Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms

Abstract

The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients.

Keywords: adult hippocampal neurogenesis; cancer treatments; cognition; depression.

Fig. 1.

The hippocampal circuitry. The hippocampus is located within the temporal lobe, extending longitudinally across the brain. It is composed of 3 distinct subregions—the DG, CA1, and CA3—each responsible for specific components of information processing. Granule cells in the DG receive inputs from the entorhinal cortex and send projections to CA3 pyramidal neurons, which connect with those of CA1, from where information is distributed to other parts of the brain. The DG is particularly known for its remarkable characteristic of generating new functional neurons throughout adulthood. The process of adult hippocampal neurogenesis starts with type 1 NSCs generating type 2 progenitors, which can differentiate into neuroblasts. Given appropriate microenvironmental conditions, these cells will mature into neurons and integrate local preexisting circuits. Because the hippocampus extends dorsoventrally, newborn neurons that integrate the dorsal circuitry are believed to regulate functions proper to the dorsal hippocampus, such as spatial memory. In turn, those integrating ventral circuits are thought to play a role in the regulation of ventral hippocampus functions, such as those related to mood and emotionality.

Fig. 2.

Consequences of cancer treatments to mental health. Cancer treatments, such as chemotherapy and radiotherapy, aim at ablating the proliferative activity of tumorous cells. However, given their unspecific action, these treatments also arrest proliferation of desirable cell populations, such as those maintaining the process of neurogenesis in the postnatal/adult brain. Adult hippocampal neurogenesis is thought to underlie an important portion of neural plasticity throughout life, with newly born neurons integrating memory and mood circuits. AHN can be downregulated directly by the antimitotic action of cancer treatments, or indirectly by the pro-inflammatory responses triggered by these agents. Chronic stress is significantly present in the routine of cancer patients and is another important contributor to lower levels of AHN. Decreased AHN, in turn, has been consistently linked with cognitive decline and depression. On the other hand, environmental factors like exercise, diet, and use of antidepressants and anti-inflammatory drugs, as well as peroxisomal proliferator-activated receptor alpha agonists, are known to increase AHN and restore cognitive abilities and mood states. They could, therefore, positively contribute to mental health among cancer patients. Other strategies, such as hippocampal sparing, cognitive stimulation, and treatment with memantine, stimulants, and ramipril, have been shown to exert positive effects on mental health in the context of cancer treatments, a phenomenon that probably occurs via protection or increase of hippocampal neurogenesis.