Factors Influencing Prefrontal Cortical Development and Behaviour. Bryan Kolb Canadian Centre for Behavioural Neuroscience University of Lethbridge

Transcription

1 Factors Influencing Prefrontal Cortical Development and Behaviour Bryan Kolb Canadian Centre for Behavioural Neuroscience University of Lethbridge

2 SPECIAL THANKS TO WENDY COMEAU ROBBIN GIBB GRAZYNA GORNY CANADIAN INSTITUTE FOR ADVANCED RESEARCH NSERC CIHR

3 OBJECTIVES 1. Understand organization of PFC 2. Understand prolonged PFC development 3. Consider factors altering PFC development 4. Recognize the prolonged and profound effects of early experience on brain functioning

4 What is the prefrontal cortex? 1. There is a region in all mammals that lies in front of the motor cortex and has a unique set of connections with the rest of the brain. 2. The PFC increases in parallel with increases in sensory representations of the external world. 3. There are multiple PFC regions.

5 What is the PFC?

6 How does the PFC do its job? Sensory input is to the brain is divided for object recognition and motor control. Conscious vs unconscious Past vs present

7 How does the PFC do its job? The prefrontal cortex combines the 2 systems. Place and time Internal & external Past, present, future

8 How do we define PFC? 1. Connections with dorsal medial nucleus of thalamus. 2. Connections with amygdala. 3. Dopamine input from VTA 4. Other connetions

9 Rhesus Monkey Stipple area: MD projection field Gray area: Amygdala projection field DA projection similar to MD field

10 Is the human PFC special? The key difference between different mammalian species is the complexity and nature of the sensory representations of the world. The human brain has the most complex representation, in part related to language, and thus the largest volume of PFC. Von Economo cells may be unique

11 What does the PFC do? Temporal organization of behaviour: -ongoing record of sensory exp =working memory

12 What does the PFC do? Temporal organization of behaviour: -ongoing record of sensory exp -ongoing record of reafference =the importance of corollary discharge =ANS monitoring

13 What does the PFC do? Temporal organization of behaviour: -ongoing record of sensory exp -ongoing record of reafference -sensory selection =attention

14 What does the PFC do? Temporal organization of behaviour: -ongoing record of sensory exp -ongoing record of reafference -sensory selection -inhibition of competing impulses =organization of behavior

15 What does the PFC do? Temporal organization of behaviour: -ongoing record of sensory exp -ongoing record of reafference -sensory selection (attention) -inhibition of competing impulses -flexible to changing contexts =social behaviour; ; spontaneity; Some forms of learning

16 =role of reward- exogenous & endogenous What does the PFC do? Temporal organization of behaviour: -ongoing record of sensory exp -ongoing record of reafference -sensory selection (attention) -inhibition of competing impulses -flexible to changing contexts -monitoring of consequences

17 Examples of deficits of temporal control: Abnormal social & sexual behaviour Disorganization in planning, esp related to ordering behaviours Short-term term memory Loss of reward Loss of spontaneity Loss of autobiographical memory

18 What does this have to do with anything? 1. Factors that alter PFC will fundamentally alter nearly all behaviour. 2. Hebb s (1949) premise: The PFC plays a fundamental role in the development of cognitive schemata. Thus, the PFC is more important in development than in adulthood.

19 Key Points 1. The emergence of PFC processes is profoundly influenced by experience 2. Prefrontal development is prolonged until at least 20 yrs

20 But, not done until at least age 20 years

21 Correlation between brain growth and reduced gray matter density: RED means the biggest changes

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23 Total Volume Gray Volume White Volume Ventricle Volume

24 Developmental Surprises 1. The OFC matures faster than the mpfc. 2. The OFC matures faster in females than males (Bachevalier monkey studies) 3. Effects of early PFC injury are different in mpfc and OFC and sexually dimorphic.

25 Measuring brain-behaviour behaviour relationships Functions of the brain can be inferred at many levels from behaviour to structure. I will focus on these two.

26 The Cortical Neuron Brain Plasticity: 1. Pruning during development. 2. Changing the wiring diagram

27 A frontal lobe pyramidal neuron Synapse number can be estimated by knowing the length of the dendritic fields and the spine density. One key feature is that both measures can go up or down with experience - thus reflecting an increase or decrease in synapse number. These changes have implications for behavioural change..

28 Arnold Scheibel s Story Cell Structure 1. Complexity of computations 2. Education 3. Sex effect

29 Thus When the brain changes, this is reflected in behavioural change. This change is known by names such as learning, memory, addiction, maturation, ageing, recovery, psychopathology, etc.

30 The principles of brain organization and development are similar for all mammals

31 Factors altering PFC development The developing PFC is altered by many pre- and postnatal events including: 1. gonadal hormones 2. stress 3. Sensory and motor experience 4. psychoactive drugs (e.g., nicotine, caffeine, antidepressants, and more ) 5. Social relationships, including play 6. Cognitive experience

32 Differences in Cortical plasticity

33 Hormones change more than genitals

34 Gonadal hormones change more than the Genitals Relative volume of cortical regions in women and men This means that females and males should behave differently!

35 Gonadal hormones have organizing effects on PFC Kolb & Stewart, 1991, J. Neuroendocrinology Males have more synapses in MF Females have more synapses in OF The effects are hormone- dependent.

36 Factors altering PFC development The developing PFC is altered by many Pre- and postnatal events including: 1. gonadal hormones 2. stress 3. Sensory and motor experience 4. psychoactive drugs (e.g., nicotine, caffeine, antidepressants, and more ) 5. Social relationships, including play 6. Cognitive experience

37 Early Experience alters stress axis Acute, mild stress Chronic stress OR high stress Development of Stress Reactivity Modest Stress Reactivity Reduced Risk for Disease Increased Stress Reactivity Increased Risk for Heart Disease, Type II Diabetes, Alcoholism, Affective Disorders, Brain Aging etc.

38 Adult Stress Altered PFC organization more synapses in OFC fewer in mpfc no change in other ctx regions Liston et al., J Neuroscience, 2006

39 Prenatal Stress 1. Smaller brains 2. Altered PFC development fewer synapses in OFC fewer in mpfc no change in other regions Halliwell, Gibb & Kolb, in progress

40 So what? The changed structure of the PFC regions means that they will function differently AND that they will respond to other experiences differently

41 Turning Gold into Lead The ACE (Adverse Childhood Experiences) Study. 17,000+ middle-aged adults in USA Findings: 1. ACEs are more common than recognized 2. ACEs have a powerful relation to adult health 50 yrs later.

42 Turning Gold into Lead Examples of ACEs: -family violence: spousal or child related -parental alcohol or drug addictions -sexual abuse -growing up in a household where someone is in jail -parental chronic depression or other mental illness -loss of one parent for whatever reason

43 Outcomes after age % experienced at least one ACE and 25% had 2 ACEs 6% had 4 ACEs MANY conditions are related to ACEs -smoking or other addictions -heart and lung disease -depression -diabetes -hypertension -macular degeneration -psoriasis -suicide (or attempted) -etc The increase in incidence varies from about 3X for smoking to 50X for drug addiction and 50X for attempted suicide with 2+

44 Why? For at least some of the outcomes, it is Likely that there are changes in PFC and HPC that lead to bad decisions. Example, 5X increase in risk of sexual assault

45 A Natural Experiment: Romanian Orphans Adopted in UK, Canada, & USA

46 Romanian Communist Policy:1966 decree Raise productivity by increasing population Establishment of the MENSTRUAL POLICE - state gynecologists who conducted monthly checks of women of childbearing age who had not borne at least 5 children OUTLAWED all contraception and abortion RESULT: A national disaster. Parents could not afford to raise the children. Thousands of children were turned over to the state to be raised in institutions.

47 A Natural Experiment: Romanian Orphans Adopted Children adopted after 6-12 mo of age show at 11 years: 1. Abnormal brain development (e.g., small brain, low metabolic activity, abnormal EEG) 2. Social and cognitive problems (e.g., IQ loss) 3. High vulnerability to behavioural problems (e.g., ADHD, aggression)

48 Factors altering PFC development The developing PFC is altered by many Pre- and postnatal events including: 1. gonadal hormones 2. stress 3. Sensory and motor experience 4. psychoactive drugs (e.g., nicotine, caffeine, antidepressants, and more ) 5. Social relationships, including play 6. Cognitive experience

49 Shaping Brain Development Complex Housing Postnatal Prenatal (even dads ) Brains are larger, have more connections The animals have enhanced cognitive and motor behaviour

50 Getting to the brain via the skin Postnatal Infant Prenatal Also can use a broad spectrum light

51 What is the effect of the tactile stimulation? -Larger brain -More connections generally in cortex -Enhanced cognitive & motor performance -Changes in the genes turned on and off (epigenetic changes) Conclusion: Experience can alter the production of proteins in the skin, which in turn can alter the PFC through effects on genes.

52 How does this work? Skin and brain are developmentally related and respond to the same factors such as FGF-2

53 And the point is? Think about parent-infant interactions. We return to this

54 Does experience have the same effects at different times in life? NO! There are qualitative differences at different stages of life. There is something fundamentally different prenatally vs infancy vs juvenile vs adult One difference is gene expression

55 Complex housing increases dendritic length at all ages Complex housing Par increases 1 Dendritic Length dendritic length at all ages Mean Total Grid Crossings Lab Condo Young Adult Old

56 Complex housing alters spine density differently in young rats Complex housing Par alters 1 Terminal spine Tip Apical density Spinesdifferently in young rats 7 Lab Condo Mean Spines per 10 μm Young Adult Old

57 Break Time?

58 Factors altering PFC development The developing PFC is altered by many Pre- and postnatal events including: 1. gonadal hormones 2. stress 3. Sensory and motor experience 4.. Psychoactive drugs 5. Social relationships, including play 6. Cognitive experience

59 Drug-induced behavioural sensitization The phenomenon whereby there is an escalating behavioral response to repeated administration of a constant dose of a psychomotor stimulant such as amphetamine, cocaine, or nicotine.

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61 Similar Results are seen in mpfc but not in sensory or motor areas Similar results are seen with cocaine & nicotine. Caffeine produces somewhat different changes

62 BUT The effects are exactly opposite in OFC!

63 Thus, Psychoactive drugs are chronically altering the the PFC and are changing the PFC in an areal-dependent manner. This must be important in understanding PFC function and dysfunction. Recall that hormones also have different effects on n the two regions

64 The drug-induced changes are not trivial: NAcc = 37% increase in total synapses per neuron PFC = 19% increase in total synapses per pyramidal neuron OFC = 20% decrease in total synapses per pyramidal neuron

65 Is this just about stimulants? NO!! Morphine THC PCP Fluoxetine (prozac) Valium Antipsychotics But the pattern of changes is drug-unique. unique.

66 What about development? Ritalin and amphetamine produce the same changes in the developing brain EXCEPT there are NO changes in N.Acc,, just the PFC. This is like THC in adults. Experience interacts with the drug effects differently in young and mature animals.

67 Are there long-term consequences? 1. Pathology of brain and behaviour.

68 There is a pathological appearance to PFC neurons in rats that self-administer cocaine. Such animals show behavioural impairments on PFC-related behavioural tasks.

69 How might the changes be related to the maladaptive behaviour of addicts? 1. The pathology in PFC function may suggest that addicts fail to have insight into their behavior because of abnormal PFC functioning. 2. The changes in orbital cortex would be consistent with poor social judgements & loss of inhibition.

70 Are there long-term consequences? 1. Pathology of brain and behaviour. 2. Both ritalin and amphetamine as juveniles produce deficits in learning of PFC-related tasks in adulthood. (But the rats are not ADHD.)

71 Drugs and later experience Drug Treatment + =? OR does experience alter the effects of drugs OR do the two interact given simultaneously

72 Are there long-term consequences? 1. Pathology of brain and behaviour. 2. Both ritalin and amphetamine as juveniles produce deficits in learning of PFC-related tasks in adulthood. 3. Amphetamine, cocaine & nicotine block later experience-dependent plasticity in adulthood and development. (REMEMBER: age-related differences)

73 What about prenatal effects? According to NIDA, 25% of pregnant moms smoke 10% of pregnant moms drink alcohol Close 100% of pregnant moms consume caffeine

74 Drug Effects in Developing Brain 1. Ritalin: mpfc hypertrophy; abnormal play; abnormal cognition 2. Prenatal Fluoxetine (Prozac): generalized atrophy of cortical neurons 3. Antipsychotics: Specific atrophy of PFC & NAcc neurons Remember: these rats were normal

75 Factors altering PFC development The developing PFC is altered by many Pre- and postnatal events including: 1. gonadal hormones 2. stress 3. Sensory and motor experience 4. psychoactive drugs (e.g., nicotine, caffeine, antidepressants, and more ) 5. Social relationships 6. Cognitive experience

76 Social Relationships 1. Play partners 2. Parent-infant interactions

77 All mammals have play behaviour with rules

78 Little Play: Adult + Juvenile Enriched Play: 4 Juveniles Bell, Pellis & Kolb, in progress Limited Play: 2 Juveniles

79 Sibling play = more complex OFC Adult play = more complex mpfc

80 Factors influencing play behavior 1. Play partners 2. OFC injury= failure to understand rules 3. Stress= reduce play initiation 4. Drugs= e.g., Ritalin effects similar to PFC injury. Conclusion: Play fundamentally alters brain development. Anything that changes play will alter brain development - and other behaviours.

81 Parents change us too All mammals show a large within-species range in contact time

82 Social Relationships There is about a 6 hr difference at the ends of the continuum of parent-infant contact. Our working hypothesis is that this alters PFC development via the effects of contact.

83 Factors altering PFC development The developing PFC is altered by many Pre- and postnatal events including: 1. gonadal hormones 2. stress 3. Sensory and motor experience 4. psychoactive drugs (e.g., nicotine, caffeine, antidepressants, and more ) 5. Social relationships, including play 6. Cognitive experience

84 Early learning alters PFC development Example: Train juveniles on PFC- Dependent tasks = increased synapses in mpfc and OFC.

85 What about other developmental Disorders? 1. Schizophrenia Weinberger model: transient hippocampal perturbation -PFC related behavioural abnormality -mpfc cell atrophy -OFC hypertrophy -NAcc atrophy

86 Schizophrenia Model Weinberger/Lipska model -neonatal HPC perturbations -mpfc-like abnormalities in behaviour -PET shows drop in activation in DL PFC Dendrites? mpfc & N.Acc. Atrophy OFC hypertrophy

87 What about other developmental Disorders? 2. Genetic predispositions

88 Fast VS Slow Kindlers FAST (kindling prone) rats act like juvenile rats indefinitely. e.g., play behaviour, activity, impulsivity, reduced fear SLOW rats act like mature rats even as juveniles.

89 FAST vs SLOW Although there Are no differences in sensory or motor areas, there was a clear mpfc vs OFC difference. mpfc: : FAST>SLOW OFC: SLOW>FAST Relationship to juvenile behaviour of the FAST? Note that the pattern is like the sex difference Note that the pattern is like psychomotor stims

90 Conclusions 1. The PFC is fundamental to the organization of complex behaviours. 2. PFC development is prolonged. 3. PFC development is profoundly altered by a wide range of experiences 4. Changes in PFC development plays a key role in understanding both normal & abnormal behaviour.

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