Dopamine: Another magic bullet in the regulation of Caregiver Responsivity? Notre Dame : Human Nature and the Early Experience:

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1 Dopamine: Another magic bullet in the regulation of Caregiver Responsivity? Notre Dame : Human Nature and the Early Experience: Centre for Research on Parenting University of Toronto Alison S. Fleming Students and colleagues

2 Maternal Behaviour: Human and Animal Models South bldg, 1966 St Joseph s, Hosp1907 Hedonics Affect Attention Memory mediated by Hormones Brain affected by NTs early experience genetics

3 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)

4 Dopamine system originates in the VTA and projects to the nucleus accumbens and the prefrontal cortex (PFC) (NAC)

5 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

6 We believe that these hormonal changes affect mothers maternal behavior by affecting brain systems and neurotransmitters related to Stimulus salience Reward Attention Affect Memory

7 Motivation to Nurture Stimulus Salience Reward a la Berridge & Robinson

8 Pup Retrieval General Licking Crouching

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

10 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

11 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, 1989

12 Virgin levels Lee, Fleming et al., 2000

13 Among Humans as well, New Mothers are Often Very Responsive to Their Infants soon after birth and are Attracted to Infants and their Cues

14 New Mothers (day 2pp) are More Attracted to Infant Body Odors, But Not to Control Odors, Than are Non-mothers (VAS, pleasantness) (0,6) Hedonics Rating Median (IQR) (-6,2) Infant T-shirt urine (-5,1) (-6,4) (-6,5) spice NEUTRAL (-6,2) Fleming, Corter, Franks, Surbey, Schneider., & Steiner, 1993

15 Mothers with More Postpartum Experience tend to also Find Infant Odors to be More Attractive 52,585 pos neg 2, ,370 15,318 1,10 105,375 Fleming, Corter et al., 1993

16 On 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., 2002

17 What about the role of BRAIN and the DOPAMINE system in mothers motivation to mother?

18 MATERNAL CIRCUIT: Brain Areas Associated with Maternal/Associated Behaviors MPOA is the FINAL COMMON PATH Inhibition of Maternal Behavior Olfactory Bulb Odor of Pups MPFC VTA VP VMH MAM MPOA NA Reinforce/ Memory attention Fear system mpfc: ATTENTION, Impulsivity MPOA and VMH: Maternal Behavior AMYGDALA: Emotions NAcc: Stimulus Salience, Rewards Motivation

19 MATERNAL CIRCUIT: Brain Areas Associated with Maternal/Associated Behaviors Here focus on the Nucleus Accumbens Inhibition of Maternal Behavior Olfactory Bulb Odor of Pups MPFC VTA VP VMH MAM MPOA NA Reinforce/ Memory attention Fear system mpfc: ATTENTION, Impulsivity MPOA and VMH: Maternal Behavior AMYGDALA: Emotions NAcc: Stimulus Salience, Rewards Motivation

20 Neural Model of MPOA Interaction with Mesolimbic" DA System and the Regulation of Maternal Responsiveness" tactile and olfactory" input from pups" GluR! out" D1" MPOA" GluR" DA" GluR! NOS" D1" NA" pup" stimuli" VP" VTA" GluR: glutamate receptor" NOS: nitric oxide synthase" DA" voluntary" maternal responses " to pup stimuli" Numan, M. (2007)

21 NAcc: Stimulus Salience, Rewards Motivation

22 Dopamine 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)

23 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, 2006

24 SAMPLING PROCEDURE SAMPLING Non-Homecage probe placement NACsh COLLECTION: 1uL/min for 8-min HPLC: Output Data Afonso et al., 2008,2009,

25 New mother rats and hormone primed rats show decreased dopamine release at baseline in comparison to cycling females

26 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., 2009

27 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) Cycling DA peaks quickly Postpartum

28 In 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 prep

29 Estrogen/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, 2009

30 Hormones 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.

31 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 circuit

32 Human Model Wonch, (unpub)

33 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

34 Own Unfamiliar > Prediction: BOLD response in all ROIs will be greater for own

35 fmri Protocol: Block design with own and other infant cry and smile faces presented in three runs, with distractor task between ISI ISI ISI

36 Activation of Limbic sites, especially NAC by own positive infant picture

37 Greater BOLD response to own infant over other infant > and to smiling faces over negative faces in NAC and Amygdala (not true of many control sites in cortex) on Positive Negative Right NAC Left NAC Positive Negative Right AMY Left AMY Right AMY Left AMY Own Unfamiliar

38 THESE 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;

39 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 )

40 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.

41 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.

42 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

43 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 Hospital