New findings from the Roberts lab have identified a specific brain circuit in primates that, when disrupted, reduces motivation and increases anxiety — symptoms closely linked to depression. The findings, published in Science, offer new insights into how therapies like transcranial magnetic brain stimulation (TMS) and ketamine may work.
The team, led by senior scientist, Dr Christian Wood and PhD student, Rana Banai-Tizkar, used advanced chemogenetic techniques to temporarily inactivate Area 46 of the dorsolateral prefrontal cortex (dlPFC) in marmoset monkeys. Disruption of this region led to a marked drop in their willingness to work for a treat and at the same time heightened their sensitivity to perceived threats — two hallmark features of depression and anxiety.
The study also revealed that these behaviours are regulated by distinct brain pathways: motivation through projections to Area 32, and anxiety through projections to ventral Area 32. Remarkably, administering ketamine restored normal motivational behaviour by acting within Area 25, a brain region often overactive in depression, a target of deep brain stimulation in patients and reciprocally interconnected with area 32.
The research also uncovered that these effects were lateralised, dependent on the left hemisphere only, mirroring the selective targeting of this hemisphere in therapies such as TMS.
By mapping the specific brain circuits involved in motivation and anxiety, and identifying the circuits responsive to antidepressants, this work could help refine and personalise future treatments for depression — particularly in cases where symptoms like anhedonia and anxiety show resistance to standard therapies.
Read the paper at www.science.org/doi/10.1126/science.adx4142