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RationaleAberrant approach-avoidance conflict processing may contribute to compulsive seeking that characterizes addiction. Exploration of the relationship between drugs of abuse and approach-avoidance behavior remains limited, especially with ethanol.ObjectivesTo investigate the effects of voluntary ethanol consumption on approach-avoidance conflict behavior and to examine the potential approach/avoidance bias to predict drinking in male and female rats.MethodsLong-Evans rats consumed ethanol for 5 weeks under the intermittent access two-bottle choice (IA2BC) paradigm. Approach-avoidance tendencies were assessed before and after IA2BC drinking using a previously established cued approach-avoidance conflict maze task and the elevated plus maze (EPM).ResultsFemale rats displayed higher consumption of and preference for ethanol than males. In the conflict task, males showed greater approach bias towards cues predicting conflict than females. In females only, a median split and regression analysis of cued-conflict preference scores revealed that the more conflict-avoidant group displayed higher intake and preference for ethanol in the first few weeks of drinking. In both sexes, ethanol drinking did not affect cued-conflict preference, but ethanol exposure led to increased time spent in the central hub in the males only. Finally, anxiety levels in EPM predicted subsequent onset of ethanol drinking in males only.ConclusionsOur results highlight sex and individual differences in both drinking and approach-avoidance bias in the face of cued conflict and further suggest that cued-conflict preference should be examined as a potential predictor of ethanol drinking. Ethanol exposure may also affect the timing of decision-making in the face of conflict.

Recent research has identified sex-dependent links between risk taking behaviors, approach-avoidance bias and alcohol intake. However, preclinical studies have typically assessed alcohol drinking using a singular dimension of intake (i.e. drinking level), failing to capture the multidimensional pattern of aberrant alcohol-seeking observed in alcohol use disorder. In this study, we sought to further explore individual and sex differences in the relationship between approach-avoidance bias, frontloading (bingeing and onset skew) and multiple addiction-like indices of ethanol seeking that included motivation for ethanol, persistence despite its absence (extinction), and ethanol-taking in the face of mild footshock. We found that female rats displayed more addiction-like phenotypes than males overall, and that frontloading patterns differed by sex, with females outdrinking males in the early part of access sessions (bingeing), but males strongly concentrating their lever pressing for ethanol in that period (onset skew). Multiple regression analyses revealed that bingeing was a strong positive predictor and onset skew a negative predictor of motivational breakpoint. Cued-conflict preference – a measure of approach-avoidance bias towards a mixed-valence conflict cue – was predictive of both extinction and footshock in males, but not females. Our data highlight key sex differences, and the relevance of both frontloading patterns and conflict preference in predicting future addiction-like phenotypes.

Successful resolution of approach-avoidance conflict (AAC) is fundamentally important for survival, and its dysregulation is a hallmark of many neuropsychiatric disorders, and yet the underlying neural circuit mechanisms are not well elucidated. Converging human and animal research has implicated the anterior/ventral hippocampus (vHPC) as a key node in arbitrating AAC in a region-specific manner. In this study, we sought to target the vHPC CA1 projection pathway to the nucleus accumbens (NAc) to delineate its contribution to AAC decision-making, particularly in the arbitration of learned reward and punishment signals, as well as innate signals. To this end, we used pathway-specific chemogenetics in male and female Long Evans rats to inhibit the NAc shell projecting vHPC CA1 neurons while rats underwent a test in which cues of positive and negative valence were presented concurrently to elicit AAC. Additional behavioral assays of social preference and memory, reward and punishment cue processing, anxiety, and novelty processing were administered to further interrogate the conditions under which the vCA1-NAc shell pathway is recruited. Chemogenetic inhibition of the vCA1-NAc shell circuit resulted in animals exhibiting increased decision-making time and avoidance bias specifically in the face of motivational conflict, as the same behavioral phenotype was absent in separate conditioned cue preference and avoidance tests. vCA1-NAc shell inhibition also led to a reduction in seeking social interaction with a novel rat but did not alter anxiety-like behaviors. The vCA1-NAc shell circuit is therefore critically engaged in biasing decisions to approach in the face of social novelty and approach-avoidance conflict. Dysregulation of this circuit could lead to the precipitation of addictive behaviors in substance abuse, or maladaptive avoidance in situations of approach-avoidance conflict.

Neural models of approach-avoidance (AA) conflict behavior and its dysfunction have focused traditionally on the hippocampus, with the assumption that this medial temporal lobe (MTL) structure plays a ubiquitous role in arbitrating AA conflict. We challenge this perspective by using three different AA behavioral tasks in conjunction with optogenetics, to demonstrate that a neighboring region in male rats, perirhinal cortex, is also critically involved but only when conflicting motivational values are associated with objects and not contextual information. The ventral hippocampus, in contrast, was found not to be essential for object-associated AA conflict, suggesting its preferential involvement in context-associated conflict. We propose that stimulus type can impact MTL involvement during AA conflict and that a more nuanced understanding of MTL contributions to impaired AA behavior (e.g., anxiety) is required. These findings serve to expand upon the established functions of the perirhinal cortex while concurrently presenting innovative behavioral paradigms that permit the assessment of different facets of AA conflict behavior.

The ability to resolve an approach-avoidance conflict is critical to adaptive behavior. The ventral CA3 (vCA3) and CA1 (vCA1) subfields of the ventral hippocampus (vHPC) have been shown to facilitate avoidance and approach behavior, respectively, in the face of motivational conflict, but the neural circuits by which this subfield-specific regulation is implemented is unknown. We demonstrate that two distinct pathways from these subfields to lateral septum (LS) contribute to this divergent control. In Long-Evans rats, chemogenetic inhibition of the vCA3- LS caudodorsal (cd) pathway potentiated approach towards a learned conflict-eliciting stimulus, while inhibition of the vCA1-LS rostroventral (rv) pathway potentiated approach non-specifically. Additionally, vCA3-LScd inhibited animals were less hesitant to explore food during environmental uncertainty, while the vCA1- LSrv inhibited animals took longer to initiate food exploration. These findings suggest that the vHPC influences multiple behavioral systems via differential projections to the LS, which in turn send inhibitory projections to motivational centres of the brain. The ventral hippocampal CA3 and CA1 subfields play a critical role in the resolution of approach-avoidance conflict. Here the authors show that the subfields contribute to the regulation of this behavior through topographically distinct projections to the lateral septum.

The infralimbic (IL) and prelimbic (PL) cortices of the medial prefrontal cortex (mPFC) have been shown to differentially control context-dependent behavior, with the PL implicated in the expression of contextually conditioned fear and drug-seeking, and the IL in the suppression of these behaviors. However, the roles of these subregions in contextually driven natural reward-seeking remain relatively underexplored. The present study further examined the functional dichotomy within the mPFC in the contextual control over cued reward-seeking, using a contextual biconditional discrimination (CBD) task. Rats were first trained to emit a nose poke response to the presentation of an auditory stimulus (e.g., X) for the delivery of sucrose reward, and to withhold a nose poke response to the presentation of another auditory stimulus (e.g., Y) in a context-specific manner (e.g. Context A: X+, Y−; Context B: X−, Y+). Following acquisition, rats received bilateral microinjections of GABA receptor agonists (muscimol and baclofen), or saline into the IL or PL, prior to a CBD training session and a probe test (under extinction conditions). Both IL and PL inactivation resulted in robust impairment in CBD performance, indicating that both subregions are involved in the processing of appetitively motivated contextual memories in reward-seeking.

Rodent and human data implicate the hippocampus in the arbitration of approach-avoidance conflict (AAC), which arises when an organism is confronted with a stimulus associated simultaneously with reward and punishment. Yet, the precise contributions of this structure are underexplored, particularly with respect to the decision-making processes involved. We assessed humans with hippocampal damage and matched neurologically healthy controls on a computerized AAC paradigm in which participants first learned whether individual visual images were associated with the reward or loss of game points and were then asked to approach or avoid pairs of stimuli with non-conflicting or conflicting valences. To assess hippocampal involvement more broadly in response conflict, we also administered a Stroop and a Go/No-go task. On the AAC paradigm, following similar learning outcomes in individuals with hippocampal damage and matched controls, both participant groups approached positive and negative image pairs at the same rate but critically, those with hippocampal damage approached conflict pairs more often than controls. Choice and response AAC data were interrogated using the hierarchical drift diffusion model, which revealed that, compared to controls, individuals with hippocampal damage were more biased towards approach, required less evidence to make a decision during conflict trials, and were slower to accumulate evidence towards avoidance when confronted with conflicting image pairs. No significant differences were found between groups in performance accuracy or response time on the response conflict tasks. Taken together, these findings demonstrate the importance of the hippocampus to the evidence accumulation processes supporting value-based decision-making under motivational conflict.

Approach-avoidance conflict is induced when an organism encounters a stimulus that carries both positive and negative attributes. Accumulating evidence implicates the ventral hippocampus (VH) in the detection and resolution of approach-avoidance conflict, largely on the basis of maze-based tasks assaying innate and conditioned responses to situations of conflict. However, its role in discrete trial approach-avoidance decision-making has yet to be elucidated. In this study, we designed a novel cued operant conflict decision-making task in which rats were required to choose and respond for a low reward option or high reward option paired with varying shock intensities on a differential reinforcement of low rates of responding schedule. Post training, the VH was chemogenetically inhibited while animals performed the task with the usual outcomes delivered, and with the presentation of cues associated with the reward vs. conflict options only (extinction condition). We found that VH inhibition led to an avoidance of the conflict option and longer latency to choose this option when decision-making was being made on the basis of cues alone with no outcomes. Consistent with these findings, VH-inhibited animals spent more time in the central component of the elevated plus maze (EPM), indicating a potential deficit in decision-making under innate forms of approach-avoidance conflict. Taken together, these findings implicate the VH in cue-driven approach-avoidance decisions in the face of motivational conflict.

Nucleus accumbens (NAc) dopamine is widely implicated in mediating the reinforcing effects of drugs of abuse. However, the precise function of the NAc itself in drug self-administration has been difficult to establish. Here we show a neural double-dissociation of the behavioral processes that underlie cocaine self-administration in rats. Whereas selective excitotoxic lesions of the NAc core had only a minor effect on the acquisition of responding for cocaine under a standard schedule of continuous reinforcement, these lesions profoundly impaired the acquisition of drug-seeking behavior that was maintained by drug-associated conditioned reinforcers and assessed using a second-order schedule of cocaine reinforcement. In contrast, selective excitotoxic lesions of the NAc shell did not impair drug self-administration or the acquisition of cocaine-seeking, but they did attenuate the psychostimulant effects of cocaine. These results further our understanding of how the NAc controls drug-seeking and drug-taking behavior.

Drug addiction is a disorder in which drug seeking persists despite aversive consequences. While it is well documented in animal models of drug sensitization that repeated drug exposure enhances positive incentive motivation for drug and natural reinforcers, its effect on negative incentive motivation, defined here as the motivation to avoid a cued aversive outcome, remains an open question. In the present study, we designed a novel active avoidance (AA) runway paradigm to assess the effects of repeated cocaine exposure on the to avoid an aversive outcome. Cocaine and saline pre-exposed rats were first trained to perform a conditioned AA lever press response to prevent the occurrence of foot shock administrations. The rats were subsequently tested in a runway apparatus, wherein they were required to traverse the length of a straight alley maze to reach the lever and emit a conditioned AA response. Run times were measured as an indication of negative incentive motivation. Cocaine pre-exposed rats demonstrated longer latencies to emit the conditioned AA response but showed no differences in latency to initiate runway behavior, nor in their acquisition of the AA response compared to the saline pre-exposed controls. Subsequent testing in an elevated plus maze revealed no differences in the expression of anxiety in cocaine pre-exposed rats compared to saline pre-exposed controls. Our results indicate that prior repeated cocaine exposure attenuated cued negative incentive motivation, which suggests that drug addiction may be attributable to a decrease in motivation to avoid aversive consequences associated with drug use.