Pavlovian fear conditioning as a behavioral assay for hippocampus and amygdala function: cautions and caveats

Maren, Stephen

doi:10.1111/j.1460-9568.2008.06485.x

Cited by 224 publications

(162 citation statements)

References 78 publications

(127 reference statements)

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“…This is consistent with previous data indicating that fear conditioning leads to synaptic plasticity outside the amygdala, including various stages of the auditory pathways (32,33), Hi (34), and mPFC (35).…”

Section: Discussionsupporting

confidence: 82%

“…We focused on the consolidation of classically conditioned fear responses to auditory cues because this form of learning was shown to cause synaptic plasticity in a widely distributed network of structures, including different amygdala nuclei (BLA and central amygdala) (28)(29)(30)(31), multiple stages of the auditory pathways (32,33), Hi (34), and mPFC (35). Thus, auditory fear conditioning constitutes an ideal model to study the role of sleep activity in system-level memory consolidation.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep

Popa

Duvarci

Popescu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

304

244

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Brain activity in sleep plays a crucial role in memory consolidation, an offline process that determines the long-term strength of memory traces. Consolidation efficacy differs across individuals, but the brain activity dynamics underlying these differences remain unknown. Here, we studied how interindividual variability in fear memory consolidation relates to neural activity in brain structures that participate in Pavlovian fear learning. From the end of training to testing 24 h later, some rats showed increased and others decreased conditioned fear responses. We found that overnight bidirectional changes in fear memory were selectively correlated with modifications in theta coherence between the amygdala, medial prefrontal cortex, and hippocampus during paradoxical sleep. Thus, our results suggest that theta coordination in the limbic system may influence interindividual differences in memory consolidation of aversive experiences.amygdala | fear conditioning | prefrontal cortex | hippocampus | Granger causality R ecently formed memories undergo a period of consolidation (1, 2), and neuronal activity taking place during sleep is thought to play a critical role in this process (3-7). Consolidation of emotional memories determines their long-term retention, and interindividual variations in memory performance have been related to various factors affecting consolidation, including neuromodulatory transmission (8), levels of circulating stress hormones (9), or genetic factors (10). Several strongly interconnected brain structures are involved in the formation and maintenance of emotional memories, including the hippocampus (Hi), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) (11-13). The latter structure in particular was shown to mediate the facilitating effects of emotions on memory consolidation (14). Indeed, we form more vivid and enduring memories for emotionally arousing experiences (15). Via the release of peripheral stress hormones (16), emotional arousal causes long-lasting increases in the firing rate of BLA neurons (17), and pharmacologic manipulations that prevent this increased activity interfere with memory for events that took place shortly before, in many learning tasks (18). Importantly, in most learning paradigms, the same interventions performed shortly before testing long-term memory recall have no effect, indicating that the BLA can facilitate the consolidation of memories in other brain structures (14,18).Potentially related to the facilitation of emotional memories by BLA activity, various lines of evidence implicate posttraining paradoxical sleep (PS) in memory consolidation (6,19). These include PS reactivation of brain areas implicated in prior learning (20) and spontaneous replay of waking activity patterns during PS (21). In fact, it was suggested that the distinct pattern of neuronal activity occurring during PS favors memory consolidation (4,22) and that emotional memories are particularly susceptible to this effect (5, 23). Indeed, after fear conditioning, the respons...

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep

Popa

Duvarci

Popescu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

304

244

View full text Add to dashboard Cite

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“…In particular, cued fear conditioning with a tone does not require an intact hippocampus, whereas contextual fear conditioning does (Kim and Fanselow, 1992;Phillips and LeDoux, 1992). The amygdala is important for both contextual and cued-based fear learning (Phillips and LeDoux, 1992), with both the lateral and central nuclei of the amygdala implicated in cued fear conditioning (see Maren, 2008 for a review). Therefore, it is perhaps not surprising that exposure to estrogens, which influence the hippocampus also influence contextual fear conditioning, but not cued fear conditioning.…”

Section: Different Estrogens Did Not Influence Amygdaladependent Cuedmentioning

confidence: 99%

Low Doses of 17α-Estradiol and 17β-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17α- and 17β-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

Barha

Dalton

Galea

2009

Neuropsychopharmacol

110

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Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17b-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17a-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17b-estradiol, estrone, and 17a-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampusindependent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17b-estradiol and 17a-estradiol enhanced, whereas high 17b-estradiol and 17a-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17b-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement therapy, was shown to have either a negative effect or no effect on learning and memory. It may be possible to use 17a-estradiol and lower doses of estrogens as potential alternatives in hormone replacement therapies.

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“…Questions about the ecological validity of the results obtained using the standard Pavlovian fear-conditioning paradigm, in which the animal is placed in a small chamber and given footshocks, have existed for several decades, since findings that conditional responses depend upon the properties of the US and its contextual cues (7,(21)(22)(23). Despite these concerns, many claims about the functional organization of the brain have been based solely on the results of fear-conditioning procedures.…”

mentioning

confidence: 99%

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

Kim¹,

Horovitz

Pellman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

158

132

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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...

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Pavlovian fear conditioning as a behavioral assay for hippocampus and amygdala function: cautions and caveats

Cited by 224 publications

References 78 publications

Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep

Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep

Low Doses of 17α-Estradiol and 17β-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17α- and 17β-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

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

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