NEUR 303 - lecture 10

What brain region is central for hormone regulation of maternal behaviour?

The medial preoptic area (MPOA). MPOA neurons are highly hormone-sensitive and strongly activated during parenting behaviours.

Which parenting behaviours are MPOA neurons activated during?

MPOA neurons are activated during maternal behaviour in females and also paternal behaviour in males, showing a shared parental circuitry.

What hormone receptors are highly expressed in parenting-related MPOA neurons?

Estrogen, prolactin, androgen, and progesterone receptors

Why is high receptor expression in MPOA neurons important?

It shows that circulating hormones can directly influence MPOA activity, shaping parental behaviour.

Which hormones involved in parenting are secreted from the hypothalamus?

Oxytocin and vasopressin.

Which parenting-related hormones are secreted by the pituitary gland?

Prolactin and growth hormone.

What key reproductive hormones are produced by the ovaries?

Estrogen, progesterone, and relaxin.

What parenting-related hormones can also be produced by the adrenal gland?

Small amounts of estrogen and progesterone (steroid hormones).

Why is the placenta important in maternal behaviour?

The placenta is a major endocrine organ that releases hormones that shape pregnancy physiology and prime the brain for parenting

What hormones does the placenta secrete?

Placental lactogen, prolactin-like hormones, growth hormone, leptin, and neuroactive hormones (and steroid hormones in many mammals).

What is unique about pregnancy and lactation hormone profiles?

They involve major increases in lactogens, plus strong changes in estradiol and progesterone.

What are lactogens?

A family of hormones that promote milk production and lactation-related adaptations, including prolactin and placental lactogen.

Which lactogenic hormones rise strongly from mid-pregnancy?

Prolactin and placental lactogen.

What is placental lactogen and why is it important?

It is a placenta-derived hormone similar to prolactin that binds the same receptor and helps prepare the mother for lactation and parenting.

What hormone changes occur during pregnancy vs lactation?

Pregnancy: increased lactogens, estradiol, progesterone.
Lactation: lactogens remain very high.

What hormones are classified as lactogenic hormones?

Prolactin, placental lactogen, chorionic somatomammotropin, and growth hormone.

How much do lactogen levels rise during pregnancy/lactation?

About a 10–20 fold increase compared to virgin females.

What is the blood–brain barrier (BBB)?

A protective barrier between blood and brain that regulates what substances can enter brain tissue.

What structures form the BBB?

Endothelial cells, astrocyte end-feet, and pericytes within the capillary basement membrane.

What is the main function of the BBB?

To maintain brain homeostasis by controlling chemical entry, immune access, and blocking xenobiotics.

How do estradiol and progesterone cross the BBB?

They are lipophilic steroid hormones, so they diffuse passively across the BBB.

Why can’t prolactin cross the BBB easily?

Prolactin is a large protein hormone (~23 kDa), so it cannot diffuse through the BBB.

How does prolactin enter the brain?

Through a receptor-mediated transport system, separate from the classical prolactin receptor.

What happens to prolactin transport into the brain during lactation?

It increases, allowing stronger hormonal influence on maternal brain circuits like the MPOA.

What is the prolactin receptor (Prlr)?

A single membrane-bound receptor (class 1 cytokine receptor family) that mediates the effects of lactogens.

Which form of the prolactin receptor is most important in the brain?

The long form, which strongly activates intracellular signalling.

What signalling pathway is activated by prolactin receptors?

The JAK/STAT pathway, producing long-term changes via gene transcription.

Describe the steps of prolactin JAK/STAT signalling.

Prolactin binds → receptor dimerises → JAK2 phosphorylates → recruits/phosphorylates STAT → STAT dimers enter nucleus → alter gene transcription.

What is pSTAT5 and why is it useful?

Phosphorylated STAT5, a marker of prolactin receptor activation that can be detected experimentally.

What does pSTAT5 labelling show in lactating mice?

Very high pSTAT5 in the MPOA, showing strong prolactin receptor activity during motherhood.

Which receptors mediate estradiol and progesterone effects in the brain?

Estradiol: Esr1 (ERα) and Esr2 (ERβ)
Progesterone: Pgr

How can estradiol and progesterone affect neurons?

Through genomic (nuclear) transcription effects and rapid membrane-mediated signalling effects.

How common is Esr1 expression in the MPOA?

About 1/3 of MPOA cells express Esr1, and about 50% of those also express Pgr.

What early evidence linked prolactin to maternal behaviour?

In the 1930s, repeated prolactin injections in virgin rats accelerated pup exposure-induced maternal behaviour.

What did experiments in the 1980s–1990s show about prolactin action?

Prolactin can induce maternal behaviour even when ovaries/pituitary are removed, and infusion into the MPOA can directly trigger maternal behaviour.

Why is placental lactogen likely important during pregnancy?

It rises strongly during gestation and has similar potency to prolactin, making it likely the main lactogen acting during pregnancy.

Why are global prolactin receptor knockout studies limited?

Because they disrupt receptors throughout the body and development, making it unclear what the receptor does specifically in the adult brain.

What technique allows prolactin receptor deletion only in the MPOA?

Cre–Lox recombination, often using AAV-Cre delivery in adulthood

What happens if prolactin receptors are deleted only from MPOA neurons?

Maternal behaviour collapses: pups die by day 2 due to maternal abandonment, but pups survive with foster mothers.

Why is deleting receptors in adulthood experimentally useful?

It avoids developmental abnormalities and isolates the receptor’s role in adult maternal behaviour.

What neuronal types were tested for prolactin receptor function?

GABAergic neurons (Vgat-Cre) and glutamatergic neurons (Vglut2-Cre).

What percentage of MPOA prolactin receptor cells are GABAergic vs glutamatergic?

~50% GABA, ~25% glutamate (together ~75%).

What happens if prolactin receptors are deleted from glutamate neurons?

No major effect: pup survival and retrieval remain normal in home and novel cages.

What happens if prolactin receptors are deleted from GABA neurons?

Partial impairment: retrieval mostly normal at home, but in stressful environments some mothers give up and nest-building/retrieval organisation worsens.

What does this suggest about prolactin action on GABA neurons?

Prolactin signalling on GABA neurons supports maternal motivation and persistence, especially under stress.

Why must prolactin act on more than just GABA or glutamate neurons?

Because deleting prolactin receptors from all MPOA neurons causes catastrophic maternal failure, but deleting from GABA/glutamate alone does not fully replicate this.

What evidence supports estradiol involvement in maternal behaviour?

Estradiol administration can induce maternal behaviour, and the MPOA is a key site of estrogen action.

What happens when Esr1 (ERα) is knocked down in the MPOA?

Lactating mice show impaired pup-directed maternal behaviour.

What are siRNAs and how do they work in Esr1 experiments?

Small RNAs that bind Esr1 mRNA and trigger degradation, reducing receptor protein expression.

What does Esr2 knockout evidence suggest?

Esr2 KO mice show no maternal deficits, meaning Esr1 is the key estrogen receptor for maternal behaviour.

What happens when Esr1 MPOA neurons are inhibited with hM4Di DREADDs?

Pup retrieval is impaired, showing Esr1 neurons are required for maternal behaviour.

What important pathway links Esr1 MPOA neurons to motivation?

The MPOA → VTA projection, which drives reward/motivation circuitry.

What happens when Esr1 MPOA→VTA neurons are optogenetically stimulated?

Maternal behaviour can be induced in virgin females, showing this pathway is sufficient.

How does stimulating Esr1 MPOA→VTA neurons affect dopamine?

It increases dopamine release in the nucleus accumbens (NAc).

How does estradiol administration affect reward circuitry?

Estradiol increases dopamine release in the NAc, supporting maternal motivation.

Why are MPOA galanin neurons important in hormone regulation of maternal behaviour?

They likely mediate estrogen/progesterone effects and control key maternal behaviours.

How do estradiol and progesterone change MPOA galanin neuron physiology during pregnancy?

Estradiol increases excitability, while progesterone increases spine density (synaptic input), synergistically priming maternal circuits.

What does increased spine density on galanin neurons suggest?

More excitatory glutamatergic synapses, making neurons easier to activate.

What does it mean that galanin neurons can be “silent but more excitable” in late pregnancy?

They fire less spontaneously but are more responsive to stimulation due to reduced inhibition or increased synaptic sensitivity.

What are the different roles of MPOA galanin projection subpopulations?

MPOA→PAG promotes pup grooming; MPOA→VTA promotes motivation to reach pups.

What is the overall hormonal model of maternal behaviour control?

Pregnancy hormones (estradiol, progesterone, lactogens) act on MPOA receptors to remodel circuits, activate galanin and reward pathways, and enable maternal behaviour at birth.