Seeking a Spotless Mind: Extinction, Deconsolidation, and Erasure of Fear Memory

154

132

The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fearconditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and warrant further examination. Hence, the present study investigated the functional relationship between the PAG and amygdala in two different settings, fear conditioning and naturalistic foraging, in rats. In fear conditioning, electrical stimulation of the dorsal PAG (dPAG) produced unconditional responses (URs) composed of brief activity bursts followed by freezing and 22-kHz ultrasonic vocalization. In contrast, stimulation of ventral PAG and the basolateral amygdalar complex (BLA) evoked freezing and/or ultrasonic vocalization. Whereas dPAG stimulation served as an effective unconditional stimulus for fear conditioning to tone and context conditional stimuli, neither ventral PAG nor BLA stimulation supported fear conditioning. The conditioning effect of dPAG, however, was abolished by inactivation of the BLA. In a foraging task, dPAG and BLA stimulation evoked only fleeing toward the nest. Amygdalar lesion/inactivation blocked the UR of dPAG stimulation, but dPAG lesions did not block the UR of BLA stimulation. Furthermore, in vivo recordings demonstrated that electrical priming of the dPAG can modulate plasticity of subiculum-BLA synapses, providing additional evidence that the amygdala is downstream of the dPAG. These results suggest that the dPAG conveys unconditional stimulus information to the BLA, which directs both innate and learned fear responses, and that brain stimulation-evoked behaviors are modulated by context. fear circuitry | learning and memory | long-term depression | long-term potentiation | synaptic plasticity D ecades of research involving various techniques have identified that the amygdala is essential for both innate and learned fear (1). Evidence indicates that neurons in the basolateral amygdalar complex (BLA) (basal and lateral nuclei) (2) are responsive to both the conditional stimulus (CS) and unconditional stimulus (US) (3, 4), undergo plastic changes during fear conditioning (5), and are necessary for producing fear responses (6, 7). Indeed, a recent study has shown that optogenetically induced depolarization of pyramidal neurons in the lateral amygdala (LA) can elicit a fear unconditional response (UR) and, when repeatedly paired with auditory CS, supports fear conditioning via Hebbian-like synaptic plasticity (8).However, stimulation-induced fear conditioning is not only achievable through the amygdala. Other studies have found that stimulation of the dorsal periaqueductal gray (dPAG) is an effective US in fear conditioning (9, 10). The PAG has long been implicated in generating defensive behaviors (11), and it has been suggested that its stimulation can support fear conditioning to a CS because it transmits the aversive US information to the LA (9, 12). Some have a...

Section: Discussionmentioning

confidence: 46%

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

Kim¹,

Horovitz

Pellman³

et al. 2013

154

132

“…Thus, whereas regions such as the amygdala, hippocampus, or prefrontal cortex may allow for the inhibition of fear expression or the modulation of that inhibition (12,21), the primary olfactory sensory system likely plays a major role in the CS sensitivity and responsiveness following a learning event and its extinction. A growing body of literature suggests that alterations in synaptic transmission within the basolateral amygdala (BLA) play an important role in the suppression of conditioned fear following extinction learning (22,23); in fact, there is evidence of depotentiation of conditioning-related amygdala synaptic transmission that occurs following extinction training (24)(25)(26)(27). These data are in line with our observation that extinction reverses aspects of conditioning-related effects, although the contribution of regions such as the amygdala in the regulation of primary sensory system structural changes remains an important area for future investigation.…”

Section: Discussionmentioning

confidence: 99%

Extinction reverses olfactory fear-conditioned increases in neuron number and glomerular size

Morrison

Dias

Ressler

2015

Although much work has investigated the contribution of brain regions such as the amygdala, hippocampus, and prefrontal cortex to the processing of fear learning and memory, fewer studies have examined the role of sensory systems, in particular the olfactory system, in the detection and perception of cues involved in learning and memory. The primary sensory receptive field maps of the olfactory system are exquisitely organized and respond dynamically to cues in the environment, remaining plastic from development through adulthood. We have previously demonstrated that olfactory fear conditioning leads to increased odorant-specific receptor representation in the main olfactory epithelium and in glomeruli within the olfactory bulb. We now demonstrate that olfactory extinction training specific to the conditioned odor stimulus reverses the conditioning-associated freezing behavior and odor learning-induced structural changes in the olfactory epithelium and olfactory bulb in an odorant ligand-specific manner. These data suggest that learninginduced freezing behavior, structural alterations, and enhanced neural sensory representation can be reversed in adult mice following extinction training.fear extinction | olfaction | neural plasticity I ncreasing evidence suggests that the cellular, neuroanatomical, and receptive field organizations of vertebrate sensory systems are continually reshaped throughout adulthood by cues from the external environment. Activity-dependent changes are known to occur both during critical periods of development and also in the adult brain, allowing the animal to optimally perform behaviors based on the demands of the surrounding environment. Postmitotic organizational changes, along with activity-dependent plasticity, have been largely implicated in shaping sensory circuits from development through adulthood (1-4). In particular, the olfactory sensory system of adult mice exhibits functional and neuroanatomical learning-dependent changes following olfactory fear conditioning in adulthood (5-7). The M71-LacZ transgenic mouse line expresses LacZ under the M71 odorant receptor (OR) promoter (encoded by the olfactory receptor 151 gene, Olfr151) (8) in the M71 OR-expressing, acetophenone-responsive population of olfactory sensory neurons (OSNs). Using this line, we previously demonstrated an increased number of M71-expressing OSNs in the main olfactory epithelium (MOE) of adult mice following olfactory fear conditioning to acetophenone (5, 7), an odorant that activates the M71/M72 ORs (9, 10). This increase in receptor-specific OSNs within the MOE was directly correlated with an increase in the area of M71+ axons innervating the M71 glomeruli within the olfactory bulbs (OBs). Behaviorally, these olfactory fear-conditioned mice also exhibited enhanced fear-potentiated startle (FPS) and freezing specific to the conditioned odor stimulus. Notably such changes were never seen with equivalent odorant exposure alone but only when the odorant was paired with an aversive or appetitive cue (5, 7), sugges...

“…During fear extinction, a previously conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US), a procedure that induces a progressive decrease in the magnitude and probability of learned fear responses, including freezing behavior. However, extinction does not erase the original fear memory; rather, it promotes the formation of a new inhibitory memory that reduces fear to the CS (2). Extinguished fear is highly context dependent, insofar as CS presentation outside the extinction context results in the recovery of the previously conditioned fear response, a phenomenon known as fear renewal (3).…”

mentioning

confidence: 99%

“…Owing to substantial progress toward understanding the neural mechanisms underlying the context specificity of fear extinction, there is now a general consensus that, for auditory fear conditioning, extinction involves three main structures: the amygdala, hippocampus (HIPP), and prefrontal cortex (PFC) (2,(5)(6)(7)(8). However, the neuronal interactions between these structures that underlie contextual retrieval of fear memory after extinction remain to be elucidated.…”

mentioning

confidence: 99%

“…This problem is further complicated by the fact that neither the amygdala nor the PFC is a homogeneous structure. Among the substructures of the amygdala, the central, basal, and lateral nuclei (Ce, Ba, and La, respectively) have been implicated in the contextual regulation of extinction memories (2). There is also growing evidence for subregional differences within the PFC: the infralimbic (IL) and prelimbic (PL) cortices have opposite influences on fear expression, inhibiting and exciting amygdala output, respectively (9-11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Functional anatomy of neural circuits regulating fear and extinction

Knapska¹,

Macias

Mikosz³

et al. 2012

Self Cite

166

132

The memory of fear extinction is context dependent: fear that is suppressed in one context readily renews in another. Understanding of the underlying neuronal circuits is, therefore, of considerable clinical relevance for anxiety disorders. Prefrontal cortical and hippocampal inputs to the amygdala have recently been shown to regulate the retrieval of fear memories, but the cellular organization of these projections remains unclear. By using anterograde tracing in a transgenic rat in which neurons express a dendriticallytargeted PSD-95:Venus fusion protein under the control of a c-fos promoter, we found that, during the retrieval of extinction memory, the dominant input to active neurons in the lateral amygdala was from the infralimbic cortex, whereas the retrieval of fear memory was associated with greater hippocampal and prelimbic inputs. This pattern of retrieval-related afferent input was absent in the central nucleus of the amygdala. Our data show functional anatomy of neural circuits regulating fear and extinction, providing a framework for therapeutic manipulations of these circuits.gene expression | hippocampus | prefrontal cortex | learning and memory T here is an increasing interest in the neural mechanisms underlying extinction of learned fear, in part because fear extinction is a useful model for exposure-based therapies for the treatment of human anxiety disorders, such as phobias and posttraumatic stress disorder (1). During fear extinction, a previously conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US), a procedure that induces a progressive decrease in the magnitude and probability of learned fear responses, including freezing behavior. However, extinction does not erase the original fear memory; rather, it promotes the formation of a new inhibitory memory that reduces fear to the CS (2). Extinguished fear is highly context dependent, insofar as CS presentation outside the extinction context results in the recovery of the previously conditioned fear response, a phenomenon known as fear renewal (3). The return of fear after extinction is a considerable challenge for the efficacy of exposure-based therapies (4). Therefore, identification of brain structures and neuronal circuits selectively implicated in extinction vs. renewal of fear is of great importance.Owing to substantial progress toward understanding the neural mechanisms underlying the context specificity of fear extinction, there is now a general consensus that, for auditory fear conditioning, extinction involves three main structures: the amygdala, hippocampus (HIPP), and prefrontal cortex (PFC) (2, 5-8). However, the neuronal interactions between these structures that underlie contextual retrieval of fear memory after extinction remain to be elucidated. This problem is further complicated by the fact that neither the amygdala nor the PFC is a homogeneous structure. Among the substructures of the amygdala, the central, basal, and lateral nuclei (Ce, Ba, and La, respectively) have been impl...