Symptoms of Depression Can’t feel joy – Anhedonia ◦ Usually withdraws from these activities Too little / Too much sleep ◦ Fatigue Cognitive problems ◦ Can’t concentrate Feelings of guilt or worthlessness Suicide

People in the US who.. Currently have major depression ◦ 1 in 20 Will have major depression in their life ◦ 1 in 5 Kessler 2005

Animal tests

Learned Helplessness Models (how long did it take them to stop moving?) F orced S wim T est T ail S uspension T est (Sleepy, not dead)

Motivation / Reward Models (Doing less of what you used to do) Sucrose Preference Social Avoidance Sexual Preference

Brain structure change Decrease in size of ◦ Hippocampus  Cognition & learning ◦ Pre Frontal Cortex ?  Emotional control  Decision making Amygdala (mixed results)  Emotional learning  Most don’t see any change

Physiological causes

Serotonin + Norepinephrine + Dopamine

Brain Derived Neurotrophic Factor (BDNF) “brain food” Neuropeptide

Brain Derived Neurotrophic Factor (BDNF) In depressed individuals ◦ Dereased  Hippocampus  Prefrontal Cortex ◦ Increased  Ventral Tegmental Area  Nucleus Accumbans

Hypothalamic – Pituitary – Adrenal axis System which controls stress responses

Genetic Depression is heritable All the mentioned systems have mutations Having genetics that make you prone to depression doesn’t mean you will have it….

Epigenetics ‘the study of changes in genome function that occur without a change in DNA sequence‘ “DNA is just a tape carrying information, and a tape is no good without a player. Epigenetics is about the tape player.”

What will you find in the papers? DNA ◦ Methylation  On the Cytosine at CpG sites  Inhibits gene expression

Methyl Group DNA methyl Transferase DNA Demethylase?

What will you find in the papers? Proteins ◦ Methyl cytosine binding protein (MeCP)  Bind methylated cytosine  Further repression

What will you find in the papers? Histones ◦ Acetylation  Increases expression ◦ Methylation  Usually decreases expression  Lysine 4 – activates  Lysine 9 – inhibits  Lysine 27 - inhibits

Methyl groups Acetyl groups Histone Deacetylase (HDAC) Histone Demethylase (HDM) Histone Acetyltransferase (HAT) Histone Methyltransferase (HMT)

The End was that so bad?

Active DNA demethylation. Wolffe A P et al. PNAS 1999;96: ©1999 by National Academy of Sciences