Impact of Life History on Fear Memory and Extinction

Abstract

Behavioral profiles are strongly shaped by an individual's whole life experience. The accumulation of negative experiences over lifetime is thought to promote anxiety-like behavior in adulthood ("allostatic load hypothesis"). In contrast, the "mismatch hypothesis" of psychiatric disease suggests that high levels of anxiety-like behavior are the result of a discrepancy between early and late environment. The aim of the present study was to investigate how different life histories shape the expression of anxiety-like behavior and modulate fear memory. In addition, we aimed to clarify which of the two hypotheses can better explain the modulation of anxiety and fear. For this purpose, male mice grew up under either adverse or beneficial conditions during early phase of life. In adulthood they were further subdivided in groups that either matched or mismatched the condition experienced before, resulting in four different life histories. The main results were: (i) Early life benefit followed by late life adversity caused decreased levels of anxiety-like behavior. (ii) Accumulation of adversity throughout life history led to impaired fear extinction learning. Late life adversity as compared to late life benefit mainly affected extinction training, while early life adversity as compared to early life benefit interfered with extinction recall. Concerning anxiety-like behavior, the results do neither support the allostatic load nor the mismatch hypothesis, but rather indicate an anxiolytic effect of a mismatched early beneficial and later adverse life history. In contrast, fear memory was strongly affected by the accumulation of adverse experiences over the lifetime, therefore supporting allostatic load hypothesis. In summary, this study highlights that anxiety-like behavior and fear memory are differently affected by specific combinations of adverse or beneficial events experienced throughout life.

Keywords: allostatic load; anxiety; behavior; conditioning; fear learning; freezing; mismatch.

Figure 1

Overview of the four different life histories and sham-handled mice. The figure shows the five different experimental groups of male C57BL/6J mice, subdivided into four different life histories (AA, AB, BA, and BB) and a sham-handled group (SH). Every life history comprises an early and a late phase, each being either adverse or beneficial. Sham-handled mice received no modifications in their social environment (n = 138) (figure modified after Bodden et al., 2015).

Figure 2

Schematic drawing of experimental paradigm of fear conditioning and extinction. (A) Mice were placed in the fear conditioning chamber (context A) and adapted twice (inter-trial interval: 6 h) to a neutral tone (neutral conditioned stimulus, CS−; 2.5 kHz, 85 dB). CS−, indicated by striped bars, was presented 6 times for 10 s with an interval of 20 s. (B) C57BL/6J mice underwent fear conditioning in context (A). Conditioned stimulus (CS+; 10 kHz, 85 dB, 10 s), indicated by black bars, was presented 3 times (interval: 30 s) followed by a 0.4 mA electrical stimulus (1 s) indicated by arrows. This was performed twice with an inter-trial interval of 6 h. (C) Animals were placed into the recording chamber (context B). After 120 s CS− was presented 4 times (interval: 30 s) followed by 4 CS+ presentations (interval: 30 s) after 40 s. This was performed 6 times (extinction training; inter-session interval: 30 min). Twenty four hours later fear extinction recall was tested with one final repetition.

Figure 3

Impact of life history on anxiety-like behavior and exploration. (A) Time spent on open arms of EPM, (B) Sum of entries into open and closed arms of EPM, (C), Time spent in and (D) Entries into light compartment of DL, (E) Time spent in center and (F) Distance traveled in OF, displayed by male mice grown up in an early adverse (AA and AB) or beneficial (BA and BB) environment and provided with later matching (AA and BB) or mismatching (AB and BA) living conditions in adulthood. Data are given as means +SEM. Statistics: ANOVA; post-hoc testing: Bonferroni. ^*p < 0.05; ^**p < 0.01; ^***p < 0.001. Animals per group: AA = 28, AB = 27, BA = 28, BB = 27, SH = 28.

Figure 4

Stacked bar graph illustrates the impact of life history on total defensive behavior (freezing, risk-assessment, flight) during behavioral baseline (preCS− in R1). Total defense (freezing, risk-assessment, flight; % of time) scored for behavioral baseline (preCS− in R1) showed a significant increase for AA and BA animals compared to AB, BB, and SH life histories prior first stimulus presentation. Analysis of proportional values for individual behaviors revealed that this effect was due to a significant increase in risk-assessment. Life histories: AA, early and late adversity; AB, early adversity and late benefit; BA, early benefit and late adversity; BB, early and late benefit; SH, sham-handled. ^***p < 0.001; animals per group: n = 15.

Figure 5

Stacked bar graphs illustrate the expression of total defensive behaviors in response to CS+ presentation during fear retrieval (R1), extinction (R6), and extinction recall (E). Total defense (TD; freezing, risk-assessment, flight; % of time) scored for mean of all four CS+ presentations during R1, R6, and E showed that (A) during R1, all groups similarly expressed defensive behaviors upon stimulus presentation. (B) R6: At the end of extinction training, AA and BA animals showed significantly elevated levels of TD in comparison to other life histories, which were mainly a result of significantly prolonged freezing periods upon stimulus presentation. (C) E: AA animals showed significantly increased TD in comparison to BB and SH animals due to elevated freezing. Life histories: AA, early and late adversity; AB, early adversity and late benefit; BA, early benefit and late adversity; BB, early and late benefit; SH, sham-handled. ^**p < 0.01; ^***p < 0.001; animals per group: n = 15.

Figure 6

Expression of freezing (% of time) in response to first CS+ presentation during retrieval (R1), extinction (R6), and extinction recall (E) dependent on different life histories. (A) Life histories: early and late adversity (AA, top left) mice showed no decline in freezing. Early and late benefit (BB, low right) was significantly accompanied with the capability of extinction learning (R1 to R6) and extinction memory consolidation (R1 to E). Mismatched life history mice (AB and BA, top right and low left) extinguished learned fear, though consolidation of extinction memory (E) was affected. (B) Sham-handled animals significantly extinguished learned fear and consolidated extinction memory. ^**p < 0.01; ^***p < 0.001; animals per group: n = 15.

Figure 7

Between-group comparison of freezing (% of time) in response to first CS+ presentation during fear retrieval (R1), extinction (R6), and extinction recall (E). (A) R1: No significant differences were detected between groups, implying that all animals acquired conditioned fear memory to the same extent. (B) R6: Comparison between groups revealed that matched life history had the strongest diverging effect during fear extinction learning. Early and late adversity (AA) compromised extinction training, while early and late benefit (BB) significantly facilitated extinction learning. Animals experiencing late life adversity (BA) also showed significantly elevated freezing, whereas late life benefit (AB) as well as sham-handled mice (SH) showed moderate levels. (C) E: Mice subdued to early life adversity (AA and AB), were significantly negatively affected when tested for extinction memory consolidation in comparison to sham-handled mice. Animals of early life benefit showed moderate expression of freezing in response to CS+. ^*p < 0.05; ^**p < 0.01; ^***p < 0.001; animals per group: n = 15.