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Psychology & Neuroscience of Affective Disorders > The role of neuroinflammation in affective disorders > Flashcards

The role of neuroinflammation in affective disorders Flashcards

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1
Q

What is an inflammation?

A

Vital immune response

Attempt to:

  • heal after injury
  • defend against foreign bodies
  • repair tissue
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2
Q

What is the biochemical inflammatory process?

A

Macrophages release cytokines (proteins) as “emergency signals”
- bringing immune cells, hormones and nutrients to fix problem

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3
Q

What are the steps of the inflammatory response?

A

Bacteria and other pathogens enter site of injury

  1. Blood platelets release proteins
  2. Most cell secretes essential factors to mediate vasodilation and vascular constriction
    - > increased delivery of blood plasma and cells
  3. Neutrophils secrete factors that kill, degrade and remove pathogens
    = phagocytosis
  4. Inflammatory response continues until foreign materials are removed and injury is repaired
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4
Q

What are the characteristics of inflammation described by Aulus Cornelius Celsus in the 1st century?

A

Cardinal signs:

  • redness and warmth
  • swelling
  • pain
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5
Q

What is the biological phenomenon underlying the redness and warmth in an inflammation?

A
  • Dilation of small blood vessels

- Increased rate of blood flow

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6
Q

What is the biological phenomenon underlying the swelling in an inflammation?

A
  • Vascular permeability

- Accumulation of plasma fluid outside blood vessels

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7
Q

What is the biological phenomenon underlying the pain caused by inflammation?

A
  • Distortion of tissue
  • Pressure of fluids or swelling through nerve endings
  • Induced by chemical mediators (e.g. serotonin)
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8
Q

Which sign of inflammation was described in the 19th century by Rudolf Virchow?

A

Loss of function

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9
Q

What is the biological phenomenon underlying the loss of function caused by inflammation?

A
  • Pain inhibits mobility

- Severe swelling preventing movement

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10
Q

What constitutes acute inflammation?

A
  1. Immediate response
  2. Activation of monocytes and macrophages
  3. Quick resolution
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11
Q

What constitutes chronic inflammation?

A
  1. Delayed response
  2. Activation of monocytes and macrophages
    AND fibroblast, lymphocytes and plasma
  3. Can last for weeks, month or years AND damage tissue
    - > may have to terminate inflammatory response
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12
Q

What are the two factors regulating inflammation?

A
  1. Hypothalamic pituitary adrenal (HPA) axis

2. Glucocorticoid receptors (GR)

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13
Q

What is the hypothalamic pituitary adrenal (HPA) axis?

A
  • Major neuroendocrine system
  • Control of stress response
  • Responds to physical and psychological stressors
  • Control of inflammation
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14
Q

What is the role of glucocorticoid receptors?

A
  • Negative feedback regulation of HPA axis

- Immunosuppressive and anti-inflammatory effect

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15
Q

What activates the hypothalamic pituitary adrenal (HPA) axis?

A

Synthesis and secretion of corticotropin releasing hormone (CRF) and vasopressin from paraventricular nucleus of hypothalamus

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16
Q

What are glucocorticoids?

A
  • Final product of HPA axis
  • Made of steroid hormones
  • Synthesised from cholesterol
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17
Q

What is the role of glucocorticoids?

A
  • Restore and maintain bodily stress-related homeostasis
  • Modulate neuroendocrine and immune responses
  • Regulate energy metabolism and inflammatory reactions
  • Influence cardiovascular function
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18
Q

What is the process of glucocorticoid receptors activation?

A
  1. When activated, GRs go from cytoplasm to nucleus
  2. In nucleus it binds to glucocorticoid response elements (GREs) located on DNA
    - > negatively or positively altering gene transcription

-> GR sensitivity to glucocorticoids is crucial to produce appropriate immune response

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19
Q

What determines GR sensitivity to glucocorticoids?

A

Number, affinity and function of glucocorticoid receptors (GRs)
- binding from cytoplasm to nucleus and other signalling pathways

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20
Q

What is the transactivation of glucocorticoid receptors (GRs)?

A

When activation of gene expression by GR stimulates the transcription rate of a respective target gene

21
Q

What is the transrepression of glucocorticoids receptors (GRs)?

A

When negative alteration of gene expression by GR suppresses other transcription factors activity

22
Q

What mediates the crucial immunosuppressive and anti0inflammatory role of glucocorticoids?

A

Mediated by GR dependent transrepression

- targets genes associated with inflammatory cytokines (including interleukins)

23
Q

What are the disturbances in the activity of the hypothalamic pituitary adrenal (HPA) axis associated to?

A

Stress related disorders

- hyperactivation or hypoactivation

24
Q

To which disorders is the hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and hypercorticolism associated to?

A
  • Major depression
  • Schizophrenia
  • Alzheimer’s disease
25
Q

To which disorders is the hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and hypocorticolism associated to?

A
  • PTSD
  • Chronic fatigue syndrome and fibromyalgia
  • Atypical depression
26
Q

What is fibromyalgia?

A

Disorder characterised by

  • widespread musculoskeletal pain
  • accompanied by fatigue, sleep, memory and mood problems
27
Q

What characterises the disturbance of the hypothalamic pituitary adrenal (HPA) axis in major depression?

A

HPA hyperactivity - hypercorticolism

> Exaggerated cortisol response to adrenocorticotropic hormone (ACTH)

> Up regulation of HPA axis activity
-> aetiology and pathogenesis of depression

> Increased cortisol concentration in
- saliva, blood, urine, CSF

> Enlarged pituitary and adrenal glands

28
Q

Why is there no established biological mechanism established underlying the causality and pathogenesis of major depression?

A

Depression has is complex and heterogeneous

29
Q

What does the genetic approach to the aetiology of depression propose?

A
  • Heritability of depression is moderate
  • Specific associated genes
  • Family history
  • Environment and major life stressors interact with genetic vulnerability
30
Q

What does the monoamine-deficiency hypothesis of depression (Schildkraut, 1965) propose?

A

Depletion of monoamine neurotransmistters

- 5-HT, norepinephrine

31
Q

What does the macrophage theory of depression (Smith, 1991) propose?

A

Excessive secretion of macrophage monokines

32
Q

What does the cytokine hypotheses of depression (Schierpers et al., 2005) propose?

A
  • Psychoneuroimmunology findings
  • Neural-immune interaction
  • Elevated levels of pro-inflammatory cytokines
33
Q

What does the hypothalamic-pituitary-cortisol hypothesis of depression (Belmaker and Agam, 2008) propose?

A

Alteration in cortisol response to stress

34
Q

What does the inflammatory and neurodegenerative hypothesis of depression (Maes et al., 2009) propose?

A

Inflammatory processes lead to diminished neurogenesis AND increased neurodegeneration

35
Q

What are the two opposite biological events taking place in depression?

A

Raised cortisol concentration (most potent anti-inflammatory hormone)
+
Increased inflammation (observed in CSF and periphery)

36
Q

Why does the raised cortisol concentration coexist with the increased inflammation in depression?

A

Glucocorticoid resistance in 80% of patients with major depression

37
Q

What is the consequence of glucocorticoid receptor resistance in depression?

A
  • Glucocorticoid hormone not effective
  • Glucocorticoid receptors show less sensitivity to the hormone and can’t inhibit corticotropin-releasing hormones (CRH)
  • > insufficient glucocorticoid signalling
  • > unregulated inflammatory response
  • > no anti-inflammatory response
  • > excessive release of pro-inflammatory cytokines

=> Higher circulating cytokines (including interleukins)
=> Higher clinical biomarkers of inflammation (C-reactive protein - CRP)
=> Association with inflammatory genes

38
Q

How is depression associated with cardiovascular disease?

A

High levels of inflammation
-> small increases in C-reactive protein (CRP)

  • > increased risk of:
  • heart attacks
  • angina
  • cardiac events

hs-CROP > 3mg/L -> higher risk of cardiovascular disease

> Depression and coronary hear disease are mutual risk factors

39
Q

Does the blood brain barrier protect from peripheral inflammatory activation levels?

A

Immunology research findings:

  • breakdown of blood brain barrier and consequent abnormal communication leads to inflammatory molecules in brain
  • > cytokine can penetrate the brain
40
Q

What does the deficient blood brain barrier hypotheses propose?

A
  • Communication between cytokine and brain can be facilitated by transport mechanisms
  • Positive diffusion at deficient site on blood brain barrier
  • > Passive penetration of cytokines into CNS
  • through binding of transporter molecules
41
Q

What is the current hypothesis on the cause of glucocorticoid resistance?

A
  • Chronic stress
  • > prolonged exposure to inflammatory cytokines
  • Inflammation reduces glucocorticoid receptor (GR) sensitivity
  • Reduced sensitivity leads to inflammation
42
Q

What do animal models show on the effects of inflammation in the brain?

A

> Excessive cytokine production
= diminished neurotropic support and neurogenesis

> Neuro-inflammatory activation
= enhanced oxidation status in CNS, stimulation of nitric oxide production
- observed in pathophysiology of depression

43
Q

How does increased inflammation induce depressive symptoms?

A
  • Modifying serotoninergic system

- Affecting kynurenine pathway of tryptophan metabolism

44
Q

How is the kynurenine pathway of tryptophan metabolism affected by increased inflammation?

A
  1. Increased pro-inflammatory cytokines enhance IDO activation (indoleamine 2,3-dioxygenase)
    and KMO enzymes (kynurenine 3-monooxygenase)
  2. Which diverts kynurenic pathway into neurotoxic path
    - with diversion of kynerine into 3-Hydroxijynurenine (producing quinolinic acid with KYNU enzyme)
  • > Reduced peripheral availability of tryptophan, putatively leading to reduced serotonin synthesis
  • > Production of neurotoxic tryptophan metabolites

=> pathophysiology of depression

45
Q

Why should we consider the treatment of neural-endocrine abnormalities and immune activation in depressed patients?

A

1/3 of depressed patients fail to respond to conventional anti-depressant therapies

46
Q

What are the ultimate clinical goals for neural-endocrine abnormalities and immune activation?

A
  • Specifically targeting inflammation-induced depression
  • Identification of inflammatory biomarkers
  • Prevention of future development of depression
  • Detection of biomarkers used for monitoring changes in vulnerability
  • Inflammation as pharmacological target to develop new antidepressants
47
Q

What makes the fight-or-flight response potentially inaccurate?

A

It is controlled by the amygdala which doesn’t distinguish real from perceived threats

  • e.g. delivering a speech may produce an inflammatory response, and increased blood pressure, heart rate and cortisol levels
  • > response due to subject’s self-esteem
48
Q

What is the potential benefit of depressive symptoms?

A
  • Inflammation response enhances host survival and reproduction
  • Evolution favoured organisms with activated inflammatory systems in response to threats

Psychology & Neuroscience of Affective Disorders (16 decks)

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