Hippocampus and Depression: The Biological Link - Essay Sample

Introduction

Clinical depression is a mental disorder associated with persistently low moods and disinterest in formerly pleasurable activities. The DSM-5 categorizes major depression as a mood disorder, among others, like bipolar and cyclothymic mood disorders. Since the establishment that depression has a biological component, studies have been carried out to explore the affected areas in the brain. Over the years, the hippocampus has been implicated in the pathogenesis of depression. The hippocampus is a structure in the brain composed of grey matter and forming the floor of the temporal horn of the lateral cerebral ventricle (Goncalves et al., 2016). It is part of the limbic system and plays a crucial role in learning, emotions, and memory. These two studies seek to provide evidence that the hippocampus is vital in the development and treatment of depression, through manipulation of the number of new neurogenic cells in this area of the brain. Neurogenesis is, therefore, the process through which new brain cells are formed throughout life (Kempermann, 2018).

Is your time best spent reading someone else’s essay? Get a 100% original essay FROM A CERTIFIED WRITER!

Save 25%

Neurogenesis is more recognized during prenatal life, as the brain tissue develops from primitive stem cells. Adult neurogenesis remains a highly debated topic since this process dramatically slows down with age (Goncalves et al., 2016). Although neurogenesis remains limited in most areas of the adult brain, the cells of the dentate gyrus in the hippocampus remain mitotically active. It is important to note that humans possess a higher population of exchangeable hippocampal neurons than experimental rodents (Roddy et al., 2019). These mitotically active cells have been subjected to experimental manipulation in a bid to study the relationship between depression and neurogenesis. These cells are then analyzed through methods such as the analysis of an immature neuronal marker, Doublecortin (DCX), positive hippocampal neurons throughout life (Kumar et al., 2019).

Temozolomide(TMZ) is an antimitotic anticancer drug used to treat brain malignancies. This drug, along with other similar compounds, was noted to induce higher levels of depression as compared to anticancer agents used elsewhere in the body. While cancer and its treatment are known to cause significant levels of psychological stress and even depression in most patients, TMZ recorded higher levels of this effect. To differentiate between depression emanating from cancer itself and the one arising from the side effects of the TMZ, a study was conducted by Egeland et al., (2017). This study directly explored the impact of TMZ on the brain as well as the behavior of mice treated with this drug against controls. The results showed that TMZ decreases adult neurogenesis through the inhibition of mitosis in the hippocampus. This inhibition is most prominent in the subgranular zone of the dentate gyrus (Pereira Dias et al., 2014). As a result, these mice displayed behavioral changes consistent with the reduced neurogenesis. Hyponeophagia was one of the most noticeable results of this study. This could be attributed to the defective processing of new information and memory as opposed to being an isolated effect of reduced neurogenesis. The mice could have shown reduced feeding due to memory and cognitive impairments resulting from the effects of TMZ suppression of the limbic system. Defective emotional processing could also explain the hypophagia, resulting from an altered perception of food. The mice elicited anhedonia, a feature of depression. They also had higher stress levels, as they produced more cortisol than the controls, in response to acute stress tests.

Hill, Sahay, and Hen (2015) published a study similar to the one above, but this time exploring the effect of increasing neurogenesis on depression. This study induced baseline stress or depressive levels through chronic administration of corticosterone. Corticosterone is the rodent counterpart of the human cortisol, since these mammals produce negligible amounts of cortisol from the zona fasciculata of their adrenal cortex, as opposed to humans (Egeland et al., 2015). The subjects' neurogenesis was increased through the deletion of the pro-apoptotic gene, Bax, from their stem cells. The cell turnover of their neurons was, therefore reduced, through decreased cell death (Hill et al., 2015). The results showed decreased responses to stress in the test subjects. There was, however, limited effects of the increased neurogenesis on the hypothalamic-pituitary-adrenal (HPA) axis. This means that the impact of increased neurogenesis is not solely dependent on the HPA axis, as seen in the TMZ experiments. However, it is possible that this limited effect on the HPA axis was due to negative feedback. The chronic administration of corticosterone could have down-regulated its production as well as that of cortisol in the adrenal cortex of the rodents. This study proved that there were other mechanisms in which adult neurogenesis influenced depressive behavior, other than through increasing cortisol.

While the TMZ study indicated that the dentate gyrus is responsible for the emotional role of the hippocampus, this study goes a step further to specify that the ventral dentate gyrus takes up the larger share of this function (Hill et al., 2015). When compared to the dorsal, the ventral dentate gyrus has different functions and connectivity. This region controls the HPA through its connections with the integration center for limbic information, the bed nucleus of the stria terminalis (Spalding et al., 2013). This function makes the ventral area of the dentate gyrus a critical target for antidepressants and the center of attention for neurogenesis studies in relation to depression. Although this research has extensively been conducted in animal models, they do not entirely apply to the human brain. Research into the human model of this experiment has been limited by the ethical implications of experimenting on people, as well as the limited availability of cadaveric brain tissue (Bergmann et al., 2015). These studies, therefore, remain highly inconclusive as to whether they perfectly apply to the human pathophysiology of depression.

Conclusion

Neurogenesis is the formation of neurons. Adult neurogenesis has sparked curiosity for the role it plays in the pathogenesis of depression. Studies conducted through the depletion of neurogenesis provided crucial evidence that there is a direct relationship between this depletion and increasing depression levels. Through the increase of neurogenesis in mice, the second study supported the conclusions from the first study, providing even more insight into this field. The ventral dentate gyrus of the hippocampus was identified as the main area regulating the HAP axis. While this axis remained relatively unaffected in the second experiment, it unarguably provides measurable parameters for the body's response to stress. However, these revelations provided new insight into the possibility of the existence of other mechanisms through which neurogenesis contributes to lower depression levels. These studies have therefore opened a window for the exploration of neurogenesis as a prophylaxis or treatment of depressive disorders in human beings.

References

Bergmann, Spalding and Frisen, 2015. Cold Spring Harbor perspectives in biology. 'Adult neurogenesis in humans' p.01. [Online] (2015) Available at https://www.ncbi.nlm.nih.gov/pubmed/26134318/ [Accessed 06/05/2020].

Egeland et al., 2017. Translational psychiatry. 'Depletion of adult neurogenesis using the chemotherapy drug Temozolomide in mice induces behavioural and biological changes relevant to depression.' Pp.e1101-e1101. [Online] (2017) Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5416706/ [Accessed 06/05/2020].

Egeland, Zunszain, and Pariante, 2015. Nature Reviews Neuroscience. 'Molecular mechanisms in the regulation of adult neurogenesis during stress.' Pp.189-200. [Online] (2016) Available at https://www.nature.com/articles/nrn3855/ [Accessed 06/05/2020].

Goncalves, Schafer and Gage, 2016. Cell. 'Adult neurogenesis in the hippocampus: from stem cells to behavior.' Pp.897-914. [Online] (2016) Available at https://www.sciencedirect.com/science/article/pii/S0092867416314040/ [Accessed 05/05/2020].

Hill, Sahay and Hen, 2015. Neuropsychopharmacology. 'Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors.' Pp.2368-2378. [Online] (2015) Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538351/ [Accessed 05/05/2020].

Kempermann, 2018. Cell stem. 'Human adult neurogenesis: evidence and remaining questions.' Pp.25-30. [Online] (2018) Available at https://www.sciencedirect.com/science/article/pii/S1934590918301668/ [Accessed 05/05/2020].

Kumar et al., 2019. Innovations in clinical neuroscience. 'Adult neurogenesis in humans: a review of basic concepts, history, current research, and clinical implications.' p.30. [Online] (2019) Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659986/ [Accessed 05/05/2020].

Pereira Dias et al., 2014. Neuro-oncology. 'Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms.' Pp.476-492. [Online] (2015) Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956361/ [Accessed 06/05/2020].

Roddy et al., 2019. Biological Psychiatry. 'The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression.' Pp.487-497. [Online] (2019) Available at https://www.sciencedirect.com/science/article/abs/pii/S0006322318318195/ [Accessed 05/05/2020].

Spalding et al., 2013. Cell. 'Dynamics of hippocampal neurogenesis in adult humans.' pp.1219-1227. [Online] (2015) Available at https://www.ncbi.nlm.nih.gov/pubmed/23746839/ [Accessed 06/05/2020].