Neural Circuitry-Neurogenesis Coupling Model of Depression

Abstract

Depression is characterized by the disruption of both neural circuitry and neurogenesis. Defects in hippocampal activity and volume, indicative of reduced neurogenesis, are associated with depression-related behaviors in both humans and animals. Neurogenesis in adulthood is considered an activity-dependent process; therefore, hippocampal neurogenesis defects in depression can be a result of defective neural circuitry activity. However, the mechanistic understanding of how defective neural circuitry can induce neurogenesis defects in depression remains unclear. This review highlights the current findings supporting the neural circuitry-regulated neurogenesis, especially focusing on hippocampal neurogenesis regulated by the entorhinal cortex, with regard to memory, pattern separation, and mood. Taken together, these findings may pave the way for future progress in neural circuitry-neurogenesis coupling studies of depression.

Keywords: depression; entorhinal cortex; hippocampus; memory; mood; neural circuitry; neurogenesis; pattern separation.

Figure 1

Concept framework of entorhinal cortex-regulated hippocampal neurogenesis in the regulation of depression-related phenotypes. The glutamatergic stimulation from the entorhinal cortex through the perforant paths to the subgranular zone of the hippocampal dentate gyrus is deciphered. The glutamatergic stimulation prompts the maturation of the dentate granule cells during hippocampal neurogenesis, which can regulate memory, pattern separation, and mood.

Figure 2

Supportive findings for entorhinal cortex-regulated hippocampal neurogenesis in the regulation of memory. (a) Entorhinal–hippocampal circuitry and hippocampal theta rhythm resetting in the regulation of human spatial memory. Deep brain stimulation on entorhinal cortex results in hippocampal theta rhythm resetting, which is accompanied with a shortened time to escape from a maze in the spatial navigation task in humans. (b) Entorhinal–hippocampal circuitry and neurogenesis in the regulation of animal spatial memory. Deep brain stimulation on entorhinal cortex results in enhanced neurogenesis, which is accompanied with a shortened time to escape in the Morris water navigation task in mice. (c) Entorhinal–hippocampal circuitry and hippocampal CA1 coding in the regulation of animal temporal memory. Optogenetic inactivation of the medial entorhinal cortex results in disruption in hippocampal CA1 coding activity, which is accompanied by the diminished temporal memory in the sequential object–treadmill–maze task in rats.

Figure 3

Supportive findings for entorhinal cortex-regulated hippocampal neurogenesis in the regulation of pattern separation. (a) Functional activities of upper hippocampal circuit regions including the entorhinal cortex in the regulation of human pattern separation. Imbalances in functional activities of the entorhinal cortex, hippocampus, and amygdala are accompanied with the diminished ability for object discrimination in humans. (b) Hippocampal neurogenesis in the regulation of animal pattern separation. X-ray irradiation on hippocampus results in ablated neurogenesis in mice, which demonstrate the diminished discrimination between the safe and unsafe representations in the contextual fear conditioning task. (c) Entorhinal–hippocampal circuitry and hippocampal neurogenesis in the regulation of animal pattern separation. Chemogenetic stimulation of entorhinal cortex results in enhanced neurogenesis in Trip8b-knockdown mouse, which is accompanied by the enhanced discrimination between safe and unsafe contexts in the contextual fear conditioning task.

Figure 4

Supportive findings for entorhinal cortex-regulated hippocampal neurogenesis in the regulation of mood. Entorhinal–hippocampal circuitry and hippocampal neurogenesis in the regulation of animal mood. Chemogenetic stimulation of entorhinal cortex results in enhanced neurogenesis in Trip8b-knockdown mouse, which is accompanied by both shorter latency to access food in the novelty-suppressed feeding task and lowered immobility in the forced swimming task.