Psychology and Neuroscience of Affective Disorders PDF

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 3 The role of neuroinflammation in affective disorders - Part 1 of 2 Dr Naghmeh Nikkheslat Post-Doctoral Researcher, Depa...

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 3 The role of neuroinflammation in affective disorders - Part 1 of 2 Dr Naghmeh Nikkheslat Post-Doctoral Researcher, Department of Psychological Medicine Lecture transcript Slide 3: Before I start, I would like you to think for a few seconds what you know about inflammation. Now think about what you know about depression and how these two can link together. If you think about inflammation as part of the immune response and then depression as a mental disorder or mood disorder, how these two possibly can link? Slide 4: Inflammation is a protective response mechanism that has evolved throughout evolution as a defence against pathogens. Inflammation is a vital part of body’s immune response. It is the body’s attempt to heal itself after an injury, defend itself against foreign invaders, such as viruses and bacteria, and repair damaged tissue. Slide 5: Inflammation involves biochemical processes that release proteins called cytokines as emergency signals to bring in your body’s immune cells, hormones and nutrients, to fix the problems. Bacteria and other pathogens enter the site of injury. Platelets from blood release blood clotting protein at one site to stop bleeding. Then we have mast cells secrete essential factors to mediate vasodilation and vascular constriction. Delivery of blood plasma and cells to injured area increases. Neutrophils secrete factors that kill and degrade and remove pathogens by the process known as phagocytosis. Macrophages secrete hormones called cytokines that attract immune system cells to the site and activate cells involved in tissue repair. Inflammatory response continues until the foreign material is eliminated and the wound is repaired. Slide 6: Inflammation is often characterised by redness, swelling, warmth, and sometimes pain and some immobility. The first four cardinal signs of inflammation were described in the first century by the Roman medical writer Celsus. Heat and redness are caused by vasodilation or dilation of small blood vessels in the area of injury and increased rate of blood flow to the microcirculation that is experienced in peripheral parts of the body, such as the skin. Swelling, also called edema, is due to vascular permeability and caused primarily by the accumulation of plasma fluids outside the blood vessels. The pain associated with inflammation results, in part, from the distortion of tissues caused by edema and the pressure of fluids and swelling through the nerve endings. It also is induced by certain chemical mediators of inflammation, such as bradykinin, serotonin, and the prostaglandins. A fifth consequence of inflammation is the loss of function or movement of the inflamed area, a feature noted by German pathologist Rudolf Virchow in the 19th century, and may result from the pain that inhibits mobility or from severe swealing that prevents movement in the area. Slide 7: Inflammation can be acute where there is immediate response to the cause involving body’s innate immune response and activation of monocytes and macrophages. This response is usually quick and will be resolved shortly. However, acute inflammation can turn into chronic state. In chronic inflammation, we see more immune cells involvement. That can include Transcripts by 3Playmedia Week 3 © King’s College London 1.  monocytes, macrophages, fibroblasts, lymphocytes, plasma cells, and so on. This response is typically delayed and may occur a time amount after involvement. And duration can last from weeks to months to years, and if severe enough, tissue can be damaged. Therefore, there is a need to terminate the inflammatory response. Slide 8: There are two important biological factors that regulate inflammation-hypothalamic- pituitary adrenal, or HPA axis, which is a major neuroendocrine system with a vital role in the control of stress response, as well as inflammation. The other factor is glucocorticoid receptors, or GR, which play a crucial role in the negative feedback regulation of the HPA axis, and also have immunosuppressive and anti-inflammatory effects. Slide 9: What is exactly HPA axis? The HPA axis is a physiological system involved in stress responses. In response to physical and psychological stressors, the HPA axis is activated by synthesis and secretion of the corticotropin-releasing hormone, or CRF, and vasopressin from the peraventricular nucleus of hypothalamus which, in turn, activate the release of adrenal corticotropin hormone, or ACTH, from the pituitary gland, which rapidly stimulates the biosynthesis and secretion of the glucocorticoids from adrenal glands. Glucocorticoids then interact with the receptors presented in multiple target tissue, including the HPA axis itself, where they are responsible for feedback inhibition of secretion of ACTH from the pituitary, and CRH from the hypothalamus. Side 10: Glucocorticoids, or cortisol, also known as a stress hormone, are the final product of the HPA axis. These steroid hormones are synthesised from cholesterol. Glucocorticoid exerts the crucial effects in almost every tissue and organ in the body. They exhibit a critical role in restoring and maintaining bodily stress-related homeostasis, modulating your endocrine and immune responses, regulating energy metabolism and inflammation reactions, and influencing cardiovascular function. Slide 11: For glucocorticoids to be effective, they need to bind to glucocorticoids receptors, or GR. The GR in its unactivated form, resides primarily in the cytoplasm in association with the multimeric complex of chaperone proteins, including several heat-shock proteins. After being bound by a steroid, the GR undergoes a conformational change and becomes activated, dissociates from the chaperone protein complex, and translocates from the cytoplasm to the nucleus, where it is responsible for up or down regulation in the expression of various genes. Therefore, GR sensitivity to glucocorticoids is crucial in order to produce an appropriate response that is determined by the number, affinity, and function of the receptors, including the ability of GR to bind the ligand, to translocate from cytoplasm into the nucleus, and to interact with other signalling pathways. Slide 12: Activation of gene expression by GR is known as transactivation, in which GR stimulates transcription rate of a respective target gene, while negative alteration of gene expression by GR is called transrepression, in which GR suppresses the other transcription factor activity. The crucial immunosuppressive and anti-inflammatory roles of glucocorticoids are, in fact, mediated through GR dependent transrepression, which targets the gene associated with inflammatory cytokines, including interleukins. Slide 13: There are lots of research done on the function of HPA axis as a regulatory system in a stress-related disorder. And the findings suggest that disturbance in HPA axis activity can be either in the form of hyper- or hypo-activation. Hyperactivity of HPA axis and subsequently high cortisol levels is observed in major depressive disorders and in other conditions, such as schizophrenia, and Alzheimer disease. On the other hand, HPA Hypoactivity and hypocortisolism have been reported in patients suffering from post- traumatic stress disorder, or PTSD, chronic fatigue syndrome, or fibromyalgia, as well as atypical depression are also associated with hyp activity of the HPA axis. Slide 14: Up regulation of HPA axis activity in major depression is one of the most consistent findings in psychiatry and is observed in a significant proportion of patients and is believed to be involved in both aetiology and pathogeneis of the disease. The majority of depressed patients, specifically in more severe cases, show increased cortisol concentration in saliva, blood, urine, and CSF. Exaggerated cortisol response to ACTH, and also an enlargement of both pituitary and adrenal glands, are other features that have been also reported in patients suffering from major depression. Transcripts by 3Playmedia Week 3 © King’s College London 2.  Slide 15: There have been mounting lines of investigation trying to understand the biological mechanism underlying the causality and pathogenesis of major depression. In spite of various theories proposed, there is no one established mechanism associated with depression due to the complexity and heterogeneous nature of this disorder. The genetic approach elucidates the heritability of depression, considering the evidence of specific associated genes, dependent or independent heritable depression-prone personality traits, and also family history of depression as one of the strong predictors. However, heritability of major depression is only moderate, and to develop depression, environmental factors and major life stressors interact with genetic vulnerability. The other approach to understand biological basis of depression is monoamine deficiency hypothesis as one of the major theories of depression that claims depletion of monoamine neurotransmitters, serotonin, and norepinephrine in the brain in depressed patients. The macrophage theory of depression, proposed by Smith, hypothesises excessive secretion of macrophage monokines as a cause of depression. In fact, there more and more recent psychiatric approaches on mechanisms involved in the pathogenesis of depression are focusing on the development in psychoneuroimmunology, considering the neural immune interaction and involving the role of inflammatory processes. The theory is now known as cytokine hypothesis of depression, developed by consistent findings of elevated levels of pre-inflammated cytokines and their action as neuromodulators in depressed patients. In addition, the hypothalamic pituitary cortisol hypothesis suggests the alteration in cortisol response to stress is an underlying mechanism of pathophysiology of depression. The latest theory has led to the inflammatory and neurodegenerative hypothesis by Maers, stating that inflammatory processes are associated with depression, leading to diminished neurogenesis and increased neurodegeneration observed in patients. Transcripts by 3Playmedia Week 3 © King’s College London 3.