Download NEUROPEPTIDES: A WINDOW TO THE SOCIAL BRAIN Sue Carter, PhD The Kinsey Institute

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.