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NEUR30002 - Neurophysiology: Neurons and Circuits > Lecture 27: Neuroinflammation and Cardiovascular Function > Flashcards

Lecture 27: Neuroinflammation and Cardiovascular Function Flashcards

1
Q

What are the circumventricular organs?

A

highly vascularised structures located around the 3rd and 4th ventricles characterised by the lack of a blood-brain barrier (BBB)

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2
Q

What makes circumventricular organs significant?

A

these areas are points of communication between the blood, brain parenchyma and CSF

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3
Q

What do neurons and glia in the circumventricular organs express and what do they receive?

A

a wide array of receptors and ion channels and receive a wide array of signals from the circulating blood

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4
Q

What do the circumventricular organs have a critical role in?

A

sodium and water balance, cardiovascular regulation, energy metabolism and immunomodulation

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5
Q

What does the subfornical organ play a role in?

A

blood pressure regulation

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6
Q

What is involved in the CNS innervation of sympathetic outflow?

A

paraventricular hypothalamic nucleus, A5 cell group, rostral ventrolateral medulla, ventromedial medulla, caudal raphe nuclei and sympathetic preganglionic nuclei

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7
Q

What does stimulation of the rostral ventrolateral medulla result in?

A

increased blood pressure and sympathetic nervous activity

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8
Q

The circumventricular organs (CVOs) are areas of the brain with an intact blood-brain barrier. (TRUE / FALSE)

A

FALSE

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9
Q

Where do primary afferents from the baroreceptors from the carotid sinus terminate?

A

nucleus of the solitary tract (NTS)

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10
Q

What has proven to be increased in hypertensive vs normotensive rats?

A

mRNA levels of pro-inflammatory cytokines in BM-derived mononuclear cells
also elevated levels of the chemokine CCL2 in the BM, serum and CSF

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11
Q

What happens if we substitute the bone marrow from hypertensive animals into normotensive animals?

A

mean arterial pressure increases in the normotensive animal

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12
Q

What happens if we substitute the bone marrow from normotensive animals into hypertensive animals?

A

mean arterial pressure decreases significantly

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13
Q

What changes do they see in microglia in these chimeric rats (where BM was replaced)?

A

activated microglia in the hypothalamic paraventricular nucleus are decreased in the hypertensive animals after reconstitution with normotensive bone marrow

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14
Q

What are activated microglia a sign of?

A

neuroinflammation

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15
Q

What is minocycline?

A

a tetracycline antibiotic used to treat bacterial infections such as pneumonia
also used in treatment of acne and rheumatoid arthritis

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16
Q

What is minocycline commonly used to inhibit?

A

microglia activation

specifically polarization to M1 phenotype

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17
Q

What is the result of administering minocycline to hypertensive animals but not normotensive animals?

A

significantly decreases blood pressure

18
Q

What do pro-hypertensive signals such as angiotensin II (Ang II) activate?

A

PVN pre-autonomic neurons to increase sympathetic nerve activity (SNA) and cause release of C-C chemokine ligand 2 (CCL2)

19
Q

How does SNA affect the bone marrow?

A

results in an increase in inflammatory cells (IC) and a decrease in angiogenic progenitor cells (APCs)
this imbalance is associated with vascular pathology and increase in BP

20
Q

Why do inflammatory progenitors migrate to the PVN?

A

as a result of an increased neuronal release of CCL2 where they differentiate into BM-derived microglia/ macrophages

21
Q

What happens when resting microglia and BM derived microglia / macrophages are activated?

A

release an array of cytokines / chemokines

22
Q

Which cytokine was increased in the bone marrow, serum and cerebrospinal fluid of hypertensive rats compared to normotensive rats?

A

CCL2

23
Q

What happened when the bone marrow from WKYs were transplanted into SHRs?

A

blood pressure decreased

24
Q

What happened to the number of microglia in the brain when SHRs were transplanted with bone marrow from WKYs (SHR-WKY)?

A

there were fewer microglia compared to SHR-SHR

25
Q

What is the subfornical organ and where is it located?

A

a CVO and lacks a BBB

located on the anterior wall of the 3V

26
Q

What does the subfornical organ send projections to and why?

A

both compartments of the paraventricular nucleus to modulate SNA and AVP release

27
Q

What does the subfornical organ show high expression of? What does stimulation of these receptors lead to?

A

high expression of AngII receptors and stimulation of these receptors elicits a drinking response

28
Q

What are the effects of TNF-alpha in the subfornical organ?

A

elicits a rise in blood pressure and heart rate

29
Q

What are the effects of TNF-alpha in the subfornical organ influenced by?

A 
captopril = ACE inhibitor
losartan = AT1 receptor antagonist
NS-398 = selective COX2 inhibitor
30
Q

What are the effects of TNF-alpha in the area postrema?

A

elicits an increase in blood pressure

31
Q

What are the effects of TNF-alpha dependent on? What is this response abolished by?

A

dose
higher doses cause a larger increase in blood pressure
pre-treatment with a TNFR1 receptor specific antibody

32
Q

What did microinjection of TNFR1 receptor blocking antibody into the area postrema of hypertensive animals result in?

A

a significant fall in blood pressure

this was not observed in non-hypertensive animals

33
Q

What does primary (neurogenic) and secondary (renal stenosis, diet) cause?

A

an increase in circulating AngII levels which results in an increase in circulating CCL2 (MCP-1)

34
Q

What does an increase in CCL2 cause in the brain?

A

leads to disruption of the BBB, infiltration of immune cells and activation of microglia (which release a number of inflammatory factors)

35
Q

What does an increase in inflammatory factors within the brain lead to?

A

exacerbation of neuroinflammation which disrupts homeostasis and activates premotor neurons
this eventually leads to an increase in SNA and hypertension

36
Q

What are some examples of inflammatory factors?

A

IL-6, TNF-a, IL-1b and CCL2

37
Q

Which hormone system appears to be critical for the actions of TNF-a and IL-1b in the subfornical organ (SFO)?

A

the renin-angiotensin system

38
Q

What are neural pathways by which gut microbiota influences the brain?

A

enteroendocrine cell release of gut hormones
afferent neural pathways, including the vagus nerve
stress hormones might influence bacterial gene expression, signalling between bacteria which might change microbial composition

39
Q

What is an immunological pathway by which gut microbiota influence the brain?

A

cytokine release from mucosal immune cells

40
Q

What is a metabolic pathway by which gut microbiota influence the brain?

A

bacterial products such as SCFA, GABA or 5-HT precursors

41
Q

What does Ang II, salt or aldosterone induced hypertension lead to?

A

activation of microglia which drives in increase in SNA from areas such as the paraventricular nucleus of the hypothalamus (PVN)

42
Q

What does an increase in SNA from areas such as the paraventricular nucleus lead to?

A

a change in gut microbiota and increased gut permeability which results in oxidative stress, change in microbial products, stimulation of inflammatory cells and release of cytokines -> potentially exacerbates neuroinflammation and hypertension

NEUR30002 - Neurophysiology: Neurons and Circuits (36 decks)

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