Adult Hippocampal Neurogenesis and Affective Disorders: New Neurons for Psychic Well-Being

Abstract

A paradigm shift in neuroscience was the discovery that new neurons are constantly produced in the adult mammalian brain of several species, including Homo sapiens. These new-born cells are formed in some main neurogenic niches, including the subventricular zone (SVZ) at the margin of the lateral ventricle and subgranular zone (SGZ) in the hippocampal dentate gyrus (DG). In the DG, neuroblasts derive from SGZ progenitors and migrate to the hippocampal granular layer becoming adult granule cells, which are integrated into functional adult circuits. It has been confirmed that adult hippocampal neurogenesis (AHN) is a long-lasting phenomenon in the human brain. The functions of hippocampal new-born cells are not fully established. Experimental studies suggest that they have unique electrophysiological properties, including hyperexcitability, which enable them to regulate adult granule cells. Their specific function depends on the anatomical hippocampal location along the hippocampal dorsal-ventral axis. Dorsal hippocampus plays a more defined role on spatial learning and contextual information, while the ventral hippocampus is more related to emotional behavior, stress resilience and social interaction. Several reports suggest a role for AHN in pattern separation, cognitive flexibility, forgetting and reversal learning. It has been proposed that deficits in AHN might impair normal DG function, including pattern separation and cognitive flexibility, which could play a role on the etiology of affective disorders, such as depression, anxiety and post-traumatic stress disorder (PTSD). In this paper, we review recent scientific evidence suggesting that impairment of AHN may underlie the pathophysiology of affective disorders even in humans and that neurogenesis-inspired therapies may be a promising approach to reduce symptoms of affective disorders in humans.

Sex-Specific Microglial Activation and SARS-CoV-2 Receptor Expression Induced by Chronic Unpredictable Stress

“…Moreover, a recent study showed that decreasing Arg1 + microglia in the hippocampus by knocking down the microglial IL4R suppressed hippocampal neurogenesis and enhanced vulnerability to CUMS, whereas increasing Arg1 + microglia in the hippocampus by enhancing IL4 signaling restored hippocampal neurogenesis and the resilience to stress-induced depression via brain-derived neurotropic factor (BDNF) ( Zhang et al, 2021 ). Activated microglia along with impaired adult hippocampal neurogenesis during chronic stress may hence jointly contribute to the pathophysiology underlying stress susceptibility in psychiatric disorders ( Madore et al, 2020 ; Gomes-Leal, 2021 ). Whether microglial regulation of adult hippocampal neurogenesis in stress susceptibility or resilience is sex-dependent warrants future research.…”

The Entorhinal Cortex and Adult Neurogenesis in Major Depression

“…Hippocampal neurogenesis is associated with the inherent depression pathophysiology as well as the response to antidepressants [ 91 , 92 ]. Hippocampal neurogenesis defects are related to depression-related symptoms, such as hopelessness and helplessness [ 13 , 14 , 93 , 94 ]. Research indicates that defective neurogenesis alters a spectrum of physiological processes, including inflammation [ 95 , 96 ], the hypothalamic–pituitary–adrenal axis [ 97 ], and neurotrophic factors [ 98 , 99 ], which are all crucial to depression or stress responses.…”

“…Pioneering preclinical studies examining entorhinal cortex-regulated hippocampal neurogenesis and cognitive and emotional symptoms of depression have led to initial advances in the neural circuitry–neurogenesis model of depression. Gomes-Leal et al [ 13 ] suggested activation of reward centers for psychic well-being, for which good feelings are mediated in reward centers, such as nucleus accumbens and tegmental ventral area. Nevertheless, the mechanism of the depression model should be further elucidated in two parallel directions.…”

“…Inevitably, the current consequences of depression therapeutics demand a more comprehensive model of depression pathogenesis to allow for theoretical concepts that target partially remitted or refractory depression. For years, there have been requirements to refine the concepts of neural circuitry and neurogenesis, which are regarded as clinically targetable [ 11 , 12 , 13 , 14 ]. Indeed, brain networks and neural stem cell niches are known to have a major impact on depression-related phenotypes.…”

“…Ample evidence emphasizes a varying spectrum of neuropathology, from defects in hippocampal activity and volumes to alterations in activity-dependent gene expression, all of which suggest defective neurogenesis in the hippocampal dentate gyrus [ 15 , 16 , 17 ]. Given that hippocampal neurogenesis operates based on neural circuitry-mediated regulation [ 13 , 14 , 18 , 19 , 20 ], there have been tentative efforts to stimulate the upstream neural circuitry to enhance hippocampal neurogenesis in depression models. Interestingly, deep brain stimulation in animal depression models showed that entorhinal cortex stimulation improves cognitive performance via hippocampal neurogenesis, resulting in improvement in pattern separation and memory [ 21 , 22 , 23 ].…”