Impaired extinction of fear and maintained amygdala‐hippocampal theta synchrony in a mouse model of temporal lobe epilepsy

Lesting, Jörg; Geiger, Matthias F.; Narayanan, Rajeevan T.; Pape, Hans‐Christian; Seidenbecher, Thomas

doi:10.1111/j.1528-1167.2010.02758.x

Cited by 35 publications

(21 citation statements)

References 54 publications

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“…Conditioned fear (freezing) was analyzed during the first presentations of the conditioned stimulus (CS+) in the first retrieval sessions (R1), at the end of extinction training (R6) and during recall of fear extinction (E) twenty-four hours later. We have focused on the first CS+ presentation, in line with previous studies related to theta oscillations [5]–[7], [21], [25]–[27]. The rational is that freezing behavior has proven to be a good measure of conditioned fear in mice, with the additional consideration that the degree of freezing tends to decline upon successive CS+ retrieval [28].…”

Section: Resultsmentioning

confidence: 93%

“…It previously has been shown that the amygdalo-hippocampal-prefrontal network exhibits an increase in theta synchrony during CS+ presentations after fear conditioning, an overall decline in theta synchrony during extinction learning, and a theta rebound particularly involving the IL-PFC during extinction recall [5], [21], [25]–[27], [33]. However, because conclusions on changes in theta activity were derived from LFP recordings, the contribution of subpopulations of neurons and their regional or directional specificity could not be disentangled.…”

Section: Discussionmentioning

confidence: 99%

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Directional Theta Coherence in Prefrontal Cortical to Amygdalo-Hippocampal Pathways Signals Fear Extinction

et al. 2013

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Theta oscillations are considered crucial mechanisms in neuronal communication across brain areas, required for consolidation and retrieval of fear memories. One form of inhibitory learning allowing adaptive control of fear memory is extinction, a deficit of which leads to maladaptive fear expression potentially leading to anxiety disorders. Behavioral responses after extinction training are thought to reflect a balance of recall from extinction memory and initial fear memory traces. Therefore, we hypothesized that the initial fear memory circuits impact behavioral fear after extinction, and more specifically, that the dynamics of theta synchrony in these pathways signal the individual fear response. Simultaneous multi-channel local field and unit recordings were obtained from the infralimbic prefrontal cortex, the hippocampal CA1 and the lateral amygdala in mice. Data revealed that the pattern of theta coherence and directionality within and across regions correlated with individual behavioral responses. Upon conditioned freezing, units were phase-locked to synchronized theta oscillations in these pathways, characterizing states of fear memory retrieval. When the conditioned stimulus evoked no fear during extinction recall, theta interactions were directional with prefrontal cortical spike firing leading hippocampal and amygdalar theta oscillations. These results indicate that the directional dynamics of theta-entrained activity across these areas guide changes in appraisal of threatening stimuli during fear memory and extinction retrieval. Given that exposure therapy involves procedures and pathways similar to those during extinction of conditioned fear, one therapeutical extension might be useful that imposes artificial theta activity to prefrontal cortical-amygdalo-hippocampal pathways that mimics the directionality signaling successful extinction recall.

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Directional Theta Coherence in Prefrontal Cortical to Amygdalo-Hippocampal Pathways Signals Fear Extinction

et al. 2013

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“…In fact, the extended amygdala is involved in fear and anxiety responses [38,39], and TLE patients with ictal fear have atrophy of the amygdala [40]. Although high dose of pilocarpine in the experimental animals induces neuronal damage in the amygdaloid complex as shown in the present study, the relation between pilocarpine model of TLE and fear/anxiety response is controversial: high dose of pilocarpine reduces anxiety-like behavior and impair fear conditioning [41], increases anxiety-like behavior [42] or impairs extinction of fear memory with no differences in basic anxiety levels [43]. These conflicting results might depend on the severity of neuronal damage due to differences in experimental conditions, such as animal species (rat or mouse), strains of animals and doses of pilocarpine.…”

Section: Discussionmentioning

confidence: 94%

Increased Histone H3 Phosphorylation in Neurons in Specific Brain Structures after Induction of Status Epilepticus in Mice

et al. 2013

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Status epilepticus (SE) induces pathological and morphological changes in the brain. Recently, it has become clear that excessive neuronal excitation, stress and drug abuse induce chromatin remodeling in neurons, thereby altering gene expression. Chromatin remodeling is a key mechanism of epigenetic gene regulation. Histone H3 phosphorylation is frequently used as a marker of chromatin remodeling and is closely related to the upregulation of mRNA transcription. In the present study, we analyzed H3 phosphorylation levels in vivo using immunohistochemistry in the brains of mice with pilocarpine-induced SE. A substantial increase in H3 phosphorylation was detected in neurons in specific brain structures. Increased H3 phosphorylation was dependent on neuronal excitation. In particular, a robust upregulation of H3 phosphorylation was detected in the caudate putamen, and there was a gradient of phosphorylated H3+ (PH3+) neurons along the medio-lateral axis. After unilateral ablation of dopaminergic neurons in the substantia nigra by injection of 6-hydroxydopamine, the distribution of PH3+ neurons changed in the caudate putamen. Moreover, our histological analysis suggested that, in addition to the well-known MSK1 (mitogen and stress-activated kinase)/H3 phosphorylation/c-fos pathway, other signaling pathways were also activated. Together, our findings suggest that a number of genes involved in the pathology of epileptogenesis are upregulated in PH3+ brain regions, and that H3 phosphorylation is a suitable indicator of strong neuronal excitation.

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“…In this context, prior studies have found that reward-learning in cats is associated with greater coherence of gamma oscillations between the BA and striatum (Popescu et al, 2009). Finally, although theta power coherence between the lateral amygdala and IL has also been linked to fear extinction learning in mice (Lesting et al, 2011a; Lesting et al, 2011b; Narayanan et al, 2011), this was not specifically tested here and no strain differences in theta power within the PL or vmPFC per se were found.…”

Section: Discussionmentioning

confidence: 95%

Prefrontal single-unit firing associated with deficient extinction in mice

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Whittle

Flynn

et al. 2014

Neurobiology of Learning and Memory

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The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal cortex (vmPFC) has been found to promote extinction, whereas the prelimbic cortex (PL) demonstrates an opposing, pro-fear, function. Studies employing in vivo electrophysiological recordings have observed that while increased IL single-unit firing and bursting predicts robust extinction retrieval, increased PL firing can correlate with sustained fear and poor extinction. These relationships between single-unit firing and extinction do not hold under all experimental conditions, however. In the current study, we further investigated the relationship between vmPFC and PL single-unit firing and extinction using inbred mouse models of intact (C57BL/6J, B6) and deficient (129S1/SvImJ, S1) extinction strains. Simultaneous single-unit recordings were made in the PL and vmPFC (encompassing IL) as B6 and S1 mice performed extinction training and retrieval. Impaired extinction retrieval in S1 mice was associated with elevated PL single-unit firing, as compared to firing in extinguishing B6 mice, consistent with the hypothesized pro-fear contribution of PL. Analysis of local field potentials also revealed significantly higher gamma power in the PL of Sthan B6 mice during extinction training and retrieval. In the vmPFC, impaired extinction in S1 mice was also associated with exaggerated single-unit firing, relative to B6 mice. This is in apparent contradiction to evidence that IL activity promotes extinction, but could reflect a (failed) compensatory effort by the vmPFC to mitigate fear-promoting activity in other regions, such as the PL or amygdala. In support of this hypothesis, augmenting IL activity via direct infusion of the GABAA receptor antagonist picrotoxin rescued impaired extinction retrieval in S1 mice. Chronic fluoxetine treatment produced modest reductions in fear during extinction retrieval and increased the number of Zif268-labeled cells in layer II of IL, but failed to increase vmPFC single-unit firing. Collectively, these findings further support the important contribution these cortical regions play in determining the balance between robust extinction on the one hand, and sustained fear on the other. Elucidating the precise nature of these roles could help inform understanding of the pathophysiology of fear-related anxiety disorders.

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Impaired extinction of fear and maintained amygdala‐hippocampal theta synchrony in a mouse model of temporal lobe epilepsy

Cited by 35 publications

References 54 publications

Directional Theta Coherence in Prefrontal Cortical to Amygdalo-Hippocampal Pathways Signals Fear Extinction

Directional Theta Coherence in Prefrontal Cortical to Amygdalo-Hippocampal Pathways Signals Fear Extinction

Increased Histone H3 Phosphorylation in Neurons in Specific Brain Structures after Induction of Status Epilepticus in Mice

Prefrontal single-unit firing associated with deficient extinction in mice

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