News & Events
The DEARC is happy to announce that Dr. Sandra Mooney was recently elected to the Advisory Board for the Fetal Alcohol Spectrum Disorders Study Group.
36th Annual RSA Scientific Meeting
June 22-26, 2013
Orlando (Grand Cypress, Florida)
Inaugural Conference for Flux
September 19-21, 2013
The inaugural Flux Congress acts as a forum for developmental cognitive neuroscientists to share their findings, expand their approaches, and be better informed of translational approaches. http://fluxcongress.com
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- Main Project 1 - Effects of EtOH on early developmental events
PI: Eric Olson (email@example.com)
- Main Project 2 - Chemosensory plasticity and EtOH choice behavior
PI: Steven Youngentob (YoungenS@upstate.edu)
- Main Project 3 - Ontogeny of response to EtOH
PI: Norman Spear (firstname.lastname@example.org)
- Main Project 4 - Contributors to adolescent EtOH sensitivities
PI: Linda Spear (email@example.com)
Main Project 1
The central nervous system develops over a protracted period; yet, there are two times of notable vulnerability to ethanol toxicity- during fetal and adolescent development. These are also times that are of critical clinical importance because many are exposed to alcohol during fetal and adolescent life. The ongoing developmental events in the fetus and adolescent are quite different, thus the potential for ethanol- induced changes also differ. Seminal events in fetal development and during adolescence are the definition of cell fate and dendritic growth and refinement, respectively. The present study will explore the effects of ethanol on these processes by testing the hypotheses that
- ethanol affects CNS composition by altering the fates of undetermined neuronal progenitors,
- ethanol affects synaptic connections that are remodeled during adolescence in a time-dependent manner, and
- plasticity in the adolescent is primed by alterations in fetal development and that such changes in the adolescent establish long-term changes in brain structure in the adult.
The focus will be the cerebral cortex because it is critical for activities such as learning, memory, and executive function, acknowledged behavioral targets of ethanol. These studies will exploit transgenic mice that have a select population of neurons, pyramidal neurons in layer V, that endogenously fluoresce. Studies will determine
- the effects of fetal ethanol exposure on neuronal fate and the contribution of the transcription factor Foxg1 in that process,
- the effects of adolescent ethanol exposure on dendritic, spine, and synaptic plasticity and the role of excitatory and inhibitory neurotransmitter systems in that plasticity, and
- whether fetal and additional adolescent exposure combine for greater and potentially permanent changes in cortical structure. Thus, the goal of this project is to test the "alcoholism generator" hypothesis central to the DEARC- that fetal programming sets up the structure of the adult brain and that this process is exacerbated by adolescent exposure to ethanol.
Main Project 2
Human studies point to a relationship between fetal ethanol exposure and the risk for adolescent ethanol abuse. Fetal exposure is highly predictive of ethanol abuse in this “at risk” age group, and there is an inverse correlation between the age of first experience and the likelihood of continued abuse. Yet, there is a relative dearth of knowledge focusing on the mechanisms underlying this progressive pattern of ethanol use and abuse. How does fetal exposure alter adolescent ethanol acceptability? How does re-exposure during adolescence increase adult acceptance? Are the consequences of exposure during these two developmental epochs distinct? The flavor attributes (integration of smell, taste and oral irritation) of ethanol are important determinants of ethanol acceptance. Our novel working hypothesis has been that fetal ethanol exposure induces developmental changes in one or more of the neural systems involved in the preference for ethanol odor and the perception and acceptability of ethanol’s flavor. This, in turn, contributes to the risk of initial ingestion and continued adolescent abuse. Further, adolescent experience with ethanol augments the fetal effect and/or perpetuates the ethanol-induced changes into adulthood. Our published work demonstrates that fetal exposure increases adolescent ethanol avidity by, in part, making it taste and smell better (decreased aversion to ethanol’s bitter and oral irritation qualities, as well as its odor). Ethanol re-exposure in adolescence augments the fetal odor-mediated effect and is critical for perpetuating it into adulthood. The expression of olfactory bulb genes involved in, for example, synaptic transmission and plasticity are altered in adolescent animals exposed to fetal ethanol. The effects ameliorate by adulthood. Together, our studies established an epigenetic chemosensory mechanism in keeping with the cascading pattern predicted by the clinical literature.
Our recent data critically extends this work by providing evidence that, in accordance with our published taste-mediated behavioral findings, fetal ethanol exposure: (1) reduces the peripheral neural response to quinine (a surrogate for ethanol’s bitter taste) and (2) decreases the expression of 16 bitter (T2r) and 1 oral irritation (Trp) receptor genes fundamental to ethanol flavor perception in adolescent rats. Notably, 6 of our identified T2rs map in a QTL region for alcohol preference and consumption, and the identified Trp (TrpV1) has been shown behaviorally both by our lab and others to be important to ethanol acceptance. Importantly, we find that binge ethanol exposure in naïve adolescent rats yields similar results to the prenatal T2r findings. Thus, our proposal’s focus on adolescence is strategic because it investigates a developmental transition point for emergent patterns of ethanol abuse.
Our long-range goal is to apply an understanding of these cellular processes to the development of clinical treatments and strategies. Applying behavioral, genomic and neurophysiologic methods, the objectives of this proposal are to understand mechanistically: (A) the ontogeny of the fetal exposure effect on oro-sensory receptor gene expression and whether the observed effects differ between fetal and adolescent exposure; (B) whether adolescent behavioral responses (following fetal exposure) are mediated by alterations in receptor gene expression; and (C) whether adolescent re-exposure augments the behavioral and receptor response to fetal exposure and/or perpetuates them into adulthood. We will also determine how alterations in the peripheral neural responses to ethanol and stimuli representing it’s component qualities (bitter, sweet and irritancy) parallel the foregoing behavioral and genomic effects.
In summary, our proposal addresses epigenetic chemosensory mechanisms by which maternal ethanol use can be transferred to offspring, and via which, the adolescent system is primed to have the effects of fetal exposure augmented and/or preserved into adulthood. Our studies will provide results within a clinically relevant framework related to adolescent ethanol intake behavior and its progression.
Main Project 3
The consequences of positive and negative ethanol reinforcement may vary during development. The present proposal tests the hypothesis that positive and negative reinforcement are differentially affected by controlling parameters and that the efficacy of ethanol reinforcement generally may differ between the second postnatal week and late adolescence.
- In humans and animals, exposure to ethanol during the prenatal and early postnatal periods increases affinity for ethanol during adolescence.
- Infant rats ingest ethanol in substantial quantities without initiation procedures (like adult rats selectively bred for high initial acceptance of ethanol), so they provide an alternative to the use of genetic selection for determining mechanisms of ethanol reinforcement. That is, tests with the developmental model hold genetic potential constant while varying age, whereas tests with a genetic model hold age constant while varying genetic potential.
- Although the critical period of adolescence for determining ethanol abuse in humans has become better understood by contrasting the sensitivity of adolescent and adult rats to ethanol, it remains uncertain whether ontogenetic progression into these aspects of adolescence is abrupt, a discrete break from earlier ages, or continuous.
Presumably then, younger animals should have vestiges of the mechanisms responsible for the adolescent's sensitivity to ethanol and susceptibility to ethanol abuse. The proposed studies will examine the early ontogeny of positive and negative ethanol reinforcement, the effect of prenatal and early postnatal exposure to ethanol on ethanol reinforcement in adolescence, and central mechanisms underlying ethanol reinforcement. Psychopharmacological experiments will examine receptor systems that change ontogenetically and have strong theoretical and empirical links to ethanol reinforcement. These studies will be supported by collaborations with the CELL/MOLECULAR BIOLOGY CORE, to assess translational and protein expression of localized mu, delta and kappa opioid receptors and three GABAA receptor subunits (2, 3, and 5) in response to the ethanol reinforcement; and with the NEUROANATOMY CORE, to determine the number of neurons expressing, in selected neural areas, cFos in response to the earlier ethanol exposure that alters ethanol intake and reinforcement in adolescence. A key feature of these experiments is application of tests for ethanol reinforcement that are comparable over a substantial range of ontogeny. The proposed experiments may clarify the relationship between early ethanol exposure and the "early debut" effect in humans. Clinical benefits may occur in terms of determining the need for differential treatment for ethanol abuse originating primarily from early exposure to sources of ethanol reinforcement, the role of pre-adolescent ethanol experience, and the potential interaction between age and "type" of ethanol reinforcement that dominates one's experience.
Main Project 4
Alcohol use by human adolescents is pervasive, with over 10% of 8th graders, 20% of 10th graders and 25% of 12th graders reporting consumption of five or more drinks in a row in the past two weeks. High levels of alcohol consumption may be fostered in adolescents in part because of their insensitivity to certain desired ethanol effects as well as to effects of ethanol used to self-monitor intake, whereas these relatively high intakes may exacerbate certain adverse ethanol effects to which adolescents may be unusually sensitive. Indeed, animal studies have shown adolescents to differ considerably from adults in their sensitivity to acute ethanol, with these alterations bi-directional in nature. Though less sensitive than adults to many ethanol effects (e.g., sedative, motor-impairing and anxiolytic effects), adolescents are conversely more sensitive than their adult counterparts to ethanol-induced social facilitation and ethanol-related impairments in LTP and spatial memory.
Recent work has shown that these effects are particularly pronounced during early adolescence, with animals of this age varying considerably in their ethanol sensitivities from older adolescents and adults. Using an established animal model of adolescence and animals generated from the ANIMAL CORE, the proposed work will examine factors contributing to the unique mosaic of behavioral sensitivities to ethanol seen in young adolescents. Psychopharmacological studies will explore contributions of developmental alterations in GABAA, NMDA (and opioid) receptor systems to an ethanol effect for which young adolescents are unusually sensitive (social facilitation) as well as for consequences of ethanol to which they are relatively resistance (e.g., anxiolysis and behavioral suppression) when compared with older adolescents and adults. Using the NEUROANATOMY CORE, additional studies will examine ontogenetic patterns of regional brain activation undergoing transformation during adolescence, including assessment of age-specific patterns of ethanol-induced cFos activation in target regions of interest.