Psychology and Neuroscience of Affective Disorders PDF - King's College London

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 2 The neurobiological aspects of stress response - part 1 of 3 Dr Patricia Zunszain Senior Lecturer, Department of Psychological...

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 2 The neurobiological aspects of stress response - part 1 of 3 Dr Patricia Zunszain Senior Lecturer, Department of Psychological Medicine Lecture transcript Slide 3: So this topic is about stress and how it is an important factor involved in affective disorders. In Part One, we will look at what the stress response is, presenting stress hormones. We will introduce the hypothalamic pituitary adrenal axis, and look at how hormones work, considering the endocrine system. In Part Two, we will look at differences between acute and chronic stress and what happens when the stress response is dysregulated, focusing on depression. In Part Three, we will look at different ways in which we can measure some of the effects of the stress. Slide 5: We can all think about stressful situations. Some of us find work or studies stressful. Others associate stress with public speaking or flying, with lack of control, or with deadlines. Most of us will be stressed if living in a conflict zone. We can associate stress with a flight or fight response. These are reactions that occur in response to what we perceive as harmful events or threats to our survival. Some stress experts are adding the word freeze, as instead of fighting or fleeing sometimes when we freeze like some animals, for example, deer in the headlights. In any case in response to anything that threatens homeostasis of the organisms, there will be physiological and behavioural responses that attempt to reinstate an equilibrium. Slide 6: Stress can be caused by any circumstances that either threaten the individual's well-being or that the individual perceives as threatening to their well-being. The concept of stress has been attributed by many to Hans Selye. Selye was an Austrian-Canadian endocrinologist of Hungarian origin who was nominated for the Nobel Prize in physiology or medicine 17 times between 1949 and 1953, for his work on endocrinology and the adaptation syndrome, for his contribution to the isolation of steroid hormones, and for his formulation of stress reactions. Slide 7: Selye was working in a traditional biochemical way, injecting rats with a new ovarian extract. He observed that the rats develop enlargement of the adrenal cortex, atrophy of the thalamus, spleen and lymph nodes, and deep bleeding ulcers in the lining of the stomach and duodenum. He initially thought he had discovered the effect of a new ovarian hormone, but he was wrong. In the control group where rats were injected with saline alone, the animals demonstrated the same changes. When he injected the rats with extracts of other organs, the same happened. He then placed animals on the roof in winter, others in the boiler room. They subjected others to forced exercise or to surgical procedures. And in each case, he observed the same outcome. So Selye concluded that the changes he saw weren't due to the ovarian extract, but were a general response to all the different stressors, either injections, heat, cold, or pain. And he called this the general Week 3 © King’s College London 2019 1.  adaptation syndrome, what we call stress response, which is the response of the body to demands placed upon it. And we now know that when this happens, stress hormones are produced. Slide 8: These stress hormones are glucocorticoids. The name contemplates glucose, cortex, and steroid. As these hormones regulate glucose metabolism, so ‘gluco’, they are synthesised in the adrenal cortex, so ‘cort’, and chemically the structure is classified as steroid, so ‘oid’, which is the last part of the word. In humans, the main stress hormone is cortisol, which after being made in the cortex of the adrenal glands is released into the blood, which transports it around the body. Being a hormone, cortisol acts through specific receptors. Almost every cell contains receptors for cortisol, and so cortisol can have lots of different actions, depending on which cells it is acting upon. Cortisol acts on two receptors, the mineralocorticoid receptor or MR, which has high affinity for endogenous glucocorticoids and in therefore already activated by low or basal cortisol concentrations and the glucocorticoid receptor or GR, which has low affinity for cortisol, and is thus predominately activated by high cortisol concentrations as they occur upon stress. So we will focus on the GR, which is a Ligand Activated Nuclear Transcription Factor. Upon ligand binding, so upon cortisol binding, the GR which resides in the cytoplasm in association with chaperone proteins translocates into the nucleus, binds to glucocorticoid response elements or GREs, which are on the DNA, and subsequently regulates gene transcription. This is covered in detail in the neuroinflammation lecture. By regulating gene expression, cortisol plays a role in the regulation of several physiological processes by controlling energy metabolism, maintaining electrolyte balance and blood pressure and importantly also by modulating immune responses. Slide 9: The production of cortisol is normally under tight control. Under a stressful trigger, neurons in the paraventricular nucleus PVN of the hypothalamus secrete corticotropin releasing hormone or factor, you will see it as CRH or CRF, and arginine vasopressin or AVP, which in turn stimulates the secretion of adrenocorticotropic hormone or ACTH from the anterior pituitary gland. ACTH travels to the adrenal glands which sit on top of the kidneys to promote the synthesis and the release of cortisol. Cortisol enables the release of stored glucose from the liver for energy. The immune system is suppressed when this happens as is discussed in the neuro-inflammation lecture. As mentioned, cortisol interacts with receptors present in multiple target tissues, and these include the HPA axis itself. If there are excessive levels of circulating cortisol, these cortisol molecules will signal the brain to regulate its production. This is known as negative feedback regulation. And there will be feedback inhibition of secretion of ACTH from the pituitary and CRH from the hypothalamus that end up with decreasing cortisol production. Hormones such as cortisol are part of the endocrine system and they work and act in different ways to neurotransmitters, which are part of the nervous system as you learned during the biological foundations of mental health module. Slide 10: The endocrine system consists of hormones, glands, and receptors. Hormones are produced by glands and are secreted into circulation to be carried toward mostly distant target organs, where they start their action by interacting with receptors. When they reach their target, hormones induce responses at the protein or genetic level which takes some time, and all this process is involuntary. As you may remember the nervous system responds rapidly to stimuli by sending electrical action potentials along neurons using neurotransmitters. The effects are often fast and short lived, as for example, when we touch something hot, where we would remove our hands fast. Although hormones act more slowly than neurotransmitters their effects tend to be longer lasting. We will look at what happens when the endocrine system is dysregulated in our next topic. In normal conditions, the body maintains a constant internal environment while also been able to respond and adapt to external events. The nervous and endocrine systems both work to bring about these adaptations, but this sometimes fails and we feel stressed. Week 3 © King’s College London 2019 2.  Slide 11: A commonly used stress scale is the Recent Life Changes Questionnaire or RLCQ, which addresses the stress levels inquiring for the presence or perception of life events during the most recent past. For example, we can never a person's life change experiences over the past year or the past few months by using a list of common sources of stress. The RLCQ has five categories: work, home and family, health, personal and social, and financial. Each of these events has a score according to the severity, so for a less severe event, we will have a lower score. If the event is more severe, you will see a more severe score. One then adds the number of life changing units, or LCU, to obtain a total score. So a 6 month score of 300 or more, or a yearly score of 500 or more indicates high stress. You can try to use the scale and you may find that you have high scores, this is quite common. But what is important is our reaction to stress, this is key. Week 3 © King’s College London 2019 3.