Transcript When Good Brains Go Bad Behavior and Disease: Depression

When Good
Brains Go
Bad
Behavior and Disease:
Depression and
Addiction
SHP – Neurobiology of
Development and Disease
The Scream by Edvard Munch
Brain vs Mind
Mind Blowing by Nicolas Cann
To what extent does your brain
determine who you are?
Your personality.
Your individuality.
Your desires.
brain
n.
a. The portion of the vertebrate central nervous system that is enclosed
within the cranium, continuous with the spinal cord, and composed of
gray matter and white matter. It is the primary center for the
regulation and control of bodily activities, receiving and interpreting
sensory impulses, and transmitting information to the muscles and
body organs. It is also the seat of consciousness, thought, memory,
and emotion.
b. A functionally similar portion of the invertebrate nervous system.
c. Intellectual ability; mind: a dull brain; a quick brain.
d. Intellectual power; intelligence. Often used in the plural: has brains
and good looks. See Synonyms at mind.
1. A highly intelligent person.
2. The primary director or planner, as of an organization or movement. Often
used in the plural.
3. The control center, as of a ship, aircraft, or spacecraft.
From www.dictionary.com
mind
n.
1. The human consciousness that originates in the brain and is manifested
especially in thought, perception, emotion, will, memory, and imagination.
2. The collective conscious and unconscious processes in a sentient organism
that direct and influence mental and physical behavior.
3. The principle of intelligence; the spirit of consciousness regarded as an
aspect of reality.
4. The faculty of thinking, reasoning, and applying knowledge: Follow your
mind, not your heart.
5. A person of great mental ability: the great minds of the century.
a. Individual consciousness, memory, or recollection: I'll bear the problem
in mind.
b. A person or group that embodies certain mental qualities: the medical
mind; the public mind.
c. The thought processes characteristic of a person or group;
psychological makeup: the criminal mind.
6. Opinion or sentiment: He changed his mind when he heard all the facts.
7. Desire or inclination: She had a mind to spend her vacation in the desert.
8. Focus of thought; attention: I can't keep my mind on work.
9. A healthy mental state; sanity: losing one's mind.
From www.dictionary.com
Phineas Gage
• On Sept 13, 1848 Gage was working in railroad track
construction outside Cavendish, VT when a tamping
iron, driven by detonation of a blasting charge, passed
through his anterior frontal cortex.
• He regained consciousness within minutes, could
speak and was stable.
• Later, he was reported to suffer from broad personality
changes
“Gage was fitful, irreverent, indulging at times in the grossest profanity (which was not
previously his custom), manifesting but little deference for his fellows, impatient of
restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet
capricious and vacillating, devising many plans of future operations, which are no sooner
arranged than they are abandoned in turn for others appearing more feasible. A child in his
intellectual capacity and manifestations, he has the animal passions of a strong man.
Previous to his injury, although untrained in the schools, he possessed a well-balanced
mind, and was looked upon by those who knew him as a shrewd, smart businessman, very
energetic and persistent in executing all his plans of operation. In this regard his mind was
radically changed, so decidedly that his friends and acquaintances said he was 'no longer
Gage'.”
Dr. J.M. Harlow (Gage’s Physician)
We will address the
development/adaptation and
pathogenesis of two behaviors:
• Anxiety
• Addiction
Anxiety
• Behavioral response that allows individuals to
become aware to dangers in their environment.
• Often genetically linked. An immediate relative
can predispose an individual to an anxiety
condition.
• 25% of all adults will, at one point in their lives,
experience an anxiety condition
• Economic cost of disorder is an estimated $40
million a year
6 Types of Anxiety Disorders
• Panic disorder: unpredictable, intense anxiety
attacks
• Generalized anxiety disorder: excessive worry in
multiple areas
• Social anxiety disorder: fear and avoidance of
social situations
• Specific phobia: intense fear with a specific
trigger (spiders, dark water etc…)
• Posttraumatic stress disorder: intrusive, anxietyprovoked memories of trauma
• Obsessive-compulsive disorder: anxious
obsessions and anxiety-reducing compulsive
behaviors
Gordon and Hen, 2004
Serotonergic Circuit
• Majority of neurons
releasing serotonin
are present in the
Raphe nuclei of the
hindbrain
• Primary site of
innervation is the
limbic system
(hippocampus,
amygdala, entorhinal
cortex,
hypothalamus)
Noradrenergic Brain Circuit
• Norepinephrine producing
neurons lie in the locus
coeruleus
• These neurons project to the
nucleus accumbens and the
hypothalamus, where they
mediate anxiety and arousal,
respectively.
Basal Anxiety is Determined
During a Critical Period in
Development
Rescue of serotonin receptor in
early development rescues
anxiety phenotype in knockout
animals
Three Classes of Drugs are Used
to Treat Anxiety/Depression
Anxiolytic Mechanisms
Mechanism of GABA Agonists
• Barbiturates, benzodiazepines
and GABA have individual
binding sites on the GABA
channel.
• Binding of more than one
ligand at a time can potentiate
opening of the channel 
increased conductance
Using Mice as a
Behavioral Model of
Anxiety
• Mice avoid open, well-lighted areas
and novel environments (where they
may be more vulnerable to predators)
• Starved mice are placed in an open
area with food in the center
• Measure the latency until mouse eats
the food pellet.
• This can be taken as a measurement
of the anxiety of the mouse.
Anxiolytic drugs (like
benzodiazepines) decrease the
latency.
Santarelli et al, 2003
Antidepressant Drugs
Increase Neurogenesis
• Rats are injected with
bromo-deoxyuridine
(BrdU) after treatment
with an antidepressant
drug.
• BrdU is taken up into
proliferating cells and you
can detect these cells by
immunohistochemistry
• These cells can be
quantified for a value of
proliferation in a tissue
under a given
condition/treatment.
Marburg et al, 2000
Control Checklist:
• BrdU is incorporated into
proliferating cells in the
hippocampus and these
develop into neurons
(NeuN positive cells) and
glia (GFAP positive cells)
• Administration of
fluoxetine (F), imipramine
(I), desipramine (D), or
DPAT (5-HT) agonist are
administered
• Neurogenesis increases
with treatment with all
drugs acutely
• Treatment with all drugs
decreases latency to
novelty suppressed
feeding
Santarelli et al, 2003
X-ray Ablation of Neurogenesis
in the Dentate Gyrus
Santarelli et al, 2003
Addiction
Addiction morbidity
• 2 billion alcohol users, 1.3 billion tobacco
users, 185 million users of illicit drugs
(WHO reports)
• In 2001, these catagories contributed to
12.4% of deaths worldwide
Vocabulary
• Addiction: increase in drug-seeking behavior
• Reinforcement: drug enhancing a desire to repeat
the use of the substance in the future
• Dependence: need for continued use of the drug
to avoid withdrawal symptoms
• Withdrawal: physical or motivational
disturbances when consumption of the drug is
ceased
• Tolerance/sensitization: specific effects of the
drug diminish under that same dosage regiment
7 Criteria for Dependence
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The need for markedly increased
amount of the substance to achieve
intoxication or desired effect, or
diminished effect with continued use of
the same amount (tolerance)
Withdrawal syndrome or use of the
substance to relieve or avoid
withdrawal symptoms
One or more unsuccessful attempts to
cut down or control use
Use in larger amount over a longer
period than intended
Important social, occupational or
recreational activities are given up or
reduced because of substance use
A larger amount of time is spent in
activities that are necessary to obtain, to
use or to recover from the effects of the
substance
Continued use despite knowledge of
having persistent or recurrent physical
or psychological problems that are
caused or exacerbated by the substance
4 Criteria for Abuse
• Recurrent use resulting in
a failure to fulfill the main
obligations at work,
school or home
• Recurrent substancerelated legal problems
• Recurrent use in
physically hazardous
situations
• Continued use despite
persistent or recurrent
social or interpersonal
problems that are caused
or exacerbated by the
substance
The Circuits of Motivation
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Circuits for motivation and reward are ancient
and beneficial for the survival of the organism as
it makes them seek out things they need (food,
water, sexual opportunities) and provides a
reinforcement when it has been attained.
Motor motivation has long been known to be
centrally driven by dopaminergic centers
(Parkinson’s Disease).
Damage to specific dopaminergic fibers was
shown to generate feeding and drinking deficits.
Administration of neuroleptics (inhibitors of
dopamine signaling) diminish the animals desire
to seek out food and water.
Identification of the Reward
Circuit
• Olds and Milner in 1954 identify sites in
the brain (lateral hypothalamic and
septal sites) which confer pleasure and
reward
• When electrodes are placed in these
regions, rats will self-stimulate by
pressing a lever.
• Rats pressed the constantly (10,000 per
hour) and, given a choice between
food/water and the stimulation, will
allow themselves to starve to death.
• This self-stimulation is blocked by
administration of the dopaminergic
inhibitor, pimozide.
Wise et al, 2004
Reward Circuit
By repeating the intracranial self-stimulation
experiments in different brain areas (but with drugs
instead of current), the target of a number of drugs of
abuse have been identified
Stimulation of Reward Pathway
Overcomes Aversive Tendencies
• By stimulating the reward
pathway, investigators were able
to make a remote-controlled rat.
• Electrodes are placed into whisker
representations on each side of the
brain and into the nucleus
accumbens
• If stimulation of a whisker
representation is followed by a
stimulation of the nucleus
accumbens, the rats learn to
follow these directions.
• Rats can be controlled in to the
open field and elevated novel
areas without latency