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.

• alucion@ufrgs.br

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

Marian Joëls and Tallie Z. Baram

Nat Rev Neurosci. 2009

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

Kellendonk, et al.,

2002

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.

Different systems are affected

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

Financial support:

Thank you

PRONEX FAPERGS/CNPq