The Biology of Depression
Neurotransmitter synthesis and transmission - a key to joy
In the brain's nervous system neurons, neurotransmitters in vesicles diffuse to neurotransmitter receptors by passing through the reuptake transporter, turning into an active state. The produced dopamine and serotonin regulate human mood, making you feel more focused, emotionally stable, happier, and calmer. Depression is linked to the imbalance of neurotransmitters dopamine and serotonin.
Dopamine: Normally, after dopamine binds to the substrate of the dopamine transporter (DAT) that regulates the dynamics of dopamine (DA) neurotransmission, dopamine enters the cell membrane. It interferes with the vesicular monoamine transporter (VMAT) and fills up multiple synaptic vesicles. The uptake of dopamine in vesicles results in the efflux of old dopamine into the cytoplasm. Dopamine then binds to dopamine acceptor, releasing hormone and prolactin that makes humans feel motivated, relieved, and concentrated. The dopamine system drives the brain’s pleasure and reward system, the brain’s pleasure, and the reward center. The human body expects to experience the same type of joy by eating certain foods to spike the dopamine levels in the brain. In this case, dopamine deficiency leads to neurodegenerative conditions in the body, contributing to the formation of clinical depression.
Serotonin Serotonin is synthesized from the amino acid L-tryptophan. Under the hydroxylation of tryptophan hydroxylase (Tph), L-tryptophan is converted into 5-hydroxytryptophan (5-HTP), which is subsequently catalyzed into serotonin by aromatic amino acid decarboxylase (AAAD). Tph1 and Tph2 are two forms of Tph. Same as dopamine, serotonin enters the cell membrane and interferes with VMAT, and fills up vesicles. The efflux of serotonin then binds to a serotonin receptor, controlling your mood, and is responsible for happiness.
Figure 1. Depiction of neurotransmitter transport in the brain nerve system
Figure 3. Dopamine binding to DAT.
Figure 2. Process of dopamine transport
"You don't understand depression until you can't stand your own presence in an empty room"
--Unknown
The Stress Hormone Cortisol is responsible for depression
Figure 4. Process of cortisol synthesis
Stress triggers a combination of signals within the body from both hormones and nerves. These signals cause your adrenal glands to release a hormone called cortisol. The result is an increased heart rate and energy as part of the fight-or-flight response.
The hypothalamic-pituitary-adrenal (HPA) axis is a well-documented endocrine system that regulates biological responses to stress, including social stress, restraint stress, and maternal separation. Stress triggers the release of Cortisol, a steroid hormone, that is synthesized from cholesterol in the zona fasciculate layer of the adrenal cortex. Stress promotes the release of corticotropin-releasing hormones from the hypothalamus, which facilitates the secretion of Adrenocorticotropic hormone (ACTH) from the pituitary gland to the systemic circulation. Followed by increased ACTH, cortisol synthesis occurs, these hormones increase LDL receptors, and LDLs then bind to the receptor and break down to release cholesterol, the enzyme then converts cholesterol to pregnenolone and further converts to cortisol. The glucocorticoids in the bloodstream are bound to either corticosteroid-binding globulin (CBG) or albumin. Function of cortisol is mediated by the glucocorticoid receptor, and binding of the glucocorticoid receptor induces the dissociation of multiple protein complexes in the cytosol, allowing the glucocorticoid receptor to translocate into the nucleus. Hypersecretion of glucocorticoids is associated with depressive symptoms, reported by high cortisol levels in depressed patients. It decreases the 5-HT1 receptor in the hippocampus, suggesting that glucocorticoid released as a result of stress activation of the HPA axis changes the function of 5-HT neurons.
CRH is a neuronal factor that interacts with the brain's 5-HT system during the stress response. In the dorsal raphe nucleus, CRH terminals contact 5-HT-containing dendrites. Furthermore, the serotonergic dorsal raphe nucleus expresses the CRH receptors. Intracerebroventricular and intraraphe administration of CRH inhibits the activity of serotonergic neurons, decreasing the 5-HT levels in the terminal region. The effect of CRH is mediated by corticotropin-releasing hormone receptor 1(CRH-R1) and corticotropin-releasing hormone receptor 2 (CRH-R2). According to a study conducted by Lukkes, social stress promotes the absorption of DRH-R1 in 5-HT neurons in the dorsal raphe, so an increase in accumbal 5-HT levels induced by higher dose CRH was blocked by antagonizing the CRH-R2 in the dorsal raphe nucleus.
MAO-A plays a major role in the biological response to stress. In serotonin synthesis, the catalytic activity of MAO-A degrades the decarboxylate of 5-Hydroxytryptophan (5-HTP) to 5-HT by 5-HTP decarboxylase. Which 5-HT oxidizes into 5-HIAA instead of serotonin. Social stress increases the 5-HIAA/5-HT ratio, an index of serotonin turnover. Moreover, the level of 5-HT released after expression from 5-HT neurons decreased, leading to a shortage of serotonin that can regulate our mood
Exposure to chronic social defeat stress increases factor 11 (KLF11) immunoreactivity in the frontal cortex, medial prefrontal cortex, and CA1 in the hippocampus of rats. KLF11 protein can regulate the expression of genes, such as MAO-A, by binding to GC-rich consensus SP1-like binding side.
Chronic social defeat stress increases SIRT1 mRNA, an NAD+-dependent protein deacetylase, which can deacetylate some transcriptional factors associated with neuronal protection, and resistance to oxidative stress. SIRT1 overexpression mice show higher MAO-A gene expression level, lower 5-HT levels, and higher 5-HIAA levels in the brain, indicating the role of SIRT1 in the regulation of MAO-A, which alter the 5-HT system and lead to depression symptoms.
Monoamine hypothesis - primary pathophysiology
Figure 5. Increased stress trigger the released of MAO-A, which damage the synthesis of serotonin, reducing the number of serotonin, leading to a series of depressed mood and symptoms.
Elevated cortisol secretion leads to decreased serotonin transporter, leading to the manifestation of a depressive state. High levels of cortisol cause a breakdown of the synaptic connections between neurons, so neurons become substantive to 5-HT. Further leads to a decreased level of homovanillic acid, acute depletion of tryptophan - a necessary precursor of serotonin and dopamine - altered dopamine receptor agonist, dopamine and serotonin fail to bind to the receptors from one neuron to another neuron in the striatum, failing to regulate mood. Also, endogenous opioids failed to bind to opioid receptors from one neuron to another, not signaling cells in the ventral tegmental area (VTA) to produce dopamine and serotonin. Furthermore, cortisol binds to the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), releasing abundant stress-response proteins that contribute to depression. Cortisol abnormalities appear to be positively correlated with depressive severity, leading to psychological symptoms of depression.