Aversion to environmental cues of predators is an integral part of defensive behaviors in many prey animals. It enhances their survival and probability of future reproduction. At the same time, animals cannot be maximally defended because imperatives of defense usually trade-off with behaviors required for sexual reproduction like display of dominance and production of sexual pheromones. Here, we approach this trade-off through the lens of arginine vasopressin (AVP) neurons within the posterodorsal medial amygdala (MePD) of mice. This neuronal population is known to be involved in sexual behaviors like approach to sexually salient cues. We show that chemogenetic partial ablation of this neuronal population increases aversion to predator odors. Moreover, overexpression of AVP within this population is sufficient to reduce aversion to predator odors. The loss of fear of the predator odor occurs in parallel with increased recruitment of AVP neurons within the MePD. These observations suggest that AVP neurons in the medial aspect of the extended amygdala are a proximate locus for the reduction in innate fear during life stages dominated by reproductive efforts.

1.
O’Connell
LA
,
Hofmann
HA
.
Genes, hormones, and circuits: an integrative approach to study the evolution of social behavior
.
Front Neuroendocrinol
.
2011
a
Aug
;
32
(
3
):
320
35
.
[PubMed]
0091-3022
2.
Bialy
M
,
Sachs
BD
.
Androgen implants in medial amygdala briefly maintain noncontact erection in castrated male rats
.
Horm Behav
.
2002
Nov
;
42
(
3
):
345
55
.
[PubMed]
0018-506X
3.
Wingfield
JC
,
Sapolsky
RM
.
Reproduction and resistance to stress: when and how
.
J Neuroendocrinol
.
2003
Aug
;
15
(
8
):
711
24
.
[PubMed]
0953-8194
4.
Fuelling
O
,
Halle
S
.
Breeding suppression in free-ranging grey-sided voles under the influence of predator odour
.
Oecologia
.
2004
Jan
;
138
(
1
):
151
9
.
[PubMed]
0029-8549
5.
Zanette
L
,
Clinchy
M
,
Smith
JN
.
Food and predators affect egg production in song sparrows
.
Ecology
.
2006
Oct
;
87
(
10
):
2459
67
.
[PubMed]
0012-9658
6.
Zanette
LY
,
White
AF
,
Allen
MC
,
Clinchy
M
.
Perceived predation risk reduces the number of offspring songbirds produce per year
.
Science
.
2011
Dec
;
334
(
6061
):
1398
401
.
[PubMed]
0036-8075
7.
Ferkin
MH
.
Odor Communication and Mate Choice in Rodents
.
Biology (Basel)
.
2018
Jan
;
7
(
1
):
7
.
[PubMed]
2079-7737
8.
Newman
SW
.
The medial extended amygdala in male reproductive behavior. A node in the mammalian social behavior network
.
Ann N Y Acad Sci
.
1999
Jun
;
877
1 ADVANCING FRO
:
242
57
.
[PubMed]
0077-8923
9.
O’Connell
LA
,
Hofmann
HA
.
The vertebrate mesolimbic reward system and social behavior network: a comparative synthesis
.
J Comp Neurol
.
2011
b
Dec
;
519
(
18
):
3599
639
.
[PubMed]
0021-9967
10.
Brennan
PA
,
Zufall
F
.
Pheromonal communication in vertebrates
.
Nature
.
2006
Nov
;
444
(
7117
):
308
15
.
[PubMed]
0028-0836
11.
Guthman
EM
,
Vera
J
.
A Cellular Mechanism for Main and Accessory Olfactory Integration at the Medial Amygdala
.
J Neurosci
.
2016
Feb
;
36
(
7
):
2083
5
.
[PubMed]
0270-6474
12.
Dorsa
DM
,
Petracca
FM
,
Baskin
DG
,
Cornett
LE
.
Localization and characterization of vasopressin-binding sites in the amygdala of the rat brain
.
J Neurosci
.
1984
Jul
;
4
(
7
):
1764
70
.
[PubMed]
0270-6474
13.
Rood
BD
,
De Vries
GJ
.
Vasopressin innervation of the mouse (Mus musculus) brain and spinal cord
.
J Comp Neurol
.
2011
Aug
;
519
(
12
):
2434
74
.
[PubMed]
0021-9967
14.
Bychowski
ME
,
Mena
JD
,
Auger
CJ
.
Vasopressin infusion into the lateral septum of adult male rats rescues progesterone-induced impairment in social recognition
.
Neuroscience
.
2013
Aug
;
246
:
52
8
.
[PubMed]
0306-4522
15.
Rood
BD
,
Stott
RT
,
You
S
,
Smith
CJ
,
Woodbury
ME
,
De Vries
GJ
.
Site of origin of and sex differences in the vasopressin innervation of the mouse (Mus musculus) brain
.
J Comp Neurol
.
2013
Jul
;
521
(
10
):
2321
58
.
[PubMed]
0021-9967
16.
Rood
BD
,
Beck
SG
.
Vasopressin indirectly excites dorsal raphe serotonin neurons through activation of the vasopressin1A receptor
.
Neuroscience
.
2014
Feb
;
260
:
205
16
.
[PubMed]
0306-4522
17.
DiBenedictis
BT
,
Nussbaum
ER
,
Cheung
HK
,
Veenema
AH
.
Quantitative mapping reveals age and sex differences in vasopressin, but not oxytocin, immunoreactivity in the rat social behavior neural network
.
J Comp Neurol
.
2017
Aug
;
525
(
11
):
2549
70
.
[PubMed]
0021-9967
18.
Smith
CJ
,
DiBenedictis
BT
,
Veenema
AH
.
Comparing vasopressin and oxytocin fiber and receptor density patterns in the social behavior neural network: implications for cross-system signaling
.
Front Neuroendocrinol
.
2019
Apr
;
53
:
100737
.
[PubMed]
0091-3022
19.
DiBenedictis
BT
,
Cheung
HK
,
Nussbaum
ER
,
Veenema
AH
.
Involvement of ventral pallidal vasopressin in the sex-specific regulation of sociosexual motivation in rats
.
Psychoneuroendocrinology
.
2020
Jan
;
111
:
104462
.
[PubMed]
0306-4530
20.
Dielenberg
RA
,
Hunt
GE
,
McGregor
IS
.
“When a rat smells a cat”: the distribution of Fos immunoreactivity in rat brain following exposure to a predatory odor
.
Neuroscience
.
2001
;
104
(
4
):
1085
97
.
[PubMed]
0306-4522
21.
Canteras
NS
.
The medial hypothalamic defensive system: hodological organization and functional implications
.
Pharmacol Biochem Behav
.
2002
Mar
;
71
(
3
):
481
91
.
[PubMed]
0091-3057
22.
Meredith
M
,
Westberry
JM
.
Distinctive responses in the medial amygdala to same-species and different-species pheromones
.
J Neurosci
.
2004
Jun
;
24
(
25
):
5719
25
.
[PubMed]
0270-6474
23.
Choi
GB
,
Dong
HW
,
Murphy
AJ
,
Valenzuela
DM
,
Yancopoulos
GD
,
Swanson
LW
, et al.
.
Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus
.
Neuron
.
2005
May
;
46
(
4
):
647
60
.
[PubMed]
0896-6273
24.
Maras
PM
,
Petrulis
A
.
Chemosensory and steroid-responsive regions of the medial amygdala regulate distinct aspects of opposite-sex odor preference in male Syrian hamsters
.
Eur J Neurosci
.
2006
Dec
;
24
(
12
):
3541
52
.
[PubMed]
0953-816X
25.
Goodson
JL
,
Kabelik
D
.
Dynamic limbic networks and social diversity in vertebrates: from neural context to neuromodulatory patterning
.
Front Neuroendocrinol
.
2009
Oct
;
30
(
4
):
429
41
.
[PubMed]
0091-3022
26.
Kondo
Y
.
Lesions of the medial amygdala produce severe impairment of copulatory behavior in sexually inexperienced male rats
.
Physiol Behav
.
1992
May
;
51
(
5
):
939
43
.
[PubMed]
0031-9384
27.
Blanchard
DC
,
Canteras
NS
,
Markham
CM
,
Pentkowski
NS
,
Blanchard
RJ
.
Lesions of structures showing FOS expression to cat presentation: effects on responsivity to a Cat, Cat odor, and nonpredator threat
.
Neurosci Biobehav Rev
.
2005
;
29
(
8
):
1243
53
.
[PubMed]
0149-7634
28.
Wang
Z
,
Bullock
NA
,
De Vries
GJ
.
Sexual differentiation of vasopressin projections of the bed nucleus of the stria terminals and medial amygdaloid nucleus in rats
.
Endocrinology
.
1993
Jun
;
132
(
6
):
2299
306
.
[PubMed]
0013-7227
29.
Ferris
CF
,
Delville
Y
,
Miller
MA
,
Dorsa
DM
,
De Vries
GJ
.
Distribution of small vasopressinergic neurons in golden hamsters
.
J Comp Neurol
.
1995
Oct
;
360
(
4
):
589
98
.
[PubMed]
0021-9967
30.
Wang
Z
,
De Vries
GJ
.
Androgen and estrogen effects on vasopressin messenger RNA expression in the medial amygdaloid nucleus in male and female rats
.
J Neuroendocrinol
.
1995
Nov
;
7
(
11
):
827
31
.
[PubMed]
0953-8194
31.
Mizukami
S
,
Nishizuka
M
,
Arai
Y
.
Sexual difference in nuclear volume and its ontogeny in the rat amygdala
.
Exp Neurol
.
1983
Feb
;
79
(
2
):
569
75
.
[PubMed]
0014-4886
32.
Cooke
BM
.
Steroid-dependent plasticity in the medial amygdala
.
Neuroscience
.
2006
;
138
(
3
):
997
1005
.
[PubMed]
0306-4522
33.
Auger
CJ
,
Coss
D
,
Auger
AP
,
Forbes-Lorman
RM
.
Epigenetic control of vasopressin expression is maintained by steroid hormones in the adult male rat brain
.
Proc Natl Acad Sci USA
.
2011
Mar
;
108
(
10
):
4242
7
.
[PubMed]
0027-8424
34.
Aste
N
,
Honda
S
,
Harada
N
.
Forebrain Fos responses to reproductively related chemosensory cues in aromatase knockout mice
.
Brain Res Bull
.
2003
May
;
60
(
3
):
191
200
.
[PubMed]
0361-9230
35.
Morris
JA
,
Jordan
CL
,
King
ZA
,
Northcutt
KV
,
Breedlove
SM
.
Sexual dimorphism and steroid responsiveness of the posterodorsal medial amygdala in adult mice
.
Brain Res
.
2008
Jan
;
1190
:
115
21
.
[PubMed]
0006-8993
36.
Ho
JM
,
Murray
JH
,
Demas
GE
,
Goodson
JL
.
Vasopressin cell groups exhibit strongly divergent responses to copulation and male-male interactions in mice
.
Horm Behav
.
2010
Aug
;
58
(
3
):
368
77
.
[PubMed]
0018-506X
37.
Hari Dass
SA
,
Vyas
A
.
Copulation or sensory cues from the female augment Fos expression in arginine vasopressin neurons of the posterodorsal medial amygdala of male rats
.
Front Zool
.
2014
a
Jun
;
11
(
1
):
42
.
[PubMed]
1742-9994
38.
He
F
,
Wu
R
,
Yu
P
.
Study of Fos, androgen receptor and testosterone expression in the sub-regions of medial amygdala, bed nucleus of stria terminalis and medial preoptic area in male Mandarin voles in response to chemosensory stimulation
.
Behav Brain Res
.
2014
Jan
;
258
:
65
74
.
[PubMed]
0166-4328
39.
Kabelik
D
,
Morrison
JA
,
Goodson
JL
.
Cryptic regulation of vasotocin neuronal activity but not anatomy by sex steroids and social stimuli in opportunistic desert finches
.
Brain Behav Evol
.
2010
;
75
(
1
):
71
84
.
[PubMed]
1421-9743
40.
Goodson
JL
,
Kelly
AM
,
Kingsbury
MA
.
Evolving nonapeptide mechanisms of gregariousness and social diversity in birds
.
Horm Behav
.
2012
Mar
;
61
(
3
):
239
50
.
[PubMed]
0018-506X
41.
Kelly
AM
,
Goodson
JL
.
Behavioral relevance of species-specific vasotocin anatomy in gregarious finches
.
Front Neurosci
.
2013
a
Dec
;
7
:
242
.
[PubMed]
1662-4548
42.
Kelly
AM
,
Goodson
JL
.
Functional significance of a phylogenetically widespread sexual dimorphism in vasotocin/vasopressin production
.
Horm Behav
.
2013
b
Nov
;
64
(
5
):
840
6
.
[PubMed]
0018-506X
43.
Harris
JA
,
Hirokawa
KE
,
Sorensen
SA
,
Gu
H
,
Mills
M
,
Ng
LL
, et al.
.
Anatomical characterization of Cre driver mice for neural circuit mapping and manipulation
.
Front Neural Circuits
.
2014
Jul
;
8
:
76
.
[PubMed]
1662-5110
44.
Xi
D
,
Long
C
,
Lai
M
,
Casella
A
,
O’Lear
L
,
Kublaoui
B
, et al.
.
Ablation of Oxytocin Neurons Causes a Deficit in Cold Stress Response
.
J Endocr Soc
.
2017
Jul
;
1
(
8
):
1041
55
.
[PubMed]
2472-1972
45.
Jiang
Z
,
Rajamanickam
S
,
Justice
NJ
.
Local Corticotropin-Releasing Factor Signaling in the Hypothalamic Paraventricular Nucleus
.
J Neurosci
.
2018
Feb
;
38
(
8
):
1874
90
.
[PubMed]
0270-6474
46.
Paxinos
G
,
Franklin
K
.
The Mouse Brain in Stereotaxic Coordinates
.
San Diego, California, USA
:
Academic Press
;
2001
.
47.
Royston
P
.
Remark AS R94: A remark on algorithm AS 181: The W-test for normality
.
J R Stat Soc Ser C Appl Stat
.
1995
;
44
:
547
51
.1467-9876
48.
Conover
WJ
,
Iman
RL
.
Rank transformations as a bridge between parametric and nonparametric statistics
.
Am Stat
.
1981
;
35
:
124
9
.0003-1305
49.
Motulsky
HJ
,
Brown
RE
.
Detecting outliers when fitting data with nonlinear regression - a new method based on robust nonlinear regression and the false discovery rate
.
BMC Bioinformatics
.
2006
Mar
;
7
(
1
):
123
.
[PubMed]
1471-2105
50.
Ruxton
GD
,
Beauchamp
G
.
Time for some a priori thinking about post hoc testing
.
Behav Ecol
.
2008
;
19
(
3
):
690
3
. 0198-5841
51.
Hedges
LV
,
Olkin
I
.
Statistical methods for meta-analysis
.
Academic press
;
2014
.
52.
Cohen
J
.
Statistical power analysis for the behavioral sciences
.
Routledge
;
2013
.
53.
Berdoy
M
,
Webster
JP
,
Macdonald
DW
.
Fatal attraction in rats infected with Toxoplasma gondii
.
Proc Biol Sci
.
2000
Aug
;
267
(
1452
):
1591
4
.
[PubMed]
0962-8452
54.
Hines
M
,
Allen
LS
,
Gorski
RA
.
Sex differences in subregions of the medial nucleus of the amygdala and the bed nucleus of the stria terminalis of the rat
.
Brain Res
.
1992
May
;
579
(
2
):
321
6
.
[PubMed]
0006-8993
55.
de Vries
GJ
,
Buijs
RM
,
Sluiter
AA
.
Gonadal hormone actions on the morphology of the vasopressinergic innervation of the adult rat brain
.
Brain Res
.
1984
Apr
;
298
(
1
):
141
5
.
[PubMed]
0006-8993
56.
Tong
WH
,
Abdulai-Saiku
S
,
Vyas
A
.
Testosterone Reduces Fear and Causes Drastic Hypomethylation of Arginine Vasopressin Promoter in Medial Extended Amygdala of Male Mice
.
Front Behav Neurosci
.
2019
Feb
;
13
:
33
.
[PubMed]
1662-5153
57.
Bialy
M
,
Nikolaev-Diak
A
,
Kalata
U
,
Nikolaev
E
.
Blockade of androgen receptor in the medial amygdala inhibits noncontact erections in male rats
.
Physiol Behav
.
2011
Jun
;
103
(
3-4
):
295
301
.
[PubMed]
0031-9384
58.
Auger
CJ
,
Vanzo
RJ
.
Progesterone treatment of adult male rats suppresses arginine vasopressin expression in the bed nucleus of the stria terminalis and the centromedial amygdala
.
J Neuroendocrinol
.
2006
Mar
;
18
(
3
):
187
94
.
[PubMed]
0953-8194
59.
Hari Dass
SA
,
Vyas
A
.
Toxoplasma gondii infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala
.
Mol Ecol
.
2014
b
Dec
;
23
(
24
):
6114
22
.
[PubMed]
0962-1083
60.
Bowen
MT
,
Dass
SA
,
Booth
J
,
Suraev
A
,
Vyas
A
,
McGregor
IS
.
Active coping toward predatory stress is associated with lower corticosterone and progesterone plasma levels and decreased methylation in the medial amygdala vasopressin system
.
Horm Behav
.
2014
Aug
;
66
(
3
):
561
6
.
[PubMed]
0018-506X
61.
Pardo-Bellver
C
,
Cádiz-Moretti
B
,
Novejarque
A
,
Martínez-García
F
,
Lanuza
E
.
Differential efferent projections of the anterior, posteroventral, and posterodorsal subdivisions of the medial amygdala in mice
.
Front Neuroanat
.
2012
Aug
;
6
:
33
.
[PubMed]
1662-5129
62.
Thibonnier
M
,
Coles
P
,
Thibonnier
A
,
Shoham
M
.
The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists
.
Annu Rev Pharmacol Toxicol
.
2001
;
41
(
1
):
175
202
.
[PubMed]
0362-1642
63.
Koehbach
J
,
Stockner
T
,
Bergmayr
C
,
Muttenthaler
M
,
Gruber
CW
.
Insights into the molecular evolution of oxytocin receptor ligand binding
.
Biochem Soc Trans
.
2013
Feb
;
41
(
1
):
197
204
.
[PubMed]
0300-5127
64.
Song
Z
,
Albers
HE
.
Cross-talk among oxytocin and arginine-vasopressin receptors: relevance for basic and clinical studies of the brain and periphery
.
Front Neuroendocrinol
.
2018
Oct
;
51
:
14
24
.
[PubMed]
0091-3022
65.
Landgraf
R
,
Neumann
ID
.
Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication
.
Front Neuroendocrinol
.
2004
Sep-Dec
;
25
(
3-4
):
150
76
.
[PubMed]
0091-3022
66.
Albers
HE
.
Species, sex and individual differences in the vasotocin/vasopressin system: relationship to neurochemical signaling in the social behavior neural network
.
Front Neuroendocrinol
.
2015
Jan
;
36
:
49
71
.
[PubMed]
0091-3022
67.
De Vries
GJ
,
Buijs
RM
.
The origin of the vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum
.
Brain Res
.
1983
Aug
;
273
(
2
):
307
17
.
[PubMed]
0006-8993
68.
Lukas
M
,
Bredewold
R
,
Neumann
ID
,
Veenema
AH
.
Maternal separation interferes with developmental changes in brain vasopressin and oxytocin receptor binding in male rats
.
Neuropharmacology
.
2010
Jan
;
58
(
1
):
78
87
.
[PubMed]
0028-3908
69.
Dumais
KM
,
Veenema
AH
.
Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior
.
Front Neuroendocrinol
.
2016
Jan
;
40
:
1
23
.
[PubMed]
0091-3022
70.
Campbell
P
,
Ophir
AG
,
Phelps
SM
.
Central vasopressin and oxytocin receptor distributions in two species of singing mice
.
J Comp Neurol
.
2009
Oct
;
516
(
4
):
321
33
.
[PubMed]
0021-9967
71.
Dumais
KM
,
Bredewold
R
,
Mayer
TE
,
Veenema
AH
.
Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex- specific ways
.
Horm Behav
.
2013
Sep
;
64
(
4
):
693
701
.
[PubMed]
0018-506X
72.
Smith
CJ
,
Poehlmann
ML
,
Li
S
,
Ratnaseelan
AM
,
Bredewold
R
,
Veenema
AH
.
Age and sex differences in oxytocin and vasopressin V1a receptor binding densities in the rat brain: focus on the social decision-making network
.
Brain Struct Funct
.
2017
Mar
;
222
(
2
):
981
1006
.
[PubMed]
1863-2653
73.
Tribollet
E
,
Audigier
S
,
Dubois-Dauphin
M
,
Dreifuss
JJ
.
Gonadal steroids regulate oxytocin receptors but not vasopressin receptors in the brain of male and female rats. An autoradiographical study
.
Brain Res
.
1990
Mar
;
511
(
1
):
129
40
.
[PubMed]
0006-8993
74.
Boothroyd
JC
.
Toxoplasma gondii: 25 years and 25 major advances for the field
.
Int J Parasitol
.
2009
Jul
;
39
(
8
):
935
46
.
[PubMed]
0020-7519
75.
Vyas
A
.
Mechanisms of Host Behavioral Change in Toxoplasma gondii Rodent Association
.
PLoS Pathog
.
2015
Jul
;
11
(
7
):
e1004935
.
[PubMed]
1553-7366
76.
Lim
A
,
Kumar
V
,
Hari Dass
SA
,
Vyas
A
.
Toxoplasma gondii infection enhances testicular steroidogenesis in rats
.
Mol Ecol
.
2013
Jan
;
22
(
1
):
102
10
.
[PubMed]
0962-1083
77.
Tan
D
,
Soh
LJ
,
Lim
LW
,
Daniel
TC
,
Zhang
X
,
Vyas
A
. (
2015
).
Infection of male rats with Toxoplasma gondii results in enhanced delay aversion and neural changes in the nucleus accumbens core.
Proceedings of the Royal Society B: Biological Sciences 282.
78.
Tan
D
,
Vyas
A
.
Toxoplasma gondii infection and testosterone congruently increase tolerance of male rats for risk of reward forfeiture
.
Horm Behav
.
2016
Mar
;
79
:
37
44
.
[PubMed]
0018-506X
79.
Magnhagen
C
.
Predation risk as a cost of reproduction
.
Trends Ecol Evol
.
1991
Jun
;
6
(
6
):
183
6
.
[PubMed]
0169-5347
80.
Candolin
U
.
Reproduction under predation risk and the trade–off between current and future reproduction in the threespine stickleback
.
Proc R Soc Lond B Biol Sci
.
1998
;
265
(
1402
):
1171
5
. 0080-4649
81.
Pavlová
V
,
Berec
L
,
Boukal
DS
.
Caught between two Allee effects: trade-off between reproduction and predation risk
.
J Theor Biol
.
2010
Jun
;
264
(
3
):
787
98
.
[PubMed]
0022-5193
82.
Öst
M
,
Lindén
A
,
Karell
P
,
Ramula
S
,
Kilpi
M
.
To breed or not to breed: drivers of intermittent breeding in a seabird under increasing predation risk and male bias
.
Oecologia
.
2018
Sep
;
188
(
1
):
129
38
.
[PubMed]
0029-8549
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