Aggression is a significant and often debilitating feature of various neurodevelopmental disorders (NDDs), severely impacting quality of life and increasing clinical burden. Despite its prevalence and negative impact, the underlying neurobiological mechanisms remain poorly understood, and treatment options are limited. Our recent findings suggest that different genetic models of NDDs exhibit aggression with distinct behavioural profiles and neuromodulatory sensitivity. Specifically, Nrxn1α knockout mice exhibit reward-driven aggression that is resistant to oxytocin, while Nlgn3 knock-in mice show non-rewarded aggression that is oxytocin-responsive. Both models activate midbrain circuits, including the ventral tegmental area (VTA), but appear to engage different functional pathways. These findings present a unique opportunity to dissect the neural circuit mechanisms driving aggression in a genotype-dependent manner, with direct implications for targeted interventions. The work aligns with current efforts in translational neuroscience to move toward mechanistically informed, circuit-specific therapies for NDDs.
Techniques and Skills to be Developed:
-In vivo electrophysiology and/or fibre photometry to monitor real-time neural activity
-Optogenetic/chemogenetic manipulation of defined circuits in vivo
-Advanced behavioural phenotyping
-Pharmacological intervention strategies
-Histological and biochemical techniques
-Quantitative analysis using Python/MATLAB, including multivariate and machine learning approaches
-Scientific writing and interdisciplinary collaboration
Overarching Aims of the Project:
To delineate and compare the circuit-level and neuromodulatory mechanisms underlying aggression in genetically distinct NDD mouse models, with the overarching aim to tractable therapeutic targets.
Specific Measurable Objectives:
Year 1:
-Complete training in in vivo methods (in vivo electrophysiology, fibre photometry, optogenetics, fMRI)
-Begin in vivo recordings of VTA activity during aggression
-Prepare literature review and submit it for publication
Year 2:
-Perform in vivo recordings in Nrxn1α and Nlgn3 mouse models
-Initiate circuit-specific optogenetic manipulations
-Analyse differences in oxytocin receptor expression and circuit responsiveness.
-Present findings at national conference and prepare first manuscript.
Year 3:
-Expand pharmacological profiling to include receptor-specific agents
-Explore additional projection targets beyond the VTA
-Continue data collection and manuscript preparation
-Present findings at international conference and complete thesis plan
Year 4:
-Complete all remaining data analysis
-Submit thesis and manuscripts for publication
Summary of a Potential 3-Month Rotation Project (MRes + PhD Pathway)
The student will perform a short-term project involving behavioural assessments coupled with electrophysiological and fMRI recordings.
This project is ideal for candidates passionate about translational neurobiology, who wish to combine cutting-edge techniques with fundamental questions about brain-behaviour relationships in NDDs.