Steven L Youngentob, Ph.D.

In Utero Ethanol Exposure, Chemosensory Plasticity and Adolescent Drug Preference.

Human studies point to a causal relationship between fetal alcohol exposure and adolescent ethanol abuse.  Fetal exposure is, perhaps, the best predictor of abuse in this "at risk" age group, and there is an inverse correlation between the age of first experience and continued abuse.  Understanding why these adolescents initiate and maintain alcohol use is critical to prevention and treatment.  How is the adolescent brain altered by fetal exposure so that ethanol avidity is enhanced? How does continued use increase adult acceptance?

The working hypothesis of my lab is that fetal ethanol experience induces developmental changes in one or more of the neural systems involved in the preference for ethanol odor and the perception of ethanol's flavor (the integration of smell, taste, and oral irritation): thus contributing to the risk of initial ingestion and continued use.  Furthermore, adolescent ethanol use (i.e., re-exposure) perpetuates these developmental changes, thereby enhancing ethanol intake into adulthood. 

To date, our studies have reported that gestational ethanol exposure "tunes" both the peripheral neural and innate behavioral olfactory responses to ethanol odor in early postnatal rats.  A parallel study showed that ethanol intake is enhanced in these animals.  This constellation of prenatal exposure effects persists into the at-risk age of adolescence.  Expression of olfactory bulb genes involved in synaptic transmission and plasticity as well as neuronal development (both cell fate and axon/neurite outgrowth) are also altered in these adolescent animals.  Importantly, we demonstrated that a significant proportion of the elevated ethanol avidity resulting from fetal exposure is directly attributable to: (1) the enhanced ethanol odor response; and (2) attenuated taste-mediated responsiveness to ethanol's bitter-like taste quality.  In short, our work has revealed that fetal ethanol exposure alters the development of the smell and taste systems so that the normally aversive odor and flavor of ethanol become more acceptable - enhancing intake.  Moreover, our studies implicate decreases in oral irritation as a potentially important contributor to this consequence, as well.

Based on this work, are now applying a set of interdisciplinary techniques (behavioral, functional and anatomical) to examine the impact of fetal ethanol exposure on: (1) specific olfactory and limbic system structures important to odor hedonics and their role in ethanol acceptability; (2) gustatory and oral somatosensory brainstem structures and their role in taste-mediated/orosensory responses to ethanol and its component qualities (sweet, bitter and irritancy); and (3) the persistence of these developmental effects into adulthood.

Analysis of Olfactory Marker Protein's (OMP) Role in Odor Processing.

We are presently combining state-of-the-art molecular biology, sophisticated animal psychophysics and neurophysiological optical recording techniques to address the functional importance of a specific protein found exclusively in olfactory sensory neurons, namely olfactory marker protein (OMP).  This direction of the laboratory highlights a surprisingly uncommon research approach despite its great potential to reveal fundamental principles of nervous system function, namely, examining and manipulating gene expression in conjunction with behavioral and neurophysiological assessments.

To date, we have behaviorally shown that mice lacking the gene for OMP have a 2 log unit elevation in threshold sensitivity and an alteration in odorant quality perception.  Moreover, the neurophysiological basis for these defects can be found in an altered response and recovery kinetics of the sensory neurons and a muting of the spatial activity patterns that are characteristic for different odorants.  In order to draw a direct link between gene deletion and the observed phenotype both the neurophysiologic and behavioral defects have been rescued by in vivo gene delivery and transient expression of the protein.  These data, taken together, have led to the hypothesis that OMP is a novel modulatory component of the odor detection/signal transduction cascade in olfactory sensory neurons.  We are continuing to further explore the mechanistic underpinnings of this hypothesis.

Selected References

Youngentob, S., Kent, P., Sheehe, P., Molina, J., Spear, N.E. and Youngentob, L.  (2007) The effect of gestational ethanol exposure on the behavioral and neurophysiologic olfactory response to ethanol odor in early postnatal and adult rats. Behav. Neurosci. 121:1293-1305.

Youngentob, S., Molina, J., Spear, N.E. and Youngentob, L. (2007) The effect of gestational ethanol exposure on voluntary ethanol intake in early postnatal and adult rats. Behav. Neurosci. 121:1306-1315.

White, T., Dishaw, L., Sheehe, P. and Youngentob S.L. (2007) The relationship between PROP and ethanol preferences: An evaluation of four inbred mouse strains. Chem. Senses 32:847-853.

Middleton, F.A, Carrierfenster, K., Mooney, S.M. and Youngentob, S. L. (2009) Experience-Induced Fetal Plasticity: Gestational Ethanol Exposure Alters the Behavioral Response to Ethanol Odor and the Expression of Neurotransmission Genes in the Olfactory Bulb of Adolescent Rats. Brain Res.  1252:105-16.

Eade, A.M., Sheehe, P.R., Molina, J.C., Spear, N.E., Youngentob, L.M. and Youngentob, S.L. (2009) Fetal Ethanol-Induced Olfactory Plasticity: The Effect of Adolescent Ethanol Re-Exposure On The Behavioral Response To Ethanol Odor. Behav. Brain Func. Jan 15; 5:3. (online publication).

Homma, R., Cohen, L.B., Kosmidis, E.K. and Youngentob, S. L. (2009) Perceptual stability during dramatic changes in olfactory bulb activation maps and dramatic declines in activation amplitudes. Eur. J. Neurosci. 29:1027-1034.

Youngentob, S.L. and Glendinning, J.I. (2009) Fetal Exposure to Ethanol Increases Postnatal Acceptance by Altering its Odor and Taste.  Proc. Natl. Acad. Sci. 106:5359-5364.