Neuro Week 7

What drives behaviour selection

Internal needs

What does optimal behaviour performance require

Coordinated physiological response

What is an example of internal needs driving behaviour

Low calories or nutrients →

"I'm hungry" →

get food = cognitive task to plan meal, gross and fine motor control of limbs, internal digestive processes

What is an example of physiological response to internal needs

Thermoeceptors sense dropping core body temp → warmth seeking behaviours (clothes, shelter) and physiological responses (shivering)

What was the adaptive need and evolutionary pressure for the nervous system

To develop mechanisms and systems to coordinate internal and external states

what does Brain–body communication is bidirectional mean

the brain regulates the same physiological state it senses

What is interoception

The nervous system's continuous sampling of the internal physiological environment

What does interoception interact with

Exteroception, cognition and action to maintain and ensure the integrity of an organism

What does interoception involve

Sensing and integrating internal physiological state from sensors → pathways → networks

is introception coscious

Often unconscious and regulatory, not just consciously perceived sensation

what does introception include

neural afferents, hormones, immune mediators and metabolites

what does introception support

autonomic, endocrine and behavioural responses

what are neural bodily signals

vagal and spinal afferents

what are endocrine bodily signals

steroid, peptide and metabolic hormones

what are immune bodily signals

cytokines, chemokines, immune-cell signalling

what are metabolic/chemical bodily signals

glucose, oxygen, CO₂, ammonia, osmolarity, electrolytes

What are the three levels of brain-body communication (hierarchial loops)

1. Central regulation and immunoception;

2. Reflexive control;

3. Local modulation

What are the three main barriers protecting the brain

Blood-brain barrier (BBB)

blood-cerebrospinal fluid barrier (BCSFB)

cerebrospinal fluid-brain barrier (CBB)

What is the blood-brain barrier (BBB) composed of

Basement membrane, pericyte, astrocyte endfeet

Where is the blood-cerebrospinal fluid barrier (BCSFB) located

In arachnoid granulations protruding into veins and choroid plexus

What is the cerebrospinal fluid-brain barrier (CBB) composed of

Pia mater and astrocytes

What are circumventricular organs

Specialized blood-brain interfaces that sense circulating hormones, metabolites and immune signals

Why are some brain regions deliberately more exposed

So the brain can access information about the internal state not captured by peripheral neural pathways

is The blood–brain barrier a wall that makes the brain biologically independent

no

What should the brain respond to

Changing physiological state, to maintain survival and homeostasis

When can the same response be adaptive vs dysfunctional

Adaptive in the short term; dysfunctional if persistent, excessive, mistimed or poorly resolved

what is the basic pathway of a physiological response

What was the historical "standard" research subject

male as default

How was the female body studied historically

The female body was studied as a reproductive body (only) or a variation (at worst, a malformation) of the male body

What did the 1977 FDA guidance do

Excluded women of childbearing potential from early drug trials

When was the FDA exclusion reversed

1993 – but female research lagged

What was the ratio of male-only to female-only animal studies in 2009 neuroscience

Male-only animal studies outnumbered female-only by ~5.5:1

How was female hormonal cycling often treated

As inconvenient biological noise that would mask effects and statistical significance

why does Sex as a Biological Variable policy matter

Sex and hormonal state can alter disease phenotype, pharmacokinetics and treatment response. Due to the lag in research, there is still a lot we don't know about female physiology

What is the key takeaway about hormonal variation

Hormonal variation is not noise, especially if it systematically changes the biology we are trying to understand

What hormones vary over predictable timescales in the menstrual cycle

Oestradiol and progesterone

Where are receptors for these hormones expressed

Across hippocampus, amygdala, hypothalamus, striatum and cortex

How do these hormones act

Through genomic and rapid signalling mechanisms

What systems are affected

Dopamine, serotonin, glutamate and GABAergic networks

What does the menstrual cycle change

The neurochemical environment in which brain circuits operate → contributes to the dynamic nature of the nervous system & neuroplasticity

What are the phases of the menstrual cycle

Follicular, Ovulatory, Luteal

What hormones peak during the follicular phase

Oestrogen rises

What hormones peak during the ovulatory phase

LH and FSH surge; oestrogen peaks

What hormones peak during the luteal phase

Progesterone rises

what do Age x estradiol and progesterone levels influence

brain connectivity

What networks were influenced by estradiol and progesterone

Whole-brain, DMN, limbic, dorsal attention, somatomotor, and subcortical networks

What is the most likely function of ovarian hormone effects

Coordinated whole-body adaptation to align neural function with reproductive and energetic context

What are the five adaptive functions of ovarian hormones

1. Motivation & reward;

2. Social & emotional processing;

3. Learning & plasticity;

4. Homeostasis;

5. Reproductive behaviour

How do ovarian hormones affect motivation & reward

Alter salience, approach behaviour and reinforcement when reproductive opportunity changes

How do ovarian hormones affect social & emotional processing

Tune sensitivity to social cues, threat and affiliation

How do ovarian hormones affect learning & plasticity

Adjust synaptic strength and network responsivity to current physiological demands

How do ovarian hormones affect homeostasis

Coordinate appetite, energy use, thermoregulation, sleep, stress responses and autonomic function with reproductive state

How do ovarian hormones affect reproductive behaviour

Integrate sexual motivation and behaviour with ovulation and fertility

Are all effects of ovarian hormones beneficial adaptations

no

what are some negative adaptations of reproductive hormones

There are pleiotropic consequences of hormones acting on widely distributed receptors

costs of repeated neural recalibration as hormone levels rise and fall

amplified in susceptible individuals when normal adaptive mechanisms become dysregulated, or due to inherent biological variability

What is the key takeaway about ovarian hormones

Ovarian hormones help the brain optimise behaviour and physiology for the body's current reproductive state; the same plasticity can also generate unintended or maladaptive effects

How does oestradiol change synaptic excitability and plasticity

Both slow (genomic) and fast (phosphorylation cascades) receptor pathways.

Enhance NMDA receptor-mediated glutamatergic signalling.

Alter AMPA/NMDA receptor trafficking and synaptic efficacy.

Increase dendritic spine and synapse formation.

Alter BDNF and other neurotrophic factors

What did Woolley & McEwen 1992 find in rats (estradiol study)

CA1 hippocampal synapse density decreased about 32% over 24h from high-estradiol → estrus

what did human studies on estradiol find

Estradiol-related changes across emotion, reward, memory and resting-state networks

when do estrogen levels rise and drop

rise towards ovulation

drop towards menstruations

What do estradiol and progesterone alter?

Dopaminergic signalling

what happens to dopamine during follicular → just after ovulation

Dopamine levels increase. Dopamine transporter and receptor expression increases

What is the dorsal striatum involved in

Action selection, learning, habits and movement

What is the ventral striatum involved in

Value, motivation, reward prediction, salience

What happens in the dorsal striatum during high estrogen (proestrus/estrus)

GABA release from SPNs decreases, and DA release increases

What happens in the ventral striatum during high estrogen (proestrus/estrus)

DA release increases by increasing VMAT activity, decreasing DAT activity, decreasing DA autoreceptor activity, and decreasing local GABA release

when were ADHD symptoms most severe in female participants (zaritski et al)

in menstruation phase

what is a proposed treatment for ADHD symptoms in menstruation

increase dose few days before, and during menstruation

What is progesterone metabolised to

Allopregnanolone (ALLO) by corpus luteum, circulating levels reflected in brain

What is ALLO

A positive allosteric modulator of GABA receptors

What is GABA

The main inhibitory neurotransmitter of the CNS

What are GABA receptors

fast-acting, ligand-gated ion channels → hyperpolarization → inhibition of neuronal firing

What is an allosteric modulator

Binds to a non-active site on a receptor or enzyme to modify the normal response (volume dial)

What is a positive allosteric modulator

Boosts the normal receptor signal

What happens to progesterone in the follicular phase

Progesterone is low

What happens to progesterone after ovulation

Progesterone rises

What happens to progesterone before menstruation

Falls rapidly

What is the sequence of progesterone effects

Progesterone ↑ and peaks mid-luteal phase →

allopregnanolone ↑ →

"Boosted" GABAA receptor activity →

Increased effectiveness of GABA-mediated firing →

Altered neuronal inhibition, stress responsivity and network excitability

Are GABAA receptors plastic

yes

what is dynamic regulation

GABAA receptor subunits composition and sensitivity changes in response to sustained progesterone exposure

What do changes to progesterone/ALLO cause

Homeostatic recalibration of the inhibitory system

What happens in the follicular phase

Low progesterone / low ALLO → baseline GABAA configuration

What happens in the early luteal phase

↑ progesterone → ↑ ALLO → stronger neurosteroid modulation → adaptive changes in GABAA receptor expression/subunit composition

What happens in the late luteal phase

Rapid ↓ progesterone / ↓ ALLO → (neurosteroid withdrawal) → GABAA receptors must recalibrate again → transient change in inhibitory tone / Excitatory : Inhibitory balance

What is Premenstrual Dysphoric Disorder (PMDD)

Affects 3-8% of women in reproductive years. Cyclic recurrence of debilitating mood symptoms in the luteal phase

What are potential causes of PMDD

Abnormal ovarian hormones? Altered dopamine dynamics? Atypical ALLO sensitivity?

what did Timby et als study on PMDD patients do

Administered IV allopregnanolone to 10 PMDD and 10 control participants.

Functional GABAA receptor activity measured by saccadic eye velocity (SEV) at baseline and after IV injection

what is saccadic eye velocity

Peak speed of rapid eye movements used to shift gaze.

Serves as a reliable, non-invasive neurophysiological marker for GABAA receptor sensitivity in the central nervous system

What were the results of Timby et al. 2016

Controls and PMDD showed opposite sensitivities to allopregnanolone depending on phase (follicular/luteal).

PMDD women were more sensitive to allopregnanolone in the luteal compared to the follicular phase, *p < 0.05

what is the evidence for the claim Ovarian hormones modulate CNS function, including dopaminergic and GABAergic signalling

Many preclinical and human neuroendocrine studies show estradiol alters dopaminergic signalling and corticostriatal responsivity, while progesterone-derived allopregnanolone dynamically modulates GABAA receptors and inhibitory tone.

what is the evidence for the claim ADHD symptoms can vary across menstrual-cycle phases in some women

Zaritsky et al., 2026: 30 women with ADHD treated with amphetamine salts completed 35 days of daily ratings; symptoms were most severe during menstruation and milder in the mid-follicular phase

what is the evidence for the claim Women with ADHD should alter medication by cycle phase

de Jong et al., 2023: case series of 9 women reporting premenstrual symptom worsening and reduced stimulant effect; temporary premenstrual dose increases improved attention, mood and energy in all 9, but the study was uncontrolled.

what is the evidence for the claim PMDD reflects altered neural sensitivity to normal hormonal fluctuations rather than abnormal hormone levels

Ovarian-suppression/add-back experiments show symptoms remit when cycling is suppressed and re-emerge when estradiol/progesterone change; reviews converge on altered sensitivity to normal neurosteroid fluctuations rather than abnormal circulating hormone levels

what is the evidence for the claim Altered allopregnanolone–GABAA signalling is implicated in PMDD

Timby et al., 2016: women with PMDD showed a different phase-dependent physiological response to IV allopregnanolone than controls, consistent with altered GABAA receptor sensitivity across the cycle.

what is the endocrine state in the menstrual cycle

endocrine context varies over days to weeks

what is the endocrine state in pregnancy/postpartum

rapid and profound hormonal transitions

what is the endocrine state in Perimenopause

fluctuating ovarian hormones, sleep and thermoregulatory disruption