Postnatal Interventions to Attenuate the Effects of

Prenatal Alcohol Exposure:A Review of Animal Literature

Reuven Sussman, Hon BSc.,FAS Clinic Coordinator, Research Coordinator

Outline

• Background• 4 Modes of intervention:

– Environmental Enrichment– Postnatal Handling– Therapeutic Motor Training– Exercise

• Discussion• Future Directions

Background

• Early identification of at-risk children is becoming more accurate

• Early intervention reduces likelihood of secondary disabilities

• There is a lack of evidence-based interventions for FASD

• Animal studies offer advantages for the preliminary study of interventions

Background – FASD Characteristics

• Poor hand-eye coordination

• Tremors• Weak grip• Poor balance• Set shifting• Rely on

somatosensory information

• Hyperactivity

• Low IQ• Memory problems• Language problems• Attention problems• Slow reaction time• Visuospatial

abilities• Executive functioning

problems• Problems with

social/adaptive functioning

Background – FASD Brain

• Brain Structures– Prefrontal Cortex,

Corpus Callosum, Basal Ganglia

– Cerebellum– Hippocampus– Hypothalamic-

Pituitary-Adrenal (HPA) Axis

General Procedures

• Pregnant dams divided into 3 groups– Alcohol Exposed (AE), Pair-fed (PF), Food/water control

(C)

• Pups are kept with dam (or fostered) until weaning (21-28 days)

• Intervention applied– Environmental Enrichment (EE), Postnatal Handling (PH),

Therapeutic Motor Training (TMT), Exercise

• Behavioural and/or physiological testing– Water maze, Radial arm maze, avoidance learning,

conditioned taste aversion learning, open field activity– Analysis of neurons from certain brain regions, testing

stress hormone levels, stimulating/measuring LTP

General Procedures – con’t

Timing and Amount of Exposure

• Dose-response curve for maternal alcohol use is unknown in humans

• In rats, 200mg/dL for 4 hours causes massive neurodegeneration (but 83mg/dL throughout gestatation may be harmful)– Reviewed studies: avg ~150mg/dL, max

278mg/dL, min 100mg/dL

• Brain growth Spurt: human 3rd trimester, rat end of gestation to P14.

Environmental Enrichment (EE)

• Intervention: 8-12 animals, toys changed regularly

EE – con’t

• Behavioural effects:– EE rats ↑ water maze and radial arm

maze; but alcohol had no effect (2-3)– AE rats had hind limb ataxia; attenuated

by EE (3)– AE rats more active in open field (1,4)

and Y-maze (1), EE ameliorated over-activity in mice one of two studies (1,4)

– AE mice showed poor taste aversion learning; Attenuated by EE (5)

EE – con’t

• Neurological Effects:– Alcohol ↓ cortical thickness of occipital

lobe; EE not able to attenuate (trend toward ↑ brain weight) (2)

– AE-EE rats did not have ↑ dendritic spine density (6)

– Alcohol reduced survival of new hippocampal neurons; EE increased survival only in non-AE mice (7)

Postnatal Handling (PH)

• Intervention: Removal of dams/pups for 3 min or 15 min and putting them in separate cages– Handling is done pre-

weaning

PH –con’t

• Behavioural Effects:– Handling attenuated AE learning deficit

in step down avoidance task (8)– Weight gain deficits ameliorated (9-12)– Handling further worsens conditioned

taste aversion in AE rats (12)

PH – con’t

• HPA axis effects:– Handling, in combination with fostering

can improve regulation of HPA axis in some cases (9-11)

– AE rats have higher CRF mRNA levels; handling reduces levels in non-AE rats only (13)

Therapeutic Motor Training (TMT)

• Intervention: 10-20 days of obstacle course training

TMT – con’t

• Behavioural effects:– At end of training AE=PF=C on

course performance (14-15)– All rats tested on 3 novel tasks:

• AE rats performed worse on novel tests unless given TMT

• TMT attenuated performance deficits(15)

– Exercise group did not improve over controls (15)

• Neurological Effects:– AE rats had ↓ Purkinje Cells,

but rehabilitation ↑ parallel fibre synapses (16)

Exercise

• Intervention: Male rats housed individually with running wheel before testing

Exercise – con’t

• Behavioural effects:– AE rats performed worse on water maze;

voluntary exercise attenuated deficit (17)

• Neurological Effects:– AE rats have ↓ capacity for LTP; exercise

increases capacity (17)

Discussion

• EE may be actually be effect of isolation

• Rodent effects of prenatal alcohol different from humans

• Human exposure is more complex

Future Directions

• Research human interventions similar to EE, TMT, PH or exercise– What is handling?– What is Therapeutic Motor Training?– How early can interventions be applied?

Thank you

References• 1 Osborne et al (1980)• 2 Wainwright et al (1993)• 3 Hannigan et al (1993• 4 Mothes et al (1996), • 5 Opitz et al (1997)• 6 Berman et al (1996)• 7 Choi et al (2005)• 8 Gallo & Weinberg (1982)• 9 Weinberg et al (1995)• 10 Ogilvie & Rivier (1997)• 11 Gabriel et al (2000) • 12 Gabriel et al (2001)• 13 Gabriel et al (2005)• 14 Klintsova et al (1997)• 15 Klintsova et al (1998)• 16 Klintsova et al (2002)• 17 Christie et al (2005)

• If you require more detailed references please ask