SALMON: Study And Learning Materials ONline
Hormones and Stress

Overview:

Hormones play an important role in modulating our behaviour, but before we can explore these effects we need to understand how the brain controls the release of hormones. The lecture begins with a description of the components and organization of the pituitary-adrenal-axis.

The effects of ACTH on behaviour motivated by fear is discussed in order to place this knowledge within a behavioural context.

The lecture concludes with a description of recent research which suggests that adrenal stress hormones may interfere with memory retrieval

Learning objectives

After studying this material you should be able to:

  1. recognise the location of human endocrine glands
  2. list the subdivisions of pituitary gland
  3. describe hypothalamic control of the pituitary gland
  4. list the subdivisions of the adrenal gland
  5. describe the organisation of the pituitary-adrenal-axis
  6. describe the effect of ACTH on acquisition and extinction of a conditioned avoidance response
  7. evaluate the hypothesis that ACTH increases fear
  8. describe a test of retrieval memory
  9. describe the effects of adrenal stress hormones on human and animal memory

Location of human pituitary and adrenal glands

The pituitary gland lies in the middle of the base of the brain below the hypothalamus. The pituitary is also known as the hypophysis.

The adrenal glands lie on the anterior surface of the kidneys. We have two adrenal glands one above each kidney.

The pituitary gland and the adrenal gland are endocrine glands.

Endocrine glands secrete hormones into the blood system.

Hormones are chemical messengers within the body.

The operation which involves removing the whole pituitary gland is known as hypophysectomy.

Removing the adrenal gland is an operation called adrenalectomy.

Hypothalamic control of the pituitary gland

Hypothalamic control of the pituitary gland

The pituitary gland consists of two major parts:

  1. the anterior pituitary or adenohypophysis
  2. the posterior pituitary or neurohypophysis

    Hypothalamic control of the anterior and posterior pituitary is fundamentally different.

    The anterior pituitary is controlled by blood borne factors released by the hypothalamus.

    The posterior pituitary is controlled by nerves originating in the hypothalamus.

Relationship between the hypothalamus and the anterior pituitary

This lecture concentrates on the role of ACTH and other hormones in the body's reaction to stress.

Cells in the hypothalamus which secrete CRF (Corticotrophin Releasing Factor) have synapses which make contact with blood vessels in the hypothalamus that transport CRF to the anterior pituitary where it stimulates the release of ACTH.

Relationship between the hypothalamus and the posterior pituitary

Hypothalamic cells that produce the hormones oxytocin and vasopressin have long axons that extend down through the infundibulum and synapse on blood vessels in the posterior pituitary.

Subdivisions of the adrenal gland

The adrenal gland consists of two parts

  1. an outer part - the adrenal cortex
  2. an inner core - the adrenal medulla.

The adrenal medulla receives messages from the brain through a nerve. In response to stimulation along nerves of the sympathetic nervous system the adrenal medulla releases the catecholamines:

  1. epinephrine (adrenaline)
  2. norepinephrine (noradrenalin)

These hormones are released in stressful situations as part of the 'flight / fight' mechanism. Just opening a rat's home cage is sufficient. Humans on piece work also show increased release of these hormones.

The adrenal cortex is controlled by ACTH which is transported through the blood system.

The adrenal cortex produces:

  1. mineralocorticoids e.g. aldosterone
  2. glucocorticoids e.g. the stress hormones corticosterone and cortisol.
    Glucocorticoids  promote conversion of protein and lipids to  carbohydrates. This replenishes energy reserves in the body.

Organization of the pituitary-adrenal-axis (PAA)

  1. Stressful environmental stimuli trigger the release of corticotrophin releasing factor (CRF) from nerve cells in the the hypothalamus into a blood system that travels to the anterior pituitary.
  2. In response to CRF, the anterior pituitary releases adrenocorticotrophic hormone (ACTH) into the blood system. ACTH is transported to the remotely located adrenal gland.
  3. ACTH stimulates the production of cortisol in the adrenal cortex.
  4. Cortisol is released into the blood stream. Cortisol affects the body's reaction to stress.

The pituitary-adrenal-axis is a complex feedback mechanism. Cortisol feeds back to the hypothalamus to control release of CRF.

High levels of cortisol in the blood tend to inhibit the release of CRF by the hypothalamus. Therefore less ACTH is released by the anterior pituitary. Consequently the amount of cortisol circulating in the blood stream is reduced. This is called a negative feedback system.

Organization of the pituitary-adrenal-axis (PAA)

Effect of stressors on hormones

Effect of stressors on hormones

The pituitary adrenal system is very sensitive to changes in an animal's environment.

Not surprisingly immobilizing an animal causes a massive release of hormones from both the adrenal medulla (epinephrine and norepinephrine) and adrenal cortex (corticosterone / cortisol).

But even opening the animals cage or transferring the cage to another room elicits hormone secretion.

  1. The term stress response refers to these physiological reactions.
  2. Stressors are the stimuli that elicit the stress response.
  3. Just to confuse things, the term stress is often used to refer to either the stress response or the stressor.

Humans are also sensitive to stressors. For example, examinations, hospital visits, oral presentations and participating in sporting events all activate the pituitary-adrenal system

Circadian release of cortisol and ACTH

Circadian release of cortisol and ACTH

The amount of cortisol in our blood stream is not just controlled by the amount of stressor we experience. There is a circadian (daily) rhythm in ACTH secretion and cortisol level which is higher in the morning. As well as reacting to stress there is a circadian pattern of plasma cortisol level in humans. ACTH levels exhibit the same circadian pattern as cortisol, except that ACTH changes precede change in cortisol level.

We now know that cortisol is secreted in several 'pulses' during the day. This was discovered by taking blood samples via an intravenous cannula that allowed blood samples to be taken at 20 minute intervals. Early studies relied on taking just one blood sample, or collecting urine over a 24 hour period for steroid analysis. This tended to obscure individual differences in the stress response.

Point to ponder:
There is also a circadian rhythm in the secretion of adrenal steroids in animals. What do you think is the impact of this on the design of experiments that involve independent groups of animal subjects tested over several days? For example, would your experiment be compromised if you tested the control group in early morning, and tested experimental groups in late afternoon? How would you overcome this problem?

Active avoidance learning

The PAA may be involved in learning about stressful situations . A number of experiments have examined the effects of ACTH and corticosterone on avoidance learning using rats. Before we examine these experiments we need to briefly consider the techniques employed to study avoidance learning in animals.

Some of these experiments use discriminated two-way active avoidance learning in a shuttle-box .

  1. This task is an example of 'discriminated' avoidance because a warning signal (light or buzzer) warns that shock is about to be delivered to the side of the shuttle-box currently occupied by the rat.
  2. The task is called 'avoidance' because the animal can avoid the shock by moving to the other side of the apparatus.
  3. The task is 'active' because the rat must emit a response (move to the other compartment) to avoid shock.
  4. It is a ' two-way ' task because the rat must shuttle between the two side of the apparatus on successive trials.

The ' pole-jump ' task is also used in some experiments; this is a discriminated one-way active avoidance task. The term 'one-way' refers to response the animal is trained to emit: The rat has to climb one-way up a pole to avoid shock delivered through the floor of the apparatus. But there is a crucial difference between the shuttlebox and pole-jump task - the role of the experimenter. In the pole-jump apparatus, the experimenter may sometimes need to remove the rat from the pole after it has made an avoidance response before the next trial begins. In contrast the shuttlebox task is completely automated - the experimenter does not handle the rat during training. Now the problem this raises is that different experimenters may handle rats in different ways and this may have some subtle effects on the animals behaviour. For example, a confident experimenter may handle the rats more gently than someone who is afraid of being bitten. Rough handling may increase a rat's level of fear.

One theory that accounts for avoidance learning is called the ' Two Factor' theory of avoidance behaviour. Briefly it invokes a mixture of classical and operant/instrumental conditioning (the two factors) to explain avoidance learning.

  1. Through classical conditioning the rat learns to fear the warning signal. In a shuttle box the light/buzzer is the CS and the shock is the UCS. After several CS/UCS pairings the presentation of the CS (light/buzzer) elicits the CR. Fear is the CR.
  2. Reduction in fear is reinforcing. Reinforced responses are learned. Therefore a response that reduces fear by removing the CS will be learned. In this way the rat learns to emit an operant response , shuttling or pole-jumping that turns off the CS. This response is reinforced because it reduces classically conditioned fear.

Experiments have studied stress hormone effects during

  1. acquisition ( initial learning ) of the avoidance response, and during
  2. extinction ( unlearning of a previously learnt response ) when the rat does not receive shock if it fails to emit the avoidance signal.

Levine (Readings in Physiological Psychology, Scientific American, Freeman) reviews a number of studies that have examined the effects of ACTH on avoidance learning. He argues that ACTH increases fear and thereby improves avoidance learning. We will now examine some of the experimental findings from David de Wied's laboratory that have been explained by Levine's theory.

Effect of ACTH on acquisition of a conditioned avoidance response

Effect of ACTH on acquisition of a conditioned avoidance response

Hypophysectomy is the name given to the operation which removes the whole of the pituitary gland.

One consequence of this operation is the loss of ACTH from the anterior pituitary which may be responsible for the profound disruption of avoidance learning in these rats.

This hypothesis is supported by the results of the experiment shown in this diagram. Injection of ACTH restores the ability of hypophysectomised rats to acquire an avoidance response in a shuttlebox.

An alternative explanation is that it is not the loss of ACTH per se that disrupts avoidance learning. It could be the decline in adrenal hormones that follows hypophysectomy that leads to the avoidance impairment.

De Wied used a special type of ACTH in these experiments called ACTH 1-10. This fragment of the complete ACTH molecule does not stimulate the adrenal cortex to produce hormones. Therefore it is unlikely that the restoration of avoidance behaviour in these rats is due to a secondary effect of ACTH on the adrenal cortex.

Now there may be a relatively simple explanation for this result involving a motor impairment. For example, hypophysectomy may make rats insensitive to electric shock, or interfere with their ability to move. If you examine the results for the hypophysectomised rats given a placebo injection you will notice that in early training sessions there is evidence of some learning, but performance deteriorates from the fourth day of training. This pattern of behaviour suggests that hypophysectomised rats are suffering from some type of motor impairment or general debilitation rather than a specific learning impairment. The next experiments investigate the more interesting possibility that ACTH is involved in motivation, learning and memory.

Effect of ACTH on extinction of a conditioned avoidance response

This diagram shows the effects of ACTH on the extinction of an avoidance response in a pole-jump avoidance task.

Two groups of normal rats were trained to avoid shock by running up a pole. One group of animals was given a placebo injection. The other group received ACTH1-10. The diagram shows that rats injected with the hormone made more avoidance responses under extinction conditions. In other words they continued to run up the pole even though electric shock was not delivered if they failed to emit the avoidance response.

This result can be explained by Levine's hypothesis that ACTH increases fear. According to Levine, ACTH increases fear and therefore these animals are more motivated to avoid shock and they continue to make the avoidance response even under extinction conditions when failure to avoid is no longer punished with shock.

Effect of ACTH on extinction of a conditioned avoidance response

Effect of adrenalectomy on extinction of a conditioned avoidance response

We have seen how adrenal steroids exert a negative feedbackeffect on the hypothalamus to reduce release of ACTH from the anterior pituitary

This gives another way of studying the role of ACTH in behaviour.

Adrenalectomy (removing the adrenal glands) leads to a loss of corticosterone and an increase in ACTH due to removing feedback effect of corticosterone.

De Weid has found that adrenalectomised rats make more avoidance responses under extinction conditions than intact rats.

Can Levine's hypothesis that ACTH increases fear account for these results?

Effect of cortisol on extinction of adrenalectomised rats

This diagram shows the results of an experiment by Endroczi in which cortisol was implanted into the hypothalamus of adrenalectomised rats.

Cortisol facilitated extinction of the conditioned avoidance response.

Can you develop an hypothesis to account for this finding. Bear in mind that adrenalectomy interferes with the mechanism by which cortisol controls ACTH secretion.

Endroczi used cholesterol as a control substance in his experiment. Cholesterol is a precursor to cortisol in the adrenal cortex. As far as we know, cholesterol is not converted into cortisol by brain tissue.

Points to ponder
Here are some additional experiments that test Levine's hypothesis that ACTH increases fear.
What outcome would Levine predict?
  1. Hypophysectomy produces a decline in ACTH and corticosterone levels. What would be the effect of hypophysectomy on extinction performance?
  2. In passive avoidance behaviour the rat must inhibit a response to avoid electric shock. What would be the effect of ACTH injections on acquisition of a passive avoidance response?

Could the effects of ACTH on behaviour that you have studied be explained in terms of an effect of the hormone on memory or attention rather than an increase in fear?

Effect of cortisol on memory

It has been suspected for some time that glucocorticoids (cortisol and corticosterone) released from the adrenal cortex during stress have adverse effects on cognitive functions such as learning and memory.

A recent report by Newcomer et al (1999) shows that high levels of the stress hormone cortisol interferes with verbal declarative memory. The study involved three groups of subjects:

  • subjects in the high steroid group were given a tablet containing 160mg of cortisol on each day of the four day experiment. This dose of cortisol produces blood levels similar to those seen in people experiencing a major stress event such as abdominal surgery
  • low steroid subjects were administered 40mg of cortisol per day which mimics the amount of cortisol circulating in the blood stream of people undergoing minor surgical procedures such as having stitches removed.
  • a third group of people were given dummy placebo tablets

All subjects were asked to listen to and recall parts of a prose paragraph. This tests their verbal declarative memory. The results show that high steroid levels disrupt this memory task. The effect is not permanent. The performance of subjects in the high steroid group returned to normal after they stopped taking the hormone tablet.

Point to ponder:
What is the the implication of this experiment for examination performance? What do you think the effect of high steroid levels before and during examinations could be on your ability to recall information that you have learned during the course?
.

Of course it is possible that the effect of cortisol on memory are due to reduced ACTH caused by the feedback of cortisol to the hypothalamus. An experiment by De Quervain et al, (1998) makes this explanation unlikely.

This experiment involved studying the effects of stress on rats' ability to remember the position of a submerged platform in a water maze. In this paradigm rats are placed in a tank containing cloudy water. After swimming around for some time they eventually encounter a submerged platform. Rats can learn the position of the platform. After several learning trials they swim straight to the platform when they are placed in the tank.

It is thought that rats use spatial cues in the laboratory to learn the position of the platform. For example, they may use the position of furniture, windows or lights in the lab to locate the platform.

In order to measure spatial memory De Quervain et al gave subjects a 60 second test of their memory for the position of the platform and measured the amount of time rats spent:

  1. close to the platform
  2. away from the platform


Stress disrupts performance on this task. Memory for the position of the submerged platform was disrupted if they were given footshock before being placed in the water maze. But crucially the impact of stress varied as a function of how long before testing the rats were stressed.

  1. stress impaired memory if it was given 30 minutes before testing, but
  2. stress had no effect if it was given 2 minutes or 4 hours before memory testing

In another experiment rats were injected with the drug metyrapone which inhibits an enzyme involved in corticosterone synthesis. Metyrapone was given before the footshock stress and interfered with the effect of stress on memory in the water maze test.

Furthermore, De Quervain et al showed that injecting corticosterone 30 minutes before memory testing impaired the rats' ability to remember the location of the submerged platform.

These results suggest that the effect of corticosterone on memory is not due to a feedback effect of the hormone on ACTH release from the anterior pituitary.

Commenting on these results Jim McGaugh said "This effect only lasts for a couple of hours, so that the impairing effect in this case is a temporary impairment of retrieval, the memory is not lost. It is just inaccessible or less accessible for a period of time."

You may have experienced the effect of stress when you sit an important examination. Your 'mind goes blank' during the exam, and you kick yourself after the exam when you remember what you should have written. You may find it helpful to practice some simple relaxation techniques such as slow, deep breathing, or closing   your eyes and picturing a tranquil scene to help you relax before and at the start of an exam.

References

  1. De Quervain et al, (1998). Nature, 394, 787-790.
  2. De Wied, (1997) The neuropeptide story, Frontiers in Neuroendocrinology, 18, 101-113.
  3. Endroczi, (1969) In Recent Developments of Neurobiology in Hungary, K. Lissak (Ed), Vol 2, pp27-50, Akademia Kiado, Budapest.
  4. Kopin, 1980, Catecholamines, adrenal hormones, and stress. In Krieger and Hughes (Eds.) Neuroendocrinology, Sinauer, Sunderland.
  5. Levine, (1971) Stress and behaviour, Scientific American, 224, 26-31.
  6. Newcomer et al, (1999). Decreased Memory Performance in Healthy Humans Induced by Stress-Level Cortisol Treatment. Archives of General Psychiatry, 56, 527-533.

Supplementary Reading

  1. Listen to an audio lecture by Dr. Robert Sapolsky - (Professor of Neuroscience at Stanford University ) " Stress and Memory: Forget It!" Can stress make you forget? Dr. Sapolsky presents an entertaining overview of the disruptive effects of stress on memory and brain aging.
  2. Schacter did important experiments on the psychological effects of epinephrine - they are described in many introductory psychology textbooks. Look in the chapter on emotion and motivation. Here is a link to Schachter and Singer's Modelin an online book Drugs, Brains and Behaviorby Timmons & Hamilton.
  3. The effects of epinephrine on learning are described by Nelson in his book An Introduction to Behavioural Endocrinology, Sinauer, Sunderland, 1995.

HEFCE, the funding body for universities and colleges for the UK, has purchased a 3 year licence to IDEAL, the Academic Press online journal library. If you are a member of a UK academic institution (HEFCE funded) you now have full access rights to this online library which enables you to read the full text of articles in Academic Press journals.
The following article in Frontiers in Neuroendocrinology, 18,1,1997 is available via IDEAL and covers topics raised in the lecture in greater depth:

  1. David de Wied, The Neuropeptide Story, Frontiers in Neuroendocrinology, 18,1,1997 p101-113

If you are using a computer within the University of Plymouth , click here for access to IDEAL. You will be able to locate Frontiers in Neuroendocrinology from the IDEAL Main Menu. Play around with this system, it is one of the most valuable resources added to university education in the last few years. You will come to rely on it increasingly over the next few years.

The story behind SALMON (Study And Learning Materials ONline)

Paul Kenyon

Study And Learning Materials ONline (SALMON) was developed and is maintained by Dr Paul Kenyon who graduated from Queens University Belfast in 1969 with a B.Sc. (Hons) in Psychology. In 1976 he was awarded a Ph.D. by the University of Reading. He lectured on the Biological Bases of Behaviour, Behavioural Neuroscience and Evolutionary Psychology in the Department of Psychology, University of Plymouth from 1973 to 2006. He has published papers in psychopharmacology, psychoteratology, physiological psychology and laboratory computing.

Paul started work on SALMON in 1994 to support his 1st, 2nd and 3rd year undergraduate students studying Evolutionary Psychology, Biological Bases of Behaviour and Psychobiology

SALMON won the 1998 Universities and Colleges Information Systems Association (UCISA) Teaching and Learning Awardfor demonstrating innovative or exemplary use of the Web and was a finalist at EASA98 held at the University of Oxford in September 1998.

SALMON was a finalist at the European Academic Software Awards (EASA)held in Oxford in 1998

Paul retired from his university post in 2006 and devotes more time than is reasonable to maintaining this website and his lifelong love of all things associated with trout and rivers. He and his colleague Geoff Stephens now operate Fly Fishing Devonwhich offers fly fishing instruction and guiding on Dartmoor and in South Devon, UK.

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