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NEUROPEPTIDES: A WINDOW TO THE SOCIAL BRAIN Sue Carter, PhD The Kinsey Institute Rudy Professor of Biology Indiana University, Bloomington SOCIAL BEHAVIOR is most easily understood in the context of evolution. Most positive social behaviors directly or indirectly support SURVIVAL social support & safety REPRODUCTION access to mates care of offspring genetic survival CONTEXT: Survival is the first law of nature. It is biologically important that we are not alone. At the Edge of the Desert by Robert Bissell CONTEXT: Sociality has survival benefits. There is safety in numbers. The Lookouts by Robert Bissell Context Most living organisms – even bacteriacan NOT SURVIVE OR REPRODUCE ALONE. The mammalian nervous system Especially functions optimally in a supportive SOCIAL environment. Social behavior is necessary for physiological and behavioral What homeostasis. Myron Hofer called “Hidden regulators” In the ABSENCE Abuse of of appropriate Drugs social interactions Food, & social bonds Mental (i.e. ISOLATION) Dysfunction, ? Substitutions May occur In the ABSENCE of appropriate Depression social interactions, Illness during forced or Shut-down self-induced even, Death ISOLATION Other reactions May occur The need for social bonds and social support is not limited to humans Photo by Jessie Williams The EVOLUTIONARY prototype for SOCIAL BONDS and LOVE in mammals is the mother-child interaction WHEN DO SOCIAL BONDS FIRST FORM OR APPEAR? In association with birth and lactation. The dependence of humans on oxytocin is best understood in the context of mammalian evolution. Historically breast-feeding was the only viable method for nourishing newborn humans – and other mammals. Oxytocin is essential for lactation and also important to birth, especially in humans with our large cranium and extended period of dependency on “mothers or others” Lactation may allow a new mother to manage stress more effectively.Less reactivity or more appropriate reactions to stressors, including stressful stimuli associated with child rearing. NURSING and the physiology of lactation are a buffer between the physiological state of pregnancy & the postpartum period - in part through effects of OXYTOCIN. One model for understanding the functions of OXYTOCIN is the Lactating Woman Lactation has major effects on the Maternal Brain & HPA axis HUMAN BIRTH presents special problems because of our • BIG CORTEX and SKULL, • BIPEDAL LOCOMOTION and • SMALL, RIGID PELVIC GIRDLE OXYTOCIN FACITATES BIRTH by STRONG UTERINE CONTRACTIONS OXYTOCIN Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 9 amino acids configured as a ring and a tail Oxytocin was classically viewed as a “FEMALE REPRODUCTIVE” Hormone, Acting primarily On the UTERUS And MAMMARY GLAND. This is only part of the story! PVN SON Post. Pituitary Oxytocin is released into the blood stream at the Posterior Pituitary, but is also released within the nervous system. Oxytocin can affect social behavior, the autonomic nervous system and the immune system,allowing the body to ADAPT, protect and heal itself in the face of challenge. Oxytocin given peripherally (IP) activates OLFACTORY BULB, BRAIN STEM AND CEREBELLUM Front. Behav. Neurosci., 17 September 2015. Distinct BOLD activation profiles following central and peripheral oxytocin administration in awake rats. C. F. Ferris, J, R. Yee, W. M. Kenkel, K.M. Dumais, K. Moore, A. H. Veenema, P, Kulkarni, A. M. Perkeybile, & C. S. Carter OXYTOCIN, administered as an intranasal spray influences physiology, the brain and esp. SOCIAL BEHAVIOR AND THE MANAGEMENT OF STRESS including CONTEXT DEPENDENT: Reductions in HPA activity Increases in measures of “Trust” Increased attention to social stimuli Increased social connectedness Increased brain activity in regions associated with social behavior Decreases in fear, socially bold? EARLY ADVERSITY MAY CHANGE THE RESPONSE TO EXOGENOUS OXYTOCIN OR VASOPRESSIN Oxytocin is not only central to the biology of social behavior, social bonds, social support, sexual behavior but also may have permitted the EVOLUTION OF THE HUMAN NERVOUS SYSTEM. The human nervous system is a consequence of evolution, with a massive increase in the cerebral cortex OXYTOCIN (OT) Reptile Human OXYTOCIN allows the transition from reptile to mammal. OT permits birth (helps expel the large-brained baby from the uterus) OT permits post-birth nutrition & supports the baby (lactation/maternal behavior/alloparenting) OT facilitates oxygenation of the brain (myelinated vagus). PERMITS HUMAN COGNITION AND SOCIAL BEHAVIOR! The human nervous system is a consequence of evolution, with a massive increase in the cerebral cortex Fish Reptile Human But, older parts of the nervous system are still represented, and can influence the actions of more modern components. Much of the wiring comes UP from the body and lower brain regions, with fewer pathways that come down. This is why it is hard to use cognition to control emotion. THIS IS WHY LOVE AND OXYTOCIN ARE SO POWERFULIN REGULATING STATES AND EMOTIONS. OXYTOCIN permitted the EVOLUTION of the MAMMALIAN NERVOUS SYSTEM and eventually the EVOLUTION of the HUMAN NERVOUS SYSTEM and the COGNITIVE EXPERIENCES WE CALL “LOVE” Oxytocin is a neuropeptide hormone/neuromodulator… 1. made primarily in the brain (hypothalamus) & released into the blood supply at the posterior pituitary from which is acts on the uterus (birth) and Mammary tissue (milk ejection) 2.also released into the brain & spinal cord where it binds to OXYTOCIN receptors OXTRs) to influence behavior & physiology 3. possibly a major factor in the body’s capacity to PROTECT or HEAL in the face of either emotional or physical challenge/stress. 4. evidence for HEALING – partial list injured skin (burns), heart (cardiac infarct) bone (osteoporosis) intestines (intestinal bowel disease) brain (stroke) mental disorders (anxiety, depression autism, schizophrenia) 5. Oxytocin is an anti-inflammatory and anti-oxidant 6. May explain effects of probiotics, such as L. reuteri Oxytocin does not act alone – for example, OXYTOCIN has a sibling hormone VASOPRESSIN - from which it differs by 2 (of 9) amino acids OXYTOCIN (OT) Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 Arginine VASOPRESSIN (AVP) Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 The EVOLUTION OF HUMAN SOCIALITY involves: A dynamic dance between Oxytocin and Vasopressin (both of which are critical to mental health) Oxytocin facilitates SOCIAL ENGAGEMENT And a Sense of Safety (love, empathy, compassion, relaxation) Vasopressin may allow DEFENSE OF SELF AND OTHERS (vigilance, hypermobilization, territoriality, arousal) Particularly helpful to our understanding of social behavior, especially SELECTIVE social behaviors, social bonds, as well as the neurobiology of OXYTOCIN and VASOPRESSIN have been SOCIALLY MONOGAMOUS RODENTS including - PRAIRIE VOLES, Microtus ochrogaster Physiological, especially neurobiological studies are most easily conducted in animals. What kinds of animals form true social bonds - that is have SELECTIVE social preferences or selective social behavior? Social bonds are most easily identified and studied in SOCIALLY MONOGAMOUS SPECIES. But such species are rare in mammals; only 3-5% of mammalian species are described as “monogamous.” Prairie voles can be studied in nature And in the Laboratory Oxytocin may be released under conditions that involve positive social interactions,including: Social Engagement & Pair bonding Sexual Behavior Paternal Behavior Maternal Behavior Alloparental Behavior (pup exposure) TRAITS OF PRAIRIE VOLES SHARED WITH HUMANS (not in mice) SOCIAL MONOGAMY (rare in mammals, common in birds) Pair bond formation & High levels of social contact Biparental & alloparental behavior Incest avoidance Social induction & suppression of reproduction Not dependent socially on gonadal hormones HIGH LEVELS OF OXYTOCIN (4X levels in rats) EPIGENETIC REGULATION OF OXTR (Shared CpG SITES) HIGH LEVELS OF PARASYMPATHETIC ACTIVITY (human-like) PRAIRIE VOLES, Microtus ochrogaster Oxytocin does not act alone – for example, OXYTOCIN has a sibling hormone VASOPRESSIN - from which it differs by 2 (of 9) amino acids OXYTOCIN (OT) Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 Arginine VASOPRESSIN (AVP) Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 Oxytocin and Vasopressin evolved from an ancestral molecule, that preceded the evolution of Vertebrates, but have different actions: PEPTIDE: OXYTOCIN VASOPRESSIN Gen. effects On Behavior: PROSOCIALITY Social attention DEFENSIVENESS Territoriality Emotions & Patterns of Coping: Relaxation/Recovery “Immobilization without fear” PASSIVE Vigilance Mobilization & Anxiety ACTIVE Effects on Healing: CHRONIC HEALING ACUTELY PROTECTIVE PARASYMPATHETIC And the Nervous system & Autonomic Nervous syst: SYMPATHETIC N.S SYMPATHETIC Nervous system Oxytocin supports or permits PATERNAL BEHAVIOR, as well As Maternal Behavior. But the physiology of fatherhood is not identical to motherhood (no pregnancy, birth or lactation) Care of infants (alloparenting) is not limited mothers, and is not limited to biological offspring or relatives. Babies in general are powerful “sign stimuli.” HOWEVER…. Not everyone is prepared to be a parent, and some of us may need hormonal help. BABIES also released OXYTOCIN in human fathers (and grandfathers and alloparents) The same hormones that affect mothering, also influence FATHERING –Although in slightly different ways. FATHERS MAY BE PARTICULARLY PROGRAMMED TO PROTECT THEIR CHILDREN, POSSIBLY IN PART THROUGH THE EFFECTS OF VASOPRESSIN – BUT THIS CAN COME WITH A BIOLOGICAL OR BEHAVIORAL PRICE. Hormones, like OXYTOCIN and VASOPRESSIN, are ADAPTIVE and can protect both father and child. Prairie Voles – When presented with a Pup Most Show Alloparental or Parental Behavior Including Reproductive Naïve Males (Parenting is does not require learning or experience in this species.) Baby vole – The size of a peanut but much more behaviorally powerful In Male Prairie Voles that have NO previous experience with young, a single brief exposure to a pup can release a brief surge of OXYTOCIN Blood levels of OXYTOCIN increased in MALES, but NOT females immediately following 10 min PUP EXPOSURE 900 800 700 MALES n=8 * FEMALES Empty Cage 600 Pup-exposed 500 n=8 400 400 n=8 350 n=9 300 n=8 n=9 300 n = 20 n = 18 250 200 200 150 100 100 50 0 0 15 min 45 min 15 min Kenkel, Paredes, Yee, Pournajafi-Nazarloo, Bales, & Carter, 2013 45 min Will Kenkel MALE PARENTAL BEHAVIOR in particular involves: A dynamic dance between Oxytocin and Vasopressin Oxytocin facilitates SOCIAL ENGAGEMENT And a Sense of Safety (immobility without fear) Vasopressin may allow DEFENSE OF SELF AND OTHERS (vigilance, hypermobilization, territoriality, arousal) Oxytocin also may be released under conditions that are negative or acutely “stressful,” Including in response to: 1.Social challenges (esp. same-sex intruders) 2. Forced restraint/immobility 3. Immune challenge (LPS) 4. Chronic social isolation (females) Oxytocin serves as a component of an adaptive, coping strategy, buffering against stressors, with effects that in some cases differ in males and females. WHAT IS OXYTOCIN?? A component of the social nervous system and stress axis, capable of regulating and integrating diverse processes including social behaviors associated with SOCIAL BONDING and SOCIAL SUPPORT Healing through anti-inflammatory and anti-oxidant effects on injured tissues, production of new cells, including NEURONS and through effects on the AUTONOMIC NERVOUS SYSTEMS (esp. the parasympathetic nervous system/vagus, which is PROTECTIVE) WHAT IS OXYTOCIN? An important neuropeptide with broad effects on physiology and behavior, in BOTH SEXES and during DEVELOPMENT. WHAT OXYTOCIN IS NOT? NOT a substitute for love. NOT well understood or studied, esp in humans. NOT something to be treated casually. For example: even in animal models we do NOT KNOW the effects of CHRONIC oxytocin on BRAIN? BEHAVIOR? IMMUNOLOGY? etc WHAT IS OXYTOCIN? One component of a complex and interactive systems of feedback loops with effects throughout the body, which may indeed allow us to shift to states compatible with social behavior and healing Do early hormonal manipulations including EXOGENOUS OT have long-lasting effects on OXYTOCIN OR VASOPRESSIN PEPTIDES? Yes VASOPRESSIN PEPTIDE (measured by immunoreactivity) DECREASED in MALES exposed to an OTA. After EXOGENOUS OT or OTA, OXYTOCINimmunoreactivity in hypothalamus… Increased Slightly in males, and Increased Significantly in FEMALES Oxytocin administered to a term pregnant female (induction of labor model) affects methylation of the oxytocin receptor in the brains of FEMALE pups Female Region Female Region 33 P < 0.0001 * DNA Methylation (%) DNA Methylation (%) 2525 * 2020 1515 1010 5 5 0 0 -934 -934 -924 -924 -901 -901 CpG Site (homologous human) CpG Site (homologous toto human) * The highest doses of OT (Pitocin) produced a none (n=9) none (n=9) saline (n=9) significant increase in DNA saline (n=9) low (n=6) methylation of the OXTR. low (n=6) medium (n=8)This effect was seen in 3 medium (n=8) high (n=6) high (n=6) separate CpG sites. This example is from hindbrain, but the effects were similar in forebrain and midbrain sections Two way ANOVA; *Bonferroni’s multiple comparison OT (high) vs. Saline, p<0.05 Jess Connelly # Vocalizations in 5 min. A comparable treatment increased vocalizations behavior in infants later in life 600 500 400 300 200 100 0 * * PND-1 PND-4 Control OT Will Kenkel CAN MATERNALLY-INJECTED OT (PITOCIN) REACH THE INFANT? Yes – at least in prairie voles * 700 plasma OT pg/mL 600 500 400 300 200 100 (n=7) (n=6) Saline OT 0 Fetal plasma OT increased following maternal OT treatment DNA Methylation (%) This increase in OTR may be due (at least in part) to DECREASED OTR Promoter Methylation, seen Following Maternal OT Treatment (LABOR AUGMENTATION) LOW DOSE OF OT (single injection) * Saline (n=8) OT (n=8) CpG Site (homologous to human) WHEN DOSES OF MATERNAL OT (PITOCIN) WERE HIGH (4 injections), THE EFFECTS WERE THE OPPOSITE: INCREASED METHYLATION OF THE OXTR, AND DECREASED GENE EXPRESSION FOR THE OXTR. VASOPRESSIN V1a RECEPTOR GENE EXPRESSION WAS DECREASED FOLLOWING A HIGH DOSE OF OT (PITOCIN) DURING BIRTH (LABOR AUGMENTATION). Methylation of the OXTR, which can be measured in DNA extracted from blood may be a “proxy” for receptor expression. High methylation – low gene expression – low capacity to respond to OXYTOCIN. For example, OXTR DNA methylation is associated with postpartum depression Bell…Connelly, Frontiers in Genetics 2015 Women who experience postpartum depression exhibit increased methylation at OXTR ALSPAC study (n=576) EPDS >13 PPD OXTR CpG site -934 DNA Methylation (%) 50 rrier 8 Cases 7 Controls 48 46 44 42 40 Odds Ratios (95% CIs) for SNP rs53576 GG vs. A Carrier OR of Likelihood of Postpartum Depression Postpartum Depression Cases Controls No Depression GG A carrier rs53576 6 5 4 3 2 1 0 10%ile (38.4) 25%ile (42.1) 50%ile (46.5) 75%ile (50.8) 90%ile (55.3) Level of Methylation at Site CpG -934 Jessica Connelly Bell … Connelly 2015 Front. Genetics Conclusions: In prairie voles OXYTOCIN EXPOSURE EPIGENETICALLY PROGRAMS THE DEVELOPING NERVOUS SYSTEM and SUBSEQUENT BEHAVIOR with EFFECTS that are due in part to: •Sex differences (MALES ESPECIALLY SENSITIVE POSTNATALLY?) •Dose dependency (LOW DOSES MAY ENHANCE SOCIAL BEHAVIOR? • HIGH DOSES APPEAR DISRUPTIVE TO SOCIAL BEHAVIOR AND MAY INHIBIT THE OXTR VIA INCREASED METHYLATION •Age-dependency (Sensitive periods - EARLY EFFECTS LONG LASTING) •Changes in ENDOGENOUS PEPTIDES, incl VASOPRESSIN •Changes in the Vasopressin Receptor (V1a)? Exogenous OT (POSTNATAL low doses in MALES) facilitated later social behavior: •INCREASED vasopressin V1a receptor binding in areas such as VENTRAL PALLIDUM associated with “reward” – (males only. •REDUCING vasopressin binding in areas implicated in anxiety and SEX DIFFERENCES ARE OFTEN NOT IDENTIFIED IN THE ABSENCE OF A CHALLENGE. *Male and female prairie voles do NOT typically differ in the distribution of either oxytocin or vasopressin RECEPTORS. (exception – Cortex?) Under optimal conditions BASAL OT is typically similar in males and females.Responses to acute stressors may appear similar, however In the face of challenges or stressors (possibly the stress of birth) – MALES AND FEMALES DIFFER in their RESPONSES including to: * Manipulations of OT/AVP during early life. * Effects of early experience (handling, nurture, etc) * Chronic stressors, such as isolation (females inc OT) MALES – ARE OFTEN MORE SENSITIVE TO THE POSTNATAL ENVIRONMENT • Evolved differential reproductive success (sperm vs eggs, subordination, etc) • XY vs XX genetics? Endogenous steroids • females – estrogen protective – may facilitate sociality - OT or OTR • males – androgens increase vulnerability, incl AVP -defense & vigilance? • MORE EPIGENETICALLY DEPENDENT ON OT/AVP POSTNATALLY Epigenetic mechanisms through which exposure to OXYTOCIN might influence behavior of the MOTHER or OFFSPRING BIRTH EXPERIENCE OT - NATURAL MATERNAL BRAIN OXYTOCIN RECEPTOR OXYTOCIN OTR DNA methylation OTR (down-regulation) ENDOGENOUS OXYTOCIN BEHAVIOR MATERNAL BEHAVIOR OFFSPRING SOCIAL BEHAVIOR Epigenetic mechanisms through which exposure to OXYTOCIN might influence behavior of the MOTHER or OFFSPRING BIRTH EXPERIENCE OT - NATURAL MATERNAL BRAIN OXYTOCIN RECEPTOR OXYTOCIN OTR DNA methylation OTR (down-regulation) ENDOGENOUS OXYTOCIN BEHAVIOR MATERNAL BEHAVIOR OFFSPRING SOCIAL BEHAVIOR OT – PITOCIN (or OTA?) HIGH DOSE (PAIN MEDS?) OTR DNA “hypermethylation?” OTR ENDOGENOUS OXYTOCIN ?? MATERNAL BEHAVIOR OFFSPRING SOCIAL BEHAVIOR esp MALES SEX DIFFERENCES ARE OFTEN NOT IDENTIFIED IN THE ABSENCE OF STRESSORS. *Male and female prairie voles do NOT usually differ in the distribution of either oxytocin or vasopressin receptors. *Also under optimal conditions BASAL OT is typically similar in males and females. However,…. In the face of challenges or stressors.. MALES AND FEMALES DIFFER in their RESPONSES including to: * Manipulations of OT/AVP during early life. * Effects of early experience (handling, etc) * Chronic stressors, such as isolation * Are FEMALES protected by more OT Receptors (in N, Accumbens) and perhaps the synthesis and release of endogenous oxytocin?? * MALES also may be normally protected by OT and/or AVP, but may be also dependent on and vulnerable to disruptions of AVP, especially in early life. Factors that disrupt AVP may leave males more “anxious,” vigilant, and “mobilized, and less capable of managing some kinds of social challenges, that require immobility – also to be continued…. Hypothesis: (see Carter, C.S. Behavioural Brain Research, 2007 for details): OXYTOCIN (and OTRs), which are ESTROGEN dependent, may be protective against some of the features of autism Possibly accounting in part for the fact that females are less likely than male to exhibit autism/ASD. VASOPRESSIN, which can be ANDROGEN dependent, may at high (or low?) levels, may be associated with a vulnerability to autism Possibly contributing to the MALE BIAS in AUTISM (ASD) PRADER-WILLI and FRAGILE-X symptoms: These may reflect decreases in functional OXYTOCIN and/or INCREASED sensitivity to VASOPRESSIN 1.OXYTOCIN IS DIFFICULT TO MEASURE 2.OXYTOCIN also can exist in several PRECURSOR or INTERMEDIATE/EXTENDED FORMS (minus the NH2 group) (Altstein & Gainer, 1988), ESPECIALLY IN FETAL LIFE, •OT (9 amino acids – CLASSIC OXYOCIN) •OT-Gly10 (10 amino acids) •OT-Gly10-Lys11 (11 amino acids) •OT-Gly10-Lys11-Arg12 (12 amino acids) 3. These forms can be biologically active or elevated in DISORDERS SUCH AS AUTISM, and especially during early/fetal life development promoting normal development and cell differentiation (Gutkowska & Janowski, 2012). However, the effects on DNA METHYLATION and the peptide receptors are not well understood. 4. Regarding the Developmental Consequences of Birth Manipulations: There are at present far more questions and gaps in knowledge than answers??? Exposure to an infant (and other forms of social behaviors as well) can increase oxytocin decreases stress hormones (cort) and we hypothesized might have either direct or indirect effects on NEUROGENESIS (birth of new neurons - even in the adult brain) Dentate gyrus (DG) is an area in which neurogenesis occurs even in adulthood. Levels of adult neurogenesis are high in prairie vole brains, compared to mice. BrdU-immunoreactivity in DG increases following PUP EXPOSURE indicating INCREASED NEUROGENESIS. Ruscio, Carter, et al., Dr. Lance W. Martin, Martin Protean Dr. Carter spoke for the first half of the talk, and then gave the floor to Dr. Lance W. Ma, of Martin Protean, Inc. Dr. Martin gave a beautiful presentation on the immense amount of work they have done in developing a commercial assay for the detection of oxytocin in the blood and cerebral spinal fluid, using Mass Spec and a number of other molecular assays. This work is not yet ready to be published.