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A BMS 381 - Developmental neurobiology > The stress axis > Flashcards

The stress axis Flashcards

1
Q

What is the function of the hypothalamus?

A

Ancient, conserved, central regulator of homeostasis

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2
Q

What are the main nuclei in the hypothalamus?

A

Paraventricular nucleus (PVN)

Arcuate nucleus (Arc)

Ventromedial nucleus (VMN)

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3
Q

Where do the neurons in the Arc and VMN nuclei develop from?

A

Progenitors that either:

1) Transiently express shh
2) Respond to shh

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4
Q

What neurons are in the Arc nucleus?

What do these neurons do?

A

PomC+ neurons

Make precursor protein (Pomc) that is made into many hormones - some that impact on CRH
–> Makes ATCH

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5
Q

What neurons are in the VMN?

What do these neurons do?

A

SF1+ neurons

Help to regulate the maturation of steroidal hormones –> form active hormones

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6
Q

Where do the neurons in the PVN develop from?

What neurons are born in the PVN?

A

EARLY where Shh is REPRESSED in progenitors

CRH/CRF neurons

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7
Q

What is useful about the hypothalamus in simpler vertebrates?

A

SAME organisation of hypothalamus and the SAME neurons in the SAME nuclei SAME neurotransmitters and neurohormones

Can investigate problems happening in humans

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8
Q

Why need very high numbers of model organisms to do behavioural work?

Why is the zebrafish a good model for the hypothalamus?

A

Many VARIABLES in behaviour

Zebrafish - good model can link genetics to behaviour (screen MANY fish)

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9
Q

What neurons are important in the production of the stress hormone and therefore the regulation of stress?

A
  • Pomc neurons (arc)
  • SF1 neurons (VMN)
  • CRH neurons (PVN)
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10
Q

Where do the CRH neurons project to?

What happens here?

A

Medial eminence

HPA axis:
1) End feet release CRH - taken up by the portal capillaries –> pituitary gland

2) In PG - regulates an endocrine cell –> release ACTH (adrenocorticotrophic hormone)
3) ACTH acts on the ADRENAL GLANDS –> release cortisol

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11
Q

What are the CRH neurons responsible for?

A

CRH released in response to stress

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12
Q

What is the main stress hormone?

Where is it released from?

A

Cortisol

Released from the adrenal gland when stimulated by ACTH

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13
Q

What is the DISC1 gene?

Results of this gene?

A

Deleted in Schizophrenia 1

High risk of mental illness

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14
Q

When was DISC1 identified?

A

Through genetic analysis of an inbred family with high-risk of mental problems:
- Each sibling/cousin had inherited a copy of the allele where this gene was deleted

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15
Q

What is the first question must ask if there is a phenotype resulting from a deleted gene?

A

WHERE is the gene NORMALLY expressed?

WHY lack of function –> mental illness

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16
Q

Where is DISC1 normally expressed?

How can see this?

A

Normally in the hypothalamus, with expression overlapping with cells expressing Fgf+ and Shh+ (early progenitors)

SPECIFIC to the hypoT - not in the rest of the body

Seen in zebrafish using IN SITU HYBRIDISATION

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17
Q

Why is it hard to determine what the DISC1 protein does?

A

Likely to interact with many proteins due to its structure:

  • Large protein
  • Globular domain at N terminus
  • Alpha-helix domain
  • Coiled coil domains
18
Q

How was a disease model of DISC1 created in the zebrafish?

A

Create 2 lines of zebrafish mutants (with different point mutation in the globular domain - N terminus)

Fish are homozygous viable but DO NOT make the DISC1 mRNA/protein

19
Q

Why were 2 zebrafish transgenic lines made in the disease model for DISC1?

A

To increase confidence in results

20
Q

How are the WT and DISC1 mutant fish different to each other?

How can this been seen?

A

DISC1 mutants:
- Not as many progenitors and progenitors differentiate PREMATURELY (Interferes with the balance of stem/progenitor/differentiated cells)

  • Hypothalamic neurons (especially ones involved in stress regulation) differentiate abnormally

Seen using ISH of zebrafish mutants/WT

21
Q

How does DISC1 interfere with progenitor levels?

A

We are not sure

22
Q

How do the hypothalamic neurons of the zebrafish DISC1 mutant differentiate abnormally?

A

Pomc+ (Arc) neurons REDUCED

Sf1+ (VMN) neurons INCREASED

Crh+ (PVN) neurons INCREASED

23
Q

What do the differences between the WT and the DISC1 mutant fish show?

A

Imbalance in early progenitors has a KNOCK-ON effect and leads to the ABERRANT DIFFERENTIATION of HYPOTHALAMIC NEURONS that are involved in STRESS REGULATION

24
Q

How can we measure an output to see if the difference in neurons has an impact on the physiology and/or behaviour of the fish?

A

1) Behavioural analysis

2) Assays - look at endocrine function

25
Q

What is the normal neuroendocrine function?

A

Upregulation of neurohormones and cortisol after stress

26
Q

How is the behaviour of the fish assayed?

A

With response to Shreckstoff or increased NaCl concentraion

27
Q

What is Shreckstoff?

A

Pheramone released from damaged fish (eg. by predator) to warn other fish

Causes a stress response in the receiving fish

28
Q

What happens to the behaviour of the fish when they are stressed?

A

Turn around and swim away quickly and erratically

29
Q

Why does NaCl evoke a stress response in zebrafish?

A

Zebrafish from the Ganges (close to the sea - zebrafish don’t survive in the sea)

Sea - higher salt conc

When detect higher salt conc, zebrafish turn around and swim away

30
Q

What is different about the stress response in WT and DISC1 mutant zebrafish?

A

DISC1 mutant - no stress response

31
Q

What is different about the neuroendocrine function in WT and DISC1 mutant zebrafish?

A

In the WT - increase in cortisol and ff1b (sf1)

In the mutant - no increase

32
Q

How can determine neuroendocrine function in zebrafish?

A

Expose to stress factor

Kill fish and extract cortisol to measure the levels

33
Q

Why is it important to test both behaviour and endocrine function of the fish?

A

Test things in different ways:

Same result –> more believable outcome

34
Q

What does cortisol do?

Why?

A

Triggers a feedback loop that down regulates the stress response

Hypothalamus works through systems that let you know when deviating away from the optimum set point

35
Q

Why is it important to have oscillations in levels in early life?

How may this be altered in humans with DISC1 mutant?

A

To be able to understand where the MEDIAL LEVEL is

May be altered in DISC1 mutant humans: may noe be able to set up optimal set point –> Knock on effect in ability to process info in a way that is not stressful

36
Q

How do we think DISC1 works in humans?

A

Effects the cells in the stress circuit and their differentiation –> crucial for the regulation of normal cortisol and behaviour

37
Q

What is the stress axis AKA?

What is this modulated by and how?

A

The hypothalamus pituitary adrenal axis

Modulated by emotional responses as:
- Emotional responses modulate the ANS, that is responsible for the fight/flight response

  • Fight/flight response carried out by the HPAA
38
Q

Describe the stress axis

A

…

39
Q

What is the function of CRH from the PVN in stress?

A

1) Released from the endfeet of CRH+ neurons in the PVN onto portal capillary
2) Portal capillary –> corticotroph cell in the pituitary gland
3) Corticotroph releases ATCH into GENERAL CIRCULATION

40
Q

What is the role of ACTH

A

Made from POMC precursor
Released from corticotroph in the pituitary gland

–> Adrenal gland to stimulate the release of the stress hormone CORTISOL

41
Q

What does cortiso do when released from the adrenal gland?

A

Acts on cells to produce a coordinated response (eg. run away)

Acts on the hypothalamus in a NEGATIVE FEEDBACK mechanism –> Return to baseline optimal level

A BMS 381 - Developmental neurobiology (17 decks)

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