Conditioned taste aversion (CTA) is a robust associative learning; liquid deprivation during this conditioning allows researchers to obtain readable measures of associative learning. Recent research suggests that thirst could be a crucial motivator that modulates conditioning and memory extinction processes, highlighting the importance of the body\'s internal state during learning. Furthermore, the histaminergic system is one of the major modulatory systems controlling several behavioral and neurobiological functions, such as feeding, water intake, and nociception. Therefore, this research aimed to assess the effect of H3 histaminergic receptor activation in the insular cortex (IC) during CTA. For this, we conditioned adult male Wistar rats under two regimens: water deprivation and water ad libitum. A classical CTA protocol was used for water deprivation. Before CTA acquisition, 10 μM R-α-methylhistamine (RAMH), an H3 receptor agonist, was injected into the IC. Results showed that RAMH injections decreased CTA in water-deprived rats without affecting the significant aversion conditioning in rats that were given water ad libitum. Moreover, RAMH accelerated the process of aversive memory extinction under ad libitum water conditions. According to our findings, the degree of liquid satiety differentially affected taste-aversive memory formation, and H3 histamine receptors were more involved under water deprivation conditions during acquisition. However, these receptors modulated the strength of aversive conditioning by altering the rate of aversive memory extinction in the absence of deprivation. In conclusion, histaminergic activity in the IC may influence taste memory dynamics through different mechanisms depending on the degree of liquid satiety or deprivation during conditioning.

BACKGROUND: Sensitivity to the adverse post-ingestive effects of ethanol likely serves as a deterrent to initiate alcohol consumption early in drinking and later may contribute to efforts to remain abstinent. Administering ethanol to naïve rats prior to Pavlovian conditioning procedures elicits robust ethanol-conditioned taste and place avoidance (CTA; CPA) mediated by its subjective interoceptive properties. The insular cortex (IC) has been implicated as a region involved in mediating sensitivity to the interoceptive properties of ethanol. Here, we examined whether bilateral lesions of the IC affect the acquisition and expression of taste and place avoidance in ethanol-induced CTA and CPA paradigms.
METHODS: Adult male and female Wistar rats received bilateral excitotoxic lesions (ibotenic acid; 20 mg/mL; 0.3 μL) of the IC prior to conditioning procedures. Subsequently, rats were conditioned to associate a novel taste stimulus (0.1% saccharin) and context with the effects of ethanol (1.0 g/kg) in a combined CTA/CPP procedure. Conditioning occurred over 8 alternating CS+/CS- days, followed by tests for expression of taste and place preferences. Data from IC-lesioned rats were compared with neurologically intact rats.
RESULTS: Our findings revealed that neurologically intact rats showed a significantly stronger ethanol-induced CTA than IC-lesioned rats. There were no significant differences in total fluid intake when rats consumed water (CS-). As with CTA effects, intact rats showed a strong CPA, marked by a greater reduction in time spent on the drug-paired context, while IC-lesioned rats failed to display CPA to ethanol.
CONCLUSIONS: These results indicate that proper IC functioning is necessary for responding to the adverse interoceptive properties of ethanol regardless of which Pavlovian paradigm is used to assess interoceptive responsivity to ethanol. Blunted IC functioning from chronic ethanol use may reduce interoceptive signaling specifically of ethanol\'s adverse effects thus contributing to increased alcohol use.

Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse activity in dopamine axons responsive to both reward and aversive stimuli. Some axons exhibited a preference for reward, while others favored aversive stimuli, and there was a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day.

Dopamine (DA) is a key regulator of associative learning and memory in both vertebrates and invertebrates, and it is widely believed that DA plays a key role in aversive conditioning in invertebrates. However, the idea that DA is involved only in aversive conditioning has been challenged in recent studies on the fruit fly (Drosophila melanogaster), ants and crabs, suggesting diverse functions of DA modulation on associative plasticity. Here, we present the results of DA modulation in aversive olfactory conditioning with DEET punishment and appetitive olfactory conditioning with sucrose reward in the oriental fruit fly, Bactrocera dorsalis. Injection of DA receptor antagonist fluphenazine or chlorpromazine into these flies led to impaired aversive learning, but had no effect on the appetitive learning. DA receptor antagonists impaired both aversive and appetitive long-term memory retention. Interestingly, the impairment on appetitive memory was rescued not only by DA but also by octopamine (OA). Blocking the OA receptors also impaired the appetitive memory retention, but this impairment could only be rescued by OA, not by DA. Thus, we conclude that in B. dorsalis, OA and DA pathways mediate independently the appetitive and aversive learning, respectively. These two pathways, however, are organized in series in mediating appetitive memory retrieval with DA pathway being at upstream. Thus, OA and DA play dual roles in associative learning and memory retrieval, but their pathways are organized differently in these two cognitive processes - parallel organization for learning acquisition and serial organization for memory retrieval.

It is unclear if protective childhood experiences (PCEs), like emotional support and economic stability, exert influence on adulthood adjustment. Prior research suggests PCEs can promote childhood resilience through increased social connection. In contrast, research has demonstrated potential life-long negative impacts of adverse childhood experiences (ACEs) on psychological health. This study examined the role of PCEs and ACEs in psychological symptoms following potentially traumatic events (PTE) in adults.
Participants (N = 128) were adults admitted to two Level 1 Trauma Centers following violence, motor-vehicle crashes, or other accidents. Participants reported childhood experiences and completed assessments of depression, PTSD, and social support at one, four, and nine months post-PTE.
Structural Equation Modeling was used to simultaneously model PCEs and ACEs as predictors of psychological symptoms over time, with potential mediation through social support. PCEs overall did not directly affect psychological symptoms nor indirectly through social support. However, the emotional support component of PCEs had an indirect effect on psychological symptoms at baseline through social support. ACEs predicted greater psychological symptoms at baseline and over time.
PCEs consisting of childhood emotional support indirectly promote adjustment in adults after PTEs through initial social support, while ACEs exert direct effects on psychological symptoms.

Pesticide exposure has been cited as a key threat to insect pollinators. Notably, a diverse range of potential sublethal effects have been reported in bee species, with a particular focus on effects due to exposure to neonicotinoid insecticides. Here, a purpose-built thermal-visual arena was used in a series of pilot experiments to assess the potential impact of approximate sublethal concentrations of the next generation sulfoximine insecticide sulfoxaflor (5 and 50 ppb) and the neonicotinoid insecticides thiacloprid (500 ppb) and thiamethoxam (10 ppb), on the walking trajectory, navigation and learning abilities of the buff-tailed bumblebee (Bombus terrestris audax) when subjected to an aversive conditioning task. The results suggest that only thiamethoxam prevents forager bees from improving in key training parameters (speed and distanced travelled) within the thermal visual arena. Power law analyses further revealed that a speed-curvature power law, previously reported as being present in the walking trajectories of bumblebees, is potentially disrupted under thiamethoxam (10 ppb) exposure, but not under sulfoxaflor or thiacloprid exposure. The pilot assay described provides a novel tool with which to identify subtle sublethal pesticide impacts, and their potential causes, on forager bees, that current ecotoxicological tests are not designed to assess.

Thirst is an essential motivational component that could modulate the strength of conditioning; pioneer studies show that the rats\' sexual dimorphism observed in the rate of aversive memory extinction of conditioned taste aversion (CTA) is affected by the state of fluid deprivation. On the other hand, previous evidence suggests that fluid intake volume and temporal context before and during conditioning may influence CTA. Furthermore, although CTA has been demonstrated using various types of stimuli, neural processing and homeostatic regulation of water and nutritional balance may differ depending on the stimulus used and the conditioning stages. Therefore, this study explored the effects of state motivated by thirst and satiation, using saccharin, as a non-caloric sweet stimulus, during CTA and the aversive memory extinction process under similar contextual and temporal conditions. First, we implemented an ad libitum water protocol in male and female adult rats to evaluate saccharin aversive memory formation; we compared this with a traditional CTA with liquid deprivation in the same context and temporal consumption conditions. Furthermore, we evaluated whether liquid satiety affects the acquisition or the aversive memory retrieval differentially. Our results show that the ad libitum liquid regimen allows reliable quantifications of basal water consumption, monitored every hour for more than five days. We observed a reliable CTA, where the magnitude of aversive memory and its extinction is significantly higher in both male and female rats; the strong CTA observed is substantially due to the satiety state during taste aversion memory retrieval. Our data show that although liquid deprivation does not affect CTA acquisition, it does induce weakness in the magnitude of aversive retrieval expression and fast aversive memory extinction, similarly in male and females. Overall, the results indicate that the need to satiate the demand for liquids during retrieval prevails over the conditioned aversion learned, suggesting, that thirst is a source of temporary variables dominating the aversive responses during CTA retrieval.

Learned behavior can be suppressed by the extinction procedure. Such extinguished memory often returns spontaneously over time, making it difficult to treat diseases such as addiction. However, the biological mechanisms underlying such spontaneous recovery remain unclear. Here, we report that the extinguished reward memory in Drosophila recovers spontaneously because extinction training forms an aversive memory that can be actively forgotten via the Rac1/Dia pathway. Manipulating Rac1 activity does not affect sugar-reward memory and its immediate extinction effect but bidirectionally regulates spontaneous recovery-the decay process of extinction. Experiments using thermogenetic inhibition and functional imaging support that such extinction appears to be coded as an aversive experience. Genetic and pharmacological inhibition of formin Dia, a downstream effector of Rac1, specifically prevents spontaneous recovery after extinction in both behavioral performance and corresponding physiological traces. Together, our data suggest that spontaneous recovery is caused by active forgetting of the opposing extinction memory.

In 2014, we participated in a special issue of Frontiers examining the neural processing of appetitive and aversive events. Specifically, we reviewed brain areas that contribute to the encoding of prediction errors and value versus salience, attention and motivation. Further, we described how we disambiguated these cognitive processes and their neural substrates by using paradigms that incorporate both appetitive and aversive stimuli. We described a circuit in which the orbitofrontal cortex (OFC) signals expected value and the basolateral amygdala (BLA) encodes the salience and valence of both appetitive and aversive events. This information is integrated by the nucleus accumbens (NAc) and dopaminergic (DA) signaling in order to generate prediction and prediction error signals, which guide decision-making and learning via the dorsal striatum (DS). Lastly, the anterior cingulate cortex (ACC) is monitoring actions and outcomes, and signals the need to engage attentional control in order to optimize behavioral output. Here, we expand upon this framework, and review our recent work in which within-task manipulations of both appetitive and aversive stimuli allow us to uncover the neural processes that contribute to the detection of outcomes delivered to a conspecific and behaviors in social contexts. Specifically, we discuss the involvement of single-unit firing in the ACC and DA signals in the NAc during the processing of appetitive and aversive events in both social and non-social contexts.

Fear is an important emotion for survival, and the cerebellum has been found to contribute not only to innate affective and defensive behavior, but also to learned fear responses. Acquisition and retention of fear conditioned bradycardia and freezing have been shown to depend on the integrity of the cerebellar vermis in rodents. There is a considerable number of brain imaging studies, which observe activation of the human cerebellum in fear conditioning paradigms. Different to what one may expect based on the initial cerebellar lesion studies, activations related to the learned prediction of threat go well beyond the vermis, and are most prominent in the lateral cerebellum. Different parts of the cerebellum likely contribute to learning of autonomic, motor, emotional and cognitive responses involved in classical fear conditioning. The neural operation which is performed in the various parts of the cerebellum is frequently assumed to be the same. One hypothesis is that the cerebellum acts as, or is part of, a predictive device. More recent findings will be discussed that the cerebellum may not only be involved in the processing of sensory prediction errors, but also in the processing of reward and reward prediction errors, which may play a central role in emotions and emotional learning. Current knowledge about the intrinsic learning mechanisms underlying fear memory in the cerebellum, and its connections with subcortical and cortical fear circuitry will be presented. The chapter will conclude with a discussion on how disordered cerebellar fear learning may contribute to affective disorders.