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Synaptic integration in the ventromedial hypothalamic nucleus in aggressive behaviour

Periodic Reporting for period 1 - ZPVMH (Synaptic integration in the ventromedial hypothalamic nucleus in aggressive behaviour)

Reporting period: 2015-06-01 to 2017-05-31

Generating appropriate behavioural responses to sensory cues is crucial to ensure the survival of species, and it is a primary skill that has evolved over millions of years. Aggression is one of such essential behaviours, and animals are frequently faced with a decision of whether to engage in a fight over food, shelter, and mates. One of the main goals in Neuroscience is to understand how the brain performs the computations underlying these decisions, and in particular, how specific sensory cues are processed and transformed into relevant behavioural responses.
In order to understand the neural computations underlying a specific behaviour one requires detailed knowledge of the neurons and circuits involved and how their biophysical properties are used for processing information. We used mice as a model and focused on understanding the neural computations in aggressive behaviour. Aggressive behaviour is essential for animals to ensure their survival, however when inappropriately expressed can be detrimental to the animal's health and well-being. In both mice and in humans, the neurons responsible for aggression are located in the hypothalamus area of the brain. Using the state of art techniques such as electrophysiology, calcium imaging and CRISPR/Cas9 manipulations we looked at specific populations of neurons in the mouse hypothalamus to determine the mechanistic explanation of their activity during aggressive behaviour. Our findings provide answers to fundamental questions, such as understanding how the brain processes information from the outside world and converts it in into behaviour, as well as could lead to potential treatments for controlling aggression.
We have investigated the biophysical properties of the neurons in the mouse hypothalamus using the state-of-art techniques such as electrophysiology, calcium imaging in freely moving animals and CRISPR/Cas9 gene editing manipulations. We discovered that hypothalamic neurons require a very small amount of information (input current) to transmit the signal to the next partner in the circuit. This property depends on the specific family of ion channels, which are highly expressed in the hypothalamus. Also, we determined the connectivity of the hypothalamic neurons with other partners in the circuit responsible for the aggressive behaviour and the inputs they receive from upstream structures in the brain that can influence the resulting behaviour. Finally, we characterised the differences in responses of the hypothalamic neurons in aggressive mice compared to the more docile mice during social interactions. Identified differences allowed us to design a way of manipulating the way hypothalamic neurons respond to the incoming information, and test our hypothesis in freely moving animals. We showed that specific family of voltage-gated channels is crucial to processing the incoming information of the hypothalamic neurons and underlies the different behavioural strategies we see in aggressive and non-aggressive mice. Manipulation of these voltage-gated channels in the hypothalamic neurons allowed us to decrease aggressive behaviour in mice.
These findings not only improve our understanding of the brain and how it processes the information about the outside world and performs neural computations that underlie aggressive behaviour, but also provide avenues for therapeutic interventions to control aggression in human patients.
These findings have been shared with the scientific community and presented at an international conference. They prompted further experiments, which once finished will be collated into a story and prepared for a publication in a top international peer-reviewed journal, as well as disseminated to the wider public via blog posts, newsletters, and social media and also through outreach activities.
We have discovered a mechanism by which hypothalamic neurons control innate behaviour in mice. Specifically, we have determined a mechanism of information processing in aggressive behaviour at the resolution of ion channels. The project is the first to implement such experimental and analysis framework to innate behaviours - a combination of electrophysiological, optical and computation techniques, and also state-of-the-art molecular biology methods (CRISPR/Cas9) manipulations of ion channels. Moreover, these results also provide key insights into the molecular and biological basis of aggressive behaviour, which have important consequences for devising new strategies for controlling aggression. The identified family of ion channels provides a tangible target for possible therapeutic interventions in human patients and can be used for further studies to devise strategies of controlling aggression in human patients. This will ultimately make the world a better and safer place.
Example of sag and rebound spike in the VMH neurons