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

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Abstract

Влияние нейровоспаления на реконсолидацию памяти о страхе слабо изучено, исследовались только острые, но не отдаленные эффекты интоксикации. В настоящей работе мы изучали влияние отдаленного провоспалительного липополисахаридного (ЛПС) стресса на реконсолидацию и угашение памяти о страхе у взрослых самцов крыс Вистар. На 3-й и 5-й постнатальный день (ПНД), во время критического периода постнатального онтогенеза, крысам подкожно вводили ЛПС (50 мкг/кг, группа LPS) или физиологический раствор (группа SAL). На 120 ПНД у крыс вырабатывали условнорефлекторный страх с помощью трех сочетаний звукового тона и удара током по лапам. Через 24 час после обучения у одной группы крыс проводили реактивацию памяти, помещая их в ту же обстановку и давая одно применение тона (Re+), другая группа крыс оставалась в домашней клетке (Re‒). Через 24 час в тесте 1 на сохранность памяти во всех группах определяли время замирания. После теста 1 в течение двух дней проводили угашение реакции, давая по 10 тонов каждый день, после чего следовал тест 2. В тесте 1 у крыс, получавших SAL, в группе Re+ по сравнению с группой Re‒ была нарушена память об обстановке, но не память о сигнале. После раннего LPS стресса уровень замирания на обстановку в группах Re+ и Re‒ не различался, что свидетельствовало о том, что раннее нейровоспаление ослабляло обновление контекстуальной памяти о страхе. Различия в уровне замирания в группах Re+ и Re‒ сохранялись во время угашения и в тесте 2. В группе LPS угашение реакции было более медленное, чем в группе SAL. Таким образом, отдаленное нейровоспаление нарушает процесс обновления и угашения памяти о страхе.

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About the authors

Grigory A. Grigoryan

Institute of Higher Nervous Activity and Neurophysiology RAS

Author for correspondence.
Email: grigorygrigoryan@hotmail.com
Russian Federation, Moscow

Irina V. Pavlova

Institute of Higher Nervous Activity and Neurophysiology RAS

Email: grigorygrigoryan@hotmail.com
Russian Federation, Moscow

Nadezda D. Broshevitskaya

Institute of Higher Nervous Activity and Neurophysiology RAS

Email: grigorygrigoryan@hotmail.com
Russian Federation, Moscow

Anastasia A. Shvadchenko

Institute of Higher Nervous Activity and Neurophysiology RAS

Email: grigorygrigoryan@hotmail.com
Russian Federation, 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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