PSYC388 M9: Systems neuroscience: Localization of a master clock in the mammalian brain

What are the two historical views on brain function localization?

Localization (functions tied to specific brain areas)

Mass Action (functions arise from broadly distributed, non-specialized brain regions).

How has the understanding of brain function localization evolved by the end of the 20th century?

Both pure localization and pure mass action views are outdated;

the brain functions via anatomically distributed but functionally specialized networks.

What is the modern model of brain function organization?

Functionally specialized yet anatomically distributed systems where functions span networks of regions instead of isolated centers.

What are the main pathways in the visual system according to the modern neuroscience model?

Sensory input from retina → thalamus (lateral geniculate nucleus) → cortex (V1),

organized in series and parallel into dorsal (object location) and ventral (object identification) streams.

What is the suprachiasmatic nucleus (SCN) and why is it important?

The SCN, located in the hypothalamus, is the master circadian clock, identified through converging experimental evidence between 1972-1990.

What does the discovery of the SCN illustrate about brain function?

It illustrates the concept of localization within distributed systems, supporting the modern view of brain function arising from networks of specialized regions

What is the main takeaway about brain function localization from this passage?

Brain functions emerge from distributed networks of specialized regions rather than isolated centers or undifferentiated mass activity.

Who used running wheels in rats to study daily rhythms and discovered free-running rhythms and entrainment?

Curt Richter (1920s-1960s).

What was Curt Richter's main approach to locating the circadian clock in the brain?

Used brain lesions and organ removals for unbiased mapping, which had limitations due to brain complexity.

What key brain region did Richter find lesions disrupted rhythmicity but could not pinpoint specifically?

The medial hypothalamus.

What was Robert Moore's rationale for studying retinal projections in circadian rhythm research?

Since light entrains circadian rhythms, the circadian clock must receive input from the retina.

Why is the retina critical for circadian entrainment in mammals?

Because mammals rely exclusively on retinal photoreception for light input to the circadian system.

What was observed in rats/mice without eyes regarding circadian entrainment?

They cannot entrain to light-dark cycles, unlike some non-mammals with extra-retinal photoreceptors.

What is the retinal projection pathway sequence relevant to circadian entrainment?

Retinal ganglion cells → optic nerves → optic chiasm → optic tracts → thalamus (LGN) and brainstem.

What did knife cut experiments on optic nerves and optic tracts reveal about circadian entrainment?

Cutting optic nerves disrupted entrainment, but cutting optic tracts did not, suggesting a pathway before the tract.

What technique did Moore use to discover the retinohypothalamic tract (RHT)?

Tritiated amino acid autoradiography, tracing protein transport from retina to brain

Where does the retinohypothalamic tract (RHT) lead in the brain?

Directly to the suprachiasmatic nucleus (SCN) above the optic chiasm.

What is the significance of the suprachiasmatic nucleus (SCN)?

It is the master circadian pacemaker in mammals.

What was the major shift in methods that led to identifying the SCN as the circadian clock?

From broad lesion mapping (Richter) to targeted anatomical tracing of retinal projections (Moore)

What role does the retinohypothalamic tract (RHT) play in mammalian circadian rhythms?

It links the retina to the SCN, enabling light-based entrainment of circadian rhythms

What is the suprachiasmatic nucleus (SCN) known as in the brain?

The master circadian clock.

What staining technique was used to first identify the SCN in rat brains?

Cresyl violet staining.

Why does the SCN appear heavily stained with cresyl violet?

Because it contains small, tightly packed neurons rich in ribosomes.

When the SCN was first identified, what was still unknown?

Its function in circadian rhythms.

What method showed direct connectivity between the retina and the SCN?

Viral tracing—injecting a virus into the eye that traveled via retinal ganglion cells to the SCN.

What did viral tracing to the SCN imply about its role?

That the SCN processes light information and may be involved in circadian entrainment.

Where is the SCN located in the brain?

Just behind the optic chiasm on the ventral side of the brain.

How can the SCN be visually distinguished in brain sections?

It appears as a slightly darker, cell-dense region due to the staining of its packed neurons.

Why did researchers decide to lesion the SCN in circadian studies?

Because autoradiography showed the SCN receives direct retinal input, and cutting the RHT wasn't feasible

What methods were used to destroy the SCN?

Electrical currents via electrolysis or heating.

What did Irv Zucker's lab measure in SCN ablation studies?

Locomotor activity and drinking rhythms.

What did Bob Moore's lab measure in SCN ablation studies?

Plasma corticosterone levels.

What were the key behavioral results of SCN lesions in rats?

Complete loss of circadian rhythms in both sighted rats (LD) and blind rats (DD).

What did Bob Moore find regarding corticosterone after SCN ablation?

no daily peak in corticosterone and no recovery of rhythmic function, even in neonatal rats.

What do SCN ablation results suggest about the SCN's role?

The SCN is critical and irreplaceable for circadian rhythm expression.

What happened to rats' sleep-wake cycles after SCN ablation (EEG study)?

Circadian rhythm disappeared and was replaced by ~3-hour ultradian cycles.

Did SCN ablation affect total sleep time?

No, total sleep time remained the same.

What remained intact in rats after SCN ablation despite circadian loss?

Sleep homeostasis—rats still showed rebound sleep after deprivation.

How were functions like eating, drinking, and body temperature affected by SCN lesions?

They averaged to normal levels but lost their rhythmic timing.

What does SCN ablation reveal about circadian vs. homeostatic control?

They are controlled by different systems—SCN for timing, other brain regions for behavior levels.

What unusual effect did SCN lesions have in squirrel monkeys?

They increased total sleep time by 50%.

What is the overall conclusion from SCN ablation studies?

The SCN is the master circadian pacemaker—it controls the timing, not the amount, of behaviors.

What key question remained after SCN lesion studies?

Whether the SCN produces circadian rhythms or just relays timing info from elsewhere.

What would confirm the SCN is a true circadian oscillator?

Direct functional evidence showing it generates and controls rhythms independently.

What happens if SCN activity is stimulated or inhibited?

It causes predictable phase shifts (advances or delays), mimicking the effects of light

How do SCN neurons behave in terms of electrical activity?

They show daily rhythmic firing, highest during the day—even when isolated from the brain.

What happens when the SCN is kept alive in a dish (e.g., slice cultures)?

It maintains a ~24-hour circadian rhythm of neural activity, even without external input.

What is the result of transplanting SCN tissue into arrhythmic animals?

Circadian rhythms are restored—only if SCN tissue is used.

What proves that the SCN itself contains the rhythm generator?

The donor's rhythm appears in the recipient (e.g., a 20-hour donor gives a 20-hour rhythm).

What types of evidence converge to support the SCN as the master pacemaker?

Lesion/stimulation studies, neural recordings, tissue cultures, and transplant experiments.

What is the overall conclusion about the SCN from convergent evidence?

The SCN is the brain’s master circadian pacemaker—it generates, maintains, and controls daily timing.

How do neurons communicate with each other?

By releasing neurotransmitters from axon terminals, which bind to receptors on nearby neurons to excite or inhibit them.

How does light affect the circadian clock through the SCN?

Light is processed by retinal ganglion cells, which send signals via the retinohypothalamic tract (RHT) to affect SCN neuron activity.

What is the prediction about stimulating the SCN with neurotransmitters?

If neurotransmitters shift the clock, then stimulating the SCN should mimic the effects of light or arousal.

What happens when the SCN is electrically stimulated?

It causes phase shifts in circadian rhythms — similar to the effects of light exposure.

What effect does injecting Neuropeptide Y (NPY) into the SCN have?

It mimics non-photic phase shifts caused by arousal (e.g., animal handling during rest).

Can neurotransmitters injected into other brain areas shift circadian rhythms?

No — only stimulation of the SCN causes clock phase shifts.

What do electrical and chemical stimulation experiments show about the SCN?

The SCN is the site where light and non-photic cues act to shift the circadian clock.

Why is SCN stimulation considered proof of clock function?

Because manipulating SCN neuron activity alone is sufficient to shift circadian rhythms.

What conclusion can be drawn from stimulation, lesion, and transplant studies?

The SCN is the location of the brain’s master circadian clock, not just a part of the pathway.

What kinds of rhythms should SCN neurons show if they are true circadian oscillators?

Rhythms in electrical activity, neurotransmitter release, metabolic activity, and gene expression.

What method was used to measure metabolic activity in the SCN?

14C-2DG autoradiography, which tracks glucose uptake.

What was observed in SCN glucose uptake rhythms?

High activity during subjective day, low at night — seen in both nocturnal and diurnal animals.

How was SCN electrical activity recorded?

Using multiple unit activity (MUA) electrodes that measure many neurons firing together.

When is SCN electrical activity highest and lowest?

Highest during the subjective day, lowest at night — opposite of when rats are most active.

What was the SCN island experiment?

Researchers cut the SCN off from the rest of the brain;

it continued oscillating for over a month, while the rest of the brain became arrhythmic.

What did the SCN island experiment demonstrate?

That the SCN can generate rhythms independently, without brain inputs or outputs.

What was the SCN in a dish experiment?

SCN slices were kept alive in nutrient solution and maintained circadian firing rhythms for days to weeks.

What did the SCN slice study show about individual neuron timing?

Neurons peak at different times, but collectively produce a stable, averaged circadian rhythm.

What do all the module 9.6 experiments suggest about SCN neurons?

They are true circadian oscillators, capable of autonomous rhythmic activity.

How do SCN neuron rhythms relate to physiology and behavior?

They align with daily patterns like sleep, activity, hormone release, and body temperature.

What does convergent evidence from multiple methods confirm about the SCN?

it is the core clock of the mammalian circadian system.

Why is brain tissue transplantation usually difficult in neuroscience?

Because the brain is complex, and replacing even known neuron types (e.g., in Parkinson's) rarely guarantees functional recovery

Which brain structure is a rare success in transplantation for restoring function?

The suprachiasmatic nucleus (SCN).

What did Menaker's 1970s study show about the pineal gland in sparrows?

Removing it made birds arrhythmic, but transplanting a pineal gland into the eye restored rhythms.

What did the pineal transplant study demonstrate about the circadian system?

That a diffusible signal, later identified as melatonin, could restore circadian rhythms.

What was the result of SCN lesion studies in rats?

Lesions to the SCN eliminated circadian rhythms.

What did SCN transplant studies in the 1980s show?

That transplanting SCN tissue into rats could restore circadian rhythmicity.

What type of SCN tissue was most successful in restoring rhythms?

Embryonic SCN tissue, taken just before birth.

Could adult SCN tissue restore rhythms effectively?

No — it was less effective than embryonic tissue.

Could brain tissue from regions other than the SCN restore circadian function?

No — only SCN tissue was successful.

What do SCN transplant results suggest about the SCN's role in circadian rhythms?

That the SCN is necessary and sufficient for generating and restoring circadian rhythms.

Why are SCN transplant findings important in neuroscience?

They provide causal, experimental proof that the SCN is the brain’s master circadian clock.

What does it mean that the SCN operates independently in transplants?

Its internal timing mechanisms work even after isolation, and can re-control behavior when reconnected.

Who discovered the tau mutant hamster, and when?

Martin Ralph in the 1980s, while working in Menaker’s lab.

What was unusual about the tau mutant hamster's behavior?

It became active 6 hours before lights-off, which is abnormal for nocturnal animals.

What was the tau mutant hamster's free-running period in constant darkness?

about 22 hours

What were the tau mutation effects in descendants?

Heterozygous: 22h rhythm

Homozygous: 20h rhythm

What did the tau mutant hamster demonstrate about circadian rhythms?

That circadian period length can be genetically inherited.

What was the main question Ralph & Menaker wanted to test using transplants?

Whether the SCN sets the circadian period (tau) or just enables rhythms.

What happened when they transplanted a WT SCN into a tau mutant hamster?

The hamster regained a 24-hour rhythm

What happened when they transplanted a tau mutant SCN into a WT hamster?

The hamster adopted a 20- or 22-hour rhythm depending on the donor’s genotype.

What did the transplant experiment show about the SCN?

That the SCN determines the rhythm’s period and acts as the master circadian clock.

What does the tau mutant hamster study prove about the SCN?

It provides strong causal evidence that the SCN’s genotype controls internal timing.

What does this experiment say about localization of function?

It strongly supports the idea that circadian timing is localized in the SCN.

What broader scientific lesson came from the tau mutant discovery?

“Luck favours the prepared mind” — recognizing scientific value in unexpected findings.

What happens to circadian rhythms when the SCN is lesioned?

Animals become arrhythmic, losing their circadian rhythms permanently.

What does SCN lesion evidence suggest about its function?

The SCN is necessary for generating circadian rhythms

How can the SCN be experimentally stimulated, and what is the effect?

With electrical or chemical stimulation, which causes phase shifts in rhythms

What does SCN stimulation evidence suggest?

The SCN is responsive to entraining signals and helps regulate timing.