I. Emotion and Affect A. Defining emotions B. Ontogeny of emotion

1. 31:241 Behavioral and Cognitive NeuroscienceProfessor A.K. JohnsonFall 2012OutlineNeurobiology of Mood, Emotion and Mental Illness11/6; 11/13; 11/15 I. Emotion and Affect A. Defining emotions B. Ontogeny of emotion C. Expression and measurement of components of emotion II. Theories of Emotion A. James-Lange B. Cannon-Bard C. Papez-MacLean III. Theories of Stress A. Cannon B. Selye C. Mason D. A contemporary view IV. Stress and Pathophysiology A. Selye's general adaptation syndrome B. Allostasis 241-5.0a

2. Neurobiology of Mood, Emotion and Mental Illness (Continued) V. Neural and Neurochemical Substrates of Fear and Anxiety A. The defense response and the conditioned emotional response (CER) 1. Neural pathways B. Neurochemistry 1. CRH 2. GABA C. Anxiety Disorders D. Somatic disease, stress and the defense response VI. Depression A. Mood disorders introduction B. Epidemiology and genetics of depression C. Physiological and biochemical correlates of depression 1. Autonomic and cardiovascular changes 2. Endocrine and cytokine 3. Biological rhythms - Seasonal affective disorder D. Theories of Depression 1. Biogenic-amine 2. Stress and the brain–pituitary-adrenal dysfunction 3. Sickness behavior, inflammatory cytokines and depressive symptomatology 4. Stress-Impaired neurogenesis E. Antidepressant drugs and electroconvulsive shock 241-5.0b

3. Key Terms and Concepts Median forebrain bundle Monamine oxidase inhibitors (MAOI) antidepressants Nociceptors Nucleus accumbens Panic disorder Papez theory of emotion Periaqueductal gray (PAG) Post-traumatic stress syndrome Simple phobia Social phobia Stress Stress response Stressor Subjective feelings Tricyclic/polycyclic (TCA) antidepressants William James' theory of emotion Anhedonia Allostasis Allostatic load Amygdala Arousal Basic emotions Brain-deprived neurotrophic factor (BDNF) Cannon-Bard theory of emotion Conditioned emotional response (CER) Corticotropic releasing hormone (CRH) or factor (CRF) Defense response Electroconvulsive therapy (ECT) Emotional response General adaptation syndrome (GAS) Generalized anxiety disorder Leukocytes MacLean's visceral brain (limbic system) theory of emotion 241-5 KTC

4. •Surprise•Fear • Interest • Disgust • Joy • Shame • Rage • Anguish • Surprise • Fear • Happiness • Disgust • Anger • Sadness Examples of Lists of Basic Emotions 241-5.1

5. A Scheme Proposed by Bridgesfor the Development of Emotions 241-5.2

6. Types of Emotional Responses Feelings Feelings Emotional Emotional Subjective Action Expression Feelings 241-5.3

7. Darwin's Expression of theEmotions in Man and Animals 241-5.4

8. Commonality of Emotional Expressionin the Faces of Animals and People 241-5.5

9. William James' Theory of Emotion 241-5.6

10. Cannon-Bard Theory of Emotion 241-5.7

11. The Papez Circuit Theory of Emotion 241-5.8

12. MacLean's Visceral Brain(Limbic System) Theory of Emotion 241-5.9

13. Originators and Popularizers of the Concept of Stress W.B. Cannon Hans Selye Cannon (1920's) used the term "stress" to characterize the physical impact of averse stimuli on an organism much as an engineer uses the term stress and strain to characterize the effect of a load placed on steel structures. Selye (1936) used the term stress to account for the generalized physiological response to different averse insults to the body. 241-5.10

14. Evolution of the Concept of Stress 241-5.11

15. Adaptive Effects of the Stress Response  Immediate increase of metabolic fuel  Increased oxygen intake  Optimization of blood flow to key tissues  Inhibition of digestion, growth immune function, reproduction and pain perception  Enhancement of sensory intake and memory 241-5.12

16. Selye's General Adaptation Syndrome (GAS) and the Consequence of Another Stressor Original Stress Normal New Stress 241-5.13

17. Pathological State Associated with Chronic Stress  Fatigue, myopathy; steroid diabetes  Hypertension  Peptic ulcers  Psychosocial dwarfism  Impotence; anovulation; loss of libido  Impaired disease resistance; cancer  Accelerated neural degeneration during aging 241-5.14

18. Bruce McEwen Allostasis and Allostatic Load  Idea evolved from concepts of homeostasis and stress.  P. Sterling and J. Eyer were the originators of the concept. Allo – prefix meaning variable.  Allostasis = maintaining stability through change; the active process of maintaining a physiological function in the face of a challenge by old control systems adjusting level of function or "new" systems being activated.  Systems involved in the stress response show dramatic responses.  Allostatic load = wear and tear on the body that results from repeated or sustained activation of processes that maintain homeostasis. Popularizer of Allostasis and Allostatic Load 241-5.15

19. The Cardiovascular Defense Response 241-5.16

20. Behavioral •Piloerection •Hissing • Halloween Posture Cardiovascular •  Cardiac Output ( HR) •  Blood Pressure •  Skeletal Muscle Blood Flow •  Renal Blood Flow •  Mesenteric Blood Flow Brain Stimulation-Induced Defense Response 241-5.17

21. The Conditioned Emotional Response (CER):A Rat Undergoing Fear Conditioning 241-5.18

22. Neural Pathways Mediating theCardiovascular (A) and the Behavioral(Freezing) (B) Components of the Defense Response 241-5.19

23. The Amygdala and Fear 241-5.20

24. Stress Pathways and the Control of Glucocorticoids 241-5.21

25. The Physiological Effects of CRF 241-5.22

26. Putative CRF Pathways and CRF1 (a) andCRF2 (b) Receptor Localization 241-5.23

27. Effects of Amygdala Lesions on the CRF Enhancement of the Startle Response 241-5.24

28. The Projections of the Amygdala That Mediate Behavioral, Physiological and Endocrine Responses to Fear Stimuli 241-5.25

29. There is a Key Role for GABA inControlling Activity of the Amygdala 241-5.26

30. The GABA Synapse 241-5.27

31. COOH COOH CH2 CH2 + CO2 CH2 CH2 H2N CH H2N CH2 COOH Glutamic Acid GABA GABA Synthesis Glutamic Acid Decarboxylase 241-5.28

32. The Interplay Between Neuronsand Glia in GABA Metabolism 241-5.29

33. Schematic Model of the GABAA Receptor Complex BDZ, benzodiazepine 241-5.30

34. Anxiety Disorders 241-5.31

35. Björn Folkow Hypothalamic StimulationProducing the Defense Responseand Chronic Hypertension The Defense Response as an Inducer of Chronic Hypertension About 50 years ago,Folkow hypothesized that sustained or repeated activation of the defense response predisposes towards developing chronic hypertension. 241-5.32

36. Multiple EnvironmentalStressor-Induced Hypertension 241-5.33

37. Mood Disorders 241-5.34

38. • Major depression is the leading cause of disability in the U.S. and worldwide. • Depressive disorders affect an estimated 9.5% of adult Americans ages 18 and over in a given year, or about 18.8 million people in 1998. Major Depression 241-5.35

39. Distribution of Mood Disorders in the U.S. Population 241-5.36

40. • Must include either pervasive depressed mood (verbal report) or pervasive loss of ability to experience pleasure or interest in other things (anhedonia). • Must include at least five of the following:- Depressed mood (require verbal report) - Feelings of worthlessness or guilt (require verbal report) - Diminished concentration (require verbal report) - Recurrent thoughts of death or suicide (require verbal report) - Weight change   - Sleep disturbance   - Psychomotor agitation or retardation   - Fatigue or loss of energy - Loss of pleasure (anhedonia) or interest *Adapted form DSM-IV-RT Symptoms and Signs of Major Depression* 241-5.37

41. DSM-IV-RT Diagnostic Criteria for Dysthymic Disorder A. Depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years. Note: In children and adolescents, mood can be irritable and duration must be at least 1 year. B. Presence, while depressed, of two (or more) of the following:• Poor appetite or overeating• Insomnia or hypersomnia• Low energy or fatigue• Low self-esteem• Poor concentration or difficulty making decisions• Feelings of hopelessness C. During the 2-year period (1 year for children or adolescents) of the disturbance, the person has never been without the symptoms in Criteria A and B for more than 2 months at a time. D. No Major Depressive Episode has been present during the first 2 years of the disturbance (1 year for children and adolescents); i.e., the disturbance is not better accounted for by chronic Major Depressive Disorder, or Major Depressive Disorder, In Partial Remission. Note: There may have been previous Major Depressive Episode provided there was a full remission (no significant signs or symptoms for 2 months) before development of the Dysthymic Disorder. In addition, after the initial 2 years (1 year in children or adolescents) of Dysthymic Disorder, there may be superimposed episodes for Major Depressive Disorder, in which case both diagnoses may be given when the criteria are met for a Major Depressive Episode. E. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode, and criteria have never been met for Cyclothymic Disorder. F. The disturbance does not occur exclusively during the course of a chronic Psychotic Disorder, such as Schizophrenia or Delusional Disorder. G. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). H. The symptoms cause clinically significant distress or impairment in the social, occupational, or other important areas of functioning. Specify if: Early Onset: if onset is before age 21 years Late Onset: if onset is age 21 years or older Specify (for most recent 2 years of Dysthymic Disorder): With Atypical Features 241-5.38

42. Criteria for Manic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:• Inflated self-esteem or grandiosity• Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)• More talkative than usual or pressure to keep talking• Flight of ideas or subject experience that thoughts are racing• Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)• Increase in goal-directed activity (either socially at work or school, or sexually) or psychomotor agitation• Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) C. The symptoms do not meet criteria for a Mixed Episode. D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar 1 Disorder. 241-5.39

43. Male/Female Prevalence of Affective Disorders 241-5.40

44. Genetic Component of Behavioral/Mental Disorders 241-5.41

45. Confirmed Linkages in Bipolar Disorder Genomic Principle IndependentLocation Report Confirmations 18p11.2 Berrettini et al., 1994 (38) Stine et al., 1995 (40); Nothen et al., 1999 (41); and 1997 (39) Turecki et al., 1999 (42) 21q22 Straub et al., 1994 (44) Detera-Wadleigh et al., 1996 (45); Smythe et al., 1996 (46); Kwok et al., 1999 (47); Morissette et al., 1999 (48) 22q11-13 Kelsoe et al., 2001 (49) Detera-Wadleigh et al., 1997 (50) and 1999 (51) 18q22 Stine et al., 1995 (40) Mcinnes et al., 1996 (52); McMahon et al., 1997 (53); De Bruyn et al., 1996 (54) 12q24 Morissette et al., 1999 (48) Ewald et al., 1998 (56); Detera-Wadleigh et al., 1999 (51) 4p15 Blackwood et al., 1996 (57) Ewald et al., 1998 (58); Nothen et al., 1997 (59); Detera-Wadleigh et al., 1999 (51) 241-5.42

46. Vegetative • Increased heart rate • Decreased heart rate variability • Increased cardiovascular reactivity to psychosocial stressors • Increased susceptibility to heart disease Endocrine • Increased plasma norepinephrine • Increased cerebrospinal fluid CRF • Increased plasma corticosterone • Altered cytokines in depressed mood Circadian • Altered sleep cycles • Increased REM • Decreased REM onset latency • Sleep deprivation and depression • Altered CRF cycle • Seasonal affective disorder Physiological and Biochemical Signs in Depression 241-5.43

47. Average Plasma Cortisol Concentrations 241-5.44

48. Patterns of the Stages of Sleep of a Normal Subject and of a Patient with Major Depression 241-5.45

49. Changes in the Depression Rating of a Depressed Patient Produced by a Single Night's Total Sleep Deprivation Mean Mood Rating of Responding and Non-Responding Patients Deprived of One Night's Sleep as a Function of the Time of Day 241-5.46

50. • Distinctive constellation of symptoms including - Overeating - Oversleeping - Carbohydrate craving • Triggered by light deficiency • Responds to phototherapy • Theories accounting for the antidepressant effects of phototherapy - Melatonin hypothesis - Circadian phase shift - Circadian rhythm amplitude Seasonal Affective Disorder (SAD) 241-5.47