Avoiding actions with negative consequences is fundamental to adaptive behavior. Traditional theories suggest GABAergic inhibition of midbrain dopamine neurons, including those within ventral tegmental area (VTADA), mediate suppression of actions that lead to aversive outcomes. However, the role of dopamine inhibition in punishment learning remains unclear. To examine this, we conducted fiber photometry, pharmacological, and chemogenetic experiments in rats to measure VTADA activity and GABA input across punishment learning, and test their causal contribution to behavior. VTADA activity and GABA input phasically increased to response-elicited outcomes, with VTADA activity being more strongly activated by rewards, while GABA input being more strongly activated by shock punishers during initial punishment. Pharmacologically blocking GABAA receptors in VTA or chemogenetically activating VTADA neurons during initial, but not later, punishment sessions produced enduring deficits in punishment avoidance. These findings suggest long-term avoidance depends upon a critical window of GABA-mediated VTADA inhibition during punishment learning.

We previously identified the roles of the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) in sensory preconditioning in male and female rats (Wong et al., 2025). Here, we used variations of a sensory preconditioning protocol to test a general theory that the BLA and PRh represent focal and peripheral states of attention, respectively. We specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N-methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus, as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required NMDAR-activation in the BLA and not the PRh, regardless of whether the stimulus and shock were presented contiguously or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required NMDAR-activation in the BLA and not the PRh. However, when a pre-exposed stimulus was indirectly paired with shock – because it was associatively activated at the time of shock or separated from the shock by another stimulus – its conditioning required NMDAR-activation in the PRh and not the BLA. These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.

Value-modulated attentional capture (VMAC) refers to the tendency for highly valued cues to capture attention even when counterproductive to an individual's goals. VMAC is thought to measure incentive salience and has been shown to correlate with multiple measures of compulsivity. The current study demonstrates the first successful back-translation of VMAC to rodents. To achieve this, mice (Experiment 1) or rats (Experiment 2) were trained to sign-track to a high-value lever signaling three pellets and a low-value lever signaling one pellet, which would later serve as distractors. Rodents were next trained to nose-poke an illuminated port for a pellet, which would serve as the "target" response. The key VMAC test phase compared nose-poke performance in the presence of high- versus low-value lever distractors. Rodents made significantly more omissions in the presence of the high- than the low-value lever distractor despite losing three times as many pellets on these trials. This replicates findings from human VMAC tasks, in which participants are consistently impaired on high-value relative to low-value distractor trials despite greater reward loss. In Experiment 2, we showed that this effect persisted despite devaluation of the pellet outcome by conditioned taste aversion, even when the disliked outcome was presented, suggesting a compulsion-like mechanism. Together, these data show that VMAC can be observed in both mice and rats, which opens new avenues for investigation of its behavioral and neural underpinnings, with implications for understanding and treating compulsive disorders. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Wong et al., 2019 used a sensory preconditioning protocol to examine how sensory and fear memories are integrated in the rat medial temporal lobe. In this protocol, rats integrate a sound-light (sensory) memory that forms in stage 1 with a light-shock (fear) memory that forms in stage 2 to generate fear responses (freezing) across test presentations of the sound in stage 3. Here, we advance this research by showing that (1) how/when rats integrate the sound-light and light-shock memories (online in stage 2 or at test in stage 3) changes with the number of sound-light pairings in stage 1; and (2) regardless of how/when it occurs, the integration requires communication between two regions of the medial temporal lobe: the perirhinal cortex and basolateral amygdala complex. Thus, ‘event familiarity’ determines how/when sensory and fear memories are integrated but not the circuitry by which the integration occurs: this remains the same.

Abstract Wong et al. (2019) used a sensory preconditioning protocol to examine how sensory and fear memories are integrated in the rat medial temporal lobe. In this protocol, rats integrate a sound-light (sensory) memory that forms in stage 1 with a light-shock (fear) memory that forms in stage 2 to generate fear responses (freezing) across test presentations of the sound in stage 3. Here, we advance this research by showing that: 1) how/when rats integrate the sound-light and light-shock memories (online in stage 2 or at test in stage 3) changes with the number of sound-light pairings in stage 1; and 2) regardless of how/when it occurs, the integration requires communication between two regions of the medial temporal lobe: the perirhinal cortex and basolateral amygdala complex. Thus, “event familiarity” determines how/when sensory and fear memories are integrated but not the circuitry by which the integration occurs: this remains the same.

Dopamine dysregulation contributes to psychosis and cognitive deficits in schizophrenia that can be modelled in rodents by inducing maternal immune activation (MIA). The selective estrogen receptor (ER) modulator, raloxifene, can improve psychosis and cognition in men and women with schizophrenia. However, few studies have examined how raloxifene may exert its therapeutic effects in mammalian brain in both sexes during young adulthood (age relevant to most prevalent age at diagnosis). Here, we tested the extent to which raloxifene alters dopamine-related behaviours and brain transcripts in young adult rats, both control and MIA-exposed females and males. We found that raloxifene increased amphetamine (AMPH)-induced locomotor activity in female controls, and in contrast, raloxifene reduced AMPH-induced locomotor activity in male MIA offspring. We did not detect overt prepulse inhibition (PPI) deficits in female or male MIA offspring, yet raloxifene enhanced PPI in male MIA offspring. Whereas, raloxifene ameliorated increased startle responsivity in female MIA offspring. In the substantia nigra (SN), we found reduced Drd2s mRNA in raloxifene-treated female offspring with or without MIA, and increased Comt mRNA in placebo-treated male MIA offspring relative to placebo-treated controls. These data demonstrate an underlying dopamine dysregulation in MIA animals that can become more apparent with raloxifene treatment, and may involve selective alterations in dopamine receptor levels and dopamine breakdown processes in the SN. Our findings support sex-specific, differential behavioural responses to ER modulation in MIA compared to control offspring, with beneficial effects of raloxifene treatment on dopamine-related behaviours relevant to schizophrenia found in male MIA offspring only.

Value-modulated attentional capture (VMAC) refers to the tendency for highly valued cues to capture attention even when counterproductive to an individual’s goals. VMAC is thought to measure incentive salience and has been shown to correlate with multiple measures of compulsivity. The current study demonstrates the first successful back-translation of VMAC to rodents. To achieve this, mice (Experiment 1) or rats (Experiment 2) were trained to sign-track to a high value lever signalling 3 pellets and a low value lever signalling 1 pellet, that would later serve as distractors. Rodents were next trained to nose-poke an illuminated port for a pellet, which would serve as the ‘target’ response. The key VMAC test phase compared nose-poke performance in the presence of high versus low value lever distractors. Rodents made significantly more omissions in the presence of the high than the low value lever distractor, despite losing 3 times as many pellets on these trials. This replicates findings from human VMAC tasks, in which participants are consistently impaired on high value relative to low value distractor trials despite greater reward loss. In Experiment 2, we showed that this effect persisted despite devaluation of the pellet outcome by conditioned taste aversion, even when the disliked outcome was presented, suggesting a compulsion-like mechanism. Together, these data show that VMAC can be observed in both mice and rats, which opens new avenues for investigation of its behavioural and neural underpinnings, with implications for understanding and treating compulsive disorders.

How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs.

This study examined the effect of danger on consolidation of neutral information in two regions of the rat (male and female) medial temporal lobe: the perirhinal cortex (PRh) and basolateral amygdala complex (BLA). The neutral information was the association that forms between an auditory stimulus and a visual stimulus (labeled S2 and S1) across their pairings in sensory preconditioning. We show that, when the sensory preconditioning session is followed by a shocked context exposure, the danger shifts consolidation of the S2-S1 association from the PRh to the BLA; and does so by interacting with processes involved in encoding of the S2-S1 pairings. Specifically, we show that the initial S2-S1 pairing in sensory preconditioning is encoded in the BLA and not the PRh; whereas the later S2-S1 pairings are encoded in the PRh and not the BLA. When the sensory preconditioning session is followed by a context alone exposure, the BLA-dependent trace of the early S2-S1 pairings decays and the PRh-dependent trace of the later S2-S1 pairings is consolidated in memory. However, when the sensory preconditioning session is followed by a shocked context exposure, the PRh-dependent trace of the later S2-S1 pairings is suppressed and the BLA-dependent trace of the initial S2-S1 pairing is consolidated in memory. These findings are discussed with respect to mutually inhibitory interactions between the PRh and BLA, and the way that these regions support memory in other protocols, including recognition memory in people.SIGNIFICANCE STATEMENT The perirhinal cortex (PRh) and basolateral amygdala complex (BLA) process the pairings of neutral auditory and visual stimuli in sensory preconditioning. The involvement of each region in this processing is determined by the novelty/familiarity of the stimuli as well as events that occur immediately after the preconditioning session. Novel stimuli are represented in the BLA; however, as these stimuli are repeatedly presented without consequence, they come to be represented in the PRh. Whether the BLA- or PRh-dependent representation is consolidated in memory depends on what happens next. When nothing of significance occurs, the PRh-dependent representation is consolidated and the BLA-dependent representation decays; but when danger is encountered, the PRh-dependent representation is inhibited and the BLA-dependent representation is selected for consolidation.

Ambiguous relationships between events may be established using interference procedures such as latent inhibition, extinction or counterconditioning. Under these conditions, the retrieval of individual associations between a stimulus and outcome is affected by contextual cues. To examine the roles of the dorsal (prelimbic) and ventral (infralimbic) medial prefrontal cortex in the contextual modulation of such associations, we investigated the context specificity of latent inhibition. Male Lister hooded rats were pre-exposed to two separate stimuli, one in each of two distinct contexts. Both stimuli were then paired with the delivery of mild foot-shock in the same one of these contexts. Finally, the strength of the resultant conditioned emotional response (CER) to each stimulus was assessed in each context. For the sham-operated control rats, the CER was attenuated for each stimulus when it was tested in the context in which it had been pre-exposed. Rats who had received lesions to the infralimbic cortex showed this effect only in the conditioning context, whereas rats with lesions to the prelimbic cortex showed the effect only in the context in which conditioning had not taken place. These findings indicate that infralimbic and prelimbic cortices play distinct, and competing, roles in the contextual modulation of initial and later learning.

Orbitofrontal cortex (OFC) lesions cause deficits in flexible behavioural control, most notably response inhibition and has historically been linked to theories of response inhibition. This general inhibition hypothesis of OFC function has since been rejected by evidence that inhibitory behavioural control can be expressed following OFC damage, however the functional role of the OFC in the explicit learning of conditioned inhibition remains untested. Here we test whether muscimol disruption of OFC function during the learning stage of a Pavlovian conditioned inhibition procedure disrupted the learning of conditioned inhibitory associations. Muscimol abolished Inhibitory behavioural control during the learning phase, however learning about the conditioned inhibitor was intact when tested drug free in subsequent summation and retardation tests of conditioned inhibition. Muscimol also significantly impaired acquisition to control cues whose cue-outcome relationship did not change. In a second experiment, conditioned inhibition was found not to play a significant role in cue extinction (non-reinforcement), an effect that was disrupted by intra-OFC infusion of muscimol. These results confirm that the OFC is not functionally necessary for the learning of inhibitory associations but is critical to both the enhancement and suppression of responding when environmental contingencies change.

Instrumental actions are initially goal-directed but with repeated performance can become habitual. Habitual actions are adaptive, learned behaviours that are automated in order to reduce cognitive load and to allow for efficient interaction with the environment. Goal-directed and habitual actions are mediated by distinct neurocircuits which centre on the dorsal striatum and involve different cortical and limbic inputs. The lateral hypothalamus (LH) has yet to be considered in this neurocircuitry despite its anatomical connections with these neurocircuits and its established role in motivated behaviour. The aim of the current study was to determine whether the LH has a role in the development of habitual actions in rats by knocking down protein expression in the LH with short hairpin RNAs (shRNA). Two shRNAs were utilised, both of which were shown to reduce the expression of two neuropeptides within the LH, orexin and melanin-concentrating hormone, compared to a saline-vehicle control. This was unexpected given that one shRNA was a control vector (i.e, scrambled sequence), and the other shRNA was supposed to selectively target orexin's precursor protein. Given this lack of specificity and that shRNA's are known to be neurotoxic, the current study examined the impact of non-selective dysfunction of the LH on habitual actions. Adult male Long-Evans rats were trained to press a lever for a food outcome and were tested for goal directed and habitual behaviour following devaluation of the food. The shRNA groups displayed goal-directed actions following moderate instrumental training, but did not develop habitual actions following extended training. That is, control rats developed the expected habitual behaviour where lever-response rates were insensitive to outcome value when tested, whilst the shRNA groups reduced rates of responding on the lever under devalued conditioned and hence remained goal-directed. This failure to demonstrate habitual actions was unlikely to be secondary to changes in motivation or arousal as the shRNA groups did not show altered food consumption, body weight, lever response rates, or motor performance on a rota rod or tapered balance beam. However, locomotor activity was reduced in an open field test, consistent with the proposed role of the LH in spontaneous locomotor activity. Therefore, this study implicates the LH in habitual learning, and adds to the emerging evidence that the LH has a role in associative learning processes. This finding has implications for human conditions where there is dysfunction or neurodegeneration in the LH, as well as altered habitual actions, such as in Parkinson's disease and drug addiction.

Reward predictive cues can selectively motivate instrumental behaviors that predict the same rewarding outcomes, an effect known as specific Pavlovian-to-instrumental transfer (PIT). This selective effect is thought to be mediated by a representation of the sensory specific properties of an outcome, that has become associated with both the Pavlovian cue and the instrumental response during initial learning. Specific satiety is a common method of outcome devaluation that reduces an outcome's value but might also lead to the habituation of the outcome's sensory properties. Previous research has demonstrated that specific PIT is insensitive to changes in specific outcome value following taste aversion devaluation, as well as general satiety manipulations, and therefore specific satiety should not disrupt specific PIT by reducing outcome value. The present rodent experiments used a specific satiety devaluation procedure immediately prior to a specific PIT test to show that habituation of these outcome specific sensory representations can disrupt its efficacy as a stimulus and abolish the specific PIT effect. Experiment 1 employed a two-lever choice test to show that a non-devalued stimulus supports specific PIT, whereas a devalued stimulus abolished the specific PIT effect. Experiment 2 replicated this procedure while controlling for response competition by using a single-lever test to confirm that a devalued stimulus abolishes the specific PIT effect. These findings demonstrate that specific satiety can disrupt the ability of an outcome specific representation to support specific PIT. Given previous findings that specific PIT is insensitive to changes in outcome value by general satiety and taste aversion devaluation, this suggests that specific satiety devaluation might disrupt the use of sensory specific outcome representations to guide behavior via a mechanism that is independent of the outcome's current value.

The orbitofrontal cortex (OFC) is a critical structure in the flexible control of value-based behaviours. OFC dysfunction is typically only detected when task or environmental contingencies change, against a backdrop of apparently intact initial acquisition and behaviour. While intact acquisition following OFC lesions in simple Pavlovian cue-outcome conditioning is often predicted by models of OFC function, this predicted null effect has not been thoroughly investigated. Here we test the effects of lesions and temporary muscimol inactivation of the rodent lateral OFC on the acquisition of a simple single cue-outcome relationship. Surprisingly, pre-training lesions significantly enhanced acquisition after over-training whereas post-training lesions and inactivation significantly impaired acquisition. This impaired acquisition to the cue reflects a disruption of behavioural control and not learning since the cue could also act as an effective blocking stimulus in an associative blocking procedure. These findings suggest that even simple cue-outcome representations acquired in the absence of OFC function are impoverished. Therefore, while OFC function is often associated with flexible behavioural control in complex environments, it is also involved in very simple Pavlovian acquisition where complex cue-outcome relationships are irrelevant to task performance.

Dopamine neurotransmission has been ascribed multiple functions with respect to both motivational and associative processes in reward-based learning, though these have proven difficult to tease apart. In order to better describe the role of dopamine in associative learning, this series of experiments examined the potential of dopamine D1- and D2-receptor antagonism (or combined antagonism) to influence the ability of rats to learn neutral valence stimulus-stimulus associations. Using a sensory preconditioning task, rats were first exposed to pairings of two neutral stimuli (S2-S1). Subsequently, S1 was paired with a mild foot-shock and resulting fear to both S1 (directly conditioned) and S2 (preconditioned) was examined. Initial experiments demonstrated the validity of the procedure in that measures of sensory preconditioning were shown to be contingent on pairings of the two sensory stimuli. Subsequent experiments indicated that systemic administration of dopamine D1- or D2-receptor antagonists attenuated learning when administered prior to S2-S1 pairings. However, the administration of a more generic D1R/D2R antagonist was without effect. These effects remained constant regardless of the affective valence of the conditioning environment and did not differ between male and female rats. The results are discussed in the context of recent suggestions that dopaminergic systems encode more than a simple reward prediction error, and provide potential avenues for future investigation.

Interpretations of the role of the infralimbic region of the medial prefrontal cortex in decision making in rats are based on a wide range of tasks, both appetitive and aversive, as well as Pavlovian and instrumental. These range in complexity from what appear to be simple procedures (such as extinction) through to more complicated tasks involving, for example, risk-based decision making and contextual biconditional discriminations. We derive from these tasks a common theme that may stimulate greater analysis of the nature of decision making tasks in order to better understand the function of prefrontal systems. One interpretation is that the infralimbic region may be important in the ability of rats to simultaneously hold competing associations with the same, single cue.

Our understanding of orbitofrontal cortex (OFC) function has progressed remarkably over the past decades in part due to theoretical advances in associative and reinforcement learning theories. These theoretical accounts of OFC function have implicated the region in progressively more psychologically refined processes from the value and sensory-specific properties of expected outcomes to the representation and inference over latent state representations in cognitive maps of task space. While these accounts have been successful at modeling many of the effects of causal manipulation of OFC function in both rodents and primates, recent findings suggest that further refinement of our current models are still required. Here, we briefly review how our understanding of OFC function has developed to understand two cardinal deficits following OFC dysfunction: Reversal learning and outcome devaluation. We then consider recent findings that OFC dysfunction also significantly affects initial acquisition learning, often assumed to be intact. To account for these findings, we consider a possible role for the OFC in the arbitration and exploration between model-free (MF) and model-based (MB) learning systems, offline updating of MB representations. While the function of the OFC as a whole is still likely to be integral to the formation and use of a cognitive map of task space, these refinements suggest a way in which distinct orbital subregions, such as the rodent lateral OFC, might contribute to this overall function. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsive disorders and related behaviors. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here, we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented rats from learning to avoid a lever that was punished with a stimulus that coterminated with footshock. Our second experiment demonstrated that retrieval of punishment learning is also somewhat mOFC-dependent, as lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent rats from reacquiring the ability to avoid a punished lever when it was learned prior to lesions being administered. In both experiments, Pavlovian fear conditioning to the stimulus was intact for all animals. Together, these results reveal that the mOFC regulates punishment learning and retrieval in a manner that is separate from any role in Pavlovian fear conditioning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.

Abstract Sufficient physical activity is crucial to maintaining independence, health and wellbeing during ageing, yet physical inactivity is common in older people. Identifying factors associated with physical activity engagement is essential to develop novel approaches to increase activity in older people. Automatic, context-dependent habits may play an important role in physical activity behaviour. The current study aimed to investigate the relationship between physical activity behaviours and their automaticity in older people. 123 community dwelling Australians aged over 65 – 88 years (M=72.2; 81 women), recruited from participant registries, hospital noticeboards and community groups, completed an online questionnaire. Current physical activity levels were measured using the Incidental and Planned Exercise Questionnaire, and automaticity of those physical activity behaviours were measured using the Self-Report Habit Automaticity Index. Participants also reported demographic information, body mass index (BMI), medical history and current mood symptoms. Participants reported an average of 2.28 hours planned walking (SD=2.33), 5.81 hours planned moderate/vigorous exercise (SD=4.02), and 20.5 hours incidental activity (SD=15.52) per week. Multiple regression analyses revealed that after controlling for age, gender, BMI and depression symptoms, higher automaticity scores were associated with more hours per week of planned walking (p=.012), moderate/vigorous exercise (p=.038), and incidental activity (p=.017). Supporting older people to make their physical activity more habitual could therefore be an effective approach to increase levels of physical activity in this population.