Neurosteroids

Question 1

What are examples of neurosteroids (made in the brain)?

Answer 1

Pregnenolone, pregnenolone sulfate, progesterone, allopregnanolone, DHEA, DHEA sulfate, pheromones

Question 2

What are examples of hormonal steroids (made in the periphery but can act in the brain)?

Answer 2

Oestradiol, progesterone, testosterone, glucocorticoid, DHEA

Question 3

What is the generic steroid hormone receptor structure?

Answer 3

AF1 N-terminus coactivator > Core DNA Binding Domain > Hinge region > Ligand binding domain - AF2 coactivator region, HSP binding

Question 4

What is the function of the AF1 N-terminus co-activator region?

Answer 4

Binds transcription factors, determines receptor activity and it is heterogeneous between receptor types

Question 5

What is the function of the core DNA binding domain?

Answer 5

DNA recognition and bings, binds hormone responsive elements in DNA, homogenous/conserved, regulates receptor dimerisation

Question 6

What is the function of the hinge region?

Answer 6

Flexible, regulates dimerisation and DNA binding

Question 7

What is the function of the AF2 coactivator ligand binding domain?

Answer 7

Ligand binding, highly specific, determines ligand binding

Question 8

What are the ways in which glucocorticoid can signal genomically?

Answer 8

Binding to positive glucocorticoid responsive elements on the DNA - activation
Binding to negative GRE - repression
Bind to transcription factor (tethering GRE) - activation OR repression
Steric hinderance, binding to DNA - repression

Question 9

How steroids act genomically downstream of non-genomic signalling?

Answer 9

1) Membrane bound receptors activating GPCRs e.g. metabotropic glutamate receptors which modulate gene expression via CREB
2) Evidence exists for an oestrogen GPCR which activates CREB

Question 10

What are the examples of non-genomic mechanisms of steroid signalling?

Answer 10

1) Membrane steroid hormone receptor coupling through GPCR modulating ion channel activity
2) Membrane steroid hormone receptor coupling through GPCR modulating intracellular signalling cascades
3) Steroid hormone metabolites modulating neurotransmitter receptor activity
4) Steroid hormones binding to phospholipids to impact membrane flexibility and thus function of ATPases.

Question 11

What is the pathway of the HPA axis?

Answer 11

Hypothalamus > Corticotophin-releasing hormone > arginine vasopressin > Pituitary gland > adrenocorticotropin hormone > Adrenal gland > Cortisol and Adrenaline/noradrenalin

Cortisol negatively feeds back to hypothalamus and pituitary gland
Adrenalin and noradrenalin positively feeds back to pituitary gland (via SNS)

Question 12

What is the pathway of the hypothalamic pituitary axis?

Answer 12

Hypothalamus > Gonadotropin Releasing Hormone > Pituitary > LH/FSH > Gonads > Androgen/Oestrogen

Androgen and oestrogen negatively feedback to hypothalamus and pituitary

Question 13

What is the pathway of the hypothalamic-pituitary-thyroid axis?

Answer 13

Hypothalamus > Thyrotropin releasing hormone > Pituitary > TSH > Thyroid > T3/T4

T3/T4 negatively feedback to pituitary and hypothalamus

Question 14

What happens to females oestradiol levels with age?

Answer 14

Begins low and increases as they get older

Question 15

What happens to male mice you maintain high levels of aromatase throughout their life?

Answer 15

They begin presenting female sex behaviours

Question 16

Activation of glucocorticoids can modulate…

Answer 16

levels of neurotransmitters and neurotransmitter receptors

Question 17

Activation of the glucocorticoid receptors induces what?

Answer 17

Glutamate release in the hippocampus, endocannabinoid production and can exacerbate glutamate induced excitotoxicity.

Question 18

Early life stress alters the HPA axis and upregulates or downregulates glucocorticoid receptors?

Answer 18

Downregulates