11. Mental Health 1: Stress Axis

Question 1

What allows us to study mental health in animal models?

Answer 1

Mental health has a biological basis

Question 2

What makes animal model studies on mental health difficult?

Answer 2

The human brain is much more complex than any other animal therefore hard to model. Tend to focus on the more evolutionary conserved areas e.g. hypothalamus, amygdala

Question 3

What are mental health conditions?

Answer 3

Refers to factors (including disorders) that influence the health of mind, brain and nervous system

Question 4

How common are mental health disorders?

Answer 4

They account for 10% of global burden of disease and as a group they are the leading cause of disability worldwide

Question 5

Apart from the disease burden, why are neuropsychiatric disorders a high priority?

Answer 5

• Treatment gaps are large, meaning those in need do not receive adequate/effective intervention
• People suffering from neuropsychiatric disorders often subjected to systematic discrimination
• Little resources are allocated to fund the necessary research to prevent and treat neuropsychiatric disorders

Question 6

What do genome wide association studies identify?

How are they performed?

Answer 6

• Mutations that correlate with disease susceptibility
• Sequence genomes of a population and look for mutations that correlate in mental health patients but not in healthy individuals
• Identifies genes that are important in mental health

Question 7

Once a gene has been identified in a GWAS, what can be done?

Answer 7

Can see if gene is causative to mental health disorder by KO in mice or zebrafish then test anxiety/stress

Question 8

Prior to GWAS, how were risk factors for mental health identified?

Answer 8

In families in which inbreeding has occurred and strong traits are preserved

Question 9

What was found in a family in which inbreeding had occurred?

Answer 9

• The gene disrupted in schizophrenia 1 (DISC1) was mutated in members of a family who all suffered a range of mental health disorders
• Identified correlation between DISC1 mutation and mental health disorders
• DISC1 is a genetic risk factor for mental illness

Question 10

What are well known social and environmental factors that can trigger mental health disorders?

Answer 10

• Stress
• Lack of sleep
• Drug abuse

Question 11

Why are mental health disorders hard to study?

Answer 11

Because many variables are likely to be involved and the manifestation of mental illness is a result of gene x environment interactions

Question 12

If many variables are influencing disease, what is important to do?

Answer 12

Analyse high n numbers (zebrafish or drosophila) so that conclusions that are drawn are statistically significant

Question 13

What did Eachus et al (2017) first do in the study of DISC1?
What were the results?

Answer 13

• Looked at where DISC1 is expressed, from this know what part of brain DISC1 protein is functioning in and therefore what part of brain is affected when DISC1 is mutated
• Found that role of DISC1 in stress response wish highly conserved and using in situ hybridisation showed DISC1 is first expressed in hypothalamic progenitors

Question 14

How is the hypothalamus involved in the stress response?

Answer 14

• Hypothalamus is an ancient, conserved part of vertebrate brain that centrally regulates responses to environmental stressors
• Hypothalamic progenitors give rise to neurones in the arcuate and venture-medial nuclei that are involved in the stress pathway
• These are Pomc, sf1 and crh neurones

Question 15

Describe the hypothalamic-pituitary-adrenal axis.

Answer 15

1. When an organism is stimulated by a stressor, information is integrated by 3 types of hypothalamic neurones:
   - Pomc - proprotein that produces ACTH
   - sf1 - produces steroidogenic factor 1 (helps to form active hormones)
   - crh - produces CRH
2. Corticotropin-releasing hormone is released by crh neurones in hypothalamus and stimulates corticotrophs in the anterior pituitary to secrete adrenocorticotropin hormone
3. ACTH stimulates cells in adrenal glands to secrete cortisol which affects all cells of body to provoke a coordinated response to stressor (e.g. run away)
4. Rising cortisol levels then negatively feedback on the hypothalamus and pituitary to return levels to baseline

Question 16

What mutant lines of zebrafish were used by Eachus et al (2017)?

Answer 16

• Generated 2 lines of DISC1 mutant fish

- Both lines did not produce full-length DISC1 mRNA or protein

Question 17

How did Eachus et al (2017) look if hypothalamic progenitors were altered in DISC1 mutants?
What were the results?

Answer 17

• Performed in situ hybridisation using a hypothalamic progenitor marker
• Showed that DISC1 mutants have fewer hypothalamic progenitors

Question 18

What was the effect of few hypothalamic progenitors in DISC1 mutant fish?

Answer 18

• Normally in nervous system development there are waves of differentiation, each producing a specific neurone class
• This process is carefully regulated to ensure enough progenitors are put aside to give the correct number of each neurone class
• In DISC1 mutants hypothalamic progenitors differentiate prematurely resulting in abnormal balance of hypothalamic neurones

Question 19

How do the number of hypothalamic neurones involved in stress pathway differ in DISC1 mutant to WT?

Answer 19

• Early neurons (sf1, crh) differentiate too quickly

- Fewer late neurons (Pomc)

Question 20

What did Eachus et al (2017) look at after they observed an abnormal balance of hypothalamic neurones?

Answer 20

• Looked if this abnormal balance of hypothalamic neurones correlated with abnormal stress response
• To do this they performed behavioural assays and looked at neuroendocrine function to see if hypothalamic neurones up regulate hormones in response to stress to increase cortisol levels

Question 21

What did the behavioural assay show?

Answer 21

• When WT fish are exposed to NaCl or schreckstoff they swim rapidly - mimics response in wild when freshwater fish swim away from salt water or peers being attacked
• When DISC1 mutants are exposed to NaCl or schreckstoff they do not respond

Question 22

What did the neuroendocrine function assay show?

Answer 22

Stressed fish with NaCl or schreckstoff and immediately measured cortisol levels

• WT fish cortisol levels increase significantly
• DISC1 mutant fish cortisol levels remain the same