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

Abstract

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.

Fig. 1

Regional specificity of modalities for transiently manipulating neuronal activity a. Model estimates of electric field strength (E) above stimulation threshold (E_th) for conventionally applied (bilateral) ECT at 800mA. Stimulation strength on the cortical surface, and representative coronal and axial slices from realistic head models are shown (adapted from) b. Model estimates of electric field strength for 1ms TMS pulse applied at 120% of the leg motor threshold. Red and purple areas indicate power above neuronal activation threshold (adapted from) c. Iso-contour lines depicting monte-carlo estimated light spread and intensity at 10mW output power with typically utilized cannula diameter (62μm top, 200μm bottom) and light wavelengths for optogenetic stimulation demonstrates the discrete area below the implanted fiber optic cannula expected to be directly impacted by light delivery (adapted from) d. The effects of optogenetic stimulation may be further refined using viral vectors with population specific promoters or Cre-recombinase dependence.

Fig. 2

Viral strategies for targeting neuronal populations. a. Targeting a population using promoter specific or Cre-dependent AAV and somatic or terminal manipulation b. Targeting a population of cells that project to a region of interest using retrograde AAV and somatic manipulation c. Intersectional AAV strategy to limit AAV vector expression to a discrete projection population.

Fig. 3

Pre-clinical neuronal manipulation methods and mPFC circuitry implicated in depression like behavior. a. Optogenetic or chemogenetic manipulations may take place at the time of testing or b. may precede testing. c. mPFC afferent (grey) and efferent (black) circuitry with behaviors reported to be impacted by optogenetic and/or chemogenetic manipulations indicated. d. mPFC cellular populations with behaviors reported to be impacted by behaviors reported to be impacted by optogenetic and/or chemogenetic manipulations indicated.