The impact of adult neurogenesis on affective functions: of mice and men

Abstract

In most mammals, new neurons are not only produced during embryogenesis but also after birth. Soon after adult neurogenesis was discovered, the influence of recruiting new neurons on cognitive functions, especially on memory, was documented. Likewise, the late process of neuronal production also contributes to affective functions, but this outcome was recognized with more difficulty. This review covers hypes and hopes of discovering the influence of newly-generated neurons on brain circuits devoted to affective functions. If the possibility of integrating new neurons into the adult brain is a commonly accepted faculty in the realm of mammals, the reluctance is strong when it comes to translating this concept to humans. Compiling data suggest now that new neurons are derived not only from stem cells, but also from a population of neuroblasts displaying a protracted maturation and ready to be engaged in adult brain circuits, under specific signals. Here, we discuss the significance of recruiting new neurons in the adult brain circuits, specifically in the context of affective outcomes. We also discuss the fact that adult neurogenesis could be the ultimate cellular process that integrates elements from both the internal and external environment to adjust brain functions. While we must be critical and beware of the unreal promises that Science could generate sometimes, it is important to continue exploring the potential of neural recruitment in adult primates. Reporting adult neurogenesis in humankind contributes to a new vision of humans as mammals whose brain continues to develop throughout life. This peculiar faculty could one day become the target of treatment for mental health, cognitive disorders, and elderly-associated diseases. The vision of an adult brain which never stops integrating new neurons is a real game changer for designing new therapeutic interventions to treat mental disorders associated with substantial morbidity, mortality, and social costs.

Fig. 1. Schematic illustration of the degree of adult neurogenesis and the delay of maturation of new neurons from rodents to humans’ brains.

The circles refer to the presence of immature neurons (or de novo production) in the adult brain. The two gradients displayed at the bottom represent the mean strength of each parameter. RMS rostral migratory stream. Created with BioRender.com.

Fig. 2. Factors potentially influencing hippocampal neurogenesis in healthy and pathological conditions.

Numerous internal and external factors have been identified as potential regulators of hippocampal neurogenesis, either positively by stimulating neurogenesis (left side) or negatively by inhibiting it (right side). These factors may be present either in healthy conditions (upper part) or in pathological conditions (lower part). Created with BioRender.com.

Fig. 3. Gut, brain and immune system interactions.

The environment, which encompasses all the external factors to which the individual is exposed (stress, diet, infection,…), can lead to a change in the intestinal microbiota. Stimulation of the immune system by post-biotics and cytokines produced by the intestinal immune system will send signals to the brain, by at least two routes: the bloodstream and the nervous route. The blood signals arriving at the brain’s barriers will cause activation of the barriers’ immune system that pass to the brain tissue, resulting in a neuroinflammatory state. The inflammatory signals are then relayed within the brain tissue by microglial cells (yellow). In hippocampus, inflammatory signals have an inhibitory effect on neurogenesis. In areas where the barriers are absent (e.g., in the circumventricular organs), the signals can be received directly in the brain and activate specific neuronal circuits. For example, an activation loop involves the nucleus tractus solitarii (NTS) and the hypothalamus, resulting in the secretion of stress hormones such as corticosterone [179] by hypothalamic–pituitary–adrenal (HPA) axis. Stress hormones have a deleterious effect on hippocampal neurogenesis. The direct nervous route involves the vagus nerve activity that transmits signals directly to the NTS. Created with BioRender.com.

Fig. 4. Assessment of affective functions linked to clinical symptoms of mania or depression.

Mood disorders, characterized by depressive state (blue) and maniac state (red), can be described by impairment of affective functions (center). These functions should be tested with specific behavioral analysis in animal models (yellow box). Created with BioRender.com.