Neurobiology of Depression: An Integrated View Of Key Findings

V. Maletic; M. Robinson; T. Oakes; S. Iyengar; S. G. Ball; J. Russell


Int J Clin Pract. 2007;61(12):2030-2040. 

In This Article

Molecular Processes Mediating Neurobiological Changes

The alteration in the hippocampus signifies a potential outcome of injurious feedback that occurs via neuroendocrine dysregulation. A consistent finding in patients with MDD is a high level of the stress hormone cortisol, which may cause impairment in neuroplasticity and cellular resistance.[41] An imbalance between glucocorticoid and mineral corticoid receptors in MDD along with high-density glucocorticoid receptors (GRs) may also contribute to the hippocampus' susceptibility to neuronal damage.[42] Subsequent hippocampal atrophy could result in further neuroendocrine dysfunction and hence a potential 'run-away' system.[43] Postmortem comparisons of brain tissue in patients with MDD and age-matched healthy controls have shown hippocampal shrinkage in depressed subjects that was caused by increased density of neuronal cells and a significant reduction in neuropil (i.e. decreased dendridic branching and spine complexities).[44]

A corollary of elevated glucocorticoids and compromised hippocampal functioning may also be the down-regulation of the GR sensitivity. Under conditions of chronic stress, decrease in GR sensitivity can have negative consequences as GR signalling becomes insufficient to 'turn off' the initial responses to stress as part of a negative feedback process.[45,46] Figure 3 Subsequently, HPA hypothalamic overactivity, in conjunction with amygdala activation, leads to increased sympathetic tone, which promotes the release of cytokines from macrophages. Increase in pro-inflammatory cytokines has been associated with loss of insulin and GR sensitivity, which further perpetuates metabolic and neuroendocrine disruption.[47] Symptomatically, disruptions as a result of proinflammatory cytokines may be experienced as fatigue, loss of appetite and libido as well as hypersensitivity to pain.[48]

Molecular processes are impacted by stress and depression. Stress results in release of glucocorticoids and corticotrophin releasing hormones (CRH) and pro-inflammatory cytokines (TNF, IL-1, IL-6). In depression, disruption of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) transmission impair the regulatory feedback loops that 'turn off´ the stress response. Sympathetic overactivity contributes to immune activation and release of inflammatory cytokines. Inflammatory cytokines further interfere with monoaminergic and neurotrophic signalling. They may also diminish central corticosteroid receptor sensitivity, leading to disruption of feedback control. Figure adapted from ref. no.[46]

Proinflammatory cytokines may also diminish neurotrophic support and monoamine neurotransmission that can lead to neuronal apoptosis and glial damage. Alterations in glia-neuron relationships have been recently emphasised in the aetiology of neuropathic pain and MDD.[47,49] Glia cells are involved in an intricate interaction with neurons in which astroglia and microglia maintain homeostasis of the neuronal environment by modulating electrolytes, neurotransmitters, cytokines and neurotrophic factors.[50] Neurons reciprocate support of glial function via neurotrophin signalling. Stress, depression and ensuing peripheral immune dysregulation lead to activation of microglia that then contribute to the existing immune disruption by additional release of inflammatory cytokines.[51]

An integral part of maintaining the health of these glial-neuron interactions may be mediated by brain-derived neurotrophic factor (BDNF).[52] Involved in neurogenesis, BDNF is the primary neurotrophin of the hippocampus. As a dimeric protein involved in cell maintenance, plasticity, growth and death (apoptosis), BDNF is structurally related to nerve growth factor and is distributed widely throughout the brain.[53] When BDNF interacts with tyrosine receptor kinase receptors (TRkB), it promotes cellular resilience and long-term potentiation. However, the precursor form of BDNF (pro-BDNF) can also precipitate reduction in dendritic spines and cell death when it binds with the p75 receptor. Thus, depending upon its expression, BDNF can prune neural networks in an activity dependent manner that is regulated by various neurotransmitters [glutamate, GABA, 5-HT, norepinephrine (NE), acetylcholine, dopamine and hormones].[54]

Preclinical and clinical studies have suggested dysregulation in BDNF occurs under conditions of chronic stress and depression. In animal models, acute and chronic immobilisation stress resulted in decreased BDNF expression using mRNA assays. Similar results were also observed following administration of acute and chronic pain stimuli.[55] Within humans, levels of serum BDNF has been found to be significantly lower in untreated patients with MDD compared with treated patients or healthy controls.[56] Similarly, postmortem analyses of brains of persons who committed suicide showed that BDNF and another neurotrophin (NT-3) were significantly reduced compared with non-suicide controls.[57]

From the above observations, the neurotrophic hypothesis has emerged as a major theory for the pathogenesis of major depression. In this model, stress and genetic vulnerability elevate glucocorticoid steroids and alter cellular plasticity via downregulation of growth factors and receptor sensitivity.[4] The reduction in growth factors, such as BDNF, impacts negatively on the structural and functional processes within the limbic system, especially for the hippocampus. Chronic and recurrent MDD may result in subsequent atrophy and further disruptions in neurocircuitry. From this hypothesis, recovery and remission of MDD would be dependent upon a reversal of these processes, such as an increase in BDNF levels.

Complementing the neurotrophic hypothesis of MDD is the monoamine theory, which postulates that depression is associated with low levels of monoamines, particularly, 5-HT and NE. A recent imaging study of patients with untreated depression found a high global receptor density for the monoamine oxidase A (MAO-A), which nonspecifically metabolises these neurotransmitters. In this updated theory, long-term monoamine loss because of this global MAO-A activity interacts with regional specific transporter densities (i.e. 5-HT, NE), resulting in the expression of the depressive illness.[58] Both 5-HT and NE ascending fibres originate from brainstem nuclei and innervate the limbic system, prefrontal cortex and associated structures involved in the regulation of mood. Descending pathways project through the dorsolateral spinal column and are instrumental in the regulation of pain.[59,60] Therefore, depending upon the specific transporter densities within these regions, various symptoms of depression (mood, cognition and pain) will be manifested within the context of the overall global reduction in monoamine levels.[58]


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