Transcript Alex Medina
Effects of early alcohol exposure on visual cortex development and plasticity Alexandre E. Medina, PhD Department of Pediatrics The retino-geniculo- pathway Retino-geniculo-cortical pathway in humans Retino-geniculo-cortical pathway in rodents What the visual cortex can tell us about FASD? • The effects of early alcohol exposure on visual processing (responsiveness, acuity, neuronal orientation tuning). • The effects of early alcohol exposure on the functional architecture of the visual cortex (orientation and ocular dominance columns) • Neuronal plasticity: The ocular dominance plasticity paradigm Most of the connectivity of the visual system is established during the second half of gestation and first weeks after birth (in humans). Our lab uses a model of “third trimester” alcohol exposure PART – I: Effects of developmental alcohol exposure on visual cortex properties. PART – II: What the visual cortex tell us about the effects of developmental alcohol exposure on neuronal plasticity? Can we reverse alcohol effects? PART – III: Using viral mediated gene transfer for restoring neuronal plasticity in a ferret model FASD PART – I: Effects of developmental alcohol exposure on visual cortex properties. What are the effects of alcohol exposure in visual cortex properties? Visual responsiveness Medina et al. 2003 J. Neuroscience Spatial frequency Krahe et al. 2009 PLoS ONE Alcohol exposure during the equivalent of late gestation in humans does not affect visual responsiveness or spatial frequency acuity in the ferret. Orientation selectivity columns and Neuronal orientation tuning Medina et al. 2005 J. Neurophysiol ; Krahe et al. 2009 PLoS ONE LS Alcohol exposure during the equivalent of late gestation in humans does disrupt the functional architecture of the visual cortex and disrupts individual orientation tuning in the ferret. Spatial frequency and Visual evoked potentials amplitude Lantz et al. 2009 unpublished Alcohol exposure during the equivalent of late gestation in humans does not affect spatial frequency acuity in mice. However, it decreases contrast sensitivity and amplitude of VEPs Future directions / Interesting developments Does early alcohol exposure affects retinotopy? From Kalatsky & Stryker (2003), Neuron Jan -7-2013 Does early alcohol exposure affects orientation selectivity in humans ? Newborn 7 weeks From Braddick , Wattan-Beel and Atkinson (1986), Nature 5 weeks PART – II: What the visual cortex tell us about the effects of developmental alcohol exposure on neuronal plasticity? How to address the problem of FASD? PREVENTION PROTECTION REHABILITATION Improvement of neuronal plasticity Neuronal plasticity is impaired in FASD Neuronal plasticity: Processes of Gain and Loss. The ocular dominance plasticity paradigm : a model of neuronal plasticity in the cortex Right eye deprived OD Plasticity is composed by different types of “plasticity” • Physiological changes – depression or potentiation of synapses • Molecular changes – Changes in receptors, number of synapses, changes in gene and protein expression. • Morphological changes – Changes in spines, dendritic arborization, axonal terminals and buttons • Behavioral – Lost vision Using the Visual Cortex as a model to study the effects of early alcohol exposure on cortical neuronal plasticity The ocular dominance plasticity paradigm Right eye deprived LS Early alcohol exposure leads to a long lasting impairment of ODP (Medina, Krahe, Coppola and Ramoa, 2003 Journal of Neuroscience) Ethanol 25% in saline I.P. or Saline as a control Dosage: 0.018 ml/g (3.5 g/Kg) Goal: reach Blood Alcohol Level (BAL) between 200-300 mg/dl Frequency: every other day Saline + MD 3 days No MD Ethanol + MD 3 days How neuronal plasticity is affected in FASD? Phosphodiesterase Inhibitors are good candidates for neuronal plasticity enhancement The impairments caused by alcohol on ODP can be reversed if you treat animals with Vinpocetine a PDE type 1 inhibitor . (Medina, Krahe and Ramoa 2006 Journal of Neuroscience) Vinpocetine improves learning in a rat model of FASD. (Filgueiras, Krahe and Medina, 2010, Neurosci letters) CONCLUSION: PDE1 inhibition by Vinpocetine was able to reverse the effects of early alcohol exposure on ocular dominance plasticity, restore the establishment of orientation selectivity columns and improve learning in animal models of FASD (ferrets, rats and mice*). Future directions Can inhibition of PDE1 by Caffeine Improve neuronal plasticity in FASD? 0.4 mg/Kg - 0.25 mg /l - 0.001mM 2.5 mg/Kg - 2 mg/l – 0.01 mM 20 mg/Kg plus daily supplemental doses of 5 mg/Kg : 20-30% of PDE1 inhibition? PART – III: Using viral mediated gene transfer to restore neuronal plasticity in a ferret model FASD ADDITIONAL READING Restoration of neuronal plasticity by genetic modification Overexpression of serum response factor restores ocular dominance plasticity in a model of fetal alcohol spectrum disorders. Paul, et al. (2010) Journal of Neuroscience Overexpression of serum response factor in astrocytes improves neuronal plasticity in a model of early alcohol exposure. Paul and Medina (2012) Neuroscience Overexpression of SRF in astrocytes improve neuronal plasticity in FASD. What molecules astrocytes are secreting?. Medina Lab THANK YOU!!!! Dr. Alexandre Medina Weili Wang Acknowledgments: Dr Thomas Krahe – VCU Dr Ray Colello - VCU Dr Claudio Filgueiras – UERJ Dr Mriganka Sur – MIT Dr Daniela Tropea – MIT Dr Benjamin Philpot – UNC, Chapel Hill Dr Eric Kandel – Columbia University Fernanda Pohl-Guimaraes – U. of Florida Arco Paul Crystal Lantz WELCOME!! Dr Pablo Trindade, Post Doc Nisha Pulimood, Graduate student Dr. Rashmin Hingrajia, Fellow Supported by: Saline Alcohol + Vinpocetine Alcohol How plastic is the brain? From Hemispherectomy: How Much Brain Do We Really Need? : Discovery Magazine 1996 Avaiable at hemifoundation.org