Lecture 27: Neuroinflammation and Cardiovascular Function

Question 1

What are the circumventricular organs?

Answer 1

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

Question 2

What makes circumventricular organs significant?

Answer 2

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

Question 3

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

Answer 3

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

Question 4

What do the circumventricular organs have a critical role in?

Answer 4

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

Question 5

What does the subfornical organ play a role in?

Answer 5

blood pressure regulation

Question 6

What is involved in the CNS innervation of sympathetic outflow?

Answer 6

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

Question 7

What does stimulation of the rostral ventrolateral medulla result in?

Answer 7

increased blood pressure and sympathetic nervous activity

Question 8

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

Answer 8

FALSE

Question 9

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

Answer 9

nucleus of the solitary tract (NTS)

Question 10

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

Answer 10

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

Question 11

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

Answer 11

mean arterial pressure increases in the normotensive animal

Question 12

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

Answer 12

mean arterial pressure decreases significantly

Question 13

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

Answer 13

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

Question 14

What are activated microglia a sign of?

Answer 14

neuroinflammation

Question 15

What is minocycline?

Answer 15

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

Question 16

What is minocycline commonly used to inhibit?

Answer 16

microglia activation

specifically polarization to M1 phenotype

Question 17

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

Answer 17

significantly decreases blood pressure

Question 18

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

Answer 18

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

Question 19

How does SNA affect the bone marrow?

Answer 19

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

Question 20

Why do inflammatory progenitors migrate to the PVN?

Answer 20

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

Question 21

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

Answer 21

release an array of cytokines / chemokines

Question 22

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

Answer 22

CCL2

Question 23

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

Answer 23

blood pressure decreased

Question 24

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

Answer 24

there were fewer microglia compared to SHR-SHR

Question 25

What is the subfornical organ and where is it located?

Answer 25

a CVO and lacks a BBB | located on the anterior wall of the 3V

Question 26

What does the subfornical organ send projections to and why?

Answer 26

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

Question 27

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

Answer 27

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

Question 28

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

Answer 28

elicits a rise in blood pressure and heart rate

Question 29

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

Answer 29

``` captopril = ACE inhibitor losartan = AT1 receptor antagonist NS-398 = selective COX2 inhibitor ```

Question 30

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

Answer 30

elicits an increase in blood pressure

Question 31

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

Answer 31

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

Question 32

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

Answer 32

a significant fall in blood pressure | this was not observed in non-hypertensive animals

Question 33

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

Answer 33

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

Question 34

What does an increase in CCL2 cause in the brain?

Answer 34

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

Question 35

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

Answer 35

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

Question 36

What are some examples of inflammatory factors?

Answer 36

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

Question 37

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

Answer 37

the renin-angiotensin system

Question 38

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

Answer 38

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

Question 39

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

Answer 39

cytokine release from mucosal immune cells

Question 40

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

Answer 40

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

Question 41

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

Answer 41

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

Question 42

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

Answer 42

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