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When Good Brains Go Bad Behavior and Disease: Depression and Addiction

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Title: When Good Brains Go Bad Behavior and Disease: Depression and Addiction


1
When Good Brains Go BadBehavior and Disease
Depression and Addiction
  • SHP Neurobiology of Development and Disease

The Scream by Edvard Munch
2
Brain vs Mind
Mind Blowing by Nicolas Cann
  • To what extent does your brain determine who you
    are?
  • Your personality.
  • Your individuality.
  • Your desires.

3
  • brain     n.
  • 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.
  • A functionally similar portion of the
    invertebrate nervous system.
  • Intellectual ability mind a dull brain a quick
    brain.
  • Intellectual power intelligence. Often used in
    the plural has brains and good looks. See
    Synonyms at mind.
  • A highly intelligent person.
  • The primary director or planner, as of an
    organization or movement. Often used in the
    plural.
  • The control center, as of a ship, aircraft, or
    spacecraft.

From www.dictionary.com
4
  • mind     n.
  • The human consciousness that originates in the
    brain and is manifested especially in thought,
    perception, emotion, will, memory, and
    imagination.
  • The collective conscious and unconscious
    processes in a sentient organism that direct and
    influence mental and physical behavior.
  • The principle of intelligence the spirit of
    consciousness regarded as an aspect of reality.
  • The faculty of thinking, reasoning, and applying
    knowledge Follow your mind, not your heart.
  • A person of great mental ability the great minds
    of the century.
  • Individual consciousness, memory, or
    recollection I'll bear the problem in mind.
  • A person or group that embodies certain mental
    qualities the medical mind the public mind.
  • The thought processes characteristic of a person
    or group psychological makeup the criminal
    mind.
  • Opinion or sentiment He changed his mind when he
    heard all the facts.
  • Desire or inclination She had a mind to spend
    her vacation in the desert.
  • Focus of thought attention I can't keep my mind
    on work.
  • A healthy mental state sanity losing one's
    mind.

From www.dictionary.com
5
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 (Gages Physician)

6
We will address the development/adaptation and
pathogenesis of two behaviors
  • Anxiety
  • Addiction

7
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

8
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,
    anxiety-provoked memories of trauma
  • Obsessive-compulsive disorder anxious obsessions
    and anxiety-reducing compulsive behaviors

Gordon and Hen, 2004
9
(No Transcript)
10
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)

11
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.

12
Basal Anxiety is Determined During a Critical
Period in Development
Rescue of serotonin receptor in early development
rescues anxiety phenotype in knockout animals
13
Three Classes of Drugs are Used to Treat
Anxiety/Depression
14
Anxiolytic Mechanisms
15
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

16
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
17
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
18
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
19
X-ray Ablation of Neurogenesis in the Dentate
Gyrus
Santarelli et al, 2003
20
Addiction
21
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

22
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

23
4 Criteria for Abuse
7 Criteria for Dependence
  • 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
  • Recurrent use resulting in a failure to fulfill
    the main obligations at work, school or home
  • Recurrent substance-related 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

24
The Circuits of Motivation
  • 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
    (Parkinsons 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.

25
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
26
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
27
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
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