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Social Defeat: Impact on Fear Extinction and Amygdala-Prefrontal Cortical Theta Synchrony in 5-HTT Deficient Mice

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Narayanan, Venu, Heiming, Rebecca S., Jansen, Friederike, Lesting, Jörg, Sachser, Norbert, Pape, Hans-Christian, Seidenbecher, Thomas·2011·PLoS ONE
DOI 10.1371/journal.pone.0022600PMC PMC3144906
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Abstract

Emotions, such as fear and anxiety, can be modulated by both environmental and genetic factors. One genetic factor is for example the genetically encoded variation of the serotonin transporter (5-HTT) expression. In this context, the 5-HTT plays a key role in the regulation of central 5-HT neurotransmission, which is critically involved in the physiological regulation of emotions including fear and anxiety. However, a systematic study which examines the combined influence of environmental and genetic factors on fear-related behavior and the underlying neurophysiological basis is missing. Therefore, in this study we used the 5-HTT-deficient mouse model for studying emotional dysregulation to evaluate consequences of genotype specific disruption of 5-HTT function and repeated social defeat for fear-related behaviors and corresponding neurophysiological activities in the lateral amygdala (LA) and infralimbic region of the medial prefrontal cortex (mPFC) in male 5-HTT wild-type (+/+), homo- (-/-) and heterozygous (+/-) mice. Naive males and experienced losers (generated in a resident-intruder paradigm) of all three genotypes, unilaterally equipped with recording electrodes in LA and mPFC, underwent a Pavlovian fear conditioning. Fear memory and extinction of conditioned fear was examined while recording neuronal activity simultaneously with fear-related behavior. Compared to naive 5-HTT+/+ and +/- mice, 5-HTT-/- mice showed impaired recall of extinction. In addition, 5-HTT-/- and +/- experienced losers showed delayed extinction learning and impaired recall of extinction. Impaired behavioral responses were accompanied by increased theta synchronization between the LA and mPFC during extinction learning in 5-HTT-/- and +/- losers. Furthermore, impaired extinction recall was accompanied with increased theta synchronization in 5-HTT-/- naive and in 5-HTT-/- and +/- loser mice. In conclusion, extinction learning and memory of conditioned fear can be modulated by both the 5-HTT gene activity and social experiences in adulthood, accompanied by corresponding alterations of the theta activity in the amygdala-prefrontal cortex network.

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Figure 1 Schematic representation of experimental design. During adaptation, animals were exposed to six CS− only and the entire session was repeated six hours later (Day 1). Conditioning took place on the following day (Day 2): the CS+ was presented three times, co-terminated with an electric footshock, during each conditioning session. Conditioned fear memory was tested on day 3 ( = extinction training); six consecutive extinction training sessions were carried out (R1 to R6), with 30 minutes intervals between sessions. Extinction memory was recalled on day 4 in one session (E). All sessions on day 3 and 4 were identical, and contained four CS− and four CS+ presentations. Stimulus parameters and intervals are marked.
Figure 1 Schematic representation of experimental design. During adaptation, animals were exposed to six CS− only and the entire session was repeated six hours later (Day 1). Conditioning took place on the following day (Day 2): the CS+ was presented three times, co-terminated with an electric footshock, during each conditioning session. Conditioned fear memory was tested on day 3 ( = extinction training); six consecutive extinction training sessions were carried out (R1 to R6), with 30 minutes intervals between sessions. Extinction memory was recalled on day 4 in one session (E). All sessions on day 3 and 4 were identical, and contained four CS− and four CS+ presentations. Stimulus parameters and intervals are marked.CC BY · PubMed Central
Figure 2 Freezing behavior and theta synchronization in naive 5-HTT mice at different stages of fear extinction. A) Freezing behavior during the first CS+ across R1-R6 and E in all three genotypes. Freezing in all the three genotypes declined from R1-R6, indicating the standard extinction of fear memory. Twenty four hours later, when all the three genotypes were tested for fear extinction recall, 5-HTT−/− mice showed significant impaired extinction recall (E), represented by significantly higher levels of freezing compared to 5-HTT+/− and 5-HTT+/+ mice (p<0.001). B) Stimulus-related theta correlation in 5-HTT mice at different stages of fear extinction. Averaged cross-correlation during the presentation of the first CS+ between LA and IL of mPFC during extinction (R1-R6) and extinction recall (E) in 5-HTT naive mice is shown. When compared with 5-HTT+/+, 5-HTT−/− mice showed significantly increased cross-correlation during extinction training (note significant at R4 and R6; p<0.05). In 5-HTT−/− mice, the correlation values remained high across the extinction training and being significantly higher than for 5-HTT+/+ mice during E. C) Freezing-related averaged cross-correlation during the first CS+ between LA and IL of mPFC during extinction training (R1-R6) and extinction recall (E) in 5-HTT naive mice. Note, that the 5-HTT−/− mice showed significantly increased cross-correlation during extinction recall (p<0.05, compared to 5-HTT+/− and 5-HTT+/+− mice). Values are mean ± SEM; *p<0.05, #p<0.001.
Figure 2 Freezing behavior and theta synchronization in naive 5-HTT mice at different stages of fear extinction. A) Freezing behavior during the first CS+ across R1-R6 and E in all three genotypes. Freezing in all the three genotypes declined from R1-R6, indicating the standard extinction of fear memory. Twenty four hours later, when all the three genotypes were tested for fear extinction recall, 5-HTT−/− mice showed significant impaired extinction recall (E), represented by significantly higher levels of freezing compared to 5-HTT+/− and 5-HTT+/+ mice (p<0.001). B) Stimulus-related theta correlation in 5-HTT mice at different stages of fear extinction. Averaged cross-correlation during the presentation of the first CS+ between LA and IL of mPFC during extinction (R1-R6) and extinction recall (E) in 5-HTT naive mice is shown. When compared with 5-HTT+/+, 5-HTT−/− mice showed significantly increased cross-correlation during extinction training (note significant at R4 and R6; p<0.05). In 5-HTT−/− mice, the correlation values remained high across the extinction training and being significantly higher than for 5-HTT+/+ mice during E. C) Freezing-related averaged cross-correlation during the first CS+ between LA and IL of mPFC during extinction training (R1-R6) and extinction recall (E) in 5-HTT naive mice. Note, that the 5-HTT−/− mice showed significantly increased cross-correlation during extinction recall (p<0.05, compared to 5-HTT+/− and 5-HTT+/+− mice). Values are mean ± SEM; *p<0.05, #p<0.001.CC BY · PubMed Central
Figure 3 Theta synchronization in different stages of fear extinction in 5-HTT (+/+ and −/−) (A) control and (B) socially defeated (loser) mice. Local field potentials (LFPs) from LA, and PFC were simultaneously recorded during early retrieval (R1) and extinction recall while monitoring the animals' behavior. The figure shows representative LFP traces (20 s) for each recording area from R1 and E during the first CS+ presentation for a control and a loser 5-HTT+/+ and −/− mouse, respectively. The behavior of the mice at the particular time is indicated above the traces (f, freezing; r, risk assessment; e, exploration; g, grooming; q, quiet), and wavelet transforms of the 20 s segments for each recording area are displayed underneath. The (a) stimulus- and (b) freezing-related cross-correlations are shown beneath the LFP traces, indicating theta synchronization. Independent of the genotype, both the control and socially defeated mice showed increased freezing behavior accompanied by high stimulus- and freezing-related theta synchrony at R1. Note, during recall of extinction (E), the 5-HTT−/− control and loser mice showed increased freezing behavior and increased theta synchrony, whereas the 5-HTT+/+ control and loser mice showed low freezing behavior and low theta synchronization between LA and PFC.
Figure 3 Theta synchronization in different stages of fear extinction in 5-HTT (+/+ and −/−) (A) control and (B) socially defeated (loser) mice. Local field potentials (LFPs) from LA, and PFC were simultaneously recorded during early retrieval (R1) and extinction recall while monitoring the animals' behavior. The figure shows representative LFP traces (20 s) for each recording area from R1 and E during the first CS+ presentation for a control and a loser 5-HTT+/+ and −/− mouse, respectively. The behavior of the mice at the particular time is indicated above the traces (f, freezing; r, risk assessment; e, exploration; g, grooming; q, quiet), and wavelet transforms of the 20 s segments for each recording area are displayed underneath. The (a) stimulus- and (b) freezing-related cross-correlations are shown beneath the LFP traces, indicating theta synchronization. Independent of the genotype, both the control and socially defeated mice showed increased freezing behavior accompanied by high stimulus- and freezing-related theta synchrony at R1. Note, during recall of extinction (E), the 5-HTT−/− control and loser mice showed increased freezing behavior and increased theta synchrony, whereas the 5-HTT+/+ control and loser mice showed low freezing behavior and low theta synchronization between LA and PFC.CC BY · PubMed Central
Figure 4 Freezing behavior and theta synchronization in 5-HTT control and loser mice at different stages of fear extinction. A) Averaged freezing behavior, D) stimulus-related and G) freezing-related LA-mPFC theta correlation during the first CS+ across R1-R6 and E in 5-HTT+/+ control and loser mice. 5-HTT+/+ loser mice showed a slightly delayed extinction learning (significant at R4) and impaired recall of extinction (significant at E) accompanied by increased stimulus-related LA-mPFC synchronization during extinction training (significant at R4). Compared to controls, 5-HTT+/+ loser mice showed increased freezing-related theta synchronization at early retrieval sessions (significant at R2). B) Averaged freezing behavior, E) stimulus-related and H) freezing-related LA-mPFC theta correlation during the first CS+ across R1-R6 and E in 5-HTT+/− control and loser mice. 5-HTT+/− loser mice showed a significantly delayed extinction learning (R3, R4) and impaired recall of extinction (E) accompanied by significant increased stimulus-related LA-mPFC synchronization across extinction learning and recall of extinction. Note, compared to controls, 5-HTT+/− loser mice showed a highly significant increase of freezing-related theta synchronization across extinction learning (R1-R6) and during recall of extinction (E). C) Averaged freezing behavior, F) stimulus-related and I) freezing-related LA-mPFC theta correlation during the first CS+ across R1-R6 and E in 5-HTT−/− control and loser mice. 5-HTT−/− loser mice showed a significant delayed extinction learning (R4, R5). Impaired recall of extinction is indicated by high freezing level in both groups. The stimulus-related correlations in 5-HTT−/− loser mice were not significantly different from 5-HTT−/− controls, but both the groups showed high synchronized LA-mPFC activity across R1-R6 and at E. Periods of freezing are accompanied by high freezing-related theta synchronization during extinction learning in 5 HTT−/− control (R1-R3) and 5 HTT−/− loser mice (R1-R6) and during extinction recall in both groups. Values are mean ± SEM; *p<0.05, **p<0.01, #p<0.001.
Figure 4 Freezing behavior and theta synchronization in 5-HTT control and loser mice at different stages of fear extinction. A) Averaged freezing behavior, D) stimulus-related and G) freezing-related LA-mPFC theta correlation during the first CS+ across R1-R6 and E in 5-HTT+/+ control and loser mice. 5-HTT+/+ loser mice showed a slightly delayed extinction learning (significant at R4) and impaired recall of extinction (significant at E) accompanied by increased stimulus-related LA-mPFC synchronization during extinction training (significant at R4). Compared to controls, 5-HTT+/+ loser mice showed increased freezing-related theta synchronization at early retrieval sessions (significant at R2). B) Averaged freezing behavior, E) stimulus-related and H) freezing-related LA-mPFC theta correlation during the first CS+ across R1-R6 and E in 5-HTT+/− control and loser mice. 5-HTT+/− loser mice showed a significantly delayed extinction learning (R3, R4) and impaired recall of extinction (E) accompanied by significant increased stimulus-related LA-mPFC synchronization across extinction learning and recall of extinction. Note, compared to controls, 5-HTT+/− loser mice showed a highly significant increase of freezing-related theta synchronization across extinction learning (R1-R6) and during recall of extinction (E). C) Averaged freezing behavior, F) stimulus-related and I) freezing-related LA-mPFC theta correlation during the first CS+ across R1-R6 and E in 5-HTT−/− control and loser mice. 5-HTT−/− loser mice showed a significant delayed extinction learning (R4, R5). Impaired recall of extinction is indicated by high freezing level in both groups. The stimulus-related correlations in 5-HTT−/− loser mice were not significantly different from 5-HTT−/− controls, but both the groups showed high synchronized LA-mPFC activity across R1-R6 and at E. Periods of freezing are accompanied by high freezing-related theta synchronization during extinction learning in 5 HTT−/− control (R1-R3) and 5 HTT−/− loser mice (R1-R6) and during extinction recall in both groups. Values are mean ± SEM; *p<0.05, **p<0.01, #p<0.001.CC BY · PubMed Central
Figure 5 Freezing behavior and theta synchronization in 5-HTT loser mice (all genotypes) at different stages of fear extinction. A) Freezing behavior during the first CS+ across R1–R6 and E. Freezing in all three genotypes declined from R1-R6, indicating the standard extinction of fear memory, but both 5-HTT+/− and −/− mice showed delayed extinction (in −/−, significant at R4, R5 and in +/− significant at R5). Twenty four hours later, when all three genotypes were tested for fear extinction recall, 5-HTT−/− mice showed significantly higher freezing behavior (impaired recall) than 5-HTT+/+ and +/− mice, and 5-HTT +/− were significantly different from 5-HTT+/+ loser mice. B) Stimulus-related theta synchronization in 5-HTT loser mice at different stages of fear extinction. Compared with 5-HTT+/+ (significant at R5) and 5-HTT−/− losers (significant at R3 and R5), the 5-HTT+/− loser mice showed a significantly higher correlation during extinction. 5-HTT +/− and −/− loser mice displayed significantly higher correlations at extinction recall (E) compared to 5-HTT+/+. C) Freezing-related averaged cross-correlation during the first CS+ between LA and IL of mPFC during extinction training (R1-R6) and extinction recall (E) in 5-HTT loser mice. Note high freezing-related theta synchronization in all three genotypes. Values are mean ± SEM; *p<0.05, #p<0.001 compared to 5-HTT+/+; $p<0.05 compared to 5-HTT+/−.
Figure 5 Freezing behavior and theta synchronization in 5-HTT loser mice (all genotypes) at different stages of fear extinction. A) Freezing behavior during the first CS+ across R1–R6 and E. Freezing in all three genotypes declined from R1-R6, indicating the standard extinction of fear memory, but both 5-HTT+/− and −/− mice showed delayed extinction (in −/−, significant at R4, R5 and in +/− significant at R5). Twenty four hours later, when all three genotypes were tested for fear extinction recall, 5-HTT−/− mice showed significantly higher freezing behavior (impaired recall) than 5-HTT+/+ and +/− mice, and 5-HTT +/− were significantly different from 5-HTT+/+ loser mice. B) Stimulus-related theta synchronization in 5-HTT loser mice at different stages of fear extinction. Compared with 5-HTT+/+ (significant at R5) and 5-HTT−/− losers (significant at R3 and R5), the 5-HTT+/− loser mice showed a significantly higher correlation during extinction. 5-HTT +/− and −/− loser mice displayed significantly higher correlations at extinction recall (E) compared to 5-HTT+/+. C) Freezing-related averaged cross-correlation during the first CS+ between LA and IL of mPFC during extinction training (R1-R6) and extinction recall (E) in 5-HTT loser mice. Note high freezing-related theta synchronization in all three genotypes. Values are mean ± SEM; *p<0.05, #p<0.001 compared to 5-HTT+/+; $p<0.05 compared to 5-HTT+/−.CC BY · PubMed Central
Figure 6 Directionality and time-lag of local field potentials between LA and mPFC at different stages of fear extinction. Negative values indicate mPFC leading, positive values indicate LA leading. A) Time-lag between LA and mPFC in 5-HTT+/+ naive control and loser mice. In controls, the interaction is started with LA (R1, R2), but later directionality between both is driven by the mPFC (R3, R4, R5 and E), and the amygdala-prefrontal cortex interactions are significantly different between R1 and E (Unpaired t-test, * p<0.05). In 5-HTT+/+ loser mice, mPFC is dominating across the entire extinction training, but the directionality changes into LA dominance during E and is significantly different in E between control and loser mice (Unpaired t-test, § p<0.05). B) In both 5-HTT +/− control and loser mice, the mPFC is dominating across R1-R6 and at E. C) In both 5-HTT −/− control and loser mice, the mPFC is leading across R1-R6, but LA is leading in 5-HTT −/− loser mice at E. Values are mean ± SEM.
Figure 6 Directionality and time-lag of local field potentials between LA and mPFC at different stages of fear extinction. Negative values indicate mPFC leading, positive values indicate LA leading. A) Time-lag between LA and mPFC in 5-HTT+/+ naive control and loser mice. In controls, the interaction is started with LA (R1, R2), but later directionality between both is driven by the mPFC (R3, R4, R5 and E), and the amygdala-prefrontal cortex interactions are significantly different between R1 and E (Unpaired t-test, * p<0.05). In 5-HTT+/+ loser mice, mPFC is dominating across the entire extinction training, but the directionality changes into LA dominance during E and is significantly different in E between control and loser mice (Unpaired t-test, § p<0.05). B) In both 5-HTT +/− control and loser mice, the mPFC is dominating across R1-R6 and at E. C) In both 5-HTT −/− control and loser mice, the mPFC is leading across R1-R6, but LA is leading in 5-HTT −/− loser mice at E. Values are mean ± SEM.CC BY · PubMed Central

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Metadata

Authors
Narayanan, V., Heiming, R. S., Jansen, F., Lesting, J., Sachser, N., Pape, H.-C., & Seidenbecher, T.
Affiliations
University of Münster (DE)
Corresponding author
Seidenbecher, Thomas
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-07-27
Volume
6
Issue
7
Pages
e22600
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0022600
PMC
PMC3144906
OpenAlex
W2051845141
Cited by
103
References
104
Citations by year
2025: 1 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 9 · 2018: 8 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 9 · 2013: 22 · 2012: 8
FWCI
6.49
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
Deutsche Forschungsgemeinschaft (TRR‐58, TP A01, SFB TRR 58)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
social defeat, fear extinction, serotonin transporter, 5-HTT knockout mice, lateral amygdala, medial prefrontal cortex, infralimbic cortex, theta synchronization, fear conditioning, fear memory, resident-intruder paradigm, emotional dysregulation, extinction recall
MeSH terms
Action Potentials, Amygdala, Animals, Cortical Synchronization, Extinction, Psychological, Fear, Genotype, Male, Nerve Net, Mental Recall, Social Behavior, Prefrontal Cortex, Mice, Knockout, Freezing Reaction, Cataleptic, Serotonin Plasma Membrane Transport Proteins, Mice

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