The effects of the early pro-inflammatory stress on reconsolidation and extinction of fear memory in male Wistar rats

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The influence of neuroinflammation on the reconsolidation of fear memory is poorly studied, using only acute but not the remote effects of intoxication. In the present work, we investigated the influence of remote pro-inflammatory lipopolysaccharide (LPS) stress on the reconsolidation and extinction of fear memory in adult male Wistar rats. On the 3rd and 5th PND, during the critical period of postnatal ontogenesis, the rats received subcutaneous injections of LPS (50 μg/kg) or saline. At 120 PND, the rats acquired a fear conditioning by the use of three pairings of tone presentations and shock. Twenty-four hours after training, one group of rats was reactivated in the same context and by a single tone presentation (Re+), while the other group remained in the home cages, (Re‒). A day later, in retention test 1, the freezing reaction was measured in all groups. After test 1, the groups underwent extinction for two days with 10 tones on each day, followed by retention test 2. In test 1, the contextual memory of the Re+ vs. Re‒ saline groups were impaired as opposed to cue memory. The early LPS stress equalized the level of freezing of both Re+ and Re‒ groups, indicating that early neuroinflammation impairs the updating of the contextual fear memory. The differences in the level of freezing between the Re+ and Re‒ groups persisted during extinction and in test 2. The extinction of the LPS group was slower than that in the SAL group. Thus, remote neuroinflammation impairs the process of memory updating and extinction of conditioned fear.

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Sobre autores

Grigory Grigoryan

Institute of Higher Nervous Activity and Neurophysiology RAS

Autor responsável pela correspondência
Email: grigorygrigoryan@hotmail.com
Rússia, Moscow

Irina Pavlova

Institute of Higher Nervous Activity and Neurophysiology RAS

Email: grigorygrigoryan@hotmail.com
Rússia, Moscow

Nadezda Broshevitskaya

Institute of Higher Nervous Activity and Neurophysiology RAS

Email: grigorygrigoryan@hotmail.com
Rússia, Moscow

Anastasia Shvadchenko

Institute of Higher Nervous Activity and Neurophysiology RAS

Email: grigorygrigoryan@hotmail.com
Rússia, Moscow

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2. Fig. 1. The timeline of the experiment.

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3. Fig. 2. The effects of neonatal LPS administration and memory reactivation on the levels of freezing time during fear conditioning (a), context/sound reminder (b) and Retention Test 1 (c). On the abscissa axis are time intervals. On A 1, 2, 3 – the numbers of sound stimuli; the intermediate values are intersignal intervals; before the first sound stimulus – interval of the chamber examination, after the 3d sound –interval of aftereffect; on (b, c) – context or sound. On the ordinate axis is the percentage of freezing time from the duration of each interval. SAL: a group of rats received saline injections in early ontogenesis; LPS: a group of rats received injections of LPS. n – the number of rats in the group. *: statistically significant differences between the Re‒ and Re+ groups (p < 0.05, factorial ANOVA, post hoc analysis, Newman-Keul test).

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4. Fig. 3. The effects of neonatal LPS administration and memory reactivation on the levels of freezing time during extinction 1 (a), (b) and 2 (c), (d), and Retention Test 2 (e). On the abscissa axis on (a) and (c) are the number of sounds, on (b), (d), (e) – SAL and LPS groups. On the ordinate axis on (а), (с) is the percentage of freezing time from the duration of each sound, on (b), (d) – the percentage of freezing time, averaged by all sound presentations. *: statistically significant differences between the Re+ and Re‒ groups; +: differences between SAL and LPS groups (p < 0.05, factorial ANOVA, post hoc analysis, Newman-Keul test). The rest designations are the same as in Fig. 2.

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5. Fig. 4. The influence of immune activation in early ontogenesis on the expression of the mRNA genes Tnf-α (a), Tgf-beta1 (b), Il-1beta (c), Il-6 (d) in the ventromedial hypothalamus (HPT), dorsal hippocampus (HPC), amygdala (AM), medial prefrontal cortex (PFC). The abscissa axis is the brain structure; the ordinate axis is the relative gene expression. *: statistically significant differences between the SAL and LPS groups (p < 0.05, Mann-Whitney U Test).

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