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. brainn. • 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. mindn. • 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 (Gage’s 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

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. 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 4 Criteria for Abuse 7 Criteria for Dependence

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 (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.

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