Altered anxiety-related and abnormal social behaviors in rats exposed to early life seizures

Abstract

Neonatal seizures are the most common manifestation of neurological dysfunction in the neonate. The prognosis of neonatal seizures is highly variable, and the controversy remains whether the severity, duration, or frequency of seizures may contribute to brain damage independently of its etiology. Animal data indicates that seizures during development are associated with a high probability of long-term adverse effects such as learning and memory impairment, behavioral changes and even epilepsy, which is strongly age dependent, as well as the severity, duration, and frequency of seizures. In preliminary studies, we demonstrated that adolescent male rats exposed to one-single neonatal status epilepticus (SE) episode showed social behavior impairment, and we proposed the model as relevant for studies of developmental disorders. Based on these facts, the goal of this study was to verify the existence of a persistent deficit and if the anxiety-related behavior could be associated with that impairment. To do so, male Wistar rats at 9 days postnatal were submitted to a single episode of SE by pilocarpine injection (380 mg/kg, i.p.) and control animals received saline (0.9%, 0.1 mL/10 g). It was possible to demonstrate that in adulthood, animals exposed to neonatal SE displayed low preference for social novelty, anxiety-related behavior, and increased stereotyped behavior in anxiogenic environment with no locomotor activity changes. On the balance, these data suggests that neonatal SE in rodents leads to altered anxiety-related and abnormal social behaviors.

Keywords: general anxiety; neonatal status epilepticus; pilocarpine; social anxiety; social behavior.

Figure 1

Number of entries into compartments with objects is shown as mean ± standard error. Control group (CTR) n = 14 and Experimental group (EXP), n = 16. The number of entries between compartments did not differ for both groups, but EXP exhibited less number of entries into both compartments. ^***p < 0.0001.

Figure 2

Number of entries (A) and time spent (B) into social (rat) and non-social (object) compartments is shown as mean ± standard error. Control group (CTR) n = 14 and Experimental group (EXP), n = 16. EXP showed less locomotor activity compared to CTR (^***p < 0.0001), but both groups spent more time on the side with unfamiliar rat.

Figure 3

Number of entries (A) and time spent (B) into compartments with familiar and novel rat is shown as mean ± standard error. Control group (CTR) n = 14 and Experimental group (EXP), n = 16. In (A), less number of entries was noted to the EXP (^***p < 0.0001), but both groups exhibited higher number of entries into compartments with unfamiliar rat (EXP, t = 2.65, ^§p < 0.05; CTR, t = 4.46, ^***p < 0.001). In (B), the CTR showed a clear preference for the social novelty spending more time with an unfamiliar rat than did the EXP (^§§p < 0.01, ^**p < 0.01).

Figure 4

Number of snout-snout contacts is shown as mean ± standard error. Control group (CTR), n = 14 and Experimental group (EXP), n = 16. EXP exhibited less preference for the social novelty than did CTR. ^**p < 0.01, ^***p < 0.0001.

Figure 5

Percentage of entries onto the open arms (A), percentage of time spent on the open arms (B) and total entries in both arms (C) are shown as mean ± standard error. Control group (CTR) n = 14 and Experimental group (EXP), n = 16. EXP exhibited less entries (A) and time (B) on the open arms as compared to CTR group (^***p = 0.0008 and ^**p = 0.001). In (C), the locomotor activity was only marginally different between groups (p = 0.055).

Figure 6

Time of immobility (A) and number of grooming episodes (B) are shown as mean ± standard error. Control group (CTR) n = 14 and Experimental group (EXP), n = 16. The EXP exhibited higher time of immobility (A) and grooming episodes (B) as compared to CTR, ^**p = 0.0037, ^***p = 0.0005, respectively.

Figure 7

Central (A), total locomotion (B) and (C) ratio of central to total locomotion are shown as mean ± standard error in both exposures. Control group (CTR) n = 14 and Experimental group (EXP), n = 16. Reduced central locomotion was noted for EXP in both exposures. In CTR, the locomotor activity in central squares decreased significantly during second exposure (A). The total locomotion did not differ between groups, but decreased significantly during 2nd exposure (B). In (C), the ratio of central to total locomotion was significantly less in EXP as compared to CTR, decreased on the 2nd exposure for CTR and was kept unchanged for EXP. ^**p < 0.001, ^***p < 0.0001 and ^§§§p < 0.0001.