Financial Disclosure. Oxytocin: A Maternal Hormone 02/01/2017. Labor Nursing Maternal Bonding. Neurobiology of Social Relationships: Implications

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1 Neurobiology of Social Relationships: Implications for ASD Larry J. Young, PhD Department of Psychiatry Conte Center for Oxytocin and Social Cognition Emory University Financial Disclosure Consultant: Trigemina, Inc. I will not discuss any data of any product produced by Trigemina, Inc. Oxytocin: A Maternal Hormone Labor Nursing Maternal Bonding 1

2 Oxytocin and Maternal Attachment Pair bonding evolved by tweaking mechanisms that promote maternal bonding? Rilling and Young, Science 214 Isolation Induced Ultrasonic Vocalizations in RKO Mice Assessing the Pair Bond in the Laboratory Social Learning 14 Number of calls / 3minutes WT KO Cohabitation With or without mating 6-24 hrs Drug manipulations 2 week Partner Neutral Stranger Partner Preference 3 hour duration Score huddling 2X with partner = PP Proximity to Mother Partner Preference Test Latency (sec) Wildtype KO Partner Stranger Trial Number 2

3 Central Oxytocin Stimulates Pair Bonding in Males and Females and AVPR Knockout Mice Have Social Amnesia % with preference No mating plus oxytocin CSF Mating plus antagonist (A) CSF A * * Duration (Sec) Social Stimuli New Female Non-Social Stimuli Knockout Wildtype new scent Insel and Hulihan, 1995 Ferguson et al., 2; Bielsky 26 Diversity in Social Organization in Voles Prairie Vole Meadow Vole Chemistry of Pair Bonding Oxytocin: Perception of social stimuli. Dopamine: Reinforcement learning. Highly Social Social Monogamy Biparental Solitary Promiscuous Uniparental Opiates: Hedonics (feel good) Oxytocin Receptors In PFC and Nacc and Bonding A Neural Model for Pair Bond Formation Wow! Who was that!?! Prairie Vole Meadow Vole PFC Cortex CP LS Cerebellum NAcc VP Hyp VTA Dopamine MeA/BST Young et al., 21 Oxytocin 3

4 Increasing the Saliency of Social Stimuli Horm Behav 216 A Unexposed Mating/veh Mating/A Perception of Olfactory Signature How does affect brain activity during social bonding How Does early life experience affect later social behavior? Antagonist or CSF 9 min Fos ICC A measure of neural activity Barrett and Young, Trans Psychiatry 215 A Early life separation (3hr/day, d 1-14) impairs pair bonding in females Horm Behav 216 Barrett et al., Transl. Psychiatry 215 4

5 Individual Variation in OXTR in Striatum And Resilience to Early Social Isolation Prairie Voles 3 hr daily neonatal social isolation Barrett et al., Transl. Psychiatry 215 Rilling and Young, Science 214 Tactile stimulation activates PVN neurons 5min sacrifice Stimulated Handled 1hr isolation 1hr isolation TS H Extraordinary Individual Variation in OXTR Density is Restricted to the NAcc and Caudate EGR1 NAcc NAcc Barrett et al., Transl. Psychiatry 215 King et al., Biol Psych in Revision Oxtr C/T C/C T/T 216 5

6 An intronic SNP robustly predicts Oxtr Expression Oxtr 7kb Central Antagonist Administration Blocks Consoling Behavior C/T T/T C/T C/C T/T C/T C/C T/T C/T C/C King et al, Biol Psych 216 Burkett, De Waal and Young, Science 216 In Humans the ACC and mpfc are Activated During Empathetic Response Tone-shock stressor Separation only Baseline Observe paired response Science 216 Singer et al., 24 Consoling Behavior following Stessor of a Partner Science, 216 Burkett, De Waal and Young, Science 216 6

7 Do animals feel empathy? "We should think of ourselves as a part of a continuum," says Larry Young, a neuroscientist at Emory University. "These animals have some basic fundamental underlying neural mechanism that cause them to engage in a behavior similar to what we do." 187 families 132 fathers 178 mothers 163 siblings Face Memory Task Skuse, et al, Young, PNAS 214 Biological Psych 212 PNAS 214 Functional Connectivity with other nodes of the Reward system in healthy (TD) and ASD youth. PNAS 213 7

8 Intranasal and ASD PNAS 21 PNAS 213 Biol. Psychiatry 26 Mol Psych 215 Intranasal Oxytocin in Humans Trust Eye Contact Face Recognition Empathy Salience of Social Stimuli Reinforcing value of social cues PNAS 213 Our conclusion is that intranasal studies are generally underpowered and that there is a high probability that most of the published intranasal findings do not represent true effects. Brain 215 8

9 Effect of MC4R agonist on Partner Preference Formation Placebo Oxytocin Change in Parent-rated Social Responsiveness Scores N=31, Age 3-8 Placebo-controlled cross-over 12 IU IN- 2 x per day 5 week treatment 4 week washout Red shift to right indicates Improved SRS scores Time Spent (min) Short Term 1 week later 6 * * Partner 4 Stranger mg/kg 1 mg/kg 1 mg/kg mg/kg 1 mg/kg Time Spent (min) MC4R Agonist Dose MC4R Agonist Dose Strategies for Drug Development for Autism Spectrum Disorders Activating neurons with MC4R agonist rescues social deficits induced by post-natal isolation Oxytocin Neuron MTII Sal Oxytocin EGR-1 Barrett and Young, Translational Psych. 215 Evoking Endogenous Dendritic Oxytocin Release using Melanocortin Agonists Central administration of MTII alone does not activate PFC or NAcc Dendrite Local Release in PVN but not in Projections ICV MT II 6 min c-fos positive cells (% of control) c-fos expression- homecage condition * acsf MTII Axon Priming the System PFC PFC NAcc NAcc PVN CeAmyg Johnson and Young, NBB 217 Fos Kittelberger et al., unpublished data 9

10 Social contact induces MT II mediated PFC and Nacc activation ICV MT II 3 c-fos expression - Social Context 6 min c-fos positive cells (% of control) * * * * acsf MTII Fos PFC NAcc PVN CeAmyg Kittelberger et al., unpublished data Young, Barrett Science 215; 347: MT II enhanced activation in social context requires OXTR signaling ICV MT II + antag 6 min Fos A A A PFC NAcc PVN CeAmyg Kittelberger et al., unpublished data Young Lab Current Jamie LaPrairie Kiyoshi Inoue Aaron Smith Hasse Walum Elissar Andari Katie Barrett Lani King James Burkett Zack Johnson Kara Kittelberger Byron Gardner Liz Ann Amadei Lorra Mathews Acknowledgements Collaborators Oliver Bosch Frans DeWaal Supported by: NIMH NSF Autism Speaks Adjunct to Behavioral Therapies 1