Steroid hormone signalling in the CNS: Flashcards
Give examples of steroid hormones, name the molecule they are derived from, and sites of synthesis.
• Examples of steroid hormones are:
o Oestradiol – produced in the gonads – cholesterol derived (lipid based)
o Cortisol (hydrocortisone) – produced in adrenal cortex – cholesterol derived (lipid based)
o Testosterone – produced in the gonads – cholesterol derived (lipid based)
• Steroid hormones are derived from cholesterol
• Some steroids can be made in “non-endocrine” tissues, including the brain
o Glia synthesise steroid hormones in the brain – these are then called neurosteroids and are synthesised from cholesterol too
With use of a diagram, outline the typical structure and function of a nuclear steroid hormone receptor
diagram + functions: lecture slides
How can steroids modulate cellular activity?
• Steroids can modulate the activity of cells through temporally distinct mechanisms:
o Regulatory – slow; hours to days – genomic action
Neuroactive steroids
o Neuromodulatory – fast; seconds to minutes – nongenomic action
Neuroactive steroids or neurosteroids
Which steroid hormone receptors are expressed in the CNS?
Oestrogen receptors – α and β subtypes Progesterone receptors – A and B subtypes Androgen receptor Mineralocorticoid receptor Glucocorticoid receptor
What effect can nuclear steroid receptors have on gene expression? How?
o Positive glucocorticoid response element (GRE) – binding glucocorticoid receptor (GR) dimers; activates genes
o Negative glucocorticoid response element – binds GR dimers; represses genes
o Composite GRE = GRE + transcription factors activation or repression of genes
o Tethering GRE = GRE + transcription factors, not GR bound to DNA activation or repression
o Steric hinderance = GR bound to DNA can prevent transcription factor binding, or prevent transcription machinery binding repression
How can genomic mechanisms be mediated by membrane steroid hormone receptors?
• Genomic mechanisms may also be mediated via membrane steroid hormone receptors:
o Classical genomic pathway – binds receptor, translocates to nucleus, then alters gene transcription
o Membrane-bound receptors – activate neighbouring GPCRs (e.g. metabotropic Glu receptors which modulate gene expression via CREB)
o Evidence exists for an oestrogen-activated GPCR which activates CREB
Give 4 examples of non-genomic mechanisms of steroid signalling
• Non-genomic mechanisms of steroid signalling:
o Membrane steroid hormone receptors coupling through GPCRs, modulating ion channel activity
o Membrane steroid hormone receptors coupling through GPCRs, modulating intracellular signalling cascades
o Steroid hormone metabolites modulating neurotransmitter receptor activity
o Steroid hormones binding phospholipids to impact membrane flexibility and therefore functions of ATPases
How else can neurosteroids function?
• Some neurosteroids, such as allopregnanolone, are allosteric modulators of GABAARs
o Bind neurosteroid binding sites on the receptor and affect inhibitory neurotransmission
o Believed to occur from glial cells
Explain the hypothalamic-pituitary-adrenal axis as an example of an endocrine feedback loop
Consists of the hypothalamus, the pituitary gland, and the adrenal gland
o Each secretes hormones in response to activity from one of the other glands, influencing physiological processes
• Complementary and cooperative action between the CNS and SNS
• Cortisol is normally secreted in a rhythmical circadian pattern
Corticosteroid receptors are expressed throughout the CNS:
o Type 1 (mineralocorticoid) receptors are saturated at basal levels of glucocorticoids
o Type 2 (glucocorticoid) receptors are saturated at peak phases of circadian rhythm and stress
o Type 1 determines the basal activity of the HPA axis
o Type 2 determines maximal HPA response to stress
Cortisol acts via glucocorticoid receptors, which are expressed throughout the body
o Glucocorticoids impact the function of virtually all tissues on some level – including the brain
o Cortisol influences the mRNA expression of up to 20% of the expressed genome
Corticotropin-releasing hormone (CRH) neurons are at the interface between the HPA axis and the SNS
o Activity of CRH neurons is regulated via physiological and neurogenic/psychological stress
Name 2 other neuroendocrine axes apart from the HPA.
Hypothalamic-pituitary-gonadal axis
Hypothalamic-pituitary-thyroid axis
In relation to sex differentiation and sexual activity, how can steroids have behavioural actions in the CNS?
o Oestrogen and progesterone receptors are expressed throughout the brain
o Sex steroid action in the CNS determines brain structure and sexual behaviours: female mice with high peripheral testosterone therefore high brain oestradiol have high testosterone, and won’t exhibit female mating behaviours – instead exhibit male mating behaviours
o Oestrogens have dual actions in regulating male sexual activity:
Neuromodulation: via action on membrane oestrogen receptors (acute) – e.g. the times during the day when the male wants to mate
Regulatory: via action on nuclear receptors regulating gonadal testosterone secretion (chronic) – e.g. the peak periods during the year when the male wants to mate
Oestrogen may mediate neuroprotective effects through interactions with neurons and glial cells (see notes for diagram)
In relation to regulation of stress, anxiety, and mood, how can steroids have behavioural actions in the CNS?
Prolonged stress can impact mood and memory:
Glucocorticoid receptors (GRs) are expressed throughout the CNS, including the:
Hippocampus
Amygdala
Activation of glucocorticoid receptor signalling can modulate levels of neurotransmitters and neurotransmitter receptors
Prolonged activation of glucocorticoid receptor signalling modulates synaptic structure and dendritic spines, in part by inhibiting brain-derived neurotrophic factor (BDNF)
BDNF is a protein which acts to support the survival of existing neurons, and encourage growth/differentiation of new neurons/synapses
It’s active in the hippocampus, cortex, and basal forebrain; also in the retina, kidney, saliva, prostate, motor neurons, skeletal muscle
Important for long-term memory
Binds to cell surface receptors – TrkB (tropomyosin receptor kinase B, important in short-term memory) and LNGFR (low-affinity nerve growth factor receptor); may also modulate the α7 nicotinic receptor.
Glucocorticoids can impact the activity of glutamatergic synapses in the hippocampus
Activation of glucocorticoid receptors rapidly induces glutamate release in the hippocampus
Also induces endocannabinoid production
Excess glucocorticoid activation can exacerbate glutamate-induced excitotoxicity/neuronal cell death
Which regions does chronic stress affect? How? What effect does this have on behaviour the brain?
Hippocampus
Dendritic atrophy, decreased GR expression
Decreased HPA feedback, decreased memory
Medial prefrontal cortex
Dendritic atrophy, decreased GR expression Decreased HPA feedback, decreased memory extinction, decreased reward
Central amygdala
Increased CRH expression and release
Increased HPA and autonomic excitability, and anxiety
Basolateral amygdala
Increased dendritic branching and stress excitability
Increased HPA and autonomic excitability, increased emotional memory, decreased reward
Paraventricular nucleus of the thalamus
Increased stress excitability
Increased HPA excitability to novel stress and decreased HPA excitability to familiar stress
Locus coeruleus
Increased neurotransmitter release, increased stress excitability of projections to cortex and hippocampus
Increased HPA excitability to novel stress
Paraventricular nucleus of the hypothalamus
Increased secretagogue synthesis and stress responsiveness, decreased GR expression
Increased excitability to novel stress
How is HPA function altered by early-life stress?
• HPA axis function is altered by early-life stress:
o A: under normal conditions, HPA-axis activity is attenuated via negative feedback through CNS GRs, including those in the hippocampus
o B: early-life stress reduces GR expression in the CNS –> reduced negative feedback inhibition of the HPA axis
diagram in notes also useful
List 5 neurosteroids
Neurosteroids (made in the brain): Pregnenolone Pregnenolone sulphate Progesterone Allopregnanolone Dehydroepiandrosterone (DHEA) Dehydroepiandrosterone sulphate Pheromones
