Pavlovian Fear Research Articles

Punishment insensitivity emerges from impaired contingency detection, not aversion insensitivity or reward dominance.

Our behaviour is shaped by its consequences - we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, that is in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats (n = 48; 18 female) trained in a conditioned punishment task that permitted concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.

Developmental emergence of fear/threat learning: neurobiology, associations and timing.

Pavlovian fear or threat conditioning, where a neutral stimulus takes on aversive properties through pairing with an aversive stimulus, has been an important tool for exploring the neurobiology of learning. In the past decades, this neurobehavioral approach has been expanded to include the developing infant. Indeed, protracted postnatal brain development permits the exploration of how incorporating the amygdala, prefrontal cortex and hippocampus into this learning system impacts the acquisition and expression of aversive conditioning. Here, we review the developmental trajectory of these key brain areas involved in aversive conditioning and relate it to pups' transition to independence through weaning. Overall, the data suggests that adult-like features of threat learning emerge as the relevant brain areas become incorporated into this learning. Specifically, the developmental emergence of the amygdala permits cue learning and the emergence of the hippocampus permits context learning. We also describe unique features of learning in early life that block threat learning and enhance interaction with the mother or exploration of the environment. Finally, we describe the development of a sense of time within this learning and its involvement in creating associations. Together these data suggest that the development of threat learning is a useful tool for dissecting adult-like functioning of brain circuits, as well as providing unique insights into ecologically relevant developmental changes.

The dorsal raphe nucleus is integral to negative prediction errors in Pavlovian fear

Prediction errors are central to modern learning theories. While brain regions contributing to reward prediction errors have been uncovered, the sources of aversive prediction errors remain largely unknown. Here we used probabilistic and deterministic reinforcement procedures, followed by extinction, to examine the contribution of the dorsal raphe nucleus to negative, aversive prediction errors in Pavlovian fear. Rats with dorsal raphe lesions were able to acquire fear and reduce fear to a non-reinforced deterministic cue. However, dorsal raphe lesions impaired the reduction of fear to a probabilistic cue and fear extinction to a deterministic cue, both of which involve the use of negative prediction errors. The results point to an integral role for the dorsal raphe nucleus in negative prediction error signaling in Pavlovian fear.

Variation in Serotonin Transporter Expression Modulates Fear-Evoked Hemodynamic Responses and Theta-Frequency Neuronal Oscillations in the Amygdala

BackgroundGene association studies detect an influence of natural variation in the 5-hydroxytryptamine transporter (5-HTT) gene on multiple aspects of individuality in brain function, ranging from personality traits through to susceptibility to psychiatric disorders such as anxiety and depression. The neural substrates of these associations are unknown. Human neuroimaging studies suggest modulation of the amygdala by 5-HTT variation, but this hypothesis is controversial and unresolved, and difficult to investigate further in humans.MethodsWe used a mouse model in which the 5-HTT is overexpressed throughout the brain and recorded hemodynamic responses (using a novel in vivo voltammetric monitoring method, analogous to blood oxygen level–dependent functional magnetic resonance imaging) and local field potentials during Pavlovian fear conditioning.ResultsIncreased 5-HTT expression impaired, but did not prevent, fear learning and significantly reduced amygdala hemodynamic responses to aversive cues. Increased 5-HTT expression was also associated with reduced theta oscillations, which were a feature of aversive cue presentation in controls. Moreover, in control mice, but not those with high 5-HTT expression, there was a strong correlation between theta power and the amplitude of the hemodynamic response.ConclusionsDirect experimental manipulation of 5-HTT expression levels throughout the brain markedly altered fear learning, amygdala hemodynamic responses, and neuronal oscillations.

Treatments that weaken Pavlovian conditioned fear and thwart its renewal in rats: Implications for treating human phobias.

In experiments using a total of 144 albino rat subjects, the authors assessed the ability of fear-weakening treatments to prevent fear renewal (relapse). Conditioned suppression of operant behavior served as the measure of fear in an A-B-A (acquisition-treatment-test) renewal paradigm. In Experiment 1, 100 nonreinforced exposures to a feared cue during treatment (extinction) did not reduce fear renewal relative to 20 exposures. In Experiment 2, explicitly unpaired (EU) treatments thwarted both renewal and reacquisition. In Experiment 3, conditioned inhibition (CI) and differential conditioning (DC) treatments weakened renewal and resisted both reacquisition and a form of reinstatement. In Experiment 4, EU, DC, and CI treatments all thwarted renewal. Evidence suggested that the ability of the treatments to do so reflected the combined effects of transfer of extinction across treatment and test contexts and habituation to the unconditioned stimulus.

Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations.

Previous findings have demonstrated that systemic dopaminergic manipulations impair the retrieval of Pavlovian conditioned fear. A second-order fear-conditioning paradigm was used to test whether the dopaminergic projection from the ventral tegmental area (VTA) to the lateral and basal amygdala (LBA) can affect conditioned fear. Phase 1 entailed conditioned stimulus-unconditioned stimulus (CS1-US) pairings. In Phase 2, drugs were infused in either the LBA or VTA prior to pairings of CS2 (a second cue) with CS1. In Phase 3, freezing behavior elicited by CS2 was tested without drugs. Infusions of the D2 agonist quinpirole into the VTA or of the D1 antagonist SCH 23390 into the LBA caused a decrease in freezing to CS2. Both manipulations decrease D1 receptor activation in the LBA. Infusions of the D1 agonist SKF 38393 into the LBA had no effect. This pattern of results is consistent with the hypothesis that the VTA-LBA dopaminergic projection modulates the retrieval of an association between a CS and footshock US.

Response characteristics of neurons in the medial component of the medial geniculate nucleus during Pavlovian differential fear conditioning in rabbits.

Recent evidence suggests that the amygdaloid central nucleus (ACE) may contribute significantly to Pavlovian fear-conditioned bradycardic responses during the presentation of conditioned emotional stimuli. Because the medial component of the medial geniculate nucleus (MGm) is a major source of input to the region of the ACE, the extracellular single-unit responses of MGm neurons were examined during Pavlovian differentially conditioned bradycardic responding in rabbits. Conditioning involved pairing one tone (CS+) with paraorbital shock and presenting another tone (CS-) in the absence of shock. Two general classes of MGm neurons were identified based on their conditioned-response characteristics. Both groups responded differentially to the CSs. One group responded with greater increases in activity and at a shorter latency to the CS+ compared with the CS-, whereas the other group responded with greater increases in activity and at a shorter latency to the CS- compared with the CS+. Recordings from MGm neurons in naive rabbits prior to conditioning provided evidence that the acoustic stimuli used subsequently as the CS+ and CS- did not evoke differential responses. These results suggest that the MGm along with the ACE may be forebrain components of a neural circuit involved in the acquisition and/or expression of Pavlovian fear-conditioned bradycardic responses.