Stress and the brain

Goals

• To discuss the stress response, and discuss its good and bad effects.
• To discuss the HPA axis and its control by brain structures.
• To discuss epigenetics and HPA axis activation
• To discuss the effects of chronic stress on three brain structures: hippocampus, amygdala, and medial prefrontal cortex.

Topic slide

Elizabeth Gould (b. 1962) is a Professor of Psychology at Princeton who identified neurogenesis in non-human primates and studied the effects of stress upon neurogenesis. Gould received her Ph.D. at UCLA and then completed a post-doc fellowship in McEwen's lab at Rockefeller.

Bruce McEwen (1938 – 2020) was a neuroscientist at Rockefeller University who studied the molecular and genetic bases of stress. He also wrote several popular science books, such as “The End of Stress as We Know It” to make his academic work accessible to the larger community.

Reading

• Review article by Roozendaal and colleagues. This article is also uploaded on Canvas/Files/Articles.

Stress

Stress has both good and bad effects

The stress response mobilizes our bodies for situations in which we are threatened. Stress is part of the ‘fight or flight’ response associated with activation of the sympathetic nervous system.

However, persistent, chronic stress can be bad for our health. While it is good in the short run to increase our heart rate and blood pressure to respond to a given threat, it is not good to have chronically high blood pressure or heart rate as this increases the wear and tear on the heart, and can lead to strokes.

The stress response involves many systems of the body that interact in complex ways. Here are just a few effects:

• Release epinephrine (also known as adrenalin) from the adrenal medulla.
  • This will increase heart rate and blood pressure
• Release of glucocorticoids (cortisol in humans) from adrenal cortex – raises levels of glucose in blood. (cortex means bark, and so the adrenal cortex is the outer part of the adrenal glands).
• This response is good in short term, but bad in the long term (diabetes, damage to hippocampus, decrease in muscle mass and bone density, increase in belly fat).

Stress and sleep

Stress interferes with sleep, and sleep loss creates stress, thus a vicious cycle is created. Some of the effects of stress-related sleep loss are as follows:

• Elevated evening cortisol, insulin and blood glucose.
• Elevated blood pressure, reduced parasympathetic activity.
• Elevated levels of pro-inflammatory cytokines.
• Elevated levels of the gut hormone, ghrelin, which increases appetite.
  • Increased hunger for comfort foods and increased caloric intake.
• Depressed mood and cognitive impairment.

Stress and immune function

Stress suppresses immune function making individuals more susceptible to infection.

Stress and fertility

Stress interferes with fertility and suppresses testosterone. I discussed a recent study showing that stress decreases the likelihood of conception in couples seeking to have children.

Stress and obesity

I discussed a study showing that glucocorticoids stimulate the production of the gut hormone ghrelin, which stimulates the nucleus accumbens (of the basal ganglia – remember our reward system discussion) – studies show that ghrelin makes food take sweeter. People desire comfort food when stressed.

• Glucocorticoids decrease satiety signals (Leptin and Insulin)
• Glucocorticoids promote the development of visceral belly fat.

Baboon study

I discussed an example of stress in the wild baboon where glucocorticoid and testosterone levels can be estimated from residuals in fecal samples. In general, glucocorticoids and testosterone have a reciprocal relationship – if one is high, the other is low. However, this can be dissociated. The general results of the study were as follows:

• Low ranking baboons show very high levels of stress, as measured by high glucocorticoids and low testosterone
• Higher ranking baboons have lower levels of glucocorticoids and higher levels of testosterone.
• The exception is the top male (alpha male) baboon – who has high levels of both testosterone and glucocorticoids. Apparently, it is very stressful at the very top. The alpha male has to protect his collection of consorts from lower ranking males, and is also frequently challenged for the top position.

The HPA Axis

The Hypothalamus-Pituitary-Adrenal (HPA) axis is instrumental in our response to stress.

Sequence of activation in HPA axis

Neurons of the Paraventricular nucleus (PVN) of the hypothalamus synthesize and secrete corticotropin-releasing factor (CRF):

• Binding of CRF in pituitary releases adrenocorticotropic hormone (ACTH) into the systemic circulation.
• The principal target for circulating ACTH is the adrenal gland, where it stimulates glucocorticoid synthesis and secretion, and epinephrine secretion.
• Glucocorticoids are the downstream effectors of the HPA axis and regulate physiological changes through ubiquitously distributed intracellular receptors.
• Glucocorticoids (cortisol in humans) are steroid hormones that regulate metabolic, cardiovascular, immune, and behavioral processes.
• There are glucocorticoid receptors in brain – e.g., hippocampus – thus, cortisol can directly influence neurons.

Brain control of HPA axis

An interesting review article that discusses neural control of the HPA axis in considerable detail can be found here.

While much of the brain is involved in the psychological aspects of stress, there are two brain structures that play a particularly important regulatory role in the HPA axis:

• Amygdala – generally activates the HPA axis.
• Hippocampus – sense glucocorticoids through its many glucocorticoid receptors and inhibits the HPA axis.

Note – the amygdala and hippocampus also directly communicate.

The ventromedial prefrontal cortex (vmPFC) is a third brain region involved in control of the HPA axis. The vmPFC generally inhibits the HPA axis.

Amygdala

The amygdala is not a single structure, but a collection of many nuclei that have different patterns of connectivity with other brain structures. The nuclei of the amygdala have been divided into three major groups: central group, basolateral group, cortical group.

The central and medial nuclei of the amygdala are connected to the hypothalamus and help initiate the stress response.

The main pathway from the amygdala to the hypothalamus is the stria terminalis. The stria terminalis terminates on the neurons o the bed nucleus of the stria terminalis,

Hippocampus

The hippocampus has many glucocorticoid receptors and is thus sensitive to glucocorticoid levels. The fimbria/fornix pathway from the hippocampus terminates in the hypothalamus (primarily to the mammilary bodies, which are part of the hypothalamus). The hippocampus projects to neurons in the region surrounding the Periventricular Nucleus.

Damage to the hippocampus leads to over activation of the HPA axis.

Glucorticoid levels influence memory, and it may be that the numerous glucocorticoid receptors play a role in the encoding into memory of stressful events.

Hypothalamus

As we have discussed in detail, the hypothalamus is also not a single structure, but is a collection of nuclei with different but interacting functions.

Epigenetics

I discussed how environment acts upon genes – silencing genes through methylation, or by influencing gene transcription into proteins by modifying histones – structural proteins that wind the DNA strands and make particular genes less accessible for transcription. I briefly mentioned study showing histone modification in response to stress in rodents.

I discussed study by Michael Meany in which the epigenetics of pup rearing in rats was examined:

• Rat mothers who licked their pups (a good thing) had pups with increased serotonin tone and increased activity in a particular gene that increased glucocorticoid receptor expression in the hippocampus.
• This resulted in less stress response in the pups.
• The female pups showed less stress when they became mothers.
• So – it appears that epigenetic effects can have life long influence upon our response to stress.

I discussed study of suicides (also by Meany):

• Three groups compared: controls who did not die by suicide, suicides with a history of child abuse (a potent stressor that might lead to epigenetic effects), suicides with no history of child abuse
• Hippocampal glucocorticoid receptor expression was decreased in the suicides who had a history of child abuse.
• This study is consistent with the study discussed above concerning rat pups

Effects of stress on the brain

Stress and Neurogenesis

There is now very convincing evidence that we create new neurons (even as adults) in our hippocampus (and olfactory bulbs). Much of this work has been done in rodents using simple conditioning memory tasks, but has also been done in non-human primates. There is still controversy about whether or not sufficient data has been put forth to definitively establish that neurogenesis occurs in humans, although it is very likely.

Stress and neurogenesis

Stress suppresses neurogenesis in the hippocampus. I discussed study by Gould and McEwen showing that a single episode of intruder stress in a monkey decreases neurogenesis in the hippocampus.

Stress and the hippocampus

Chronically elevated levels of glucocorticoids can be affect hippocampal neurons, apparently by interfering with the glucose transporter. This puts neurons at metabolic risk. Cushing’s disease (when untreated) results in very high levels of circulating glucocorticoids, and results in atrophy within the hippocampus. This atrophy is at least partially reversible after treatment reduces the glucocorticoid levels. Apparently, neurons can ‘retract’ dendrites and spines in response to high stress, and neurogenesis is suppressed – both mechanisms leading to volume change in the hippocampus.

Quoting below from a review by a review of the glucocorticoid vulnerability hypothesis by Cheryl Conrad.

… chronic stress or prolonged exposure to glucocorticoids can compromise the hippocampus by producing dendritic retraction, a reversible form of plasticity that includes dendritic restructuring without irreversible cell death. Conditions that produce dendritic retraction are hypothesized to make the hippocampus vulnerable to neurotoxic or metabolic challenges. Of particular interest is the finding that the hippocampus can recover from dendritic retraction without any noticeable cell loss. When conditions surrounding dendritic retraction are present, the potential for harm is increased because dendritic retraction may persist for weeks, months or even years, thereby broadening the window of time during which the hippocampus is vulnerable to harm, called the Glucocorticoid Vulnerability Hypothesis.

Individuals with post-traumatic stress disorder (PTSD) have smaller hippocampi than controls without chronic stress. The HPA axis plays a modulatory role in memory – individuals with PTSD have poorer memory, and a study discussed in lecture showed that the memory loss in individuals with PTSD is correlated with the loss of hippocampal volume.

Hippocampal atrophy: Cause or effect?

Is the hippocampal volume loss the result of PTSD stress, OR, is a smaller hippocampus a vulnerability for developing PTSD?

• Discussed study of twins – one who went to war and one who did not.
• The hippocampal volume predicted PTSD severity in the twin who went to war. But the hippocampal volume of the twin who did NOT go to war also predicted their twin’s PTSD severity.
• This suggests that a small hippocampus may be a predisposing factor to developing PTSD, and not a consequence of stress per se.
• This issue is complicated by pre-existing levels of stress in both twins – and the effects of early life stressors on epigenetics.

Stress and the amygdala.

I discussed studies that show increased fMRI activation in the amygdala to individuals with anxiety disorders – an oft reported finding (also seen in individuals with PTSD).

It is unclear whether one should predict a larger or smaller amygdala volume with stress – if the amygdala activates the HPA axis and causes the stress response – we might expect a larger amygdala associated with more stress. Indeed, in one study with rodents discussed in your reading by Roozendall, a stress event (2 hours of immobilization) triggered an increase in anxiety and spine density in the basolateral amygdala after several days.

In a study of rats selectively raised over generations to have small, medium, or large amygdala, the rats with smaller amygdala showed less extinction learning (i.e., they didn’t learn that they were no longer going to be shocked) and higher cortisol levels in response to a swimming challenge. It looks like a smaller amygdala confers a greater response to stress.

In a study of blood pressure reactivity (a measure of stress in humans) using fMRI, individuals exhibiting greater stressor-evoked blood pressure reactivity showed greater amygdala activation, and lower amygdala gray matter volume. Again, it looks as though a smaller amygdala is associated with higher stress reactivity.

In combat exposed veterans, PTSD was associated with a smaller amygdala volume compared to combat exposed veterans who did not develop PTSD (resilient veterans) and to veterans without PTSD who were not exposed to combat. Again – it looks like a smaller amygdala is associated with PTSD.

However, when the non-PTSD individuals were studied – i.e., the veterans who were exposed to combat stress had a larger amygdala than the veterans who were not exposed to combat stress.

The amygdala volume story with stress is complicated and will require additional studies to unravel. Amygdala changes may reflect both cause and effect. Here is a current summary:

• Smaller amygdala could be genetic vulnerability that results in higher stress reactivity and to increased risk for developing PTSD.
• However, resilient veterans (those that do NOT develop PTSD) may respond with increase in amygdala volume when exposed to trauma. This suggests that stress can increase the size of the amygdala in non-vulnerable populations.
• Vulnerable individuals do not respond with increase in amygdala volume and develop PTSD.

Serotonin and stress

Genetic effects upon amygdala response was discussed. The neuromodulator serotonin is associated with two common variations (alleles) in the serotonin transporter gene. One allele – the short (S) form – is associated with a mild increase in the response to stress, while the long form (L) is not. Individuals with two S genes (one from each parent) show greater fMRI activation in the amygdala in response to fearful faces than do individuals with two L genes.

Stress and the ventromedial prefrontal cortex (vmPFC)

The vmPFC is highly connected to the amygdala. As we will see in the forthcoming lectures, the vmPFC is associated with emotion.

Extinction retention (i.e., remembering that shock is no longer going to occur following the conditioned stimulus – a good thing) is associated with a thicker vmPFC.

Videos

The following videos were prerecorded for 2020.

Previously recorded live lectures.

The video embedded below was recorded in Fall, 2019. It constitute the first part of the lecture on stress, and ends with the discussion of the effects of stress upon the hippocampus.