Psychology and Neuroscience of Affective Disorders PDF

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 3 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 3 of 3 Dr Patricia Zunszain Senior Lecturer, Department of Psychological Medicine Lecture transcript Slide 3: In this part, we will look at different ways in which we can study some biological effects of stress. We can study animals which allow us to get access to blood samples, and also to brain samples. In humans, we can look at circulation, we can look at blood. We can look at a urine samples, we can collect saliva or even hair, and look at the effect of stress. Now, we need to remember that what happens in the periphery is not necessarily what is happening in the brain. So in the case of humans, another important way of studying effects of stress is by using stem cells. Slide 4: So let's look at some examples in animals. In rodents, corticosterone is the main glucocorticoid, would be the equivalent to cortisol in humans. This adrenal steroid was the first endogenous compound to be identified as a factor affecting hippocampal neurogenesis. To date, adrenal steroids are well known to regulate both the proliferation and differentiation of new neurons in the dentate gyrus. In rats, sustained increase in plasma corticosterone caused a decrease in neurogenesis. While reciprocally, adrenalectomy, that is the removal of adrenal glands, meaning no corticosterone present, increased neurogenesis. Slide 5: Another way to study stress is to expose rats to fox odor. Analysis of the number of BrdU- labeled cells reveal that exposure to fox odor but not to other nose threatening odors like mint or orange, rapidly decrease the number of proliferating cells in the dentate gyrus of these animals. This effect was depending on a stress induced rise in adrenal hormones, as exposed to fox odor, resulted in an increase of circulating corticosterone levels. When animals were subjected to an adrenalectomy, there was no suppression of cell proliferation. Importantly, the decrease in the number of new granule cells in the animals exposed to fox odor was transient, meaning that the effects of the stress, at least in this experimental paradigm, do not cause permanent damage. Slide 6: In the year 2000, Jacobs and colleagues, proposed in the journal Molecular Psychiatry, a novel theory in what was called the millennium article. What they said was that all the rates of neurogenesis in the adult hippocampus might underline either the development of major depression or the recovery from it. They observed that neurogenesis is highly changeable. Stress and raised glucocorticoids decrease it, whereas exercise and antidepressant drugs do the opposite. The ideas of Jacobs and colleagues were largely based on this, since high cortisol and adversity are risks for depression whilst exercise and antidepressants hasten recovery in humans. Slide 7: We know that chronic stress alters neural circuits in the brain, increasing the risk of depression and anxiety. Let's look at the very interesting study published in January 2018. Researchers in this study reveal a novel cellular pathway that contributes to the pathophysiology of Week 3 © King’s College London 1.  stress-induced disorders. They look at what happens to the brain's microglia under conditions of chronic stress. You may remember that microglia are the brain's resident immune cells, being responsible for fending off infections. Microglia also help remodel neural circuits. In this study, mice were intermittently exposed to stressful conditions, what is called chronic unpredictable stress which as suspected, provoke anxiety and depression-like behaviours. The authors look at neurons in the brain's prefrontal cortex, finding increased messenger RNA levels of colony stimulating factor one or CSF1, and changes in microglia which corresponded with reduced dendritic spine density on pyramidal neurons in layer one of the medial prefrontal cortex, so meaning a reduction in their synaptic connections. This is important because limited connectivity in the prefrontal cortex has been linked to major depression in clinical studies. Interestingly, increased CSF1 messenger RNA levels were also detected in the postmortem dorsolateral prefrontal cortex of individuals with depression.When this researcher prevented neurons from producing CSF1 by viral knockdown, mice exposed to chronic stress did not develop symptoms of anxiety or depression. This suggests that interacting stress-induced signalling between neurons and microglia, might be a way to treat anxiety and depression in patients. Slide 8: Let's move to some examples of experiments done with human stem cells. You learned how we can use stem cells to study mental health, so we will look at some data we obtained using a clinically relevant model of human hippocampal progenitor cells. This is a cell line that has been genetically modified to proliferate indefinitely in the presence of growth factors and a chemical, and upon removal of this chemical and growth factors, these cells differentiate and produce neurons, astrocytes and oligodendrocytes. Once cells are treated with high doses of cortisol, we observe a reduction in neurogenesis, as seen in green in the top pictures, where cells were stained for BrdU. Similarly, we observed a reduction of doublecortin-positive neuroblast as indicated in red, and MAP2-positive neurons as indicated in green, now in the bottom pictures. Slide 9: We also looked at the effects of antidepressants using dexamethasone, a synthetic glucocorticoid that is a specific GR agonist, so meaning no action on MR as cortisol. If you remember, we said that cortisol acts on both MR and GR, so dexamethasone, acting just on the GR, decreased the number of MAP2 positive neurons and of doublecortin-positive neuroblasts by 27 and 25% respectively, as we can see in the black columns. Now, co-treatment of these cells with a selective serotonin reuptake inhibitor, sertraline and dexamethasone, abolished the reduction of MAP2 and Dcx-positive cells, as seen in the red columns. Slide 10: Let's look now at some examples of cortisol measurements in patients and in controls. So the production of cortisol follows a circadian rhythm: cortisol concentrations increase prior to awakening and for the following 30 to 45 minutes, cortisol values will show a sharp increase. This is termed the cortisol awakening response or CAR. Levels then decrease during the day, and there are many ways that this regulation of the HPA axis can be assessed. We can be sampling diurnal basal secretion; we can look at levels of cortisol in response to a stress task or a pharmacological challenge, and we can look at it during awakening. And we are particularly interested in cortisol awakening response as it has been found to show unique associations with the range of lifestyle factors and psychological traits, often different from those found with the profile which is observed over the remainder of the day. Slide 11: Traditionally, the assessment of cortisol in observational surveys has been through measurements in blood, in saliva, or in urine. Now, collecting saliva samples is now a common method as it is minimally intrusive. Participants must refrain from eating, smoking, drinking, or brushing teeth within 15 minutes prior to collection. Saliva samples can be obtained using swabs at several time points, which are then put into tubes for centrifugation. Because of the pulsatile secretion of cortisol, single measurements reflect short-term levels and provide information which is not useful if we want to look at long-term cortisol secretion. Now, long-term levels may be important in the aetiology of chronic disease because the cumulative effect of frequent HPA axis activation may be associated with maladaptive effects of the organism. To have a measurement of cortisol levels over time, we can either use urine which is not practical, or we can use hair which is now a good alternative. It is non-invasive and can be performed by non-healthcare workers at any time of the day. Now more and more we're starting to see experimental results obtained through hair samples. Slide 12: So let's look at some examples. This slide shows data from almost 1,600 participants of the Week 3 © King’s College London 2.  Netherlands Society of Depression and Anxiety, who were recruited from the community, general practice care and specialised mental health care. Here three groups were compared: control subjects without psychiatric disorders, those with remittent major depressive disorders and those with a current major depressive disorder diagnosis. Participants collected saliva samples at home at awakening, and at 30, 45, and 60 minutes later. Both the remitted and the current depressed groups showed a significantly higher cortisol awakening response compared with control subjects. Because higher cortisol awakening response was observed among those subjects with current and remitted depression, this may be indicative of an increased biological vulnerability for depression. Slide 13: This other study investigated the younger production of saliva cortisol in women with symptoms of depression postnatally. Here, depressed and non-depressed women has seven and a half weeks postpartum and non-perinatal controls collected saliva at awakening, 30 minutes, and 3 and 12 hours post awakening. Women who were not depressed postnatally, show a pattern of cortisol secretion, over the day, which was similar to that of the non-perinatal controls, but the depressed women had significant higher cortisol levels at awakening and no increase at 30 minutes later. The lack of a morning rise in the depressed women is similar to that reported for post- traumatic stress disorder and chronic fatigue syndrome, and may reflect the response in vulnerable women to the marked cortisol withdrawal that occurs after delivery. Slide 14: Finally, let's look at the Whitehall II study. This is an occupational cohort originally recruited from London-based civil service departments between 1985 and 88. Hair cortisol concentrations were measured from the 3 centimetre hair segment near the scalp in 3,500 participants. Prevalent diabetes, use of systemic corticosteroids and cardiovascular medication were independently associated with higher cortisol levels. In relation to depressive symptomatology, these were associated with higher levels following adjustment for physical disease and medication. In this study, the mental health status was assessed using the for Epidemiological Studies-Depression scale CES- D, which is a 20-item scale that measures symptoms of depression in the general public, and the authors considered a cut-off of more than 16 as has previously been used to classify depression. Slide 15: Let's finish with this diagram from Weger and Sandi. Highly anxious individuals show behavioural alterations and more reactive physiological stress responses. Molecular variations either due to epigenetic or genetic factors in key neurobiological systems such as neurotransmitter systems, or the HPA axis, might define the high anxiety trait phenotype, but only in combination with suboptimal environmental conditions such as stressful life events, high anxiety traits will provide a vulnerability phenotype for the development of psychopathology, such as anxiety disorders or depression. Remember, stressful life events have been found to be associated with the onset of major depressive episodes. But not everyone will develop a depressive disorder in response to stressful events. As assigned to Selye, it is not stress that kills us, it is our reactions to it. Slide 16: These are some links to videos that may be of use, they may help you understand the topic and some further reading of a particular book if you're interested. Week 3 © King’s College London 3.