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Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions


Our understanding of depression and its treatment has advanced with the advent of ketamine as a rapid-acting antidepressant and the development and refinement of tools capable of selectively altering the activity of populations of neuronal subtypes. This work has resulted in a paradigm shift away from dysregulation of single neurotransmitter systems in depression towards circuit level abnormalities impacting function across multiple brain regions and neurotransmitter systems. Studies on the features of circuit level abnormalities demonstrate structural changes within the prefrontal cortex (PFC) and functional changes in its communication with distal brain structures. Treatments that impact the activity of brain regions, such as transcranial magnetic stimulation or rapid-acting antidepressants like ketamine, appear to reverse depression associated circuit abnormalities though the mechanisms underlying the reversal, as well as development of these abnormalities remains unclear. Recently developed optogenetic and chemogenetic tools that allow high-fidelity control of neuronal activity in preclinical models have begun to elucidate the contributions of the PFC and its circuitry to depression- and anxiety-like behavior. These tools offer unprecedented access to specific circuits and neuronal subpopulations that promise to offer a refined view of the circuit mechanisms surrounding depression and potential mechanistic targets for development and reversal of depression associated circuit abnormalities.

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Fig. 1: Regional specificity of modalities for transiently manipulating neuronal activity.
Fig. 2: Viral strategies for targeting neuronal populations.
Fig. 3: Preclinical neuronal manipulation methods and mPFC circuitry implicated in depression-like behavior.


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This work was supported by the USA NIMH (RO1 MH105910-04 and RO1 MH093897-06A1 to RSD), and the USA Brain and Behavior Research Foundation (to BDH).

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Correspondence to Brendan D. Hare.

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We declare that RSD has consulted and/or received research support from Naurex, Lilly, Forest, Johnson & Johnson, Taisho, and Sunovion. The remaining authors have no competing financial interests.

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Hare, B.D., Duman, R.S. Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions. Mol Psychiatry 25, 2742–2758 (2020).

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