Reward and aversion encoding in the lateral habenula for innate and learned behaviours

Throughout life, individuals experience a vast array of positive and aversive events that trigger adaptive behavioural responses. These events are often unpredicted and engage actions that are likely anchored on innate behavioural programs expressed by each individual member of virtually all animal species. In a second step, environmental cues, that are initially neutral, acquire value through the association with external sensory stimuli, and become instrumental to predict upcoming positive or negative events. This process ultimately prompts learned goal-directed actions allowing the pursuit of rewarding experience or the avoidance of a danger. Both innate and learned behavioural programs are evolutionarily conserved and fundamental for survival. Among the brain structures participating in the encoding of positive/negative stimuli and contributing to innate and learned behaviours is the epithalamic lateral habenula (LHb). The LHb provides top-down control of monoaminergic systems, responds to unexpected appetitive/aversive stimuli as well as external cues that predict the upcoming rewards or punishments. Accordingly, the LHb controls a number of behaviours that are innate (originating from unpredicted stimuli), and learned (stemming from predictive cues). In this review, we will discuss the progresses that rodent’s experimental work made in identifying how LHb activity governs these vital processes, and we will provide a view on how these findings integrate within a complex circuit connectivity.

Honey bees can store and retrieve independent memory traces after complex experiences that combine appetitive and aversive associations

Real-world experiences do often mix appetitive and aversive events. Understanding the ability of animals to extract, store and use this information is an important issue in neurobiology. We used honey bees as model to study learning and memory after a differential conditioning that combines appetitive and aversive training trials. First of all, we describe an aversive conditioning paradigm that constitutes a clear opposite of the well known appetitive olfactory conditioning of the proboscis extension response. A neutral odour is presented paired with the bitter substance quinine. Aversive memory is evidenced later as an odour-specific impairment in appetitive conditioning. Then we tested the effect of mixing appetitive and aversive conditioning trials distributed along the same training session. Differential conditioning protocols like this were used before to study the ability to discriminate odours, however they were not focused on whether appetitive and aversive memories are formed. We found that after a differential conditioning, honey bees establish independent appetitive and aversive memories that do not interfere with each other during acquisition or storage. Finally, we moved the question forward to retrieval and memory expression to evaluate what happens when appetitive and the aversive learned odours are mixed during test. Interestingly, opposite memories compete in a way that they do not cancel each other out. Honey bees showed the ability to switch from expressing appetitive to aversive memory depending on their satiation level.

Functional organization of the midbrain periaqueductal gray for regulating aversive memory formation

Innately aversive experiences produce rapid defensive responses and powerful emotional memories. The midbrain periaqueductal gray (PAG) drives defensive behaviors through projections to brainstem motor control centers, but the PAG has also been implicated in aversive learning, receives information from aversive-signaling sensory systems and sends ascending projections to the thalamus as well as other forebrain structures which could control learning and memory. Here we sought to identify PAG subregions and cell types which instruct memory formation in response to aversive events. We found that optogenetic inhibition of neurons in the dorsolateral subregion of the PAG (dlPAG), but not the ventrolateral PAG (vlPAG), during an aversive event reduced memory formation. Furthermore, inhibition of a specific population of thalamus projecting dlPAG neurons projecting to the anterior paraventricular thalamus (aPVT) reduced aversive learning, but had no effect on the expression of previously learned defensive behaviors. By contrast, inactivation of dlPAG neurons which project to the posterior PVT (pPVT) or centromedial intralaminar thalamic nucleus (CM) had no effect on learning. These results reveal specific subregions and cell types within PAG responsible for its learning related functions.

Aversive memory formation in humans is determined by an amygdala-hippocampus phase code

Memory for aversive events is central to survival, but can also become maladaptive in psychiatric disorders. Emotional memory relies on the amygdala and hippocampus, but the neural dynamics of their communication during emotional memory encoding remain unknown. Using simultaneous intracranial recordings from both structures in human patients, we show that in response to emotionally aversive, but not neutral, visual stimuli, the amygdala transmits unidirectional influence on the hippocampus through theta oscillations. Critically, successful emotional memory encoding depends on the precise amygdala theta phase to which hippocampal gamma activity and neuronal firing couple. The phase difference between subsequently remembered vs. not-remembered emotional stimuli translates to ∼25-45 milliseconds, a time period that enables lagged coherence between amygdala and downstream hippocampal gamma activity. These results reveal a mechanism whereby amygdala theta phase coordinates transient coherence between amygdala and hippocampal gamma activity to facilitate the encoding of aversive memories in humans.

Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors

The neuropeptide oxytocin (OXT) is well recognized for eliciting anxiolytic effects and promoting social reward. However, emerging evidence shows that OXT increases aversive events. These seemingly inconsistent results may be attributable to the broad OXT receptor (OXTr) expression in the central nervous system. This study selectively activated septal neurons expressing OXTr using chemogenetics. We found that chemogenetic activation of septal OXTr neurons induced anxiety- but not depressive-like behavior. In addition, septal OXTr neurons projected dense fibers to the horizontal diagonal band of Broca (HDB), and selective stimulation of those HDB projections also elicited anxiety-like behaviors. We also found that septal OXTr neurons express the vesicular GABA transporter (vGAT) protein and optogenetic stimulation of septal OXTr projections to the HDB inactivated HDB neurons. Our data collectively reveal that septal OXTr neurons increase anxiety by projecting inhibitory GABAergic inputs to the HDB.

Anticipation of aversive visual stimuli lengthens perceived temporal duration

Subjective estimates of elapsed time are sensitive to the fluctuations in an emotional state. While it is well known that dangerous and threatening situations, such as electric shocks or loud noises, are perceived as lasting longer than safe events, it remains unclear whether anticipating a threatening event speeds up or slows down subjective time and what defines the direction of the distortion. We examined whether the anticipation of uncertain visual aversive events resulted in either underestimation or overestimation of perceived duration. The participants did a temporal bisection task, where they estimated durations of visual cues relative to previously learnt long and short standard durations. The colour of the to-be-timed visual cue signalled either a 50% or 0% probability of encountering an aversive image at the end of the interval. The cue durations were found to be overestimated due to anticipation of aversive images, even when no image was shown afterwards. Moreover, the overestimation was more pronounced in people who reported feeling more anxious while anticipating the image. These results demonstrate that anxiogenic anticipation of uncertain visual threats induce temporal overestimation, which questions a recently proposed view that temporal underestimation evoked by uncertain threats is due to anxiety.

Distributed and multifaceted effects of threat and safety

Sustained anticipation of unpredictable aversive events generates anticipatory processing that is central to anxiety. In the present functional Magnetic Resonance Study (fMRI) study, we examined how sustained threat is processed in the human brain. We used a relatively large sample (N = 109) and employed a Bayesian multilevel analysis approach to contrast threat and safe periods. Our analyses demonstrated that the effect of sustained threat is heterogeneous and distributed across the brain. Thus, the impact of threat is widespread, and not restricted to a small set of putatively emotion-related regions, such as the amygdala and the bed nucleus of the stria terminalis. Both transient and sustained, and increased and decreased responses during threat were observed. Our study reveals that transitioning between threat and safe states, and vice versa, leads to a widespread switch in brain responding that involves most of the brain.

High avoidance and low approach motivation affect cognitive reappraisal generation in the face of anger

This study investigates the link between the revised reinforcement sensitivity theory (RST) and individuals’ capacity to spontaneously invent alternate appraisals for aversive events. Eighty-two women completed the Reappraisal Inventiveness Test for anger-eliciting situations, and quantity and quality of reappraisal ideas were correlated with BIS, BAS, and FFFS sensitivity (RST-Personality Questionnaire). Results revealed that high BIS and high FFFS reduced the total number of reappraisal ideas, indicating that combined heightened sensitivity of the two avoidance systems may deplete individuals’ repertoire of potential reappraisals. RST effects on the quality of generated reappraisals were also found. High BIS and low BAS lowered individuals’ propensity to produce positive re-interpretations, which are considered a more adaptive reappraisal tactic. High FFFS sensitivity was linked to a lower preference for problem-oriented reappraisals. This study underlines that certain interactions of motivational subsystems may be particularly detrimental for successful reappraisal of anger-eliciting events. Our findings reveal potential links between revised RST effects and adaptive emotion regulation.

Early acquisition of threat conditioning in a selectively-bred anxiety-like rat phenotype: regulation by maternal presence and FGF2

Temperament is an innate, stable predisposition towards particular emotional and behavioral responses. In humans, certain temperaments are associated with a heightened risk of developing anxiety later in life. Non-human animals, including rodents, also exhibit innate, stable dispositions; these are referred to as behavioral phenotypes. The interaction between behavioral phenotype and early life adverse events is critical for the development of maladaptive anxiety. Rodent studies of typically developing animals have identified a number of mechanisms that protect against aversive experiences in early life. One such mechanism is an early life quiescence of threat learning, which protects against the effects of stress and facilitates safety and attachment learning. However, little is known about the factors that alleviate the effects of early life aversive events on phenotypes vulnerable to pathological anxiety. Here, we examined threat learning and the stress response in selectively-bred infant rats that show an anxiety-like phenotype relative to typically developing animals. We investigated the potential roles of maternal presence and the anxiolytic neurotrophic factor fibroblast growth factor 2 (FGF2) in regulating threat learning and the stress response in infant anxiety-like phenotype animals. We observed that rats selectively-bred for anxiety-like behaviors could acquire conditioned freezing earlier in life than typically developing animals. FGF2 administration on postnatal day 1 (PND 1) and maternal presence during threat conditioning were both capable of suppressing this early emergence of conditioned freezing. However, neither FGF2 nor maternal presence during threat conditioning were associated with reduced corticosterone levels during threat conditioning. Our results suggest that although an anxiety-like phenotype may be associated with early threat learning, environmental factors (such as maternal presence) and pharmacological intervention (such as modulation of the FGF2 system) may be capable of counteracting that early aversive learning. Interventions in vulnerable infants may thus decrease the impact of aversive events.

Prediction errors for aversive events shape long-term memory formation through a distinct neural mechanism

SUMMARYPrediction errors (PEs) have been known for decades to guide associative learning, but their role in episodic memory formation has been discovered only recently. Using an encoding task in which participants learned to predict which stimuli are followed by aversive shocks, combined with univariate, multivoxel, and large-scale network analyses of fMRI data, we show that enhanced memory for events associated with negative PEs was linked to reduced hippocampal responses to PEs and increased crosstalk between the ‘salience network’ and a frontoparietal network commonly implicated in memory formation for events that are in line with prior expectation. These PE-related effects could not be explained by mere changes in physiological arousal or the prediction itself. Our results suggest that superior memory for events associated with high PEs is driven by a distinct neural mechanism that might serve to set memories of high PE events apart from those with expected outcomes.