Experience-Dependent Dopamine Modulation of Male Aggression in Mice

Academic Background

Aggression is a common social behavior in the animal kingdom, crucial for territory defense, resource competition, and mate protection. Although the role of dopamine in regulating aggression has been extensively studied, its specific neural mechanisms remain unclear. Previous research has shown that dopamine receptor antagonists are commonly used to suppress aggressive behavior in humans, while elevated dopamine levels (e.g., through drugs like amphetamines) may enhance aggression. However, the variability of these effects is significant, and the precise mechanisms of dopamine’s role in aggression are not fully understood. Therefore, this study aims to reveal the experience-dependent modulation mechanism of dopamine in male mouse aggression, particularly through the bidirectional regulation of aggression by dopaminergic neurons in the ventral tegmental area (VTA).

Source of the Paper

This paper was co-authored by researchers from the Neuroscience Institute at NYU Grossman School of Medicine, including Bing Dai, Bingqin Zheng, Xiuzhi Dai, and others, in collaboration with institutions such as the State Key Laboratory of Membrane Biology at Peking University and the PKU-IDG/McGovern Institute for Brain Research. The paper was published in Nature in 2024 under the title “Experience-dependent dopamine modulation of male aggression.”

Research Process and Results

1. Research Process

1.1 Chemogenetic Modulation of VTA Dopaminergic Neurons

The researchers first modulated the activity of VTA dopaminergic neurons using chemogenetics. They used DAT-Cre mice and injected AAV8-hSyn-DIO-hM4Di-mCherry (inhibitory receptor) or AAV5-hSyn-DIO-hM3Dq-mCherry (excitatory receptor) viruses into the VTA to specifically regulate dopaminergic neuron activity. The experiments were divided into two groups: “novice aggressors” (mice with less than three days of attack experience) and “expert aggressors” (mice that had won in standard resident-intruder (RI) tests for eight consecutive days).

1.2 Aggression Behavior Testing

After chemogenetic modulation, the researchers assessed aggressive behavior through RI tests. In these tests, a non-aggressive BALB/c male mouse was introduced into the experimental mouse’s cage, and behavioral metrics such as attack duration and attack latency were recorded. Additionally, the mice’s sexual behavior and locomotor activity were tested to rule out non-specific effects of dopamine modulation on other behaviors.

1.3 Gene Editing of Dopamine Synthesis

To further validate the role of dopamine in aggression, the researchers used CRISPR-SaCas9 technology to knock out tyrosine hydroxylase (TH) in VTA dopaminergic neurons, thereby blocking dopamine synthesis. The experiments were again divided into novice and expert aggressor groups to observe the effects of TH knockout on aggression.

1.4 Real-Time Monitoring of Dopamine Release

The researchers used the third-generation dopamine sensor GRABDA3H to monitor dopamine release in the dorsal lateral septum (DLS) in real-time through fiber photometry. They recorded dynamic changes in dopamine levels during different stages of aggression experience and compared them with dopamine release in the nucleus accumbens (NAc).

1.5 Synaptic Plasticity and Neural Circuit Mechanisms

Finally, the researchers investigated the effects of dopamine on synaptic plasticity in DLS neurons through electrophysiological experiments. They used optogenetics to activate VTA dopaminergic neuron projections and recorded inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) in DLS neurons, analyzing dopamine’s role in regulating information flow from the hippocampus to the DLS.

2. Main Results

2.1 Experience-Dependent Modulation of Aggression by VTA Dopaminergic Neurons

The study found that the modulation of aggression by VTA dopaminergic neurons is experience-dependent. In novice aggressors, inhibiting VTA dopaminergic neurons significantly reduced attack duration and increased attack latency, while in expert aggressors, this modulation disappeared. Conversely, activating VTA dopaminergic neurons enhanced aggression in novice aggressors but had no significant effect in expert aggressors.

2.2 Impact of Dopamine Synthesis on Aggression

The TH knockout experiments showed that blocking dopamine synthesis in the VTA completely prevented the development of aggression in novice aggressors but had no effect on the aggression of expert aggressors. This indicates that dopamine plays a critical role in the initial formation of aggression but becomes dispensable once aggression stabilizes.

2.3 Dynamic Changes in DLS Dopamine Release

Real-time monitoring revealed that dopamine release in the DLS significantly increased in novice aggressors, particularly during the first attack. As attack experience accumulated, dopamine release gradually decreased, eventually becoming negligible in expert aggressors. This suggests that dopamine is crucial in the initial formation of aggression but becomes less important as aggression stabilizes.

2.4 Dopamine’s Effect on Synaptic Plasticity in DLS Neurons

Electrophysiological experiments showed that dopamine, through D2 receptors (D2Rs), weakens local inhibition in DLS neurons, thereby enhancing information flow from the hippocampus to the DLS. This mechanism is particularly significant in novice aggressors, while in expert aggressors, local inhibition in DLS neurons naturally weakens, reducing dopamine’s modulatory role.

3. Conclusions and Significance

This study reveals the experience-dependent modulation mechanism of dopamine in male mouse aggression. VTA dopaminergic neurons regulate local inhibitory synaptic plasticity through projections to the DLS, influencing the formation and maintenance of aggression. This discovery not only deepens our understanding of dopamine’s role in aggression but also provides new insights into the neural circuit mechanisms of aggression. Furthermore, the findings suggest that early interventions targeting dopamine receptors may help prevent the escalation of aggression and provide a theoretical basis for sex-specific aggression management strategies.

4. Research Highlights

• Experience-Dependent Modulation: The study is the first to reveal that dopamine’s modulation of aggression is experience-dependent, offering a new perspective on the neural mechanisms of aggression.
• Neural Circuit Mechanisms: It elucidates the mechanism by which VTA-DLS dopamine projections regulate local inhibitory synaptic plasticity to influence aggression.
• Technological Innovation: The study combines advanced techniques such as chemogenetics, optogenetics, CRISPR gene editing, and fiber photometry to comprehensively analyze dopamine’s role in aggression.

5. Other Valuable Information

The study also found that DLS neurons in expert aggressors exhibit reduced responsiveness to dopamine, which may be related to the weakening of the local inhibitory network in the DLS. This finding provides a new direction for further research into the neural plasticity of aggression.