior, but increased running distance and duration across subsequent weeks without affecting running speed or escalation. To determine whether dorsal striatal dopamine contributes to these effects, we inhibited the substantia nigra (SN) to dorsolateral striatum (DLS) pathway on the first day of VWR. This manipulation reduced the immediate and long-term effects of initiating VWR during Pro on running duration and distance but not speed or escalation. These findings identify behavioral initiation as a critical window during which hormones and nigrostriatal signaling influence future engagement in physical activity. Furthermore, analysis of individual components of VWR architecture reveals that distinct features of VWR behavior can be dissociated mechanistically and thus could be used to investigate separate motivational processes underlying physical activity.

Ventral tegmental area neurons participate in reward learning, motivation, and movement but also have an emerging role in the regulation of aversive behaviors. While these diverse contributions have been attributed to distinct projections of ventral tegmental area neurons, it remains unresolved how these neurons inherit their array of behavioral functions. The ventral tegmental area is rich with acetylcholine receptors and receives dense cholinergic input from the mesopontine tegmentum. While it is known that acetylcholine release in the ventral tegmental area can increase dopamine output we lack an understanding of the scenarios which necessitate ventral tegmental area acetylcholine release. We sought to provide a comprehensive overview of the participation of ventral tegmental area acetylcholine signaling across valence to motivated behavior. Rats were trained on a diverse array of tasks that allowed for the isolation of the contribution of acetylcholine release in the ventral tegmental area to cue- and context-driven behavior. We used intracranial pharmacology to determine the receptor mechanisms that contribute to acetylcholines effects. Ultimately, we found that acetylcholine release in the ventral tegmental area is necessary for appetitive and aversive states to become motivationally relevant and spur reward-seeking and threat-avoidance. We propose that this state-dependent contribution allows ventral tegmental area acetylcholine to act as a motivational gate for behavior across valence. This work expands our view of the interaction between neuromodulatory systems in the brain and opens new directions to the understanding of ventral tegmental area neurons in health and disease.

Social isolation has profound effects on behavior and cognition, but these effects can differ across sex and behavioral domains. We asked how social isolation shapes foraging decisions in male and female rats using a patch-leaving task that combines spatial navigation with sequential stay-or-go choices across varying travel costs and reward depletion rates. All groups scaled patch residence times with travel cost in a manner consistent with the marginal value theorem yet consistently overstayed beyond the optimal leaving time. The magnitude of overstaying was shaped by a strong interaction between sex and social status, with socially isolated females leaving patches closest to optimal and consuming food at the highest rate. Their foraging was accompanied by a coherent spatial and behavioral profile where the socially isolated females spent more time idle, preferentially occupying protected regions near the door and corridor, and avoiding the exposed patch center during both active foraging and periods of idling. These patterns are consistent with a conservative, safety-oriented strategy that simultaneously minimizes exposure and maximizes caloric return. Social isolation does not uniformly impair cognition but can selectively bias female rats toward efficiency-maximizing foraging decisions, consistent with the ecological pressures faced by outcast females in wild rat colonies.

Cigarette smoking remains one of the most important preventable causes of premature death worldwide. However, the mechanisms sustaining nicotine dependence and relapse are incompletely understood, particularly the role of impulsive action in persistent tobacco use. Dopamine D1 and nicotinic acetylcholine receptors both regulate nicotine-related behavior, but whether they contribute differently to nicotine-motivated responding and nicotine-induced impulsive action is unclear. The present study examined the effects of D1 receptor blockade and stimulation in male and female rats trained to self-administer nicotine intravenously in a Go/No- Go task. Nicotine was available during Go periods but not during No-Go periods, and impulsive action was measured as the percentage of active lever responses during No-Go periods. The D1 receptor antagonist SCH23390 reduced nicotine intake and active lever responding during Go periods and affected the percentage of active lever responses during No-Go periods. However, SCH23390 also reduced inactive lever responding, so its effect on impulsive action could not be separated from a general reduction in operant output. In contrast, the D1 receptor agonist A77636 reduced nicotine intake and Go-period responding without affecting No-Go responding, indicating that D1 receptor stimulation reduced nicotine-motivated responding without altering impulsive action. Rats showed greater No-Go responding during nicotine self-administration than during saline self-administration, indicating that nicotine increased impulsive action rather than general operant responding. The non-selective nicotinic antagonist mecamylamine reduced nicotine-motivated responding and decreased No-Go responding, indicating reduced impulsive action. These findings suggest that nicotinic acetylcholine receptor signaling plays a major role in nicotine-induced impulsive action, whereas D1 receptor signaling contributes more clearly to nicotine-motivated responding. D1 receptor agonism may reduce nicotine-motivated behavior without affecting nicotine-induced impulsive action.

BackgroundSex differences in psychostimulant-related behaviors are often attributed to biological sex; however, individual variability may also strongly influence behavioral outcomes. The new MISSING (Mapping Intrinsic Sex Similarities as an Integral quality of Normalized Groups) model identifies mixed-sex behavioral groups in which differences are driven primarily by individual variability rather than sex. The goal of this study was to validate the MISSING model for psychostimulant/sucrose self-administration. MethodsLong Evans rats self-administered methamphetamine (METH, male n = 25, female n = 32, 0.1 mg/kg/infusion, FR1, 6h per day for 20 days), sucrose (male n = 20, female n = 22, one-20 mg pellet/delivery, all other conditions being equal) and saline (male n = 3, female n = 10, other things being equal). We developed a new Quantitative Structure of Curve Analytical (QSCAn) model (using exponential-plateau and linear fit) for the assessment of individual drug self-administration time curve profiles irrespective of biological sex. We analyzed our data using regression analysis and ANOVA. ResultsQSCAn identified three distinct self-administration profiles (consisting of both sexes), which we named exponential-plateau negative (EP-), exponential-plateau positive (EP+), and undefined (EP0). There were no differences in self-administration profiles when we compared males and females within the same group. Differences between sexes (when observed) were due to mismatched comparisons (males from one group versus females from a different group). ConclusionsOur study reinforces the MISSING model for psychostimulant and sucrose self-administration by indicating that differences between males and females (when observed) may not necessarily be driven by biological sex. Significance StatementCurrent approaches often interpret variability in psychostimulant self-administration between males and females primarily through the lens of biological sex. However, this framework may overlook meaningful behavioral phenotypes shared across sexes. The present quantitative model suggests that individual patterns of behavior may better account for variability than sex alone, particularly in behaviors not strongly driven by sex-hormone-dependent mechanisms such as drug self-administration. By classifying animals according to behavioral profiles rather than biological sex, this approach may foster the identification of clinically and biologically relevant phenotypes underlying psychostimulant reinforcement.

It is becoming increasingly clear that chronic exposure to lower levels of ethanol impact learning and behavior. To determine the impact of chronic low-dose ethanol exposure on sensitivity to changes in stimulus value, a conditioned taste aversion procedure was used. Adult male and female mice underwent a sucrose two bottle-choice drinking paradigm. Each day, mice received an injection of either low-dose ethanol (0.5g/kg) or saline two hours after sucrose access for 20 days. This was followed by a lithium chloride (LiCl)-induced conditioned taste aversion (CTA) paradigm in which 0.15M LiCl or vehicle injection was administered immediately after sucrose consumption for three days. On the fourth day, changes in sucrose consumption were analyzed. Chronic exposure to low-dose ethanol did not affect sucrose consumption in either female of male mice during two-bottle choice. In female mice, a history of chronic low-dose ethanol exposure blocked the development of LiCl-induced CTA. A history of chronic low-dose ethanol did not impact LiCl-induced CTA in male mice as both ethanol-naive and -exposed male mice who underwent LiCl pairing reduced sucrose consumption. This suggests that low-dose ethanol alters aversion-related learning in female mice which may have implication for development of aberrant behavior and risk for alcohol use disorder (AUD).