Brain mechanisms of antidepressant action

According to the WHO, depression is now the leading cause of poor health and disability worldwide. But despite many years of research, there has been limited recent progress in the development of new treatments. Drug-discovery has primarily focussed on treatments targeting neurotransmitters such as serotonin, but such therapeutics require weeks to act and are not universally effective. However, there is emerging evidence that the brain’s principal excitatory neurotransmitter, glutamate, plays a central role in depression. Indeed, we and others find that the antidepressant tianeptine (Zhang et al., 2013, Molecular Psychiatry 18:471-484), and HNK (a metabolite of ketamine), rapidly enhance glutamatergic synaptic transmission. Importantly, ketamine and its metabolite exhibit rapid-onset antidepressant properties. These findings may fundamentally change the landscape of antidepressant therapy. Recent studies have identified “reward” circuits encompassing the nucleus accumbens (NAc) as an important locus in depression. This project will focus on investigating two excitatory inputs to the NAc in rodents—one from the hippocampus and one from prefrontal cortex. These glutamatergic pathways appear to have opposite effects on depressive behaviours, with high synaptic strength associated with depressive symptoms for the hippocampal input, but resilience for the prefrontal input. However, the action of antidepressant drugs in these two pathways is not known. You will join well-equipped and staffed laboratories and be trained in behavioural and electrophysiological techniques by experienced researchers in a supportive environment. Our goal is to facilitate the search for more effective antidepressants by increasing our understanding of their mechanisms of action within the brain’s reward circuitry.