Enhancement of Aggression Induced by Isolation Rearing is Associated with a Lack of Central Serotonin

Abstract

Isolation rearing (IR) enhances aggressive behavior, and the central serotonin (5-hydroxytryptamine, 5-HT) system has been linked to IR-induced aggression. However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2^-/- and Lmx1b^-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1b^-/- mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1b^-/- mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1b^-/- mice. Our results link the serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.

Keywords: 5-HT; Aggression; Dopamine; Lmx1b; Social isolation.

Fig. 1

Schematics of experimental methods. A Resident-intruder test. B Open field. C Elevated plus maze. D Beam walking. E Rotarod test. F Acoustic startle response. G Forced swimming. H Tail suspension. I Passive avoidance test. J Morris water maze.

Fig. 2

Central 5-HT-deficient mice showed enhanced aggression. Tph2^−/− (A, C, E) and Lmx1b^−/− mice (B, D, F) showed greater aggression as measured by the frequency of attack, latency to first attack, and average duration of fighting than WT mice in both the socially-reared (Ctl) and isolated (SI) groups (n = 8/group). In the Tph2 group, there was interaction between central 5-HT loss and social isolation on the regulation of frequency and duration, but no interaction on the regulation of latency (F_fre (2, 42) = 10.45, F_lat (2, 42) = 0.2267, F_dur (2, 42) = 4.353). In the Lmx1b group, there was interaction between central 5-HT loss and social isolation on the regulation of frequency and latency, but no interaction on the regulation of duration (F_fre (3, 56) = 22.28, F_lat (3, 56) = 3.924, F_dur (3, 56) = 2.58). Data are represented as mean ± SEM. **P < 0.01 vs WT mice, ^##P < 0.01 vs socially-reared mice.

Fig. 3

Depletion of 5-HT with pCPA increased aggression in WT mice and 5-HT reversed the enhanced aggression in Lmx1b^−/− mice. A, C Levels of 5-HT and 5-HIAA in various brain regions decreased with central pCPA treatment (n = 3/group). E, F, G Aggression increased in WT mice treated with pCAP centrally (n = 8/group). B, D Levels of 5-HT and 5-HIAA in various brain regions increased with central 5-HT treatment (n = 3/group). H, I, J Aggression decreased in Lmx1b^−/− mice treated with 5-HT centrally (n = 8/group). Data represent mean ± SEM. **P < 0.01 vs vehicle-treated group.

Fig. 4

Levels of DA and its metabolites were downregulated in Lmx1b^−/− mice. The levels of DA, DOPAC, and HVA were measured in the substantia nigra (A–C), striatum (D–F), and hippocampus (G–I). DA and its metabolites decreased in the substantia nigra and striatum but not in the hippocampus (n = 3/group). Data represent mean ± SEM. **P < 0.01 vs WT mice, ^##P < 0.01 vs vehicle treatment group.

Fig. 5

L-DOPA reversed the enhanced aggression, while central delivery of L-DOPA reduced the aggression in socially-isolated Lmx1b^−/− mice (n = 8/group). Data represent mean + SEM. **P < 0.01 vs vehicle treatment group, ^##P < 0.01 vs 5-HT and L-DOPA alone groups.