Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters

Abstract

Like many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions.

Keywords: caudate putamen; dominance; fragile X mental retardation protein; glutamate; prefrontal cortex; reward; social interaction; synaptic plasticity.

Figure 1

Aggressive behavior over two and five consecutive days of aggressive interactions (5 min each). (A) Image of an adult female Syrian hamster biting the lower flank of an intruding adult male Syrian hamster. (B) There was no change in the latency to initiate an attack for female Syrian hamsters that experienced two consecutive days of aggressive interactions (non-significant = N.S.) (Days 1–2, n = 11). (C) There was a decrease in the latency to initiate an attack for female Syrian hamsters that experienced five consecutive days of aggressive interactions (* p < 0.05). (Days 1–5, n = 9). Data are presented as mean +/− standard deviation.

Figure 2

The effect of aggressive interactions on the phosphorylation and the expression of intracellular signaling molecules that regulate Fragile X Mental Retardation Protein (FMRP) in the nucleus accumbens (NAc). (A) There is no change in the phosphorylation of ribosomal S6 kinase (S6K) (phosphorylates FMRP) in the NAc 10 min following either 2 or 5 consecutive days of aggressive interactions compared to control female Syrian hamsters that had no social interaction experience (N.S.). (B) There is an increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) 10 min following 2 days of aggressive interactions compared to control female Syrian hamsters that had no social interaction experience and compared to levels following 5 days of aggressive interactions (* p < 0.05). (C) However, there was no change in the overall protein expression of ERK1/2 in the NAc (N.S.). (D) There is an increase in the ratio of the phosphorylation of ERK1/2 to the phosphorylation of S6K in the NAc following two and five days of aggressive interactions compared to female hamsters that had no social interaction experience (* p < 0.05). (Control n = 7–8, 2 Days n = 11, 5 Days n = 11). Data are presented as mean +/− standard deviation.

Figure 3

The effect of aggressive interactions on the phosphorylation and the expression of intracellular signaling molecules that regulate FMRP in the medial prefrontal cortex (mPFC). (A) There was a decrease in the phosphorylation of mammalian target of rapamycin (mTOR) (phosphorylates S6K) in the mPFC 10 min following 2 consecutive days of aggressive interactions compared to female Syrian hamsters that had no social interaction experience (* p < 0.05). (B) There was no change in the overall protein expression of mTOR in the mPFC 10 min following 2 consecutive days of aggressive interactions compared to female Syrian hamsters that had no social interaction experience (N.S.). (Control n = 7–8, 2 Days n = 9–11, 5 Days n = 8–11). Data are presented as mean +/− standard deviation.

Figure 4

Hypothesized model of intracellular signaling molecules regulating FMRP phosphorylation and de-phosphorylation. (A) Shortly after aggressive interactions there is a decrease in the phosphorylation of mTOR in the mPFC and an increase in the phosphorylation of ERK1/2 in the NAc. Immediately following the activation of mGluR5 there is an increase in the activity of ERK1/2 and PP2Ac and a decrease in the activity of S6K in the nucleus accumbens. This pushes the balance of the activity of FMRP towards a decrease in phosphorylation, resulting in the translation of protein. However, in the medial prefrontal cortex following the activation of mGluR5 there is a decrease in the activity of mTOR, which would increase the activity of PP2Ac and decrease the activity of S6K. This also pushes the balance of the activity of FMRP towards a decrease in phosphorylation, resulting in the translation of protein. A delayed effect for both the nucleus accumbens and medial prefrontal cortex is an increase in the activity of mTOR, which then inhibits PP2Ac, but increases the activity of S6K. This pushes the balance of the activity of FMRP towards an increase in phosphorylation, resulting in the blocking of the translation of proteins. (B) Representative effect of the number of aggressive interactions on the phosphorylation of mTOR in the mPFC and ERK1/2 in the NAc 10 min following the last aggressive episode in female Syrian hamsters. From Figure 2 and Figure 3.