Neurodevelopment and Depression- Where Do They Meet?

Priasha Dutta, Amity University Kolkata

Depression is currently one of the most well-known psychiatric disorders with an increasing number of patients every year. Existing research reveals the role played by different cellular, neuroendocrine and neurochemical mechanisms on the pathophysiology of depression. Since the last two decades, studies of neuroanatomical changes in depression, mainly in the prefrontal cortex (PFC), amygdala, and the hippocampus; and the neurodevelopmental process being the cause for these alterations have been reported. Thus, it has been suggested that depression is an outcome of an early neurodevelopmental disruption. Genetic and environmental factors are also said to influence the normal neurodevelopment of regions related to emotional function early on, thus snowballing the risk of developing depression later in life.

NORMAL BRAIN DEVELOPMENT –

Human neurodevelopment is a dynamic process that commences early all through the prenatal period amid the third and fourth week of gestation. The neuroanatomical and functional changes during neurodevelopment are correlated. For example, the development of PFC is associated with cognitive functions like attention, memory, and inhibition. The regions of the human brain develop at different periods. Lower-order sensorimotor areas are the first to mature whereas higher-order association regions have a late maturation. Important anatomical changes in the human brain have been identified during different life periods, especially during fetal development, childhood, puberty, and early adolescence. For instance, it has been reported that a faster maturation of frontal and temporal brain areas occurs during fetal life. Electroencephalographic studies have shown an increase in structural complexity of the frontal area during puberty and early adolescence. This suggests that human neurodevelopment is a long and dynamic process.

HOW DIFFERENT IS THE DEPRESSIVE BRAIN?

The presentation of the depressive syndrome varies among patients. Several neuroanatomical, biochemical, and functional studies imply that depression is a complex brain disorder. Magnetic resonance imaging (MRI) studies suggest a total brain volume decrease in depression because of grey matter atrophy. Constant anatomical changes have been observed in the hippocampus, amygdala, PFC, and anterior cingulated cortex (ACC). In cases of depression, MRI has also shown a substantial reduction of the serotonin transporter (5-HTT) in the amygdala. Post-mortem studies have revealed a loss of glial cell density and a decreased neuronal size in the depressive brain. The hippocampus has an increased density in pyramidal neurons, granule cells, and glial cells. All of these findings may help in understanding the neuropathology of depressive syndrome. However, the severe complexity of the neurobiological processes involved in the illness raises important questions about the significance of different brain regions in the neuropathology of the disease.

The following points help us understand the neurobiology of depression through neurodevelopment-

• DEPRESSION, A MONOAMINE AND SEROTONIN DISORDER –

5-hydroxytryptamine (HT) or serotonin has been identified in the fetal nervous system, playing a role in neurodevelopmental signaling. On the maturation of the 5-HT system, a peak during the postnatal/early childhood period has been noted. Serotonin is involved with the development of synapse formation, network construction, and cell adhesion. The serotonin receptor 5-HT1A has been detected in brain regions that have been linked to the neuropathology of depression, such as the hypothalamus, hippocampus, and amygdala. Receptors 5-HT1A and 5-HT2A/C are involved in various circuit activities, given their expression in both inhibitory interneurons and excitatory neurons. A disrupted 5-HT level early in neurodevelopment can trigger both morphological and behavioral alterations. Dopamine modulates several processes in neurodevelopment, such as neuronal proliferation and migration, dendritic and axonal growth, synaptogenesis, and spinogenesis. Altered dopamine levels as seen in depressive patients suggest an underlying relation. During adolescence, a blockade of MAOA (monoamine oxidase-A protein; which normally functions in the breakdown of neurotransmitters) disrupts the metabolism of dopamine, serotonin, and norepinephrine. This implies that monoamine signaling is important in shaping brain architecture and adult behavior. Dysfunctional monoamine during sensitive neurodevelopmental periods is highly involved in causing depressive syndrome.

• THE ROLE OF NEUROTROPHINS –

Neurotrophins are proteins that play a major role in proliferation, differentiation, neurodevelopment, influencing cell survival, plasticity, and function. The neurotrophic factors are expressed early in the development in brain areas that have been linked with the depressive syndrome. Neurotrophins like brain-derived neurotrophic factor (BDNF) have an important regulatory function of neuronal circuits. A lessened level of BDNF has been associated with increased chances of developing depression. Its expression is further negatively influenced by stress, inducing hippocampal and PFC atrophy. The exact cause for the decrease in BDNF is unknown but is hypothesized to be associated with different pathways and life events. The BDNF–tyrosine kinase receptor B pathway has been recognized for neuronal survival and depressive neuropathology. Thus, it is a possible target for antidepressant medication. 

• THE ROLE OF THE NEUROIMMUNE SYSTEM –

Dendritic cells and macrophages are responsible for brain immunity. Microglia cells are macrophages of the central nervous system and share similarities with peripheral immune cells. Brain immunity response includes the production of pro-inflammatory cytokines and prostaglandins that, in a constant immune response, induce depression-like symptoms. Cytokines, like interleukin-1b and tumor necrosis factor-a, glutamatergic and serotoninergic neurotransmission alterations, and cortisol hypersecretion forms the basis of these symptoms. The immune system also plays a major role in brain development. During neurodevelopment, microglia cells and cytokines have not only an immunological function but vital in the formation of both neuronal architecture and cellular circuits. Changes in both neurogenesis and neurotrophic factor expression have been associated with the noted behavioral abnormalities, where cytokines have been suggested as the source of these changes. The current information about the neuroimmune system provides a close correlation between the endocrine, immune and nervous systems. Also, these communications seemingly play a key role in the development of depression.

• NEUROENDOCRINOLOGY OF DEPRESSION –

The endocrine system and brain chemistry are strongly intertwined. The hypothalamic-pituitary-adrenal (HPA) axis is vital for growth, immunity, metabolism, and gonadal function. The HPA and its end product, glucocorticoid, play a major role in the system’s homeostasis after the stress response. Dysfunction of the HPA axis produces a neurotransmitter imbalance, inducing depression. A higher percentage of depressive patients show high cortisol secretion. Early and/or later life social and/or environmental stressors have been linked to an increased risk of developing behavioral alterations and metabolic disorders like hyperlipidemia, hyperglycemia, and insulin resistance. Micro- and macro-anatomical brain changes, cognitive alterations have been related to HPA hyperactivity. Neuroanatomical, neurochemical, and behavioral changes have also been noted in depressive individuals. It may be due to the early changes at the level of DNA methylation that was induced by difficult childhood experiences. In general, the interaction between neurodevelopment and the endocrine system has a strong role in the biology of depression.

CONCLUSION –

Continuous research is being conducted to find other underlying mechanisms causing depression and finding suitable therapeutics to tackle them. However, more evidence is required to find an answer to the question – “Is depression primarily a neurodevelopmental disorder?” Whether it’s neurobiology, genetic vulnerability, immunology, stressful life events, unpleasant memories, or medical problems; there is plenty that proves that depression is real and not just exhibited for seeking attention. If one is facing such problems with their mind, help should be asked for. Awareness and importance of mental health need to be discoursed and normalized further. With the stigma surrounding mental health conditions gradually wearing down, one can always bounce back with resilience. Just like the words of author John Green, “There is hope, even when your brain tells you there isn’t”.

Also read: Liquid biopsy and droplet digital PCR help to detect Colorectal cancer

REFERENCES-

1. Lima-Ojeda, J. M., Rupprecht, R., & Baghai, T.C., (2018). Neurobiology of depression: A neurodevelopmental approach. World J Biol Psychiatry, 19(5), 349-359. DOI: 10.1080/15622975.2017.1289240
2. Chen, F., Bertelsen, A. B., Holm, I. E., Nyengaard, J. R., Rosenberg, R., & Dorph-Petersen, K.-A. (2019). Hippocampal volume and cell number in depression, schizophrenia, and suicide subjects. Brain Research, 1727, 146546. https://doi.org/10.1016/j.brainres.2019.146546
3. Gałecka, M., Bliźniewska-Kowalska, K., Maes, M., Su, K.-P., & Gałecki, P. (2021). Update on the neurodevelopmental theory of depression: is there any ‘unconscious code’?. Pharmacol. Rep 73, 346–356. https://doi.org/10.1007/s43440-020-00202-2

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