Not Just a Mood Disorder─Is Depression a Neurodevelopmental, Cognitive Disorder? Focus on Prefronto-Thalamic Circuits

Abstract

Depression is one of the most burdensome psychiatric disorders, affecting hundreds of millions of people worldwide. The disease is characterized not only by severe emotional and affective impairments, but also by disturbed vegetative and cognitive functions. Although many candidate mechanisms have been proposed to cause the disease, the pathophysiology of cognitive impairments in depression remains unclear. In this article, we aim to assess the link between cognitive alterations in depression and possible developmental changes in neuronal circuit wiring during critical periods of susceptibility. We review the existing literature and propose a role of serotonin signaling during development in shaping the functional states of prefrontal neuronal circuits and prefronto-thalamic loops. We discuss how early life insults affecting the serotonergic system could be important in the alterations of these local and long-range circuits, thus favoring the emergence of neurodevelopmental disorders, such as depression.

Keywords: cognitive alterations; depression; prefronto-thalamic loops; serotonin.

Figure 1

Prefronto-thalamic projections. (a) Schematic overview of MD–PFC inputs. MD neurons predominantly project to superficial layers, and, to a lesser extent, to deep layers of the PFC. MD projections to layer I mostly target distal dendrites of PNs located in other layers. In layer II/III, MD neurons project to both PNs and interneurons. Interneurons excited by MD axons form a feedforward inhibitory microcircuit. Layer II/III PNs project to neurons in other layers or the contralateral hemisphere. MD neurons also project to layer V pyramidal neurons. Layers V and VI are the main output-generating layers in the PFC and project it to the MD. Inputs from layers V and VI differ in their morpho-functional properties. Colors of triangles represent subpopulations of pyramidal neurons residing in different layers. Round PFC neurons represent PV IN. Oval-shaped MD neurons represent a thalamic excitatory neuron. (b) Projection of MD axons to the PFC. Micrograph illustrating infection of AAV-ChR2-mCherry in the MD. mCherry-positive fibers can be detected in medial PFC. MD axons project both to superficial and deep layers. Note the dense accumulation of fibers in superficial and middle layers of the mPFC.

Figure 2

Developmental axis of the PFC and MD. (a) In-situ hybridization at P4, 7, 10, and 14 shows time-sensitive, transient SERT expression in the PFC during early postnatal development. (b) SERT+ pyramidal neurons in the PFC are located in layers V and VI but not in superficial layers. Immunolabeling against Ctip2 (red, layer V marker), Foxp2 (purple, layer VI marker), and GFP (green, SERTCre/+) in the PFC. Panels a and b modified with permission from ref (97). Copyright 2019 Springer Nature Limited. (https://creativecommons.org/licenses/by/4.0/) (c) Developmental timeline of the MD and PFC in the rodent brain. Panel reproduced from ref (91). Copyright 2015 Ferguson and Gao.