Developmental biology - Brain|
The Neurobiology Of Aggression
Signalling in our brain shapes our social behavior and understanding of social hierarchy, bullying and aggression...
Duke-NUS is the National University of Singapore Medical School, working in collaboration with Duke University in Durham, North Carolina, USA. Researchers in both institutions working together have discovered a growth factor protein, called brain-derived neurotrophic factor (BDNF), along with its receptor tropomyosin receptor kinase B (TrkB) affects social dominance in mice. Their research has implications for understanding the neurobiology of aggression and bullying.
"Humans and rodents are social animals. Our every interaction follows rules according to a social hierarchy. Failure to navigate this hierarchy can be detrimental in each species. Our paper may be the first to demonstrate that specific molecular signalling pathways in specialized nerve cells, in a particular location in the brain, are important for the balanced navigation of social hierarchies."
Hyunsoo Shawn Je, Assistant Professor, Neuroscience and Behavioural Disorders Signature Research Program, Duke-NUS Medical School and senior author.
Difficulties in navigating these hierarchies can lead to problems like aggression and bullying. According to Je: "Given the heavy societal cost of bullying and aggression, understanding the biological causes is a step towards their effective prevention and treatment."
Activity within the brain is brought about by circuits made of excitatory neurons that ramp up activity, and GABAergic interneurons that inhibit or quiet those same excitatory neurons. Studies show BDNF-TrkB signals are important in maturing GABAergic interneurons and developing brain nerve circuits. However, no research as yet pinpoints any consequences from disrupting BDNF-TrkB signals.
Therefore, Je's team created transgenic mice with the TrkB receptor removed — specifically in GABAergic interneurons in part of the brain regulating emotional and social behavior — the corticolimbic system. These transgenic mice did exhibit unusual aggressive behavior when housed together with normal mice. To understand why, Je's team conducted behavior tests finding the mice were not being aggressive to protect their territory. They were also not being aggressive because they were stronger, as transgenic mice were injured more than other mice during acts of aggression. Instead, their aggressive behavior was a result of increased fighting for status and dominance over other mice in the group.
Researchers found in transgenic mice without BDNF-TrkB signalling, GABAergic interneurons were weak at inhibiting excitatory cells — so excitatory cells became overactive and shut down a specific area in transgenic mice brains. Re-establishing the "excitatory/inhibitory" balance "instantaneously reversed the abnormal social dominance," according to Shawn Pang Hao Tan PhD, Duke-NUS post-doctoral research fellow and first author of the paper. The study was published in Proceedings of the National Academy of Sciences or PNAS.
Together with other recent findings, it demonstrates that both genetic and biological factors play an unexpected role in social behaviors.
The tight balance between synaptic excitation and inhibition (E/I) within neocortical circuits in the mammalian brain is important for complex behavior. Many loss-of-function studies have demonstrated that brain-derived neurotrophic factor (BDNF) and its cognate receptor tropomyosin receptor kinase B (TrkB) are essential for the development of inhibitory GABAergic neurons. However, behavioral consequences of impaired BDNF/TrkB signalling in GABAergic neurons remain unclear, largely due to confounding motor function deficits observed in previous animal models. In this study, we generated conditional knockout mice (TrkB cKO) in which TrkB was ablated from a majority of corticolimbic GABAergic interneurons postnatally. These mice showed intact motor coordination and movement, but exhibited enhanced dominance over other mice in a group-housed setting. In addition, immature fast-spiking GABAergic neurons of TrkB cKO mice resulted in an E/I imbalance in layer 5 microcircuits within the medial prefrontal cortex (mPFC), a key region regulating social dominance. Restoring the E/I imbalance via optogenetic modulation in the mPFC of TrkB cKO mice normalized their social dominance behavior. Taken together, our results provide strong evidence for a role of BDNF/TrkB signalling in inhibitory synaptic modulation and social dominance behavior in mice.
Shawn Tan, Yixin Xiao, Henry H. Yin, Albert I. Chen, Tuck Wah Soong, and H. Shawn Je.
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The corticolimbic system consists of several brain regions including (1) the rostral anterior cingulate cortex, (2) hippocampal formation, and (3) basolateral amygdala. The anterior cingulate cortex has a central role in processing emotional experiences at the conscious level and selective attentional responses. Emotionally related learning is handled through the interactions of the basolateral amygdala and hippocampus and motivational responses are processed through the dorsolateral prefrontal cortex. Credit: ResearchGate