Faculty Bibliography

The brain mechanisms of fear have been studied extensively using Pavlovian fear conditioning, a procedure that allows exploration of how the brain learns about and later detects and responds to threats. However, mechanisms that detect and respond to threats are not the same as those that give rise to conscious fear. This is an important distinction because symptoms based on conscious and nonconscious processes may be vulnerable to different predisposing factors and may also be treatable with different approaches in people who suffer from uncontrolled fear or anxiety. A conception of so-called fear conditioning in terms of circuits that operate nonconsciously, but that indirectly contribute to conscious fear, is proposed as way forward.

While it is common to think that neuroscientists are proponents of basic emotions theory, this is not necessarily the case. My ideas, for example are more aligned with cognitive than basic emotions theories.

Pavlovian threat conditioning is a behavioral paradigm that has been successfully utilized to define the mechanisms underlying threat (fear) memory formation. The amygdala is a temporal lobe structure required for the acquisition, consolidation, and expression of threat (fear) memories. In particular, the lateral nucleus of the amygdala (LA) is the major input structure of the amygdala and is required for all aspects of threat learning and memory. The LA expresses many neurotransmitter and neuromodulator receptors. This chapter covers the molecular mechanisms that occur downstream of these receptors and how they influence LA-dependent Pavlovian threat learning.

Aversive Pavlovian conditioned stimuli (CSs) elicit defensive reactions (e.g., freezing) and motivate instrumental actions like active avoidance (AA). Pavlovian reactions require connections between the lateral (LA) and central (CeA) nuclei of the amygdala, whereas AA depends on LA and basal amygdala (BA). Thus, the neural circuits mediating conditioned reactions and motivation appear to diverge in the amygdala. However, AA is not ideal for studying conditioned motivation, because Pavlovian and instrumental learning are intermixed. Pavlovian-to-instrumental transfer (PIT) allows for the study of conditioned motivation in isolation. PIT refers to the ability of a Pavlovian CS to modulate a separately-trained instrumental action. The role of the amygdala in aversive PIT is unknown. We designed an aversive PIT procedure in rats and tested the effects of LA, BA, and CeA lesions. Rats received Pavlovian tone-shock pairings followed by Sidman shock-avoidance training. PIT was assessed by comparing shuttling rates in the presence and absence of the tone. Tone presentations facilitated instrumental responding. Aversive PIT was abolished by lesions of LA or CeA, but was unaffected by lesions of BA. These results suggest that LA and CeA are essential for aversive conditioned motivation. More specifically, the results are consistent with a model of amygdala processing in which the CS is encoded in the LA and then, via connections to CeA, the motivation to perform the aversive task is enhanced. These findings have implications for understanding the contribution of amygdala circuits to aversive instrumental motivation, but also for the relation of aversive and appetitive behavioral control.

Individuals exposed to traumatic stressors follow divergent patterns including resilience and chronic stress. However, researchers utilizing animal models that examine learned or instrumental threat responses thought to have translational relevance for Posttraumatic Stress Disorder (PTSD) and resilience typically use central tendency statistics that assume population homogeneity. This approach potentially overlooks fundamental differences that can explain human diversity in response to traumatic stressors. The current study tests this assumption by identifying and replicating common heterogeneous patterns of response to signaled active avoidance (AA) training. In this paradigm, rats are trained to prevent an aversive outcome (shock) by performing a learned instrumental behavior (shuttling between chambers) during the presentation of a conditioned threat cue (tone). We test the hypothesis that heterogeneous trajectories of threat avoidance provide more accurate model fit compared to a single mean trajectory in two separate studies. Study 1 conducted 3 days of signaled AA training (n = 81 animals) and study 2 conducted 5 days of training (n = 186 animals). We found that four trajectories in both samples provided the strongest model fit. Identified populations included animals that acquired and retained avoidance behavior on the first day (Rapid Avoiders: 22 and 25%); those who never successfully acquired avoidance (Non-Avoiders; 20 and 16%); a modal class who acquired avoidance over 3 days (Modal Avoiders; 37 and 50%); and a population who demonstrated a slow pattern of avoidance, failed to fully acquire avoidance in study 1 and did acquire avoidance on days 4 and 5 in study 2 (Slow Avoiders; 22.0 and 9%). With the exception of the Slow Avoiders in Study 1, populations that acquired demonstrated rapid step-like increases leading to asymptotic levels of avoidance. These findings indicate that avoidance responses are heterogeneous in a way that may be informative for understanding both resilience and PTSD as well as the nature of instrumental behavior acquisition. Characterizing heterogeneous populations based on their response to threat cues would increase the accuracy and translatability of such models and potentially lead to new discoveries that explain diversity in instrumental defensive responses.

Aversive Pavlovian memory coordinates the defensive behavioral response to learned threats. The amygdala is a key locus for the acquisition and storage of aversive associations. Information about conditioned and unconditioned stimuli converge in the lateral amygdala, which is a hot spot for the plasticity induced by associative learning. Central amygdala uses Pavlovian memory to coordinate the conditioned reaction to an aversive conditioned stimulus. Aversive associations can also access the brain networks of instrumental action. The offset of an aversive conditioned stimulus can reinforce behavior, recruiting a pathway that includes the lateral and basal amygdala, as opposed to the lateral and central amygdala circuit for Pavlovian reactions. Aversive conditioned stimuli can also modulate ongoing behavior, suppressing appetitive actions and facilitating aversive actions. Facilitation depends on an amygdalar network involving the lateral and central, as well as medial, nuclei. Thus, aversive Pavlovian memory has wide-reaching effects on defensive behavior, coordinating reactive to active responses to environmental threats.

Pavlovian conditioned stimuli (CSs) play an important role in the reinforcement and motivation of instrumental active avoidance (AA). Conditioned threats can also invigorate ongoing AA responding [aversive Pavlovian-instrumental transfer (PIT)]. The neural circuits mediating AA are poorly understood, although lesion studies suggest that lateral, basal, and central amygdala nuclei, as well as infralimbic prefrontal cortex, make key, and sometimes opposing, contributions. We recently completed an extensive analysis of brain c-Fos expression in good vs. poor avoiders following an AA test (Martinez et al., 2013, Learning and Memory). This analysis identified medial amygdala (MeA) as a potentially important region for Pavlovian motivation of instrumental actions. MeA is known to mediate defensive responding to innate threats as well as social behaviors, but its role in mediating aversive Pavlovian-instrumental interactions is unknown. We evaluated the effect of MeA lesions on Pavlovian conditioning, Sidman two-way AA conditioning (shuttling) and aversive PIT in rats. Mild footshocks served as the unconditioned stimulus in all conditioning phases. MeA lesions had no effect on AA but blocked the expression of aversive PIT and 22 kHz ultrasonic vocalizations in the AA context. Interestingly, MeA lesions failed to affect Pavlovian freezing to discrete threats but reduced freezing to contextual threats when assessed outside of the AA chamber. These findings differentiate MeA from lateral and central amygdala, as lesions of these nuclei disrupt Pavlovian freezing and aversive PIT, but have opposite effects on AA performance. Taken together, these results suggest that MeA plays a selective role in the motivation of instrumental avoidance by general or uncertain Pavlovian threats.

Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala-PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC-amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders.