Dopamine: Another magic bullet in the regulation of - Caregiver Responsivity? Alison S. Fleming
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Dopamine: Another magic bullet in the regulation of
Caregiver Responsivity?
Notre Dame : Human Nature and the Early Experience:
Alison S. Fleming
Students and colleagues
Centre for Research on Parenting
University of Toronto
Maternal Behaviour:
Human and Animal Models
South bldg, 1966 St Joseph’s, Hosp1907
Hedonics Hormones
mediated early experience
Affect Brain affected by
by
Attention NTs genetics
Memory
Today’s ‘magic bullet’ is to describe how maternal
behavior is affected by the dopamine system
• ONSET OF MB-today
–stimulus salience, ‘reward’
• Nucleus accumbens (NAcc)
• ONGOING QUALITY OF MB
–attention, response inhibition, memory
• Medial prefrontal cortex (mPFC)
Dopamine system originates in the VTA and projects
to the nucleus accumbens and the prefrontal cortex
(PFC)
(NAC)
HORMONES: Changes in the estrogen /progesterone ratio during pregnancy
associated with onset of PP maternal behavior (rats) and early attachment
attitudes (human)
In rats and humans •RAT
Prolactin,
Oxytocin, and
Glucocorticoids also
enhance mothering
•HUMAN
Reviewed in
Numan, Fleming, & Levy, 2006
• We believe that these hormonal changes affect mothers’ maternal behavior by affecting brain systems and neurotransmitters related to – Stimulus salience – Reward – Attention – Affect – Memory
‘Motivation’ to Nurture
Stimulus Salience
Reward
a la Berridge & Robinson
Pup Retrieval General Licking
Crouching
New Mother Rats are More Attracted to Lactating
Nest Odors than to Clean or Diestrous Nest Odor
Virgin Rats Show No significant Preference
pup nest-clean=0
Pre-part Post-part
Adapted from Bauer, 1983
Variances homogeneous See also Fleming et al.,, 1987, 1989
This shift from avoidance of pups prior to parturition to approach to pups after birth results from both – the increase in positive valence of pups – decrease in ‘fear’ and withdrawal tendencies Both must occur for mothers to retain proximity to young and care for them
Olfactory Preferences for Lactating Nest Odours
also shown by Virgins Primed with (P & E) Hormones
That also activate maternal behaviour in virgins
Fleming et al., 1987, 1989Virgin levels
Lee, Fleming et al., 2000Among Humans as well, New Mothers are
Often Very Responsive to Their Infants soon
after birth and are Attracted to Infants and their CuesNew Mothers (day 2pp) are More Attracted to
Infant Body Odors, But Not to Control Odors,
Than are Non-mothers (VAS, pleasantness)
(0,6)
(-6,5)
Hedonics Rating
(-6,2)
Median (IQR)
(-6,4)
urine
NEUTRAL
Infant spice
T-shirt (-5,1)
(-6,2)
Fleming, Corter, Franks, Surbey, Schneider., & Steiner, 1993Mothers with More Postpartum Experience tend
to also Find Infant Odors to be More Attractive
pos
52,585 neg
2,210
120,370
15,318
1,10
105,375
Fleming, Corter et al., 1993On self-report measures (VAS) new mothers are
more sympathetic , and more alerted, in response to
infant cries than are non-mothers. They also have
higher overall levels of heart rate.
VAS cry stimuli Heart-rate monitor Stallings et al., 2002What about the role of BRAIN and
the DOPAMINE system in mothers
motivation to mother?MATERNAL CIRCUIT: Brain Areas
Associated with Maternal/Associated Behaviors
MPOA is the FINAL COMMON PATH
Inhibition of Maternal Behavior Olfactory Bulb Odor of Pups
MPF
C
VMH
NA Reinforce/
VP MPOA
Memory
attention
MAM
VTA
Fear system
mPFC: ATTENTION, Impulsivity MPOA and VMH: Maternal Behavior
AMYGDALA: Emotions NAcc: Stimulus Salience, Rewards
MotivationMATERNAL CIRCUIT: Brain Areas
Associated with Maternal/Associated Behaviors
Here focus on the Nucleus Accumbens
Inhibition of Maternal Behavior Olfactory Bulb Odor of Pups
MPF
C
VMH
NA Reinforce/
VP MPOA
Memory
attention
MAM
VTA
Fear system
mPFC: ATTENTION, Impulsivity MPOA and VMH: Maternal Behavior
AMYGDALA: Emotions NAcc: Stimulus Salience, Rewards
MotivationNeural Model of MPOA Interaction with Mesolimbic"
DA System and the Regulation of Maternal
Responsiveness"
tactile and olfactory"
input from pups"
GluR!
MPOA"
GluR!
D1" NOS" D1" NA"
GluR"
out"
DA" pup"
stimuli"
VP"
VTA" DA" voluntary"
maternal responses "
GluR: glutamate receptor" to pup stimuli"
NOS: nitric oxide synthase"
Numan, M. (2007)NAcc: Stimulus Salience, Rewards
MotivationDopamine Action in Nucleus Accumbens is
important for retrieval behavior AND maternal
memory
established by use of
• Dopamine receptor agonist (D1) (Numan et. al., 2007)
• DA receptor antagonists (D1 &/ D2) (Li & Fleming, 2004ab;
Numan et al., 2005; Stern & Lonstein, 2001; Parada et al., 2008)Dopamine release is associated with mothering
(microdialysis studies assessing dopamine by HPLC)
Dopamine is Released in the Nucleus Accumbens in
response to pups and is affected by
1. Postpartum status
2. Hormones (gestational
/part)
3. Maternal Experiences
4. Early Postnatal Experinces
• Afonso et al., 2008,2009, in press; see also Champagne & Meaney, 2006SAMPLING PROCEDURE
SAMPLING probe placement
Non-Homecage
NACsh
COLLECTION:
1uL/min for 8-min
HPLC: Output
Data
Afonso et al., 2008,2009,New mother rats and hormone primed rats show decreased dopamine release at baseline in comparison to cycling females
New mother rats show sustained increased dopamine response
in NAC to pup stimuli; virgins do not
Postpartum
MATERNAL IN OWN CAGE,
NOT IN DIALYSIS CHAMBER
Cycling
NOT MATERNAL IN OWN CAGE
OR IN DIALYSIS CHAMBER
Parity diff /baseline covariate also sig at 16 and 24 Afonso et. al., 2009DA 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
Cycling
PostpartumIn PP animals, there is an increase in DA to pups,
but not to food, on simple exposure (no behavior).
Not so with cycling animals
Afonso, Shams, & Fleming, in prepEstrogen/Progesterone-primed virgin rats show sustained
increased dopamine response to pups in the absence of prior
pup-experience; control sham animals do not.
HORMONE
NOT MATERNAL IN HOME
CAGE OR IN CHAMBER
BUT SNIFFING PUPS
SHAM
NOT MATERNMAL IN HOME
CAGE OR IN CHANBER
Afonso, Burton, Novakov, & Fleming, 2009Hormones of pregnancy/part affect DA by reducing baseline levels, and hence by increasing the signal/ noise ratio when the signal (pups) are presented. DA system is therefore primed by hormones (and by experience) which functions to enhance salience of the pup stimulus.
NUCLEUS ACCUMBENS, AND DOPAMINE IN
HUMAN MOTHERS?
Hard to establish a role for dopamine in
human mothering.
Have embarked on a series of fmri
studies exploring activation patterns in NAC and
other brain sites in the maternal circuitHuman Model •Wonch, (unpub)
Brain fMRI Study:
New mothers presented with pictures of own and other infants in
fMRI magnet and measures BOLD response
Blood Oxygenation Level Dependent (BOLD) signal
indirect measure of brain activity summ of -postsynaptic poten across ROI)
20 (7 primiparous, 13 multiparous) 3-5 mo.
•Barrett, Wonch, Hall, Steiner, & Fleming, in prep•Own •Unfamiliar
•
>
•Prediction: BOLD response in all ROIs will be greater for ownfMRI Protocol: Block design with own and other
infant cry and smile faces presented in three
runs, with distractor task between
ISI ISI ISIActivation of Limbic sites, especially NAC by own ‘positive’ infant picture
Greater BOLD response to own infant over other >infant
and to smiling faces over negative faces in NAC and
on
Amygdala (not true of many control sites in cortex)
Right NAC
0.3 Left NAC Right AMY
Left AMY
0.5
0.25
0.45
0.4
0.2
0.35
0.3
0.15
0.25
0.2
0.1
0.15
0.1
0.05
0.05
0
0 Positive Negative
Positive Negative
Right AMY
Left AMY
0.5
0.4
0.3
0.2
0.1
0
Own UnfamiliarTHESE BEHAVIORAL AND
NEUROLOGICAL SYSTEMS ARE SET UP
BY EARLY NEONATAL AND
PREWEANING EXPERIENCES
As main effects and in interaction with genetics
In both rat and human mothers
Gonzalez & Fleming, 2001; Lovic & Fleming, 2004; Burton et al., 2008; Gonzalez et al., 2009;
Krpan et al., 2005; Giardino et al., 2008; zhang et al., 2005, Barret et al., in prep;A teaser Genetics Studies. In a recent study we related polymorphisms in dopamine and serotonin genes to maternal behaviour and to maternal ‘sensitivity’ in new mothers. We focussed on the interaction between gene polymorphisms and aspects of early experiences in the mothers’ family of origin. (n=166) (Mileva, Sokolowski, Meaney, Kennedy, Steiner, & Fleming, in prep )
• Environment moderates the genetic effects on
maternal behaviour in 6 mo. PP. mothers
Mothers with the GG genotype on DRD1 (rs686) marker look away
more frequently from their infants A) when they experience higher
levels of early adversity or B) when they report having greater
current stress in their lives.Summary • Young are first attractive, then rewarding, to the new mother as a result of both hormones and experience • Rewarding and salient young regulate mothers’ approach to and contact with the young. They enhance her motivation to mother.
Summary, cont’d • Attraction to young is mediated by the ‘reward’ dopamine system, especially the mesolimbic system possibly activated by E/P /Prl/OXY • The development of these brain systems are affected by previous experiences and by genetics
Thanks to All My Students, Colleagues, and participants Without Whom These
Studies Would Not Have Been Done
• Veronica Afonso
• Viara Mileva
• Jennifer Barrett
• Vedran Lovic
• Kathleen Wonch
• Diptendu Chatterjee
• May Parada
• Samantha King
• Meir Steiner
• Hiwote Belay
• Diane Ruble
• Marla Sokolowski
• Michael Meaney
Xavier and all the folks at St. Joseph’s HospitalYou can also read
