Fear extinction, the reduction of fear by repeated exposure to the object of fear, is a crucial paradigm of inhibitory learning and the acknowledged preclinical model for behavior therapy of human anxiety. Recent insights have clarified roles for infralimbic prefrontal cortex, hippocampus and periaqueductal gray in extinction learning, while maintaining a central role for the basolateral amygdaloid nucleus in the acquisition and storage of this learning. Simultaneously, molecular insights have implicated several neurotransmitter and second messenger systems in extinction learning, and revealed that extinction is surprisingly easy to improve, yielding the promise of a novel approach to improved psychiatric treatments for a variety of human anxiety disorders.
"This impaired extinction indicates that the WKY rat is an overly avoidant animal that is willing to expend energy and continue displaying the avoidance response during extinction rather than occasionally testing whether the reinforcement contingency is still present. Such resistance to extinction has been implicated in neuropathology of human anxiety (Myers and Davis, 2002; Barad, 2005). A curious feature that appears across avoidance learning paradigms emerges when one looks at behavior within, rather than across, sessions. "
[Show abstract][Hide abstract] ABSTRACT: Avoidance behaviors, in which a learned response causes omission of an upcoming punisher, are a core feature of many psychiatric disorders. While reinforcement learning (RL) models have been widely used to study the development of appetitive behaviors, less attention has been paid to avoidance. Here, we present a RL model of lever-press avoidance learning in Sprague-Dawley (SD) rats and in the inbred Wistar Kyoto (WKY) rat, which has been proposed as a model of anxiety vulnerability. We focus on "warm-up," transiently decreased avoidance responding at the start of a testing session, which is shown by SD but not WKY rats. We first show that a RL model can correctly simulate key aspects of acquisition, extinction, and warm-up in SD rats; we then show that WKY behavior can be simulated by altering three model parameters, which respectively govern the tendency to explore new behaviors vs. exploit previously reinforced ones, the tendency to repeat previous behaviors regardless of reinforcement, and the learning rate for predicting future outcomes. This suggests that several, dissociable mechanisms may contribute independently to strain differences in behavior. The model predicts that, if the "standard" inter-session interval is shortened from 48 to 24 h, SD rats (but not WKY) will continue to show warm-up; we confirm this prediction in an empirical study with SD and WKY rats. The model further predicts that SD rats will continue to show warm-up with inter-session intervals as short as a few minutes, while WKY rats will not show warm-up, even with inter-session intervals as long as a month. Together, the modeling and empirical data indicate that strain differences in warm-up are qualitative rather than just the result of differential sensitivity to task variables. Understanding the mechanisms that govern expression of warm-up behavior in avoidance may lead to better understanding of pathological avoidance, and potential pathways to modify these processes.
"Anxiety disorders are often treated clinically through behavioral extinction in which the individual is exposed to the threatening stimulus in the absence of an aversive outcome (Barad, 2005; Foa, 2000; Rothbaum & Schwartz, 2002; Wolpe, 1969). Affective reactions to the stimulus are gradually reduced as the person learns that the cue does not predict danger. "
[Show abstract][Hide abstract] ABSTRACT: Extinction learning underlies the treatment for a variety of anxiety disorders. Most of what is known about the neurobiology of extinction is based on standard "delay" fear conditioning, in which awareness is not required for learning. Little is known about how complex, explicit associations extinguish, however. "Trace" conditioning is considered to be a rodent model of explicit fear because it relies on both the cortex and hippocampus and requires explicit contingency awareness in humans. Here, we explore the neural circuit supporting trace fear extinction in order to better understand how complex memories extinguish. We first show that the amygdala is selectively involved in delay fear extinction; blocking intra-amygdala glutamate receptors disrupted delay, but not trace extinction. Further, ERK phosphorylation was increased in the amygdala after delay, but not trace extinction. We then identify the retrosplenial cortex (RSC) as a key structure supporting trace extinction. ERK phosphorylation was selectively increased in the RSC following trace extinction and blocking intra-RSC NMDA receptors impaired trace, but not delay extinction. These findings indicate that delay and trace extinction require different neural circuits; delay extinction requires plasticity in the amygdala whereas trace extinction requires the RSC. Anxiety disorders linked to explicit memory may therefore depend on cortical processes that have not been traditionally targeted by extinction studies based on delay fear.
Neurobiology of Learning and Memory 09/2013; 113. DOI:10.1016/j.nlm.2013.09.007 · 3.65 Impact Factor
"In the laboratory, conditioned fear is frequently studied by pairing a neutral conditioned stimulus (CS; e.g., a tone) with an intrinsically frightening stimulus [unconditioned stimulus (US); e.g., shock]. Later, the CS is sufficient to produce a variety of physiological and species-specific behavioral reactions (e.g., increases in heart rate, freezing) that have been associated with the subjective feelings of fear and anxiety (Barad, 2005). These conditioned emotional response (CER) paradigms model a variety of human anxiety disorders such as phobias and post-traumatic stress disorder (PTSD; for review, see Herry et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Due to its relevance to clinical practice, extinction of learned fears has been a major focus of recent research. However, less is known about the means by which conditioned fears re-emerge (i.e., spontaneously recover) as time passes or contexts change following extinction. The periaqueductal gray represents the final common pathway mediating defensive reactions to fear and we have reported previously that the dorsolateral PAG (dlPAG) exhibits a small but reliable increase in neural activity (as measured by c-fos protein immunoreactivity) when spontaneous recovery (SR) of a conditioned taste aversion (CTA) is reduced. Here we extend these correlational studies to determine if inducing dlPAG c-fos expression through electrical brain stimulation could cause a reduction in SR of a CTA. Male Sprague-Dawley rats acquired a strong aversion to saccharin (conditioned stimulus; CS) and then underwent CTA extinction through multiple non-reinforced exposures to the CS. Following a 30-day latency period after asymptotic extinction was achieved; rats either received stimulation of the dorsal PAG (dPAG) or stimulation of closely adjacent structures. Sixty minutes following the stimulation, rats were again presented with the saccharin solution as we tested for SR of the CTA. The brain stimulation evoked c-fos expression around the tip of the electrodes. However, stimulation of the dPAG failed to reduce SR of the previously extinguished CTA. In fact, dPAG stimulation caused rats to significantly suppress their saccharin drinking (relative to controls) - indicating an enhanced SR. These data refute a cause-and-effect relationship between enhanced dPAG c-fos expression and a reduction in SR. However, they highlight a role for the dPAG in modulating SR of extinguished CTAs.
Brain research 11/2012; 1493. DOI:10.1016/j.brainres.2012.11.029 · 2.84 Impact Factor
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