Circuit structural plasticity by a neurotrophin with a Toll modifies behaviour

Experience shapes the brain, as neural circuits can be modified by neural stimulation or the lack of it. How this modifies behaviour, and the underlying molecular mechanisms, are poorly understood, but could reveal how the brain works, in health and disease. Subjective experience requires dopamine, a neuromodulator that assigns a value to stimuli, and it also controls behaviour, including locomotion, learning and memory. In Drosophila, Toll receptors are ideally placed to translate experience into structural brain change. Toll-6 is expressed in dopaminergic neurons (DANs), raising the intriguing possibility that Toll- 6 could regulate structural plasticity in dopaminergic circuits. Drosophila neurotrophin-2 (DNT-2) is the ligand for Toll-6, but whether it is required for circuit structural plasticity was unknown. Here, we show that DNT-2 expressing neurons are connected with DANs and they modulate each other. Loss of function for DNT-2 or its receptors Toll-6 and kinase-less Trk-like kek-6 caused DAN and synapse loss, impaired dendrite growth and caused locomotion deficits. By contrast, over-expressed DNT-2 increased dendrite complexity and promoted synaptogenesis. Neuronal activity increased the levels of DNT-2 and its maturation, and induced synaptic remodelling, which required DNT-2, Toll-6 and kek-6 . Altering the levels of DNT-2 or Toll-6 could also modify dopamine-dependent behaviours, including locomotion and long-term memory. We conclude that an activity-dependent feedback loop involving dopamine and DNT-2 labelled the circuits engaged, and DNT-2 with Toll-6 and Kek-6 induced structural plasticity in this circuit, modifying brain function. SHORT BLURB Drosophila neurogenetics reveals a novel mechanism of neural circuit structural plasticity, providing insights into how experience modifies brain structure and resulting memory and behaviour. ### Competing Interest Statement The authors have declared no competing interest.