Psychobiology of Mothering:

Alison S. Fleming

Centre for Study of Biological Communications University of Toronto at Mississauga

a comparison of rat and human mothers

Maternal Behavior: Human and Animal Models

• SENSORYSENSORY• HORMONESHORMONES• EXPERIENCEEXPERIENCE• DEVELOPMENT• NEURAL • GENETIC

• SENSORY• HORMONES• EXPERIENCE• DEVELOPMENT• NEURAL• GENETIC

•St Joseph’s, 1907•Erindale, 1963

•Our work is done•In S Ontario under a veil of•smog in •beautiful buildings,•with all their original•features essentially untouched

•human •Rat

TWO PSYCHONEUROLOGICAL SYSTEMS

• Liking/Wanting – stimulus salience, ‘reward’– Nucleus accumbens (NAcc)

• Doing (or, the quality of) – Attention (selective, shifting, flexibility, strategies),

attentiveness– Medial prefrontal cortex (mPFC)

Setting up the straw woman

One (of a number) of unifying principles tying these systems and functions together may be the dopamine

system

(NAC)

(PFC)

One (of a number) of unifying principles tying these systems and functions together is the dopamine system

(NAC)

(PFC)

Adapted from Bauer, 1983-pup odours• See also Fleming et al.,, 1987, 1989-odors pups• Farrell & Alberts, 2002-ultrasound pup

• Lee, Fleming et al., 2000-bar press rat• Mattson, Williams, Rosenblatt, & Morrell (2000)-cpp rat• Fleming, Corter, Franks, Surbey, Schneider., & Steiner, 1993-odor humans• Stallings et al., 2002-cries humans• Purhonen et al., 2001; in press-cries eeg

• Fleming, Ruble, Flett, & Van Wagner, 1990-increase response to babies• Lovic & Fleming, 2004; Lovic, in prep-attention and mothering• Lovic & Fleming, 2004; Lovic, in prepGonzalez, Steiner, & Fleming., in prepFleming & Gonzalez, 2008-attention and mat behavior-humansNuman et. al., 2007-di agonist and mat behavior rat(Li & Fleming, 2004ab; Numan et al., 2005; Stern & Lonstein, 2001-da antagonists and mb(Fleming, Korsmit, & Deller, 1994)- da antagonists and cpp

• attentio

Stimulus SalienceReward

LIKING / WANTING

Crouching

General LickingPup Retrieval

Maternal responsiveness grows across pregnancy and peaks at parturition under influence of hormones

Onset Pregnancy Day 16 Parturition

No maternal experience

HIGH

LOW

P, E, Prl, Oxy

CORT, Prl, Oxy

MPOAlimbic system

Maternal experience

-150

-100

-50

0

50

100

150

200

250

300

me

an

dif

fere

nc

e s

co

res

(s

ec

)

(-5

+5

, x

+ S

E)

Mothers

Non-mothers

.

Adapted from Bauer, 1983See also Fleming et al.,, 1987, 1989

pup nest-clean=0

Pre-part Post-part

New Mother Rats are More Attracted to Lactating Nest Odors than to Clean or Diestrous Nest Odor

Virgin Rats Show No significant Preference

Olfactory Preferences for Lactating Nest Odoursalso shown by Virgins Primed with (P & E) Hormones

Fleming et al., 1987, 1989

0

100

200

300

400

500

pro

xim

al o

rien

tati

on

dif

fere

nce

fro

m b

asel

ine

(s)

MothersNon-mothers

.

New Mother rats are more alerted by Pup Ultrasounds (pup ultrasounds vs. pup silent)

than are Virgin Non-maternal Rats

BEFORE BIRTH PART AFTER BIRTH

a

abcd

b

cd

Farrell & Alberts, 2002

Attractive stimuli become rewarding stimuli:Attractive stimuli become rewarding stimuli: New Mother Rats Show a Higher Level of Bar-press New Mother Rats Show a Higher Level of Bar-press

Responses Than do Virgins When Pups are Used as the Responses Than do Virgins When Pups are Used as the

Reward Stimuli (CRF schedule)Reward Stimuli (CRF schedule)

Lee, Fleming et al., 2000

0

5

10

15

20

25

30

35

40

-2 -1 1 2 3 4 5 6 7 8 9 10B

ar-p

ress

es/3

0 m

in

VIRGIN

POSTARTUM

.

Pregnancy Days post-partun

VIRGIN LEVELS-not maternal

birth

Virgin levels

0102030405060708090

Early Middle Late

Stage Post-partum

perc

en

tag

e o

f d

am

s

.

New Mothers Prefer Pup-associated chamber to Cocaine-associated chamber in CPP

(early postpartum period; days 4-7) Preference is Reversed to Non-postpartum Levels Later

in Postpartum Period (days 12-15)

Mattson, Williams, Rosenblatt, & Morrell (2000)

pup cocaine

Among Humans as well, New Mothers are Often Very Responsive to Their Infants and

Find Infant Cues Attractive

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

stimulus odor prsented in Baskin Robbins containers

HE

DO

NIC

RA

TIN

GS

(-5+

5,

x +

SE

)

MothersNon-mothers

.InfantT-shirt

spiceNEUTRAL

Fleming, Corter, Franks, Surbey, Schneider., & Steiner, 1993

New Mothers (day 2pp) are More Attracted to Infant Body Odors, But Not to Control Odors, Than are Non-mothers (VAS, pleasantness)

urine

0

20

40

60

80

100

120

140

contact interval nurse interval Time in closeproximity to infant

Tim

e in

min

ute

s (

me

dia

n(I

QR

))

.

Mothers with More Postpartum Experience tend to also Find Infant Odors to be More Attractive

2,210

1,10

15,318

52,585

120,370

105,375

Fleming, Corter et al., 1993

pos

neg

On self-report measures (VAS) Mothers are more alerted by infant cries than are non-

mothers

Heart-rate monitorcry stimuliVAS

Stallings et al., 2002

•Using auditory Event Related Potentials (N100) , mothers are more alerted to infant cries than are non-mothers

- however they are also more alerted to a novel tone-hence, effects are non-specific

Purhonen et al., 2001; in press

With Postpartum Experience New Mothers Become Increasingly More Positive About the Baby- and less

positive about their partners(DON’T WORRY, IT RETURNS IN TIME FOR THE NEXT BABY)

0

4

Post-partum

Ra

tio

of

po

sit

ive/n

eg

ati

ve

s

tate

me

nts

(m

ea

n +

se

)

Baby

Husband

Self

Fleming, Ruble, Flett, & Van Wagner, 1990

ATTENTION (selective,flexibility)Maternal attentiveness and sensitivity

DOING

General Licking

Mothers Exhibiting Higher Levels of Selective Attention Show Increased Pup Licking , and fewer movements

into and out of nest

R=-0.667

ATTENTION (ID/ED Task)

Relationship Between ID Shiting and Pup Licking

0

2

4

6

8

10

12

14

0 20 40 60 80 100 120 140 160

Duration of Pup Licking (seconds)

ID S

hif

t (1

6-t

ria

ls t

o c

rite

rio

n)

Lovic & Fleming, 2004; Lovic, in prep

r=0.62, P<.05

Licking

atte

ntio

n

Human Mothers also show large variations in Maternal ‘Sensitivity’ and Contingent

Responding

More Variation

Mothers who Show Reduced Attention (on CANTAB: Set-Shifting Task) also Show Reduced Maternal

Sensitivity

Maternal Sensitivity

.

-.25

Numbers=stand. β weights

Gonzalez, Steiner, & Fleming., in prepFleming & Gonzalez, 2008

AttentionED Shift on CANTAB

Ainsworth Sensitivity

Rating Scales

Cambridge Neuropsychological Test Automated BatteryAdministered via a touch screen computer

Measures components of executive functioning;

Summary

• Pups are first attractive, then rewarding, to the new mother

• Rewarding properties of pups enhanced by hormones and by experience

• Rewarding and salient pups regulate mothers’ approach and contact with the young. They enhance her motivation to mother

• To mother ‘sensitively’ and appropriately mothers must not only be motivated, but must also be attentive to the infant, and show flexibility; HENCE, SHOW GOOD EXECUTIVE FUNCTION

WHAT ABOUT THE BRAIN?

MATERNAL CIRCUIT: Brain Areas

Associated with Maternal/Associated Behaviors

MPOA is the FINAL COMMON PATH

MPFC

NA

MPOA

Inhibition of Maternal Behavior

VTA

Fear system

VMH Reinforce/Memoryattention

MAM

mPFC: ATTENTION, Impulsivity

AMYGDALA: Emotions NAcc: Stimulus Salience, Rewards

Motivation

MPOA and VMH: Maternal Behavior

VP

Odor of Pups

Olfactory Bulb

MATERNAL CIRCUIT: Brain Areas

Associated with Maternal/Associated Behaviors

Here focus on the Nucleus Accumbens

MPFC

NA

MPOA

Inhibition of Maternal Behavior

VTA

Fear system

VMH Reinforce/Memoryattention

MAM

mPFC: ATTENTION, Impulsivity

AMYGDALA: Emotions NAcc: Stimulus Salience, Rewards

Motivation

MPOA and VMH: Maternal Behavior

VP

Odor of Pups

Olfactory Bulb

Dopamine Action in Nucleus Accumbens is important for the onset of maternal behavior

• Dopamine receptor agonist (D1) enhances onset of maternal behavior (Numan et. al., 2007)

• DA receptor antagonists (D1 &/ D2)

• delay onset of maternal behavior, primarily retrieval (Li & Fleming, 2004ab; Numan et al., 2005; Stern & Lonstein, 2001)

• block formation of a CPP preference for pup-paired box (over other box) (Fleming, Korsmit, & Deller, 1994)

Infusions of DA antagonists into Nucleus Accumbens Immediately After a Maternal Experience also,

Block Consolidation of Maternal Experience at retention

D1&D2 ANT

CONTD2 ANT (sulperide)

D1 ANT (SCH)

Parada et al., 2008

1. Postpartum status

2. Hormones (gestational/part)

3. Maternal Experiences

microdialysis studies assessing dopamine by HPLC

Dopamine is Released in the Nucleus Accumbens in response to pups and is affected by

Dopamine release is associated with mothering THREE MICRODIALYSIS STUDIES

Students on project: Veronica Afonso, Samantha King , Stephanie Grella, Natalia Pinzon , Christine Burton

Diptendu Chatterjee

NACsh

probe placement

COLLECTION: 1uL/min for 8-min

Baseline sampling (no stimuli)

Pup-stimuli sampling(24 min, 3 samples)

Food-reward stimuli sampling(8 min, 1 sample)

TEST 1 (samples collected at 1ul/min)

TIME

HPLC: Output Data

SAMPLING Non-Homecage

SAMPLING PROCEDURE

• See Afonso et al.

• HPLC with ECD

Sprague-Dawley Intact Rats(N=11)

Mated and have litterLactating

Cycling virgin

pups removed 6-12 hr prior to sampling and

presented with pups (PND1).

1st pup experience at

sampling.

1. Postpartum Influence

Afonso, King,Chatterjee, & Fleming, IN PREP

Dopamine Response

Time (min)0 8 16 24 32 40

Mea

n %

of

ba

seli

ne

0

100

200

300

400

500

a

aa

a p<0.05 POSTPARTUM difference.

PUP STIMULI

Postpartum

Cycling

New mother rats show sustained increased dopamine response in NAC to pup stimuli; virgins do not.

MATERNAL IN OWN CAGE, NOT IN DIALYSIS CHAMBER

NOT MATERNAL IN OWN CAGE OR IN DIALYSIS CHAMBER

Parity diff /baseline covariate also sig at 16 and 24

Time (min) after basline established32 40 48 56

Mea

n R

espo

nse

(% o

f B

asal

leve

ls)

0

100

200

300

400

a*

*

Food RewardStimuli

Postpartum

Cycling

DA effects are non-specific; All females show increased DA to FOOD-stimuli , however virgins show higher levels than do

postpartum animals (reverse of pattern to pups)

• DA peaks quickly

Sprague-Dawely OVXed Rats(N=10)

E + P Salastic CapsulesHORMONE

Sham Salastic CapsulesSHAM

1st Experience with pups.

(P capsules removed 24 hr prior to sampling).

2. Hormonal Influence

Afonso, Burton, Novakov, & Fleming

Dopamine Response

Time (min)0 8 16 24 32 40

Mean

% o

f B

aseli

ne

0

100

200

300

400

500

aa a

a p<0.05 HORMONE TREATMENT difference.

PUP STIMULI

HORMONE

SHAM

Hormonally-primed virgin rats show sustained increased dopamine response to pups in the absence of prior pup-

experience; control sham animals do not.

NOT MATERNAL IN HOME CAGE OR IN CHAMBER

BUT SNIFFING PUPS

NOT MATERNMAL IN HOME CAGE OR IN CHANBER

Sprague-Dawely Cycling Rats(N=31)

Multiparous(n=11)

Nulliparous(n=13)

Sensitized(n=6)

NonSensitized(n=5)

NonSensitized(n=5)

Sensitized(n=8)

PARITY EXPERIENCE

PUP-SENSITIZATION EXPERIENCE

3. Maternal Experience Influence

Afonso, Grella, Chatterjee, & Fleming, 2008.

MultiparousSensitized

MultiparousNonSensitized

NulliparousSensitized

pup

NulliparousNonSensitized

Rats given previous mothering experience show only an initial dopamine response in NAC to pup stimuli, related to sniffing.

Experience effects ARE ADDITIVEThe multiparous sensitized animals showed the greatest DA response.

Afonso, Grella, Chatterjee, & Fleming, 2008.

MATERNAL CIRCUIT: Brain Areas

Associated with Maternal/Associated Behaviors

Here focus on the Medial Prefrontal Cortex

MPFC

NA

MPOA

Inhibition of Maternal Behavior

VTA

Fear system

VMH Reinforce/Memoryattention

MAM

mPFC: ATTENTION, flexibility

AMYGDALA: Emotions NAcc: Stimulus Salience, Rewards

Motivation

MPOA and VMH: Maternal Behavior

VP

Odor of Pups

Olfactory Bulb

Rats with Medial Prefrontal Lesions (NMDA) all Show Maternal retrievals, BUT they Show disrupted Sequencing of retrievals and reduced Licking

Afonso, Lovic, et al., 2008;

mPFC lesions also produce

• reduced Attention – on a PPI task (attentional filtering) (Afonso et al., 2008)

and – on an attention set shifting task (Birrel & Brown, 2000)

fMRI Activation in the PFC (dl) occurs during Attentional Shifting

• Figures show similar fMRI brain activation in macaque monkeys and humans during successful shifts in attention (Nakahara et al. 2002)

Macaque Monkey Human

Frontal sites associated

With performance on executive

And attention tasks

are also

Activated by infant cues

Gonzalez et al., 2008

THESE BEHAVIORAL AND

NEUROLOGICAL SYSTEMS ARE SET UP BY EARLY NEONATAL AND

PREWEANING EXPERIENCES

Gonzalez & Fleming, 2001; Lovic & Fleming, 2004

Early Experience

(prenatal+post-partum)

CORT

Response to stress

Attention(prepulse inhibition 84)

Pups experiencing early maternal/litter deprivation show reduced attention,

reduced licking as well as structural and functional changes in NAC and MPFC

Burton, Lovic, & Fleming, 2006See also Zhang et al., 2005Afonso et al., 2007; 2008; in prep

Severity

ActivityOpen-field test

Synapse Integrity

NAC and MPFCELEVATED BASAL

DA

‘Anxiety’Elevated plus maze

MaternalLicking/

Crouching

Early Experience

Family Instability

CORTISOL(area under curve)

Attention errors

Mothers Who Experienced Early Adversity Show Reduced Attention (CANTAB: Set-Shifting Task) and

Reduced Maternal ‘Sensitivity’

.27

Maternal Sensitivity

.

-.25.21

.21

Numbers=stand. β weights

Gonzalez et al., in prep

AttentionED Shift on CANTAB

Ainsworth Sensitivity

Rating Scales

Two Psycho- and Neuro-logical Systems That Mediate Adaptive (and Maladaptive) Mothering

Through their actions on the Maternal Neural Circuit and that are affected by early –life experiences

Hedonics

Attention/Flexibility

PFC

NAC

Doing

Wanting

Thanks to All My Students and Colleagues Without Whom These Studies Would Not Have Been Done

• Vedran Lovic • Emis Akbari• Veronica Afonso• Stephanie Rees• Marko Novakov• May Parada• Samantha King• Christie Burton• Stephanie Grella• Andrea Gonzalez• Meir Steiner• Joy Stallings• DIptendu Chatterjee• Diane RubleXavier and all the folks at St. Joseph’s Hospital