2015 Donald B. Giddon Lecture: The Brain on Stress | Bruce S. McEwen, PhD

Introduction

The speaker introduces the lectureship and the lecturer, and presents an award to a student.

Student Award

• DENTSPLY presents an award for student research.

• Mr. Cameron Lee is awarded the plaque for his post-presentation work.

• DENTSPLY sponsors Mr. Lee to represent Harvard University at ATA in DC.

GUID Lectureship

• Bruce Dolph introduces the GUID lectureship sponsored by Dr. Don Ingber.

• Dr. Ingber has been a long-term faculty member at Palmer Head and Dean of NYU School of Dentistry.

• The lecture brings individuals of high caliber to the School of Dental Medicine.

• Dr. Bruce S McEwen is introduced as today's lecturer.

Lecture on Brain and Stress

Dr. McEwen talks about how physical and social environments affect the function of the entire body throughout life acting.

Brain Function

• The brain plays a role in many different aspects related to health and disease.

Physical Environment

• No significant points made in this section.

Social Environment

• No significant points made in this section.

Epigenetic Mechanisms of Brain Plasticity Throughout Life Course

• No significant points made in this section.

Introduction to Stress and Allostasis

This section introduces the concept of stress and allostatic load. It explains how stressors, physiological and behavioral responses, individual differences, genes, experiences through life, and the brain all play a role in determining what is stressful or threatening.

The Concept of Allostasis

• Allostasis refers to the process by which our body adapts to stressors using physiological responses such as cortisol, adrenaline, sympathetic inflammation.

• When these mediators are dysregulated due to chronic activation from stressors or unhealthy lifestyle choices, they can lead to wear and tear on the body and brain known as allostatic load.

Cortisol as a Mediator

• Cortisol is one of many mediators that help us adapt to stress.

• In low levels, it enhances immune function, improves memory, promotes energy replenishment and efficient cardiovascular function.

• However, when present in high levels chronically it can suppress immune function impair memory promote bone mineral loss muscle wasting.

Interactions between Mediators

• There are many other mediators besides cortisol that affect different systems of the body from metabolism to immune function.

• These mediators interact with each other in a nonlinear profile because each one shows an inverted U-shape dose-response curve.

• Unhealthy lifestyle choices such as toxic chemicals or elevated inflammation can contribute to this wear and tear on the body known as allostatic load.

The Role of Health Behaviors

• Our health behaviors such as sleep patterns eating habits exercise routines smoking drinking etc. all contribute positively or negatively towards our allostatic load.

The Hippocampal Formation

This section discusses how the hippocampus plays a crucial role in the stress response and how it is closely connected to the amygdala.

The Discovery of Glucocorticoid Receptors

• The hippocampus was discovered to be the place where most of the highest intensity of uptake and retention of glucocorticoid occurs.

• This discovery was made by autoradiography using radioactive cortical stirring which is the glucocorticoid in rats injected into adrenal ekta mised animals so there was no competition by endogenous hormone.

The Connection between Hippocampus and Amygdala

• The hippocampal formation is closely connected to the amygdala, which plays a crucial role in processing emotions such as fear and anxiety.

Hormones and Brain Plasticity

This section discusses the impact of hormones on brain plasticity, specifically in the hippocampus.

Hormones as Targets for Brain Plasticity

• The whole brain is a target for circulating hormones, including sex hormones and stress hormones.

• Neurons in the brain can experience plasticity, with dendrites growing or shrinking based on experiences.

• Neurogenesis in the dentate gyrus region of the hippocampal formation continues into adult life and can be reactivated through physical activity.

Hippocampal Formation and Alzheimer's Disease

• The hippocampal formation receives input from the antirattle cortex, which degenerates in early stages of Alzheimer's disease.

• Seizures can lead to cell damage and loss in the hippocampus.

Stress and Brain Remodeling

• Repeated stress leads to reversible shrinkage of dendrites in ca3 neurons.

• Prolonged stress causes a decrease in cell proliferation, volume of the hippocampus, and number of granule cells.

• Glutamate is essential for stress-induced remodeling but also contributes to depression, neurological diseases, and brain aging.

Epigenetics

This section defines epigenetics as changes above the genome that regulate gene expression without changing DNA sequence.

Epigenetic Regulation

• Epigenetics refers to modifications that regulate how genes are expressed without changing DNA sequence.

• Histone modification can activate or repress genes by folding or unfolding chromatin.

• Transcription regulators can bind to DNA and activate or repress genes.

Epigenetics and Stress

This section discusses the relationship between epigenetics and stress, including the impact of histone acetylation and methylation on gene expression.

Histone Acetylation and Methylation

• Histone acetylation, specifically of lysine 27 on histone H3, is associated with increased transcription.

• Bias at elating the histone leads to the unfolding of chromatin and causes upregulation of M glue, which slows down excessive glutamate release. This has been shown to have an antidepressant effect.

• Histone deacetylase inhibitors block degradation and have a rapid effect on depressive-like behavior.

• Stress applied to an animal produces different patterns of gene expression depending on whether it is a naive animal, a chronically stressed animal, or a recovered animal. Even though there appears to be reversibility of dendritic shrinkage when stress ends, the patterns of gene expression are distinctly different.

Methylation of Lysine 9 on Histone H3

• An acute restraint stress in a naive animal causes a huge increase in the methylation trimethylation of histone H3 throughout the hippocampus.

• The DNA that is trapped and not able to do its job includes transposons and retrotransposons as well as structural genes. Some transposon-like elements produce regulatory RNAs whose expression is decreased by this.

• With repeated stress or aging, this repression is lost. One question is whether this leads to genomic instability.

Conclusion

Epigenetic changes play an important role in how animals respond to stress. Stress can cause changes in histone acetylation and methylation, which can lead to changes in gene expression. These changes are not always reversible and may have long-term effects on an animal's ability to adapt to stress.

Glucocorticoid Receptors and Their Actions

This section discusses the different actions of glucocorticoid receptors in the nucleus and mitochondria, as well as their role in regulating calcium balance and protecting against free radical damage. It also covers how high doses of glucocorticoids can endanger cells and stimulate the release of glutamate.

Glucocorticoid Receptors in Nucleus and Mitochondria

• Glucocorticoid receptors work synergistically with other transcription factors to activate transcription factors like CREB.

• They can also translocate into mitochondria where they regulate calcium balance.

• Physiologic levels of glucocorticoids promote calcium reuptake and protect against free radical damage.

• High doses of glucocorticoids have the opposite effect, causing increased levels of free radicals which can endanger cells.

Release of Glutamate

• Glucocorticoids directly activate the release of glutamate through a membrane-associated mineralocorticoid receptor.

• They also stimulate the production of endocannabinoids which act on presynaptic cb1 receptors to inhibit the release of glutamate.

• Some cells have specialization of cb1 receptors on gaba cells so they're inhibiting the release of gaba which allows excitatory tone to increase.

Dose Response Curve

• The dose response curve for glucocorticoids is inverted U-shaped.

• Low doses improve excitability and memory while higher doses inhibit excitability and impair certain kinds of memory.

Effects on Brain Plasticity

This section discusses how repeated stress affects brain plasticity, including suppression of neurogenesis, dendritic remodeling, and adaptive plasticity. It also covers how traumatic events can cause damage and lead to anxiety or depressive disorders.

Effects of Repeated Stress

• Repeated stress leads to suppression of neurogenesis, dendritic remodeling, and adaptive plasticity.

• Traumatic events such as head trauma, stroke, or seizures can cause damage by working together with glucocorticoids and excitatory amino acids.

• Brain aging also causes loss of resilience which may lead to anxiety or depressive disorders.

Hippocampus

• The human hippocampus becomes smaller with time in major depression, type 2 diabetes, chronic PTSD, and Cushing's disease.

• Correction of hypercortisolism can partially reverse the effects on the hippocampus.

• Chronic stress from chronic jetlag, lack of exercise, and chronic inflammation also cause the hippocampus to become smaller.

Effects of Sleep Deprivation on Brain Function

This section discusses the physiological effects of short-term and long-term sleep deprivation on brain function, including inflammation, metabolic dysregulation, elevated cortisol levels, and impaired cognitive function.

Physiological Effects of Sleep Deprivation

• Short-term and long-term sleep deprivation can lead to increased blood pressure, decreased parasympathetic tone, elevated levels of cortisol in the evening along with glucose and insulin which can lead towards a metabolic syndrome-like state.

• Chronic sleep deprivation can cause inflammation and metabolic dysregulation leading to chronic pain or migraines. It also leads to an increase in appetite for comfort foods, depressed mood, and impaired cognitive function.

• Regular exercise increases hippocampus size and improves memory. Exercise is one of the best treatments for moderate depression. Elderly couch potatoes who walked an hour a day five out of seven days a week showed an increase in hippocampal volume over six months to a year.

Hormonal Communication Between Periphery and Brain

• Metabolic hormones like leptin produced by fat growlin produced by the gut igf-1 produced by the liver insulin produced by the pancreas are all transported in the brain. The hippocampus being a target for these hormones.

• Leptin and insulin resistance resulting from metabolic syndrome can impair pro-cognitive effects on this brain area. Blocking systemic levels of IGF-1 prevents exercise from increasing neurogenesis.

Effects of Chronic Stress on Brain Architecture

This section discusses how chronic stress affects brain architecture in areas such as the amygdala, prefrontal cortex (PFC), and hippocampus. It also explains how changes in architecture can alter the activity of these brain areas and their relationship to each other.

Effects of Chronic Stress on Brain Architecture

• Chronic stress causes dendritic debranching in the medial prefrontal cortex and hippocampus. In contrast, there is an expansion of dendrites in the basal lateral amygdala and orbital frontal cortex.

• An overactive amygdala and underactive PFC are associated with signs of early cardiovascular disease because of overactivity of the sympathetic nervous system and time glucocorticoid deprivation.

• Overactivity of the amygdala is associated with anxiety and depression. Effective treatment for chronic anxiety can reduce amygdala volume.

Effects of Chronic Stress on Anxiety

This section discusses how chronic stress affects anxiety levels in animals, including rats and mice.

Effects of Chronic Stress on Anxiety

• Animals become more anxious when exposed to chronic stress. For example, if you take a rat or mouse and put it into a bag with a breathing hole to take a blood sample from the tail over ten days, the animal develops more spine synapses on basolateral neuron dendrites.

The Protective Effect of Glucocorticoids

This section discusses the protective effect of glucocorticoids against PTSD and cognitive rigidity.

Glucocorticoids and PTSD

• Elevating glucocorticoids even modestly at the time of acute stress can prevent PTSD.

• People vulnerable to PTSD have low normal levels of glucocorticoids.

• Maintaining high levels of glucocorticoids during surgery in people with low normal levels reduces PTSD-like symptoms.

• Giving glucocorticoids to people who had a car accident and were taken into the emergency room could reduce PTSD symptoms.

Glucocorticoids and Cognitive Flexibility

• High perceived stress reduces cognitive flexibility and functional connectivity within a circuit that involves the prefrontal cortex.

• Changes in cognitive flexibility are reversible after a vacation.

• Chronic circadian disruption causes obesity, insulin resistance, leptin resistance, dendritic shrinkage, and cognitive rigidity in animals.

Cognitive Aging

This section discusses how chronic stress affects cognitive aging.

Dendritic Shrinkage Recovery

• In young animals, there is full recovery of dendritic length and branching after three weeks of recovery from chronic stress.

• In middle-aged animals (12 months old), there is only partial recovery even though there's the same amount of dendritic shrinkage as in a 20-month-old animal.

• Cognitive aging is a question that arises from the partial recovery of dendritic shrinkage.

Protecting Against Cognitive Aging

• Treating animals with Rallos all, which promotes glutamate uptake, protects animals starting at ten to fourteen months of age that showed impaired memory functions by essentially protecting them from cognitive aging.

• In young animals, clustered thin spines increase communication between different cells and are part of new young spines that were absent in old animals that had not been treated with Rallos all but were present in older animals that were treated with Rallos all.

• Ongoing study to see if Rallos all has a benefit for people with early abilities which also seems agents.

Gender Differences

This section discusses gender differences in chronic stress effects.

Hippocampal Shrinkage

• Female animals did not show the hippocampal shrinkage that males did with chronic stress.

Dendritic Shrinkage

• Rebecca Schinsky found that in females we could not see the shrinkage of dendrites that we could see in males after chronic stress.

Retrograde Tracing

• Using retrograde tracing from the amygdala to the prefrontal cortex determined that these neurons would

Sex Differences in the Brain

This section discusses how sex differences in the brain can affect neural functions and behavior.

Estrogens and Synaptic Connections

• Estrogens promote spine synapse formation in the hippocampus, prefrontal cortex, hypothalamus, and possibly other brain regions.

• Genetic sex and the presence or absence of estrogens interact to affect synaptic connections.

• The whole brain expresses receptors for steroid hormones such as estrogen, progestin, spoofer corticoids, and androgens.

Neural Functions Affected by Sex Hormones

• Attention, memory, motor coordination, pain sensitivity are some of the neural functions affected by sex hormones.

• Men and women perform many tasks equally well but use different strategies and parts of the neural architecture.

Early Life Influences on Health

This section discusses how early life experiences can have lasting effects on health outcomes.

Importance of Early Life Experiences

• Early life experiences can have a lasting influence on what happens later in life.

• Low socioeconomic status results in marked differences in language skills which have effects over the life course.

• Chaos in the home results in greater helplessness and distress.

Effects of Early Life Adversity

• Animals bred to be more anxious died 200 days sooner than less anxious animals.

• Early life adversity can result in obesity, elevated blood pressure, increased cardiovascular reactivity, and poor dental health.

• Risky families may not involve outright abuse but lack of attachment and unsupportive environments.

The transcript is incomplete and some parts are missing context.

Adverse Childhood Experiences (ACEs)

This section discusses the impact of adverse childhood experiences on health outcomes later in life.

ACE Score and Associated Disorders

• The ACE score is a measure of the number of adverse childhood experiences an individual has had.

• A higher ACE score is associated with an increased risk for heart disease, smoking, obesity, drug abuse, high-risk behavior, depression, anxiety, anger control issues, and social problems.

Biological Embedding

• Adverse childhood experiences can lead to biological embedding.

• Methylation of cytosine residues is one epigenetic factor that has been recognized as playing a role in this process.

• Studies have shown that individuals with a history of early life abuse have lower methylation on the glucocorticoid receptor promoter. This means that fewer glucocorticoid receptors are expressed and they are less able to do their adaptive functions.

Inflammation

• Early life abuse is associated with an increase in inflammatory markers such as fibrinogen CRP and white blood cell count.

• Harsh language used by parents was associated with an increasing frequency of inflammatory markers such as IL-6.

• Sympathetic activation without adequate parasympathetic activity can turn on the inflammatory response in white blood cells.

Interventions

• Physical activity has beneficial effects on mental health and aging.

• Mindfulness-based stress reduction can decrease anxiety and reduce amygdala volume and activity.

• Programs like the Experience Corps, which involve elderly volunteers working in schools, can improve executive function and overall health.

• Antidepressants like Prozac may increase the possibility of plasticity but targeted behavioral interventions are necessary for change.

• Caloric restriction and corticosterone can simulate bilaterally and get a binocular vision.

Mechanisms of Natural Plasticity

In this section, the speaker discusses how natural plasticity works in the brain and how it can be influenced by glucocorticoids.

Glucocorticoids and Motor Learning

• The formation and disappearance of spines synapses can be seen over 24 hours using a tiny dose of dexamethasone that shuts off the faucet in the pituitary but doesn't get into the brain.

• Motor learning is most efficient during certain times of day when glucocorticoid levels are elevated.

• Elevating glucocorticoids at the wrong time or inhibiting them during this active period can prevent or slow down motor learning.

Potential for Using Natural Plasticity

• The adult brain shows plasticity, which suggests potential for using it for our benefit.

• Collaborators were responsible for the work and many of the ideas presented.

Genes and Their Effects on Health

In this section, the speaker discusses genes that affect health outcomes and how they interact with environmental factors.

11 Hydroxy Steroid Dehydrogenases

• There are two forms of 11 hydroxy steroid dehydrogenases: one favors removal of hydrogen to generate cortisone from cortisol, while another causes reverse.

• Overexpression of eleven HSD one in liver or fat creates metabolic syndrome and liver damage.

• Removing this gene from the brain slows aging.

Orchid vs Dandelion Phenotypes

• Certain genes may lead to different outcomes depending on environment.

• The orchid phenotype is very sensitive to both negative or positive experiences, while the dandelion phenotype is tough but doesn't necessarily lead to great heights or sinking to lows.

RNA and Its Role in the Brain

In this section, the speaker discusses RNA and its role in the brain.

• The role of microRNAs in survival and translation is one example of RNA's function.

• RNAs produced by retrotransposons may have roles beyond replicating viruses.

• More research is needed in this area.

The HPA Response and Stress

This section discusses the HPA response and how it is regulated by various factors, including glucocorticoids, circadian rhythms, and metabolic elements. It also explores how an individual's sense of self-esteem and ability to control things can affect their response to stress.

Regulation of the HPA Response

• The HPA response is regulated by various factors, including glucocorticoids, circadian rhythms, and metabolic elements.

• Glucocorticoids do not act as a thermostat to turn off the ACTH response. Instead, it is neurologically mediated on and off.

• Circadian priming leads to efficient turn on and turn off of the HPA response.

• Metabolic elements like sugar load also play a role in determining the turning on and turning off of the HPA response.

Self-Esteem and Control in Response to Stress

• An individual's sense of self-esteem and ability to control things can affect their response to stress.

• Good neural mechanisms for controlling stress and good self-esteem can lead to positive outcomes when facing challenges.

• People with low self-esteem may react differently to challenges due to past negative experiences.

• Low self-esteem has been linked with a smaller hippocampus which may be involved in regulating cortisol levels.

• Chronic inflammation associated with early adverse life experiences can be seen even in children as young as 12 years old.

Early Adverse Life Experiences

This section discusses how early adverse life experiences can affect an individual's health and well-being, including their dental health and risk for inflammation.

Dental Health

• Poor dental health has been associated with early adverse life experiences.

• Chronic inflammation associated with early adverse life experiences can lead to obesity, metabolic syndrome, and other conditions.

Burnout in High-Stress Professions

This section discusses burnout in high-stress professions and how it can affect the HPA response.

Burnout

• Burnout is a condition that affects individuals in high-stress professions such as teachers, dentists, nurses, and surgical recovery rooms.

• Burnout tends to level out the HPA response, leading to depressive symptoms.