3.3 Unraveling the neurobiology of stress-induced reward seeking

What is meant by fight or flight?

A fast response of the body to acute danger involving the sympathetic nervous

system.

What does the fight or flight response induce?

Stress

What is stress?

A non-specific response of the body to any demand for change.

What is another word for stimulus (in terms of stress)?

Stressor

How is the body made prepared for a fight or flight response?

The stress hormones (nor)adrenaline and dopamine are delivered to the body by the midbrain and hypothalamus. These hormones travel by blood, relatively quickly to the rest of the body.

What happens when the hypothalamus is made active by a stressor?

Glucocorticoids (cortisol) are released.

Where does cortisol work?

The entire body, even the brain because it can pass the BBB.

What does cortisol make possible?

Energy recovery

Why is cortisol slow(er)?

Because it has an effect on recovery.

What has nothing to do with the first reaction in the stress response?

HPA-axis

What happens to the hunger of a person when a stressor is present?

The sympathetic nervous system is activated, which leads to suppression of hunger. Then, the HPA-axis will become active which increases the hunger to get energy from the first reaction back.

What is the name for glucocorticoids signaling through (brain) in humans and rodents?

• Humans: cortisol

• Rodents: corticosterone

What is the difference between mineralocorticoid (MR) an glucocorticoid receptors (GR)?

• MR = Mini Reactie → actief bij lage cortisol (basale toestand)

• GR = Grote Reactie → actief bij hoge cortisol (stress)

What leads to the resistance in animals when presented something nicely? And which has the largest effect?

• Corticosterone (more effective)

• ACTH (less effective)

What did the outcome of the trier social stress test suggest?

High-stress responders eat more fat & sugar.

How did the trier social stress test work?

Humans had to give a presentation in an unpleasant environment. During this experiment their cortisol levels were measured. There are two groups: low reactors and high reactors. After the presentation they were exposed to food, and it was visible that the high reactors eat more fat/sugar than the low reactors.

When do scarce resources / energy taxing stressors come in handy and why?

In the wild, because it can solve the energy deficiency quickly.

What is the effect of abundant food sources / sedentary stress?

The body responds to stress as if there is danger, but the humans are not. Moreover, the humans have a lot of food to their order. Therefore, humans eat too much and do not move often.

Why are abundant food sources / sedentary stress a problem for vulnerable individuals?

It can lead to (binge) eating disorders and/or overweight/obesity.

Which eating disorders are defined by the DSM-5?

• Boulimia Nervosa (BN);

• Binge Eating Disorder (BED);

• Anorexia Nervose (AN), binge/purge subtype (b/p).

Why do patients with an ED end up in a circle of stress and food

A lot of ED’s are triggered by stress, but it can also lead to negative feelings and stress.

What is an overlapping element in all the ED’s?

Binge eating

What is needed in order to help assigning a function to different parts of the brain?

Techniques with a high resolution

What are limitations to fMRI?

• It only gives a general image;

• Voxel still has cells with different functions;

• The temporal resolution is bad.

What is correlated with increased emotional eating?

Higher connectivity between hypothalamus and midbrain.

Where does VTA-activity lead to?

LHA-activity; there is a strong connection between the two.

What are the 3 different cell types in VTA and LHA?

• Gabaergic;

• Glutamergic;

• Dopamergic.

How can we model stress-driven eating in mice?

Social stress in a mouse is induced by placing a small mouse with a large mouse.

What was the outcome of the study of stress-driven eating in mice?

Social stress drives palatable food choices; social stress makes the mice eat more fat/sugar, so not necessarily more food in general. They eat more calorie-rich food.

What are the principles of calcium imaging?

More fluorescence = more calcium = more activity.

What are the 3 steps in the mechanism of action of calcium imaging?

• Action potentials drive intracellular Ca2+;

• Binds to a Ca2+ indicator (GCaMP);

• Emits fluorescence.

Why do virally expressive techniques offer flexibility?

• You can pick the direction (anterogade/retrogade)';

• Cell specificity.

What kind of change takes place during social stress?

LHAglu → VTA

How can calcium levels of specific neurons be measured in transgenic mouse?

Administering a virus with GCaMP.

What causes more plasticity?

During stress there is a lot of activity between neurons of the hypothalamus and VTA. This can be measured in vivo.

How can VTA-LHA connection strength be measured?

AAV with channelrhodopsin is placed in the LHA. When lights shines on it, these channels/proteins will let sodium (Na2+) through. The neurons with these channels will thus become active during stimulation with blue light.

How can the activity of the neurons be researched?

With the use of electrophysiology by administering electric signals to a brain slice.

What does stress lower?

Stress lowers LHA -> VTA DA I/E balance

What is important to understand when researching what’s happening in the dopamergic neuron?

The balance between GABA and glutamate.

Where does the balance between GABA and glutamate move towards during stress?

Glutamate

What is thus the outcome of social stress (in terms of balance between GABA and glutamate)?

It causes a shift in GABa/AMPA receptors and plasticity.

What does the GR agonist strengthen?

LHAglu → VTAda synapses and feeding.

How can the increase in food intake, caused by LHAglu → VTAda, synapses be researched?

The reinforced synapses are imitated by to see if it leads to an increase in food intake. By administering a stress hormone (glucocorticoid) to non-stressed animals, it was visible that the LHA → VTA connection became stronger. This leads to an increase in fat food.

How can you weaken the connection between LHA and VTA?

By stimulating it with low frequencies.

How can you see if weakening LHAglu → VTAda synapses have an impact on stress-driven food choices?

By weakening the connection between LHA → VTA,and weakening the neurons in vivo to look ad the food intake. The stress mice started eating more fat food, but the effect is less strong when the synapses are are not weakened beforehand.