Translational approaches to the neurobiological study of conditional discrimination and inhibition: Implications for psychiatric disease.

There is a growing number of studies investigating discriminatory fear conditioning and conditioned inhibition of fear to assess safety learning, in addition to extinction of cued fear. Despite all of these paradigms resulting in a reduction in fear expression, there are nuanced differences among them, which could be mediated through distinct behavioral and neural mechanisms. These differences could impact how we approach potential treatment options in clinical disorders with dysregulated fear responses.

Conditioned inhibition of fear and reward in male and female rats.

Stimuli in our environment are not always associated with an outcome. Some of these stimuli, depending on how they are presented, may gain inhibitory value or simply be ignored. If experienced in the presence of other cues predictive of appetitive or aversive outcomes, they typically gain inhibitory value and become predictive cues indicating the absence of appetitive or aversive outcomes.

Suppressing fear in the presence of a safety cue requires infralimbic cortical signaling to central amygdala.

Stressful events can have lasting and impactful effects on behavior, especially by disrupting normal regulation of fear and reward processing. Accurate discrimination among environmental cues predicting threat, safety or reward adaptively guides behavior. Post-traumatic stress disorder (PTSD) represents a condition in which maladaptive fear persists in response to explicit safety-predictive cues that coincide with previously learned threat cues, but without threat being present.

Psychological and physiological correlates of stimulus discrimination in adults.

The discrimination of cues in the environment that signal danger ("fear cue") is important for survival but depends critically on the discernment of such cues from ones that pose no threat ("safety cues"). In rodents, we previously demonstrated the underlying neurobiological mechanisms that support fear versus safety discrimination and documented that these mechanisms extend to the discrimination of reward as well. While learning about reward is equally important for survival, it remains an under-studied area of research, particularly in human studies of conditional discrimination.

Encoding of conditioned inhibitors of fear in the infralimbic cortex.

Cues in the environment signaling the absence of threat, i.e. safety, can influence both fear and reward-seeking behaviors.

Interaction of stress and alcohol on discriminating fear from safety and reward in male and female rats.

Rationale: Stressful events can have lasting and impactful effects on behavior, especially in terms of appropriate fear regulation and reward seeking. Our prior work in rats has shown baseline sex differences in fear expression and sucrose seeking in a discriminative reward-fear-safety conditioning task.

Objectives: The objectives of the current study were to determine how prior stress may affect alcohol consumption across a reward-fear-safety learning task, and how prior alcohol history may interact with stress to impact learning in this task.

Elevated dopamine in the amygdala disrupts infant's approach to mother: Implications for development of neurotypical social behaviors and networks.

In this issue of Neuron, Opendak et al. (2021) use a suite of techniques that are typically challenging in infant rat pups to examine the role of dopaminergic input to the basolateral amygdala in social behavior deficits in response to early-life adversity.

Environmental certainty influences the neural systems regulating responses to threat and stress.

Flexible calibration of threat responding in accordance with the environment is an adaptive process that allows an animal to avoid harm while also maintaining engagement of other goal-directed actions. This calibration process, referred to as threat response regulation, requires an animal to calculate the probability that a given encounter will result in a threat so they can respond accordingly. Here we review the neural correlates of two highly studied forms of threat response suppression: extinction and safety conditioning.

On the basis of sex: Differences in safety discrimination vs. conditioned inhibition.

Inaccurate discrimination between threat and safety cues is a common symptom of anxiety disorders such as Post-Traumatic Stress Disorder (PTSD). Although females experience higher rates of these disorders than males, the body of literature examining sex differences in safety learning is still growing. Learning to discriminate safety cues from threat cues requires downregulating fear to the safety cue while continuing to express fear to the threat cue.

Juvenile stress facilitates safety learning in male and female high alcohol preferring mice.

Adversities during juvenility increase the risk for stress-related disorders, such as post-traumatic stress disorder (PTSD) and alcohol use disorder. However, stress can also induce coping mechanisms beneficial for later stressful experiences. We reported previously that mice selectively bred for high alcohol preference (HAP) exposed to stress during adolescence (but not during adulthood) showed enhanced fear-conditioned responses in adulthood, as measured by fear-potentiated startle (FPS).

Differential effects of prior stress on conditioned inhibition of fear and fear extinction.

Resistant and generalized fear are hallmark symptoms of Post-Traumatic Stress Disorder (PTSD). Given PTSD is highly comorbid with addiction disorders indicates a maladaptive interaction between fear and reward circuits. To investigate learning processes underlying fear, reward and safety, we trained male rats to discriminate among a fear cue paired with footshock, a reward cue paired with sucrose and an explicit safety cue co-occurring with the fear cue in which no footshocks were delivered.

Know safety, no fear.

Every day we are bombarded by stimuli that must be assessed for their potential for harm or benefit. Once a stimulus is learned to predict harm, it can elicit fear responses. Such learning can last a lifetime but is not always beneficial for an organism.

Sex differences in fear regulation and reward-seeking behaviors in a fear-safety-reward discrimination task.

Reward availability and the potential for danger or safety potently regulate emotion. Despite women being more likely than men to develop emotion dysregulation disorders, there are comparatively few studies investigating fear, safety and reward regulation in females. Here, we show that female Long Evans rats did not suppress conditioned freezing in the presence of a safety cue, nor did they extinguish their freezing response, whereas males did both.

Adolescent conditioning affects rate of adult fear, safety and reward learning during discriminative conditioning.

Fear and reward memories formed in adulthood are influenced by prior experiences. Experiences that occur during sensitive periods, such as adolescence, can have an especially high impact on later learning. Fear and reward memories form when aversive or appetitive events co-occur with initially neutral stimuli, that then gain negative or positive emotional load.

Altering D1 receptor activity in the basolateral amygdala impairs fear suppression during a safety cue.

Accurate discrimination among cues signifying reward, danger or safety initiates the proper emotional response in order to guide behavior. Appropriate conditioned inhibition of fear in the presence of a safety cue would allow an organism to engage in reward seeking behaviors. There is currently little known about the mechanisms of reward, fear and safety cue discrimination and how a safety cue can inhibit fear and release reward seeking from inhibition.

Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction.

Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al.

Heightened fear in response to a safety cue and extinguished fear cue in a rat model of maternal immune activation.

Maternal immune activation (MIA) during pregnancy is an environmental risk factor for psychiatric illnesses such as schizophrenia and autism in the offspring. Hence, changes in an array of behaviors, including behavioral flexibility, consistent with altered functioning of cortico-limbic circuits have been reported in rodent models of MIA. Surprisingly, previous studies have not examined the effect of MIA on the extinction of fear conditioning which depends on cortico-limbic circuits.

Alterations in reward, fear and safety cue discrimination after inactivation of the rat prelimbic and infralimbic cortices.

Accurate discrimination of environmental cues predicting reward, fear, or safety is important for survival. The prelimbic and infralimbic cortices are implicated in regulating reward-seeking and fear behaviors; however, no studies have examined their roles in discriminating among reward, fear, and safety cues. Using a discriminative conditioning task that includes presentations of a reward cue (paired with a reward pellet), fear cue (paired with footshock), and a compound fear+safety cue (no footshock) within the same sessions allowed us to assess the flexibility and precision of fear and reward-seeking behaviors to these cues.

Safety encoding in the basal amygdala.

Learning to fear and avoid life-threatening stimuli are critical survival skills but are maladaptive when they persist in the absence of a direct threat. Thus, it is important to detect when a situation is safe and to increase behaviors leading to naturally rewarding actions, such as feeding and mating. It is unclear how the brain distinguishes between dangerous and safe situations.

Inhibition of fear by learned safety signals: a mini-symposium review.

Safety signals are learned cues that predict the nonoccurrence of an aversive event. As such, safety signals are potent inhibitors of fear and stress responses. Investigations of safety signal learning have increased over the last few years due in part to the finding that traumatized persons are unable to use safety cues to inhibit fear, making it a clinically relevant phenotype.

Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory.

Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65 isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD).

Patterns of coupled theta activity in amygdala-hippocampal-prefrontal cortical circuits during fear extinction.

Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules.

Deficiency of the 65 kDa isoform of glutamic acid decarboxylase impairs extinction of cued but not contextual fear memory.

Extinction procedures are clinically relevant for reducing pathological fear, and the mechanisms of fear regulation are a subject of intense research. The amygdala, hippocampus, and prefrontal cortex (PFC) have all been suggested to be key brain areas in extinction of conditioned fear. GABA has particularly been implicated in extinction learning, and the 65 kDa isoform of glutamic acid decarboxylase (GAD65) may be important in elevating GABA levels in response to environmental signals.

Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala.

A deficient extinction of memory is particularly important in the regime of fear, where it limits the beneficial outcomes of treatments of anxiety disorders. Fear extinction is thought to involve inhibitory influences of the prefrontal cortex on the amygdala, although the detailed synaptic mechanisms remain unknown. Here, we report that neuropeptide S (NPS), a recently discovered transmitter of ascending brainstem neurons, evokes anxiolytic effects and facilitates extinction of conditioned fear responses when administered into the amygdala in mice.

Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory.

Evidence suggests that plasticity of the amygdalar and hippocampal GABAergic system is critical for fear memory formation. In this study we investigated in wild-type and genetically manipulated mice the role of the activity-dependent 65-kDa isozyme of glutamic acid decarboxylase (GAD65) in the consolidation and generalization of conditioned fear. First, we demonstrate a transient reduction of GAD65 gene expression in the dorsal hippocampus (6 h post training) and in the basolateral complex of the amygdala (24 h post training) during distinct phases of fear memory consolidation.