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Early life environmental interventions: social
behaviors and neuroendocrine outcomes Symposium: Mechanisms of Stress Disorders: Models and
Targets of Intervention
• Aldo B. Lucion
• Neuroscience Program, Departament of Physiology.
• Universidade Federal do Rio Grande do Sul (UFRGS)
• Porto Alegre RS, Brazil.
VI Reunião do IBNeC - Instituto Brasileiro de Neuropsicologia e
Comportamento.
Gramado, RS. September 01-04, 2015.
Canalization of Development
. Outcomes adaptative
. Or pathologies
. Slight deviation
- Chaos Theory
Long-lasting effects of early life events
Mental and neurocognitive illnesses commence
predominantly early in life, suggesting the need to
explore events in early life that predispose and contribute
to disease onset.
The organization and maturation of the CNS during fetal
and early postnatal life are governed by genetic factors
and are further modulated by the environmental inputs
experienced by the developing brain.
(Fragmentation and Unpredictability of Early-life Experience in Mental
Disorders. T.Z. Baram et al. Am J Psychiatry 2012; 169:907–915.)
Importance of the environment
Nature versus Nurture
Epigenetics
Schools, Skills, and Synapses. James J. Heckman, 2008
Policies in early life investment
Due to dynamic complementarity, or
synergy, early investments must be
followed by later investments if maximum
value is to be realized.
- The importance of analyzing mechanisms
- Treat symptoms
- Prevalence of neurological and psychiatric
deseases compared to other
The infant interaction with the
mother
After birth the complexity of the
environment increases.
Number of variables increases.
Uncertainty increases.
Survive.
Mother as a buffer
Olfactory learning
AMPc
- Noradrenalina
β-adrenérgico
PKA
CREB CREBp
CRE
Núcleo
Citoplasma
McLean & Harley, 2004
Some experimental protocols to analyze effects of
early life environmental intervention:
1. Maternal separation (usually 3 hours or more).
Harlow, Levine, Suchecki, Pryce, Baram
2. Neonatal handling (1 to 15 min per day during
lactation period). Levine, Pryce, Meaney
3. Reduced nest material (abusive mothers).
Baram, Raineki
4. High and low licking mothers. Meaney
5. Increased aggression. Intruder to the nest area.
The neonatal handling procedure
in rats.
Considered a mild intervention ???
Environmental intervention:
1 min per day from PDN 1 to 10
Considering the wide range of changes that have been described,
we may suppose the existence of biologically relevant pathways
that are activated in the pups by the repeated brief maternal separations
and manipulation. (Raineki et al., Neuroscience 2009)
Neonatal handling and the structure of
maternal behavior
Reis et al., Behav. Brain
Res. 2014
Parent–infant synchrony Ruth Feldman. J. Child Psychol. Psychiatry,
2007
Long-lasting effects of neonatal
handling on the HPA axis
• Reduce stress response. Due to increase in
glucorticoid expression in the
hippocampus.
• Reduce fear/anxiety
• Explanation: Increase in licking/groomig
Epigenetic regulation of the glucocorticoid receptor in
human brain associates with childhood abuse.
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G,
Meaney MJ. Nature Neuroscience, 2009.
In humans, childhood abuse alters HPA stress responses and increases the risk of
suicide. We examined epigenetic differences in a neuron-specific glucocorticoid
receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide
victims with a history of childhood abuse and those from either suicide victims with
no childhood abuse or controls.
We found decreased levels of glucocorticoid receptor mRNA, as well as
mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and
increased cytosine methylation of an NR3C1 promoter.
These findings translate previous results from rat to humans and suggest a
common effect of parental care on the epigenetic regulation of hippocampal
glucocorticoid receptor expression.
However:
• Different systems may be differently
affected.
• A different and balanced physiology
seems to develop.
Locus
Coeruleus
Ovary
NE/EPI
Neurovegetative Response
to Stress
mPOA
LHRH
Anterior
Pituitary
NO
NE
E2 LH
Afferent inputs
Summary of Neuroendocrine Basis of Ovulation
Effects of neonatal handling on plasma LH of
female rats in proestrus
0
10
20
13 14 15 16 17 18 19 20
Pla
sma
LH (
ng/
mL)
Time (hours)
Nonhandled (n=16)
Handled (n=16)
* * * *
Neonatal handling and reproductive function in female rats
C M Gomes, C Raineki, P Ramos de Paula, G S Severino, C V V Helena, J A Anselmo-Franci, C R Franci, G L
Sanvitto and A B Lucion J. Endocrinolgy 2005
Neonatal handling reduces the number of cells in the medial preoptic area of female
rats Camozzato TSC, Winkelmann-Duarte EC, Padilha CB, Miguel SPR, Laisa Bonzanini L, Anselmo-Franci JA,
Fernandes MC, Lucion AB. Hormones and Behavior 2009
Reduction in the number of cells in the neonatal period
Positive versus negative outcomes
Neonatal handling reduces number of neurons in the LC
of 11-day-old female rats
Winkelmann-Duarte, data not published
Raineki; Lucion et al., Neuroscience, 2009
Raineki;Lucion et al., Developmental Psychobiology 2012
Neonatal handling and the preference
for the nest odor in 7-day-old rat pups
Gender Effects.
Mother-infant bonding
Play behavior 35 days
NH H0
10
20
30
40
50
60
70Non handled (n=12)
Handled (n=10)
*
Su
m o
f a
ll p
lay
ac
tiv
itie
s
Neonatal Handling Induces Deficits in the
Development of Social Behaviors
Karkow et al., Psychology Neuroscience 2013
Reduction in:
1. Social behaviors (stable throughout life)
2. Fear/anxiety in adulthood
Duration of the Encounter
Con MxM Han MxM Con FxF Han FxF0
50
100
150
200
Groups
Tim
e (
s)
Effects of Neonatal Handling on Social Behaviors in Adult
Rats. Gender Effects.
Todeschin, et al., Hormones & Behavior, 2009.
Social non aggressive
interaction in male rats
Defensive versus
aggressive behaviors
Effects of Neonatal Handling on the number of
OT-cells in the pPVN
Todeschin et al., Hormones and Behavior, 2009
Pair bonding
Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints.
Vargas-Pinilla et al., PNAS, 112(1): 88–93, 2015.
OT-OTR system and male parental care in monkeys
Conclusions and future directions:
1. Mild environmental intervention (brief separation from the
mother and tactile stimulation) may disrupt the structure of
mother-infant relationship.
2. Short-term effect in the infant: reduce preference for the
maternal odor.
3. Long-term effects: reduced social affiliative behaviors and
increased aggression.
4. Short and long-term effect: change development of brain areas
(mainly reduce number of neurons).
5. Future directions: Complex system (several variables affecting
one another, difficult to isolate a single one). Importance of
multifactorial experimental approaches to address the
mechanisms involved.
Charlis
Gabriela
Carmen
Elisa
Sandro
Laissa
Maiara
Anelise
Tatiane
Márcia A.
Márcia G.
Maria da Graça
Isabel
Fernando
Paulo
Luis Felipe
Osni
Martin Cammarota
Lia Bevilaqua
Ivan Izquierdo
Carla Dalmaz
Gilberto Sanvitto
Janete A. Anselmo-Franci
Celso R. Franci
Artur
Francine
Maristela Padoin
Natalia
Camila
Fabiana
Márcio
Ana Raquel
Ana Lúcia
Marta
Luciano
Vinicius
Tatiana B.
Vanise
Felipe
Raphael Szawka
Adolfo
Patricia P. Silveira
Participantes