Reparto di Neuroscienze comportamentaliDipartimento di Biologia cellulare e NeuroscienzeIstituto Superiore di Sanità

IL RUOLO DEL NERVE GROWTH FACTOR (NGF)NELLO STRESS E COPING

DEI RODITORI E DELL’UOMO

Enrico Alleva (alleva@iss.it)

First, it is impossible to think effectively aboutdepression outside the context of biology.Second, it is impossible to think effectively aboutdepression as only being a matter of biology.Finally, despite the vast quantities of excellentresearch on which those two conclusions rest, weremain woefully inadequate at effectively treatingdepression in vast numbers of its sufferers.

NERVE GROWTH FACTOR exerts thefollowing actions:

- TROPIC

- DIFFERENTIATIVE

- TROPHIC

Rita Levi-Montalcini and Luigi Aloe

SOCIAL INTERACTIONS ANDAGGRESSIVE BEHAVIOR

SOCIAL INTERACTIONS ANDAGGRESSIVE BEHAVIOR

BEHAVIOURAL “STRESS SYNDROMES”EITHER PRODUCING OR NOT PRODUCING NGF RELEASE

INTO THE BLOODSTREAM

NON- PSYCHOSOCIALInescapable footshock NOEscapable footshock NOCold water swimming NO*Restraint stress NOForced biting NO

PSYCHOSOCIALMale fighting YES (high, < 100-300 ng/ml serum >)Female fighting YES (low, < 3-13 ng/ml serum >)Pre-copula arousal (F) YES (low, < 2-9 ng/ml serum >)

*In developing rats unpublished observations indicate a decrease of NGF level and NGF receptor expressionin the striatum following cold-water swimming stress while an increase was shown in the hippocampus.

Alleva E, Aloe L (1989) Physiological roles of nerve growth factor in adult

rodents: a biobehavioral perspective. Int J Comp Psychol 2:213-230

“Hypothalamic NGF release

could also play a crucial role

in linking the "emotional"

status caused by a

psychosocial stressor and

the biological needs of the

organism (and of its brain) to "remember" the events leading

to an appropriate (or inappropriate) coping with the stressor

itself”(p. 223)

Brigata Paracadutisti "Folgore"

ACTH AND NGF LEVELS IN THE BLOOD OFPARACHUTISTS BEFOREAND AFTER JUMPING

Aloe L. et al. (1994) Proc Natl Acad Sci USA

0

20

40

60

80

AC

TH

, p

g/m

l

NG

F, p

g/m

l0

150

100

50

controls before jump after jump

PassionateLoveScale

ROMANTIC LOVE and NGF

Romantic love induces an increase of circulating NGF (160-170% of basallevels) lasting about a year

Emanuele et al. Psychoneuroendocrinology 2006

LONG-TERM EFFECTS OF EARLY SOCIAL EXPERIENCE

- adult social behaviour

- brain neurotrophin levelsNGF and BDNF levels

social/agonistic behaviour

- early social enrichment

communal nesting

MOTHER-OFFSPRING INTERACTION

The mother is the mostpervasive, powerful andleast understood sourceof early experience forthe mammalian infant

Basic physiological sy-stems are regulated bythe mother, includingbrain development

MOTHER-OFFSPRING INTERACTION

licking and grooming

nursing

retrieving

Nelson, 1995

MOTHER-OFFSPRING INTERACTION

effects on physiology and behaviour of adult offspring- Seymour ‘Gig’ Levine (University of Stanford)- Michael Meaney (McGill University)

maternal behaviour of the female offspring

Capone, Bonsignore,and Cirulli, 2005,Current Protocols inToxicology

coping response to stress

social behaviour

emotional response

cognitive abilities ?

EARLY MANIPULATION: COMMUNAL NESTING

Communal nesting (CN): three mothers keep their pups together in a single andshare care-giving behaviour from birth to weaning (postnatal day 25)

compared to standard nesting laboratory condition (SN)

COMMUNAL NESTING: MATERNAL BEHAVIOUR

higher levels of maternalcare were shown under CN

### = p < 0.001, CN vs. SN mice. n = 8for each group. Data are means ± S.E.M

arched back nursingBranchi et al, Biol Psychiatry, 2006

SN mice learn session after session to play their social role

ADULT SOCIAL/AGGRESSIVE BEHAVIOUR

1 3 5day

1 3 5day

ATTACK

Branchi et al, Biol Psychiatry, 2006

CN mice show higher social competencies, playing morepromptly a social role

** = p < 0.01 vs. the relative SN group (i.e., either dominants orsubordinates

ADULT SOCIAL/AGGRESSIVE BEHAVIOUR

1 3 5day

1 3 5day

ATTACK

Branchi et al, Biol Psychiatry, 2006

* and ** = respectively p < 0.05 and < 0.01 vs. the relativeSN group (i.e., either dominants or subordinates); ### =respectively p < 0.001, CN vs. SN mice

ADULT SOCIAL/AGGRESSIVE BEHAVIOUR

Branchi et al, Biol Psychiatry, 2006

CN mice display higher propensity to interact socially

nose sniffing

ADULT SOCIAL BEHAVIOUR

Branchi et al, Biol Psychiatry, 2006

NEUROTROPHIN LEVELSBrain neurotrophin levels are modulated by early and/or adult social experiences

** and *** = respectively p <0.01 and < 0.001 vs. SN mice.$, $$ and $$$ = respectively p< 0.05, p < 0.01 and < 0.001vs. same nesting conditiondominant mice. ## and ### =respectively p < 0.01 and <0.001, CN vs. SN mice

Branchi et al, Biol Psychiatry, 2006Branchi et al, J Neurosci Res, 2006

(SOCIAL) STRESS

(SOCIAL) COPING

RENEWED BRAIN PLASTICITY

ENHANCED VULNERABILITY TODEPRESSION (MOOD DISORDERS)

“PARA”PHYSIOLOGICALGROWTH FACTOR(S) LEVELS

NGF for what ? BDNF for what ?

Aloe L, Bracci-Laudiero L, Alleva E, Lambiase A, Micera A, Tirassa P (1994) Emotionalstress induced by parachute jumping enhances blood nerve growth factor levelsand the distribution of nerve growth factor receptors in lymphocytes. Proc NatlAcad Sci U S A 91:10440-10444.

Aloe L, Tuveri MA, Guerra G, Pinna L, Tirassa P, Micera A, Alleva E (1996) Changes inhuman plasma nerve growth factor level after chronic alcohol consumption andwithdrawal. Alcohol Clin Exp Res 20:462-465.

Emanuele E, Politi P, Bianchi M, Minoretti P, Bertona M, Geroldi D (2005) Raisedplasma nerve growth factor levels associated with early-stage romantic love.Psychoneuroendocrinology.

Hadjiconstantinou M, McGuire L, Duchemin AM, Laskowski B, Kiecolt-Glaser J, GlaserR (2001) Changes in plasma nerve growth factor levels in older adults associatedwith chronic stress. J Neuroimmunol 116:102-106.

Lang UE, Gallinat J, Kuhn S, Jockers-Scherubl C, Hellweg R (2002) Nerve growthfactor and smoking cessation. Am J Psychiatry 159:674-675.

Luppi P, Levi-Montalcini R, Bracci-Laudiero L, Bertolini A, Arletti R, Tavernari D,Vigneti E, Aloe L (1993) NGF is released into plasma during human pregnancy:an oxytocin-mediated response? Neuroreport 4:1063-1065.

PSYCHOSOCIAL STRESS INCREASES CIRCULATING NGF LEVELS

Alleva E, Francia N (2009) Psychiatric vulnerability: suggestions from animal modelsand role of neurotrophins. Neurosci Biobehav Rev 33:525-536.

Cirulli F, Alleva E (2009) The NGF saga: From animal models of psychosocial stress tostress-related psychopathology. Front Neuroendocrinol. in press

PSYCHOSOCIAL STRESS INCREASES CIRCULATING NGF LEVELS

Recent Reviews

NGF, NEUROTROFINE E

RIABILITAZIONE NEURO-MOTORIA:

prospettive per una interazione tra

l’Istituto Ortopedico Rizzoli

e l’Istituto Superiore di Sanità