NEUROBIOLOGY OF (MAL)ADAPTATION
I. INTRODUCTION – B. Roozendaal
Learning goals
• Understand the concept of stress, and the neuroanatomical basis of stress biology.
• Explain the impact of stressful experiences during early development on brain programming
and later responding to threatening situations in adulthood.
• Explain genetic and environmental factors contributing to individual differences in the
perception, appraisal and coping style to threatening situations.
• Distinguish different levels of analysis in research into effects of stress on brain function,
ranging from molecule to population and from basic neuroscience to clinical practice.
• Understand how fundamental, translational, and clinical research into cognitive and neural
(mal)functions is performed and can help to explain and advance diagnosis and treatment
of stress-related psychopathology.
• Evaluate and explain scientific literature in this field.
Content
• 12 lectures
o For each lecture there are one or more (review/background) articles -> These papers are
a part of the exam when teachers talk about those in their lecture
o Written exam (6 short exam questions, 1 per teacher)
• Two workshops
o Brain explorer: the Allen Brain Atlas
o Human stress test development
• One seminar: Report
• Final grade: written exam (6/8), workshop (1/8) and seminar (1/8)
I. BIOPHYSIOLOGY OF EMOTION, STRESS AND HEALTH
– B. Roozendaal
Confusing concepts
• Stress and emotion are ill-defined concepts and used rather loosely in the scientific
literature
• Stress elicits emotions, but is an emotional response (behavior, physiology) always a stress
response?
Emotion: definition
• An emotion is a particular subjective state or feeling, a quality of conscious awareness
and a way of responding accompanied by physiological arousal.
• Emotions may have positive or negative affect/hedonic valence.
– Examples:
o Fear/anxiety
o Sadness/grief
o Anger/aggression
o Hate
o Frustration
o Love/devotion
, o Hope
o Joy/happiness
• Emotional behavior (e.g. Observable motor patterns)
• Emotional response (e.g. Measurable physiological indices)
The expression of emotions
• Emotional related facial expression
o Not only humans, but also animals
• In 1872, Darwin wrote The Expression of Emotions in Man and Animals
o Made apparent the absolute relevance of studying emotion in animal models
o Laid out idea that autonomic responses are an intrinsic part of emotional experience
• The peripheral skeletomotor, and autonomic aspects of emotion serve important functions
in communication with others and in preparation for behavioral responses
The bodily emotional arousal/stress reactions - Fight-flight-freeze
response
Adaptive fight-flight response to a predator
• Hypothalamus activates sympathetic division of nervous system
• Heart rate, blood pressure and respiration increase
• Adrenal medulla secretes epinephrine and norepinephrine
• Blood flow to skeletal muscles increases
• Stomach contractions are inhibited
Walter B. Cannon (1871-1945)
• Homeostasis concept: The regulation of physiological variables to maintain a stable
internal environment, where deviations from preferred set points are counteracted to
restore balance by physiological responses
• Fundamental role of the Sympathetic Nervous and Adrenomedullary System (Adrenaline)
• Fight/Flight response – SAM system
o Rapid, immediate stress response activated by the hypothalamus
which stimulates the sympathetic nervous system. The adrenal
medulla release adrenaline and noradrenaline, leading to
increased heart rate, blood pressure, accelerated breathing and
energy mobilization
• Selfregulation – return to baseline (The wisdom of the body)
Philip Bard (1898-1977)
• Conducted studies using serial transections to disconnect the
cerebral cortex from outflow pathways in cats
• When transection included the forebrain (cerebrum, thalamus and
hypothalamus) (B), cats exhibited a range of behaviors characteristic
of rage (woede) when presented with innocuous stimuli
o These behaviors included: arching of the back, extension of
claws, hissing, splitting, pupil dilation and increased blood
pressure, heart rate and adrenal secretion
• Presence of these responses depended on an intact connection to
the hypothalamus. When the hypothalamus was disconnected from
the brainstem, these responses were no longer observed (A).
, o Critical role of the hypothalamus in generating autonomic and behavioral
responses.
o Critical role of the prefrontal cortex to have an inhibitory influence on different brain
regions like the hypothalamus, helping to regulate emotional responses
▪ Similar to the well-known case of Phineas Gage, where damage to the prefrontal
cortex resulted in impaired emotional control due to a lack of inhibition over
subcortical structures like the hypothalamus
Hans Selye (1907-1982)
• Introduced the term stress
• The word stress comes from Italian, and it means that there is
friction
• Stress is the non-specific response of the body to any noxious
stimulus or demand.
o So, the stimulus in not necessarily the stressor, but the body
response is stress.
• General Adaptation Syndrome (GAS): alarm (flight/fight), resistance (adapt/restore its
normal functions) and exhaustion (resources depleted & unable maintain normal functions)
• HPA-system as the main hormonal mediator of stress
o Slower, prolonged stress response. The hypothalamus releases CRH, stimulating the
anterior pituitary gland to produce ACTH, which triggers the adrenal cortex to release
cortisol, which results in physiological changes supporting
flight-or-fight responses.
The two main physiological emotional response pathways
• Nervous system (SAM axis) plays a crucial role in immediate
reaction to stress
• HPA axis is more important for chronic stress responses and
restoring homeostasis after stress
James-Lange theory of emotion (somatic theory of emotional
response)
• Emotion has two components: feeling and physiological response
• James-Lange suggested: Do we run from a bear because we are
afraid or are we afraid because we run? / Is feeling influencing
response or is response influencing how we feel?
• He suggested that after a stimulus, we first experience behavioral
responses (e.g., running), which then trigger physiological
(endocrine) and emotional responses. This would imply that "we
are afraid because we run."
• He suggested that after a stimulus, you first get behavioral
responses, which causes next the rest of the responses (the
endocrine system e.g.) and emotional responses. So, this would
mean that ‘because we run away from the bear, we become afraid’
o Physiological responses are essential in inducing the feeling
Theories of emotion
• Common-Sense View: Perception of bear -> Feeling of fear -> Physiological reactions
• James-Lange View: Perception of bear -> Physiological reactions -> Feeling of fear
• Cannon-Bard View: Feeling of fear <- Perception of bear -> Physiological reactions
, o If psychological response would determine how you feel, then for
every emotion you should have a different psychological response.
But both when you are in love or afraid you make an increasing
heart rate. -> Psychological response and feeling are independent
of each other
• Modern Biopsychological View: All the theories are correct -> The
perception of the bear can cause both responses and feeling of fear.
But also feeling of fear can cause physiological reactions and vice
versa.
o Communication between those two systems
o Physiological reaction can directly change the feeling by stress
hormones by entering the brain
o Feeling or physiological reaction can change the perception -> If
you afraid for the bear, the bear looks larger-> Way you see things is
also determined by the way you feel
Target organs of stress hormones
• Brain
o Neuroendocrine receptor mechanisms
o Neurotransmitter systems
▪ Serotonin: Mood
▪ Noradrenaline: Alertness/Stress
▪ Dopamine: Motivation
• Periphery
o Cardiovascular system
o Immune system
Steroid hormones talk back to the brain: negative/positive feedback regulation
• HPA-axis: CRH -> ACTH -> glucocorticoids -> brain
o Cortisol receptors are distributed throughout
the brain, particularly in regions involved in
stress and emotion
• Glucocorticoids provide negative feedback to
the brain and all other steps in the HPA axis
o Hippocampus and prefrontal cortex provide
negative feedback
• Amygdala provide positive feedback, enhancing
the stress response
• → Control how much cortisol is released
Limbic system
• In 1937, Papez proposed that the part of the cortex
dedicated to processing emotion is the limbic lobe,
as defined by Broca.
• Limbic lobe comprises a ring of ‘primitive’ cortex
around the brainstem, including the cingulate cortex,
the parahippocampal gyrus, and the hippocampal
formation
• Hypothalamus important for expression of emotion and cingulate cortex important for
feeling / emotion experience
o Expression influence feeling and vice versa
I. INTRODUCTION – B. Roozendaal
Learning goals
• Understand the concept of stress, and the neuroanatomical basis of stress biology.
• Explain the impact of stressful experiences during early development on brain programming
and later responding to threatening situations in adulthood.
• Explain genetic and environmental factors contributing to individual differences in the
perception, appraisal and coping style to threatening situations.
• Distinguish different levels of analysis in research into effects of stress on brain function,
ranging from molecule to population and from basic neuroscience to clinical practice.
• Understand how fundamental, translational, and clinical research into cognitive and neural
(mal)functions is performed and can help to explain and advance diagnosis and treatment
of stress-related psychopathology.
• Evaluate and explain scientific literature in this field.
Content
• 12 lectures
o For each lecture there are one or more (review/background) articles -> These papers are
a part of the exam when teachers talk about those in their lecture
o Written exam (6 short exam questions, 1 per teacher)
• Two workshops
o Brain explorer: the Allen Brain Atlas
o Human stress test development
• One seminar: Report
• Final grade: written exam (6/8), workshop (1/8) and seminar (1/8)
I. BIOPHYSIOLOGY OF EMOTION, STRESS AND HEALTH
– B. Roozendaal
Confusing concepts
• Stress and emotion are ill-defined concepts and used rather loosely in the scientific
literature
• Stress elicits emotions, but is an emotional response (behavior, physiology) always a stress
response?
Emotion: definition
• An emotion is a particular subjective state or feeling, a quality of conscious awareness
and a way of responding accompanied by physiological arousal.
• Emotions may have positive or negative affect/hedonic valence.
– Examples:
o Fear/anxiety
o Sadness/grief
o Anger/aggression
o Hate
o Frustration
o Love/devotion
, o Hope
o Joy/happiness
• Emotional behavior (e.g. Observable motor patterns)
• Emotional response (e.g. Measurable physiological indices)
The expression of emotions
• Emotional related facial expression
o Not only humans, but also animals
• In 1872, Darwin wrote The Expression of Emotions in Man and Animals
o Made apparent the absolute relevance of studying emotion in animal models
o Laid out idea that autonomic responses are an intrinsic part of emotional experience
• The peripheral skeletomotor, and autonomic aspects of emotion serve important functions
in communication with others and in preparation for behavioral responses
The bodily emotional arousal/stress reactions - Fight-flight-freeze
response
Adaptive fight-flight response to a predator
• Hypothalamus activates sympathetic division of nervous system
• Heart rate, blood pressure and respiration increase
• Adrenal medulla secretes epinephrine and norepinephrine
• Blood flow to skeletal muscles increases
• Stomach contractions are inhibited
Walter B. Cannon (1871-1945)
• Homeostasis concept: The regulation of physiological variables to maintain a stable
internal environment, where deviations from preferred set points are counteracted to
restore balance by physiological responses
• Fundamental role of the Sympathetic Nervous and Adrenomedullary System (Adrenaline)
• Fight/Flight response – SAM system
o Rapid, immediate stress response activated by the hypothalamus
which stimulates the sympathetic nervous system. The adrenal
medulla release adrenaline and noradrenaline, leading to
increased heart rate, blood pressure, accelerated breathing and
energy mobilization
• Selfregulation – return to baseline (The wisdom of the body)
Philip Bard (1898-1977)
• Conducted studies using serial transections to disconnect the
cerebral cortex from outflow pathways in cats
• When transection included the forebrain (cerebrum, thalamus and
hypothalamus) (B), cats exhibited a range of behaviors characteristic
of rage (woede) when presented with innocuous stimuli
o These behaviors included: arching of the back, extension of
claws, hissing, splitting, pupil dilation and increased blood
pressure, heart rate and adrenal secretion
• Presence of these responses depended on an intact connection to
the hypothalamus. When the hypothalamus was disconnected from
the brainstem, these responses were no longer observed (A).
, o Critical role of the hypothalamus in generating autonomic and behavioral
responses.
o Critical role of the prefrontal cortex to have an inhibitory influence on different brain
regions like the hypothalamus, helping to regulate emotional responses
▪ Similar to the well-known case of Phineas Gage, where damage to the prefrontal
cortex resulted in impaired emotional control due to a lack of inhibition over
subcortical structures like the hypothalamus
Hans Selye (1907-1982)
• Introduced the term stress
• The word stress comes from Italian, and it means that there is
friction
• Stress is the non-specific response of the body to any noxious
stimulus or demand.
o So, the stimulus in not necessarily the stressor, but the body
response is stress.
• General Adaptation Syndrome (GAS): alarm (flight/fight), resistance (adapt/restore its
normal functions) and exhaustion (resources depleted & unable maintain normal functions)
• HPA-system as the main hormonal mediator of stress
o Slower, prolonged stress response. The hypothalamus releases CRH, stimulating the
anterior pituitary gland to produce ACTH, which triggers the adrenal cortex to release
cortisol, which results in physiological changes supporting
flight-or-fight responses.
The two main physiological emotional response pathways
• Nervous system (SAM axis) plays a crucial role in immediate
reaction to stress
• HPA axis is more important for chronic stress responses and
restoring homeostasis after stress
James-Lange theory of emotion (somatic theory of emotional
response)
• Emotion has two components: feeling and physiological response
• James-Lange suggested: Do we run from a bear because we are
afraid or are we afraid because we run? / Is feeling influencing
response or is response influencing how we feel?
• He suggested that after a stimulus, we first experience behavioral
responses (e.g., running), which then trigger physiological
(endocrine) and emotional responses. This would imply that "we
are afraid because we run."
• He suggested that after a stimulus, you first get behavioral
responses, which causes next the rest of the responses (the
endocrine system e.g.) and emotional responses. So, this would
mean that ‘because we run away from the bear, we become afraid’
o Physiological responses are essential in inducing the feeling
Theories of emotion
• Common-Sense View: Perception of bear -> Feeling of fear -> Physiological reactions
• James-Lange View: Perception of bear -> Physiological reactions -> Feeling of fear
• Cannon-Bard View: Feeling of fear <- Perception of bear -> Physiological reactions
, o If psychological response would determine how you feel, then for
every emotion you should have a different psychological response.
But both when you are in love or afraid you make an increasing
heart rate. -> Psychological response and feeling are independent
of each other
• Modern Biopsychological View: All the theories are correct -> The
perception of the bear can cause both responses and feeling of fear.
But also feeling of fear can cause physiological reactions and vice
versa.
o Communication between those two systems
o Physiological reaction can directly change the feeling by stress
hormones by entering the brain
o Feeling or physiological reaction can change the perception -> If
you afraid for the bear, the bear looks larger-> Way you see things is
also determined by the way you feel
Target organs of stress hormones
• Brain
o Neuroendocrine receptor mechanisms
o Neurotransmitter systems
▪ Serotonin: Mood
▪ Noradrenaline: Alertness/Stress
▪ Dopamine: Motivation
• Periphery
o Cardiovascular system
o Immune system
Steroid hormones talk back to the brain: negative/positive feedback regulation
• HPA-axis: CRH -> ACTH -> glucocorticoids -> brain
o Cortisol receptors are distributed throughout
the brain, particularly in regions involved in
stress and emotion
• Glucocorticoids provide negative feedback to
the brain and all other steps in the HPA axis
o Hippocampus and prefrontal cortex provide
negative feedback
• Amygdala provide positive feedback, enhancing
the stress response
• → Control how much cortisol is released
Limbic system
• In 1937, Papez proposed that the part of the cortex
dedicated to processing emotion is the limbic lobe,
as defined by Broca.
• Limbic lobe comprises a ring of ‘primitive’ cortex
around the brainstem, including the cingulate cortex,
the parahippocampal gyrus, and the hippocampal
formation
• Hypothalamus important for expression of emotion and cingulate cortex important for
feeling / emotion experience
o Expression influence feeling and vice versa
