Bryan Kolb: Factors influencing Prefrontal Cortical Development and ...

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

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

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…

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.

What is the PFC?

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

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

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

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

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…

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

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

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

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

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

=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

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

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.

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

But, not
done until
at least age
20 years…

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

Total Volume
Gray Volume
White Volume
Ventricle Volume

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.

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.

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

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..

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

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.

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

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

Differences in
Cortical plasticity

Hormones change more than genitals…

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!

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.

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

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.

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

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

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

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.

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

Outcomes after age 55
1. 50% 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+

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

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

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.

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)

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

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

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

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.

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

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

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…

Complex housing increases dendritic length at all ages
Complex housing
Par
increases
1 Dendritic Length
dendritic length at all ages
Mean Total Grid Crossings
130
120
110
100
90
80
Lab
Condo
70
60
50
40
Young Adult Old

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
6
5
4
3
2
Young Adult Old

Break Time?

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

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.

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

BUT…
The
effects are exactly opposite in OFC!

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…

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

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

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.

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

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

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.

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.)

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

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)

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

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”

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

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

All mammals have play
behaviour with rules

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

Sibling play = more complex OFC
Adult “play” = more complex mPFC

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.

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

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.

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

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

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

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

What about other developmental
Disorders?
2. Genetic predispositions

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.

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

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.