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Oliver Bosch
Dr. Max MustermannReferat Kommunikation & Marketing Verwaltung
Prof. Dr. Oliver BoschThe Maternal GroupDept for Behavioural and Molecular Neurobiology
University of Regensburg
From Pair Bondto Partner LossNeuropeptidesare Indispensible
Oliver Bosch
Formation of social bonds
First & strongest social bond in life
infant to its mother
Evolutionary origin to form adult social bonds
Broad overlap in brain regions, pathways, neurotransmitters
Numan & Young, 2016 Horm Behav
Oliver Bosch
Animal model for social relationships
Prairie vole (Microtus ochrogaster)
‐ biparental species‐ socially monogamous‐ form enduring and selective pair bonds
e.g. Carter & Getz, 1993; Carter et al., 1995; DeVries et al., 2002; Young & Wang, 2004; Lim et al., 2004, 2007; Donaldson et al., 2010; McGraw & Young, 2010; Keebaugh et al., 2015; Johnson & Young, 2015; Walum & Young, 2018
Oliver Bosch
Assessing the pair bond in the laboratory
Partner Preference Test3 hour duration, Score huddling2X with partner = PP
‐ oxytocin (OT) ‐ vasopressin‐ CRF ‐ dopamine
© L. Young
e.g. Carter & Getz, 1993; Carter et al., 1995; DeVries et al., 2002; Young & Wang, 2004; Lim et al., 2004, 2007; Donaldson et al., 2010; McGraw & Young, 2010; Keebaugh et al., 2015; Johnson & Young, 2015; Walum & Young, 2018
Partner Neutral Stranger
0
20
40
60
80
100
120
Time in com
partmen
t [min]
PartnerNeutralStranger
Prairie vole Montane vole
Oliver Bosch
nonapeptide
synthesized in hypothalamus
one type of GPCR OTR
functions
peripherally uterus contractionmilk ejection reflex
centrally neurotransmitter/‐modulator positive emotions social behavior buffers against stressors
The oxytocin system
Jurek & Neumann, 2018 Physiol Rev
Oliver Bosch
Oxytocin facilitates the pair bond in both sexes
Higher OTR densities in the NAc of prairie volesthan in non‐monogamous vole species
e.g. Liu & Wang 2003; Ross et al. 2009a,b; Keebaugh & Young 2011; Keebaugh et al., 2015; Johnson et al., 2016; King et al., 2016; Schneidermanet al., 2012; Scheele et al., 2013; Hurlemann & Scheele, 2016
prairie vole
montane vole
Natural genetic polymorphism in the OTR gene robustly influences OTR density in the NAc predicts partner preference formation
OT signaling in the NAc requiredfor partner preference formation
In humans: less evidence
But intranasal OTmen rate attractiveness of
their partners higher heightened NAc activation
Oliver Bosch
Oxytocin facilitates benefits arising from positive social relationships
For example: decreased risk for cardiovascular disease decreased risk for infectious disease increased stress resilience reduced likelihood to develop depression
and anxiety disorders
e.g. Clayton & Darvish, 1979; House et al., 1988; Berkman, 1995; Biondi & Picardi, 1996; Uchino et al., 1996; Zisook et al., 1997; Shear & Shair, 2005; Hensley et al., 2009; Resendez & Aragona, 2013
Positive social relationships essential for healthy psychological development
and well‐being
Oliver Bosch
Partner presence acts soothing after stress‐ role of oxytocin in the PVN
Recovery in presence of partner
observer increases social behavior
Smith et al., 2014 Biol Psychiatry
which ‐ in turn ‐ prolonges OT release inthe PVN of demonstrator
1h stress(immobilization)
recovery alone
recovery with partner
anxietycorticosterone
↑ ↑
↔ ↔
Oliver Bosch
Mediated via OT signaling in the anterior cingulate cortex linked to empathy in humans Lamm et al., 2011
Burkett et al., 2016 Science
I feel for you‐ observer shows consoling behavior
Oliver Bosch
Consequences of partner‐loss
Negative impact on physiological and mental health
For example, with loss of spouse
the odds of physical illness can increase by 40x
mortality rates double in first year
depressive symptoms develop in appr. 40% ofindividuals within one month
e.g. Clayton & Darvish, 1979; House et al., 1988; Berkman, 1995; Biondi & Picardi, 1996; Uchino et al., 1996; Zisook et al., 1997; Shear & Shair, 2005; Hensley et al., 2009; Resendez & Aragona, 2013; Sun et al., 2014; Chen et al., 1999; Thompson et al., 1984; Boyle et al., 2011; Kaprio et al., 1987; Schaefer et al., 1995
Prairie vole animal model Bosch & Young, 2018 CTBN
Oliver Bosch
Animal model for pair bond separation
Co‐housing for 5 days‐ with female partner fp‐ with male partner sp
Bosch et al., 2009 NPP
Oliver Bosch
paired separatedfp female partner sp sibling partner
Consequences of separation in males
floating [s]
0
20
80
60
40
fp sp
**
0
40
80
120
immob
ility [s]
fp sp
**
forced swim test tail suspension test
‐ increased passive stress‐coping infp separated1,2
‐ increased basal cort1,2 & adrenalweight in fp separated1
‐ increased CRF mRNA in mBNST in fp10
20
40
60
CRF mRN
Amea
n grain coun
t
fp sp
*
1Bosch et al., 2009 NPP2McNeal et al., 2013 Auton Neurosci
‐ increased heart rate in fp separated2
‐ overall effect of separation on anxiety1
Oliver Bosch
Consequences of short‐term separation in lactating mothers
0
10
5
20
fsfp
15
occu
rrenc
e/ h
0
20
10
40
30
ABN on nestblanket/contact
licking/grooming
25
unaltered maternal care…
Bosch et al., 2018 BehavBrainRes
entries0
30
70
floating
fsfp
50
time0
40
20
80
60
40
10
20
* (*)
time
[s]
60
*
perc
enta
geop
en a
rm [%
]
A B
…but increased emotionality
Oliver Bosch
Sun et al., 2014 Behav Brain Res
Co‐housing for 24 hrswith female partner
separated
testing after 2w and/or 4w
separation 2 weeks 4 weeks short‐term
passive stress‐coping not tested
anxiety not tested
partner preference yes no yes
aggression not tested not tested
plasma corticosterone
Consequences of long‐term separation
Oliver Bosch
Assessing the pair bond in the laboratory
Partner PreferenceCohabitation
‐ oxytocin (OT) ‐ CRF‐ vasopressin‐ dopamine
© L. Young
e.g. Carter & Getz, 1993; Carter et al., 1995; DeVries et al., 2002; Young & Wang, 2004; Lim et al., 2004, 2007; Donaldson et al., 2010; McGraw & Young, 2010; Keebaugh et al., 2015; Johnson & Young, 2015
Partner Neutral Stranger
Oliver Bosch
0 5 10
FS TS PPsurgery
day
paired separated or paired
3 8 9
Experimental schedule
Bosch et al., 2009 NPP
osmotic minipump
flow moderator
vinyl tubingholder
infusioncannula
neuropeptidesCRF
Urocortin1Urocortin2Urocortin3
receptors
CRF‐R1
CRF‐R2
CRF‐binding protein
The brain CRF system
Oliver Bosch
0
40
80
120
floating [s]
0
40
80
120
VEH CRF‐R1 ant CRF‐R2 ant
*#
##
0
60
120
180
immob
ility [s]
VEH CRF‐R1 ant CRFR‐2 ant
*
##
##
floating [s]
0
20
80
60
40
VEH0
40
80
120
immob
ility [s]
CRF‐R antVEHCRF‐R ant
* *
paired separated
Effects of chronic central CRF‐R blockade
CRF‐R‐blockade prevents passive stress‐coping after separation‐ without affecting partner preference
Bosch et al., 2009 NPP
hudd
ling [m
in]
0
60
100
stranger partner
VEH CRF‐R ant
* * **
20
40
80
Partner preference test
stranger partner
Oliver Bosch
fp VEH fs VEH fs D-Phe
0
4
8
12
16
-60 -30 +30 +60 +90
mea
noc
cure
nce
[n]
####
ABN
++
++treat
men
tinf
usio
n
emotionality
entries0
30
70
floating
50
time0
40
20
80
60
40
10
20
time
[s]
60
perc
enta
geop
en a
rm [%
]
**
**
Effects of acute central CRF‐R blockade on single moms
maternal care
CRF‐R‐blockade normalizes maternal care and emotionalityfollowing separation‐induced stress
Oliver Bosch
What do we know about the Nacc?CRF system in prairie voles
‐ CRF immunoreactive fibres and CRF receptors Lim et al., 2007
‐ CRF‐R2 more and CRF‐R1 less abundant in monogamous versusnon‐monogamous vole species Lim et al., 2005
‐ pair bond formation is facilitated by acute CRF signalling in the NAccDeVries et al., 2002; Lim et al., 2007
CP
LV
NAcc shell / core
…and in rats
‐ severe stress switches CRF actions from being appetitive to aversive Lemos et al., 2012
‐ CRF‐R activation increases depressive‐like behaviorChen et al., 2012
‐ In NAcc shell of rats, OT axons mainly from PVNRoss et al., 2009
‐ OT mediates social buffering against stressors in female prairie volesSmith and Wang, 2014
‐ In rats, >99% of OT neurons in the hypothalamus co‐express CRF‐R2Dabrowska et al., 2011
OT system
Oliver Bosch
Venus Merge
0
90
120
150
OT
mR
NA
[gra
yde
nsity
]
*
30
60
paired separatedfp female partner sp sibling partner
0
90
120
30
60
PVN SON
sp0
60
80
100
OTR
bin
ding
[gra
yde
nsity
]
fp
*
20
40
spfp
NAcc shell NAcc core
0
60
80
100
20
40
NAcc shell
PVN
Oxytocin neurons in PVN and NAcc shell
OT
90% of OT fibres innervating NAcc shelloriginate from PVN
(OT‐Venus virus)
Bosch et al., 2016 PNEC
Oliver Bosch
90% of OT fibres innervating NAcc shelloriginate from PVN
(OT‐Venus virus)
OT Venus Merge
3V 3V3V**
***
***
*
*
*
*
*
*
*
*
*
*
OTCRF-R2Merge
Co‐localization of CRF‐R2 on OT neurons(immunohistochemistry)
NAcc shell
PVN
Oxytocin neurons in PVN and NAcc shell
Bosch et al., 2016 PNEC
Oliver Bosch
0
10
20
30
40flo
atin
g[s
]
vehicle
##
paired separated
CRF-R2 ant
*
CRF-R2
*
OT0
20
100
float
ing
[s]
vehicle
*
##
40
60
80
paired separated
60
100
180
sample 1 2 3 4 5
OT
[% b
asel
ine]
20
140
*
*
vehicle CRF-R2 antCRF-R2
infusion
*
*
ICV
Separation impairs OT signalling via CRF‐R2 activation in NAcc
OTR ant
**++
++
Bosch et al., 2016 PNEC
Oliver Bosch
Ephys evidence for CRF‐R2 – OT neuron interaction in PVN
recordings from OT axons in the NAcc not feasible record from PVN neurons
Identification via double‐labelling OT‐Venus
Activation of CRF‐R2 by stresscopin
acts primarily at pre‐synaptic locus to regulate excitatory drive onto OT neurons
CRF‐R2 activation decreases glutamate drive and excitability of OT neurons
JoannaDabrowska
Bosch et al., 2016 PNEC
Oliver Bosch
well‐being ↑ well‐being ↓
separation acts as chronic stress
encourages reunionwith the partner
In humans:activated NAcc incomplicated griefO’Connor et al., 2008Tobias Pohl
Bosch & Young, 2018 CTBNPohl et al., 2019 Int J Psychophysiol
Oliver Bosch
Martina FuchsGabi Schindler
The Neumann Lab
Meera ModiTodd Ahern
Catherine BarrettAlaine KeebaughZachary Johnson
Valery Grinevich
NIH, NSF
GRK 2174GRK 2174
Tobias Pohl
Joanna Dabrowska
Maurice Manning
Larry Young
