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 3 rd 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: 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 ( 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