Steven L Youngentob, PhD
Research Programs and Affiliations
- Biomedical Sciences Program
- Neuroscience Program
- Research Pillars
Education & Fellowships
- Postdoctoral Fellow: SUNY Health Science Center at Syracuse
- PhD: SUNY Upstate Medical Center, 1984
- In utero ethanol and nicotine exposures and chemsensory systems plasticity, olfactory biomarkers of ADHD, olfactory signal transduction, peripheral and central mechanisms of odorant quality coding.
HealthLinkOnAir Radio Interview2/6/14 Exploring why the urge to smoke begins in utero
Link to PubMed (Opens new window. Close the PubMed window to return to this page.)
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.
In Utero Nicotine Experience and Chemosensory PlasticityThere are remarkable parallels between the neurodevelopmental sequelae associated with the toxic effects of fetal nicotine exposure and those stemming from prenatal ethanol. We propose there are epigenetic chemosensory mechanisms by which maternal patterns of drug use are transferred to offspring. Given that many licit (e.g., tobacco products) and illicit (e.g., marijuana) drugs have noteworthy chemosensory components, we believe the extension of our studies to fetal nicotine exposure has broad implications for establishing the general relationship between maternal patterns of drug use, child development and postnatal vulnerability. These new studies and are currently focused on determining the relationship between fetal nicotine exposures, early postnatal and adolescent odor-guided responsiveness to and orosensory mediated acceptance of nicotine, and sensory function.
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.
Olfactory Biomarkers for Attention Deficit Hyperactivity Disorder (ADHD) (with S. Faraone)
The multi-factorial nature of ADHD and the involvement of both genes and environment early in its development, suggests that an effective biomarker should be sensitive to both the environmental and genetic risks known to increase the risk for ADHD. Using behavioral and molecular methods, we have been pursuing the novel hypothesis that such a biomarker can be derived through the study of olfaction and gene expression in the olfactory epithelium (OE). Of particular relevance to our work is the observation that the intracellular cascade of signal transduction events involving the G-protein-dependent elevation of cyclic AMP (cAMP) has been implicated in ADHD through both molecular genetic studies in humans and studies of ADHD relevant toxic exposures in rodents. For example, GNAL, Calmodulin, and CAMKII show significant changes in gene expression subsequent to prenatal PCB exposure in a rat model; these genes are also implicated in a genome-wide association scan of ADHD patients. These findings are noteworthy since olfactory sensory transduction occurs through G-protein dependent signaling. Further, deficits in olfactory function have been anecdotally associated in the literature with ADHD in humans. Taken together, these data suggest the provocative possibility that behavioral and molecular olfactory abnormalities could be both prognostic of and diagnostic for specific underlying etiologies of ADHD. We are currently pursuing this by studying whether ADHD patients suffer from impaired olfactory ability. In a preliminary study of twenty-seven patients, all but one showed evidence of olfactory dysfunction. We are now planning molecular studies in which we will be assessing the OE of ADHD patients for many of the genes relevant to ADHD, such as those regulating dopaminergic transmission, calcium signaling, etc. We hypothesize that the genetic variants and neurodevelopmental toxic exposures that cause ADHD, lead to a lifelong pattern of dysregulated gene expression that can be detected in OE cells. If we are correct, our work will provide an objective biomarker that may eventually replace or supplement the subjective judgments currently used to diagnose the disorder.
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.
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).
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.
Eade, A.M., Sheehe, P.R. and Youngentob, S.L. Ontogeny of the enhanced fetal- ethanol-induced behavioral and neurophysiologic olfactory response to ethanol odor. Alcohol: Clinc Exp. Res. 34: 206-213, 2010.