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Learn More. The Neurobiology of Adolescent Drinking in Adulthood NADIA Consortium has focused on the impact of adolescent binge drinking on brain development, particularly on effects that persist into adulthood. Adolescent binge drinking is common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure during this developmental period and the underlying mechanisms.
These behavioral changes are associated with multiple molecular, cellular, and physiological alterations in the brain that persist long after AIE exposure. At the cellular level, AIE history is associated in adulthood with reduced expression of cholinergic, serotonergic, and dopaminergic neuron markers, attenuated cortical thickness, decreased neurogenesis, and altered dendritic spine and glial morphology.
This constellation of molecular and cellular adaptations to AIE likely contributes to observed alterations in neurophysiology, measured by synaptic physiology, EEG patterns, and functional connectivity. NADIA researchers are now elucidating mechanisms of these adaptations.
Adolescent binge drinking remains a ificant public health issue in the United States. Inmore than 4. What is less clear is how binge drinking affects brain development, and whether such neurobiological effects resolve with time or persist into adulthood. To address the causes of excessive adolescent drinking, the National Institutes of Health has funded longitudinal research in youth to track which factors may predispose adolescents to binge drink.
However, factors that predict alcohol use in humans can confound determination of the consequences of binge drinking, another major aspect of the public health issue and a question that can be systematically examined by modeling binge exposure in rodents that controls alcohol exposure across development.
The Consortium gathered basic neuroscientists with multidisciplinary expertise to explore the impact of adolescent binge alcohol on adult neurobiology and psychopathology using rodent models. Individual laboratories would conduct independent but coordinated experiments, building a body of data that in aggregate could support or refute hypotheses on adolescent alcohol exposure. To integrate the projects and the resulting data, the Consortium agreed to a set of procedural guidelines.
Second, alcohol exposure targeted the rat adolescent period, involving early adolescence, puberty, and young adulthood i. Assessments following maturation to stable adult characteristics reduce developmental confounds that muddle multilaboratory replication efforts. The goal of these guidelines was to increase replication and extension of findings across NADIA Consortium components as well as to other alcohol research laboratories.
The NADIA Consortium deed dependent measures to probe a wide variety of behavioral, physiological, cellular, and molecular endpoints. Behavioral outcomes in adulthood, such as cognition, affect, and alcohol drinking, were essential to provide face validity for the AIE models. Next, the Consortium focused attention on mechanistic studies that cannot be performed in humans, using sophisticated neurobiological measures to characterize neural systems altered by AIE exposure and evaluating potential approaches for prevention or reversal of effects.
The adolescent brain appears to be particularly vulnerable to the effects of binge alcohol exposure as compared to the adult brain, according to comparisons of animals exposed to ethanol EtOH during adolescence versus adulthood Broadwater et al. While these comparisons provided the foundation for the formation of the NADIA Consortium, the current mandate is to focus on persistent AIE effects on brain and behavior and their underlying mechanisms.
Alcohol consumption in rodents is known to vary by species, strain, method, and environment Crabbe et al. These studies use a variety of AIE exposures as well as alcohol consumption paradigms. Thus, across rat strains, laboratories, and routes of administration, AIE often increases adult alcohol drinking.
This finding is specific to males Dannenhoffer et al. Specifically, it is well known that the behavioral expression of anxiety and disinhibition can compete depending on the characteristics of the test situation Ennaceur, Investigations of the potential effects of AIE on learning and decision making in adulthood have revealed highly specific cognitive effects. While initial instrumental learning is generally unaffected Boutros et al. These findings are interesting and can be interpreted as a loss of executive function and behavioral efficiency Crews et al.
AIE also has been shown to increase risky choices Boutros et al. Together, these findings have led to the hypothesis that AIE promotes behavioral inflexibility: Behavioral choices are biased toward rewards and incentive cues, and behaviors perseverate despite changing circumstances. Importantly, those changes do not appear to be related to tolerance, but rather to enduring physiological, and possibly molecular, alterations. A similar conclusion has been reached from a recent review of studies in humans and rodents examining predisposing factors that predict adolescent alcohol consumption and the cognitive, behavioral, and neurobiological consequences of adolescent alcohol exposure Spear, Conclusion: AIE exposure is sufficient to produce many behavioral characteristics anxiety, behavioral inflexibility, increased drinking, and altered response to alcohol observed in humans with alcohol use disorder AUD.
Additional studies are needed to clearly define the contribution of adolescent alcohol abuse to AUD. NADIA studies have found that AIE persistently changes neuroimmune, neurotrophic, and epigenetic gene regulation and that these are key mechanisms underlying the AIE effects on adult physiology and behavior for reviews, see Crews et al.
These mechanisms involving epigenetic regulation of gene expression and noncoding RNA, particularly microRNA, involve aling across neurons, astrocytes, and microglia that shift transcription, with increases in transcription of proinflammatory genes and reduced transcription of trophic factors.
Moreover, similar increases in gene expression were observed in postmortem brains of humans with AUD Crews et al. While the persistent proinflammatory gene induction by AIE was initially surprising, neuroimmune genes and microglia are known to contribute to brain development at multiple levels Brenhouse and Schwarz, ; Cowan and Petri, ; Lenz and Nelson, Comparisons of adolescent and Free Judson Indiana 50 plus sex chat neuroimmune responses to EtOH and endotoxin i. Low initial innate immune responses, like those in adolescence, are associated with modest but persistent increases in proinflammatory cytokines that sensitize to repeated exposure, a potential mechanism of the allostatic changes associated with repeated alcohol exposure Coleman and Crews, ; Crews et al.
Molecular mechanisms of persistent changes in proinflammatory and trophic gene expression induced by adolescent intermittent ethanol AIE exposure. Top: Neurobiology of Adolescent Drinking in Adulthood NADIA findings support an overall hypothesis that complex mechanisms involving epigenetic and noncoding RNA, particularly microRNA miRNAcontribute to a persistent increase in proinflammatory gene expression and a loss of trophic factor expression due Free Judson Indiana 50 plus sex chat aling across neurons and glia, which contribute to persistent changes in adulthood.
Bottom: Adolescent development involves aling across neurons, microglia, and astrocytes that regulate synaptic maturation and neurocircuitry. Other proteins, growth factors, and epigenetic markers are persistently increased or decreased after AIE exposure right. These aling mechanisms control gene expression in neurons, astrocytes, and microglia and can thereby alter synapses that change circuits.
Neuroimmune aling among microglia, astrocytes, and neurons regulates epigenetic enzymes that open or silence chromatin architecture leading to altered gene expression. For example, AIE exposure, but not identical adult EtOH exposure, causes a persistent loss of adult hippocampal dentate gyrus neurogenesis that is associated with increased neuroimmune gene expression Broadwater et al.
Small miRNA are released in vesicles and al across cells regulating synaptic plasticity Cohen et al. Levels of TLR7 are increased by alcohol exposure contributing to neuroimmune activation Coleman et al. These alterations in turn may contribute to decreased trophic factor gene expression that impacts the adult brain synaptic transcriptome. NADIA studies have found that AIE exposure changes adult brain regional gray and white matter, brain neurogenesis, cholinergic, dopaminergic, and serotonergic phenotypic markers, dendritic morphology, microglia, astrocytes, and expression of various peptide transmitters.
Although less well explored, AIE reduces serotonergic markers as indicated by a loss of both serotonin and tryptophan hydroxylase 2 Vetreno et al. Emerging research shows that neurocircuitry is regulated in part through glial—neuronal aling, with microglia, astrocytes, oligodendrocytes, and neurons all contributing e. For example, astroglia surround synapses, regulate synaptic transmission, and al synapse formation, while microglia initiate and remove neuronal synapses Fig. AIE produces adult increases in hyperramified microglia morphology characterized by increases in protrusions and proinflammatory cytokine—chemokine secretion.
It is unknown whether this priming is specific to AIE or whether similar effects would occur in response to adult alcohol exposure. Similarly, astrocyte activity is altered by AIE. Thus, aling across glia and neurons is altered by AIE, consistent with the induction of synaptic changes in multiple brain regions.
Adolescent brain development occurs in part through maturation of neurocircuits and synapses. Synaptic development is regulated through astroglia and microglia. Thrombospondins TSP are aling proteins released by astrocytes that promote synaptogenesis and are increased in adult hippocampus following adolescent intermittent ethanol AIE; Risher et al.
Similarly, AIE has been found to alter microglia, inducing a hyperramified state. Microglia regulate synapses in part through complement proteins, particularly C1q: complement component 1q, a protein complex that interacts with complement receptor 3 CR3 Walter and Crews, AIE increases adult microglial sensitivity to stimulation. Dendritic spine changes are brain region—specific; for example, in the central and medial, but not basolateral amygdala, AIE exposure reduces total dendritic spine density Jury et al.
The functional status of decreased dendritic spines in the amygdala in adulthood after AIE is not known. However, we recently demonstrated that AIE reduces several synaptic markers in the amygdala in adulthood Kyzar et al. Furthermore, synaptophysin labeling a marker of synapses was decreased in the central and medial amygdala after AIE in adulthood Kyzar et al.
These recent findings combined with decreased dendritic spines in the amygdala Pandey et al. Neurogenesis, the formation of new neurons, continues in rat brain hippocampus and subventricular zone throughout adolescence into young adulthood, providing an index of brain plasticity.
In adults, EtOH exposure reduces hippocampal neurogenesis; however, abstinence in restoration after several weeks Crews and Nixon, In contrast, adolescents have high levels of hippocampal neurogenesis that are more sensitive to EtOH inhibition than adults. NADIA studies across laboratories, using multiple routes of EtOH administration and rat strains, find that AIE persistently decreases neurogenesis in both the hippocampus and subventricular zones Broadwater et al. Similar to humans, rat brain white matter grows throughout adolescence, contributing to changes in cortical thickness; however, one difference is that male rat brain continues to grow in adulthood.
Diffusion tensor imaging DTI anisotropy provides both white and gray matter integrity information, and AIE alterations in DTI hippocampal anisotropy correlate with cognitive dysfunction Vetreno et al. Cortical thickness changes across adolescence in humans Ehlers et al.
MRI connectivity studies are emerging as a convergent translational approach to Free Judson Indiana 50 plus sex chat preclinical and clinical research. Conclusion: AIE exposure induces enduring cellular and anatomical changes in adult brain, many of which have been observed in humans with AUD. These cellular and structural changes are likely to underlie many of the consequences on AIE exposure on neurocircuitry and behavior. AIE, but not equivalent adult exposure, maintains an adolescent level of tonic current EtOH sensitivity into adulthood Fleming et al. Dopaminergic neurotransmission in the PFC modulates cognitive function and changes dramatically during adolescence.
Another study Schindler et al. Together, these studies suggest that synaptic and circuit changes following AIE are likely to underlie observed changes in decision making and alcohol drinking. NADIA studies found that AIE exposure can lead to deficits in a of electrophysiological and behavioral responses in adulthood that extend mechanistic studies and translate to humans.
For instance, AIE reduced EEG prepulse inhibition of startle response, and that reduction was ificantly associated with reduced hippocampal size Ehlers et al. The electrophysiological endpoints represent opportunities for translation of NADIA findings to human studies Ehlers et al.
Future functional connectivity studies are expected to integrate rat AIE findings of the NADIA Consortium to emerging studies on human adolescence, providing critical links to molecular mechanisms that translate to humans. Several NADIA studies have reported prevention or reversal of AIE pathology using exercise, the antiinflammatory drug indomethacin, the anticholinesterase drug donepezil, the anticonvulsant gabapentin, and the histone deacetylase inhibitor trichostatin A TSA. One consequence of AIE that has proven to be malleable is blunted neurogenesis Fig. Exercise Vetreno et al. All of these treatments reduce proinflammatory gene expression, and many increase trophic gene expression through complex mechanisms.
Donepezil may act directly on microglia Hwang et al. D Swartzwelder et al. Donepezil, an anticholinesterase with antiinflammatory activity, was administered for 4 days 2.
The studies demonstrating reversal of a persistent AIE effect are surprising and exciting, although more studies are needed to integrate these prevention and reversal mechanisms. Exercise is generally accepted as improving health through complex mechanisms that include increased trophic factor expression and reduced proinflammatory responses.
Reversal of the loss of cholinergic neurons by exercise was surprising, prompting experiments on mechanisms that led to the discovery of epigenetic silencing of cholinergic phenotypic genes. As AIE did not reduce forebrain neurons indexed via NeuN or induce basal forebrain neurogenesis assessed via BrdUthe AIE reductions of cholinergic neurons appeared to involve a loss of the cholinergic phenotype and associated cognitive deficits that did not involve neuronal death.
Note different ordinate scales. Prevention and reversal of adolescent intermittent ethanol AIE neuropathology by multiple strategies. Top: Epigenetic mechanisms involving histone and DNA methylation and acetylation are known mechanisms regulating gene expression, that is, silencing or enhancing transcription, and are persistently altered by AIE.
Together, these physiological changes may manifest as AIE alterations in a variety of neuronal circuit and behavioral effects bottomincluding disrupted sleep, anxiety, risky decisions, alcohol drinking, and cognitive inflexibility. The NADIA Consortium initially hypothesized that adolescent binge drinking can lead to persistent changes in adult neurobiology.
Somewhat unexpectedly, NADIA investigators discovered that AIE is sufficient to enhance many adult behavioral characteristics that were ly thought to represent trait vulnerabilities, such as anxiety, behavioral inflexibility, risky decisions, altered response to alcohol, and increased alcohol consumption—characteristics observed in individuals with AUD. Moreover, some of the cellular and molecular consequences of AIE are translational and observed in postmortem brains of humans with AUD. Further, these newly discovered mechanisms are likely to emerge as major developmental plasticity processes modulated by alcohol and other environmental factors that impact adolescent development and adult neurobiology.
The AIE model of adolescent binge drinking followed by abstinence into adulthood was developed specifically to investigate the impact of adolescent binge exposure and is not focused on preclinical lifelong drinking models. Human adolescent alcohol abuse is difficult to model. Preclinical models are impacted by differences in experimental de e. Moreover, while initial evidence suggests sex differences in some of these effects, the role of sex has yet to be explored in detail. The extent to which AIE model and conclusions vary as a consequence of these differences is important but unknown; nevertheless, the relative consistency of AIE exposure on adult alcohol drinking, anxiety, disinhibition, and cognitive flexibility indicates that the alcohol exposure reliably impacts brain development.
The NCANDA and ABCD longitudinal studies of human adolescents were deed to provide insight into individual psychological and physiological phenotypes associated with different drinking trajectories in both males and females, and the NADIA Consortium can use that information to de preclinical mechanistic studies. NADIA findings indicate that AIE changes brain regional gene expression, synapses, synaptic physiology, cortical thickness, and white matter, as well as altering cholinergic and other neuronal phenotypes.
Additional studies are needed to fully integrate the Free Judson Indiana 50 plus sex chat and synaptic mechanisms and define the neural circuits that underlie the changes in physiology and behavior across cortical and subcortical brain regions. Recent studies find that molecular epigenetic modifiers of RNA and DNA can be inherited, including those that modify alcohol and stress responses Chastain and Sarkar, that appear to underlie AIE molecular mechanisms. Human and preclinical studies are converging upon endpoints to test the validity of these findings. NADIA discoveries support a role for adolescent epigenetic programming in the development of AUD; while inherited genetic factors also clearly contribute, additional studies are needed to better understand the how genetic and epigenetic factors influence adolescent developmental neurobiology and risks for AUD.
In preclinical studies, exercise has been shown to increase trophic factor expression and blunt proinflammatory gene expression.
The observations that the antiinflammatory indomethacin and the histone deacetylase inhibitor TSA can reverse some of the AIE effects support these hypothetical mechanisms, and suggest they are persistent but not permanent. Thus, NADIA discoveries of unique adolescent programming of persistent changes in neurobiology through novel molecular mechanisms offer potentials for reversal via discovery of novel mechanisms and treatment targets for AUD. They have identified several tractable drug targets that can be useful in AUD treatment. Finally, these studies provide additional support for the public health importance of reducing and preventing underage drinking.
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