Anna Klintsova - Academia.edu (original) (raw)

Papers by Anna Klintsova

bioRxiv (Cold Spring Harbor Laboratory), Sep 28, 2023

Background Fetal Alcohol Spectrum Disorders (FASD) encompass a group of highly prevalent conditio... more Background Fetal Alcohol Spectrum Disorders (FASD) encompass a group of highly prevalent conditions resulting from prenatal alcohol exposure. Alcohol exposure during the third trimester of pregnancy overlapping with the brain growth spurt is detrimental to white matter growth and myelination, particularly in the corpus callosum, ultimately affecting tissue integrity in adolescence. Traditional neuroimaging techniques have been essential for assessing neurodevelopment in affected youth; however, these methods are limited in their capacity to track subtle microstructural alterations to white matter, thus restricting their effectiveness in monitoring therapeutic intervention. In this preliminary study we use a highly sensitive and clinically translatable Magnetic Resonance Elastography (MRE) protocol for assessing brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. Methods Rat pups were divided into two groups: alcohol-exposed (AE) pups which received alcohol in milk substitute (5.25 g/kg/day) via intragastric intubation on postnatal days (PD) four through nine during the rat brain growth spurt (Dobbing and Sands, 1979), or sham-intubated (SI) controls. In adolescence, on PD 30, half AE and SI rats were randomly assigned to either a modified home cage with free access to a running wheel or to a new home cage for 12 days (Gursky and Klintsova, 2017). Previous studies conducted in the lab have shown that 12 days of voluntary exercise intervention in adolescence immediately ameliorated callosal myelination in AE rats (Milbocker et al., 2022, 2023). MRE was used to measure longitudinal changes to mechanical properties of the whole brain and the corpus callosum at intervention termination and one-month post-intervention. Histological quantification of precursor and myelinating oligoglia in corpus callosum was performed one-month post-intervention.

Brain plasticity, Nov 16, 2023

Brain plasticity, also termed neuroplasticity, refers to the brain's lifelong ability to reorgani... more Brain plasticity, also termed neuroplasticity, refers to the brain's lifelong ability to reorganize itself in response to various changes in the environment, experiences, and learning. The brain is a dynamic organ capable of responding to stimulating or depriving environments, activities, and circumstances from changes in gene expression, release of neurotransmitters and neurotrophic factors, to cellular reorganization and reprogrammed functional connectivity. The rate of neuroplastic alteration varies across the lifespan, creating further challenges for understanding and manipulating these processes to benefit motor control, learning, memory, and neural remodeling after injury. Neuroplasticity-related research spans several decades, and hundreds of reviews have been written and published since its inception. Here we present an overview of the empirical papers published between 2017 and 2023 that address the unique effects of exercise, plasticity-stimulating activities, and the depriving effect of social isolation on brain plasticity and behavior.

Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impai... more Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impairments in executive functioning (EF). Specifically, the domains of working memory, inhibition, and set shifting are frequently impacted by prenatal alcohol exposure. Coordination between prefrontal cortex and hippocampus appear to be essential for these domains of executive functioning. The current study uses a rodent model of human third-trimester binge drinking to identify the extent of persistent executive functioning deficits following developmental alcohol by using a behavioral battery of hippocampus-and prefrontal cortex-dependent behavioral assays in adulthood. Alcohol added to milk formula was administered to Long Evans rat pups on postnatal days 4-9 (5.25 g/kg/day of ethanol; intragastric intubation), a period when rodent brain development undergoes comparable processes to human third-trimester neurodevelopment. Procedural control animals underwent sham intubation, without administration of any liquids (i.e., alcohol, milk solution). In adulthood, male rats were run on a battery of behavioral assays: novel object recognition, object-in-place associative memory, spontaneous alternation, and behavioral flexibility tasks. Alcohol-exposed rats demonstrated behavioral impairment in objectin-place preference and performed worse when the rule was switched on a plus maze task. All rats showed similar levels of novel object recognition, spontaneous alternation, discrimination learning, and reversal learning, suggesting alcohol-induced behavioral alterations are selective to executive functioning domains of spatial working memory and set-shifting in this widely-utilized rodent model. These specific behavioral alterations support the hypothesis that behavioral impairments in EF following prenatal alcohol exposure are caused by distributed damage to the prefrontal-thalamo-hippocampal circuit consisting of the medial prefrontal cortex, thalamic nucleus reuniens, and CA1 of hippocampus.

Journal of Neuroimmune Pharmacology, Dec 22, 2017

Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apo... more Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apoptosis, and synaptic pruning. Sex differences in microglia colonization of the developing brain have been reported, but have not been established following alcohol insult. Developmental alcohol exposure represents a neuroimmune challenge that may contribute to cognitive dysfunction prevalent in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. Most studies have investigated neuroimmune activation following adult alcohol exposure or following multiple exposures. The current study uses a single day binge alcohol exposure model (postnatal day [PD] 4) to examine sex differences in the neuroimmune response in the developing rat hippocampus on PD5 and 8. The neuroimmune response was evaluated through measurement of microglial number and cytokine gene expression at both time points. Male pups had higher microglial number compared to females in many hippocampal subregions on PD5, but this difference disappeared by PD8, unless exposed to alcohol. Expression of pro-inflammatory marker CD11b was higher on PD5 in alcohol-exposed (AE) females compared to AE males. After alcohol exposure, CC motif chemokine ligand 4 (CCL4) was significantly increased in female AE pups on PD5 and PD8. Tumor necrosis factor-α (TNF-α) levels were also upregulated by AE in males on PD8. The results demonstrate a clear difference between the male and female neuroimmune response to an AE challenge, which also occurs in a time-dependent manner. These findings are significant as they add to our knowledge of specific sex-dependent effects of alcohol exposure on microglia within the developing brain.

Synapse, Jun 17, 2015

Developmental alcohol exposure in humans can produce a wide range of deficits collectively referr... more Developmental alcohol exposure in humans can produce a wide range of deficits collectively referred to as Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments in executive functioning later in life suggest long-term damage to the prefrontal cortex (PFC). In rodent neonates, moderate to high levels of alcohol exposure decreased frontal lobe brain size and altered medial PFC pyramidal neuron dendritic morphology. Previous research in our lab demonstrated that neonatal alcohol exposure decreased basilar dendritic complexity but did not affect spine density in Layer II/III pyramidal neurons in 26-30 day old rats. The current study adds to the literature by evaluating the effect of neonatal alcohol exposure on mPFC Layer II/III basilar dendritic morphology in adolescent male rats. Additionally, it examines the potential for voluntary exercise to mitigate alcohol-induced deficits on mPFC dendritic complexity. An animal model of binge drinking during the third trimester of pregnancy was used. Rats were intubated with alcohol (alcohol-exposed, AE; 5.25g/kg/day) on postnatal day (PD) 4-9; two control groups were included (suckle control and sham-intubated). Rats were anesthetized and perfused with heparinized saline solution on PD 42, and brains were processed for Golgi-Cox staining. Developmental alcohol exposure decreased spine density and dendritic complexity of basilar dendrites of Layer II/III neurons in the medial PFC (mPFC) compared to dendrites of control animals. Voluntary exercise increased spine density and dendritic length in AE animals resulting in elimination of the differences between AE and SH rats. Thus, voluntary exercise during early adolescence selectively rescued alcohol-induced morphological deficits in the mPFC.

Behavioural Brain Research, May 1, 2021

Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impai... more Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impairments in executive functioning (EF). Specifically, the domains of working memory, inhibition, and set shifting are frequently impacted by prenatal alcohol exposure. Coordination between prefrontal cortex and hippocampus appear to be essential for these domains of executive functioning. The current study uses a rodent model of human third-trimester binge drinking to identify the extent of persistent executive functioning deficits following developmental alcohol by using a behavioral battery of hippocampus- and prefrontal cortex-dependent behavioral assays in adulthood. Alcohol added to milk formula was administered to Long Evans rat pups on postnatal days 4–9 (5.25 g/kg/day of ethanol; intragastric intubation), a period when rodent brain development undergoes comparable processes to human third-trimester neurodevelopment. Procedural control animals underwent sham intubation, without administration of any liquids (i.e., alcohol, milk solution). In adulthood, male rats were run on a battery of behavioral assays: novel object recognition, object-in-place associative memory, spontaneous alternation, and behavioral flexibility tasks. Alcohol-exposed rats demonstrated behavioral impairment in object-in-place preference and performed worse when the rule was switched on a plus maze task. All rats showed similar levels of novel object recognition, spontaneous alternation, discrimination learning, and reversal learning, suggesting alcohol-induced behavioral alterations are selective to executive functioning domains of spatial working memory and set-shifting in this widely-utilized rodent model. These specific behavioral alterations support the hypothesis that behavioral impairments in EF following prenatal alcohol exposure are caused by distributed damage to the prefrontal-thalamo-hippocampal circuit consisting of the medial prefrontal cortex, thalamic nucleus reuniens, and CA1 of hippocampus.

Neurotoxicology and Teratology, Mar 1, 2018

The long-term effects of developmental alcohol and stress exposure are well documented in both hu... more The long-term effects of developmental alcohol and stress exposure are well documented in both humans and non-human animal models. Damage to the brain and attendant lifelong impairments in cognition and increased risk for psychiatric disorders are debilitating consequences of developmental exposure to alcohol and/or psychosocial stress. Here we discuss evidence for a role of epigenetic mechanisms in mediating these consequences. While we highlight some of the common ways in which stress or alcohol impact the epigenome, we point out that little is understood of the epigenome's response to experiencing both stress and alcohol exposure, though stress is a contributing factor as to why women drink during pregnancy. Advancing our understanding of this relationship is of critical concern not just for the health and well-being of individuals directly exposed to these teratogens, but for generations to come.

Neuroscience, Jun 1, 2016

Aberrant activation of the developing immune system can have long-term negative consequences on c... more Aberrant activation of the developing immune system can have long-term negative consequences on cognition and behavior. Teratogens, such as alcohol, activate microglia, the brain's resident immune cells, which could contribute to the lifelong deficits in learning and memory observed in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. The current study investigates the microglial response of the brain 24 hours following neonatal alcohol exposure (postnatal days 4-9, 5.25 g/kg/day). On postnatal day 10, microglial cell counts and area of cell territory were assessed using unbiased stereology in the hippocampal subfields CA1, CA3 and dentate gyrus, and hippocampal expression of pro-and anti-inflammatory genes was analyzed. A significant decrease in microglial cell counts in CA1 and dentate gyrus was found in alcoholexposed and sham-intubated animals compared to undisturbed suckle controls, suggesting overlapping effects of alcohol exposure and intubation alone on the neuroimmune response. Cell territory was decreased in alcohol-exposed animals in CA1, CA3, and dentate gyrus compared to controls, suggesting the microglia have shifted to a more activated state following alcohol treatment. Furthermore, both alcohol-exposed and sham-intubated animals had increased levels of pro-inflammatory cytokines IL-1β, TNF-α, CD11b, and CCL4; in addition, CCL4 was significantly increased in alcohol-exposed animals compared to sham-intubated as well. Alcoholexposed animals also showed increased levels of anti-inflammatory cytokine TGF-β compared to both sham-intubated and suckle controls. In summary, the number and activation of microglia in the neonatal hippocampus are both affected in a rat model of FASD, along with increased gene expression of pro-and anti-inflammatory cytokines. This study shows that alcohol exposure during development induces a neuroimmune response, potentially contributing to long-term alcohol-related changes to cognition, behavior and immune function.

Vitamins and hormones, 2017

Fetal alcohol spectrum disorders (FASDs) are a result of the teratogenic effects of alcohol on th... more Fetal alcohol spectrum disorders (FASDs) are a result of the teratogenic effects of alcohol on the developing fetus. Decades of research examining both individuals with FASDs and animal models of developmental alcohol exposure have revealed the devastating effects of alcohol on brain structure, function, behavior, and cognition. Neurotrophic factors have an important role in guiding normal brain development and cellular plasticity in the adult brain. This chapter reviews the current literature showing that alcohol exposure during the developmental period impacts neurotrophin production and proposes avenues through which alcohol exposure and neurotrophin action might interact. These areas of overlap include formation of long-term potentiation, oxidative stress processes, neuroinflammation, apoptosis and cell loss, hippocampal adult neurogenesis, dendritic morphology and spine density, vasculogenesis and angiogenesis, and behaviors related to spatial memory, anxiety, and depression. Finally, we discuss how neurotrophins have the potential to act in a compensatory manner as neuroprotective molecules that can combat the deleterious effects of in utero alcohol exposure.

International Journal of Developmental Neuroscience, Aug 4, 2020

Developmental alcohol exposure results in altered neuroimmune function in both humans and rodents... more Developmental alcohol exposure results in altered neuroimmune function in both humans and rodents. Given the critical role for the principle neuroimmune cell, microglia, in maintaining synaptic form and function, microglial dysfunction in the cerebellum may be an important mechanism underlying the aberrant cerebellar connectivity observed in rodent models of fetal alcohol spectrum disorders. Using an established rodent model of alcohol exposure during human third-trimester fetal development, we examine the cerebellum of male and female Long Evans rats to determine the impact of early postnatal alcohol exposure on cerebellar microglia, and the potential therapeutic effects of an adolescent intervention consisting of voluntary exercise (running). All cerebelli were examined at postnatal day 42 (i.e., late adolescence), and microglia were labeled with Iba1, a microglia-specific protein. Early postnatal alcohol exposure caused an increase in microglial density throughout cerebellum and a reduction in cerebellar volume, and a reduction in the proportion of fully ramified (often called "resting state") microglia selective to lobules 1-4. In contrast, adolescent exercise decreased microglial density throughout cerebellum and increased cerebellar volume, while activating microglia (as indicated by increases in amoeboid microglia, and reductions in fully and partially ramified microglia) selectively in lobules 1-4. These results suggest that adolescent exercise may be a suitable intervention to ameliorate alcoholinduced neuroimmune dysfunction as it alters microglia density and cerebellar volume in opposite to the effects of developmental alcohol exposure. Importantly, exercise intervention can be flexibly implemented well after the time window of vulnerability to alcohol.

Neuroscience, May 1, 2020

Fetal alcohol spectrum disorders (FASD) constitute a prevalent, yet preventable, developmental di... more Fetal alcohol spectrum disorders (FASD) constitute a prevalent, yet preventable, developmental disorder worldwide. While a wealth of research demonstrates that altered function of hippocampus and prefrontal cortex may underlie behavioral impairments in FASD, only one published paper to date has examined the impact of developmental alcohol exposure on the region responsible for coordinated prefrontal-hippocampal activity: thalamic nucleus reuniens (Re). In the current study, we used a rodent model of human third trimester alcohol exposure to examine both the acute and lasting impact of a single-day alcohol exposure on Re. We administered 5.25 g/kg of ethanol to male and female Long Evans rat pups on postnatal day (PD) 7. We used unbiased stereological estimation to evaluate cell death or cell loss at three time points: 12 hours after alcohol administration; 4 days after alcohol administration (i.e., PD11); in adulthood (i.e.,postnatal day 72). Alcohol exposure on PD7 increased apoptotic cell death in Re on PD7, and caused short-term cell loss on PD11. This relationship between short-term cell death versus cell number suggests that alcohol-related cell loss is driven by induction of apoptosis. In adulthood, alcohol-exposed animals displayed permanent cell loss (mediating volume loss in the Re), which included a reduction in neuron number (relative to procedural controls). Both procedural controls and alcohol exposed animals displayed a deficit in non-neuronal cell number relative to typically-developing controls, suggesting that Re cell populations may be vulnerable to early life stress as well as alcohol exposure in an insult- and cell type-dependent manner.

ISMRM Annual Meeting

Developing preclinical MRE techniques that are comparable to human MRE is important for translati... more Developing preclinical MRE techniques that are comparable to human MRE is important for translational studies. This pilot study investigates the efficacy of the nonlinear inversion algorithm on rat brain MRE data. Whole-brain MRE scans were performed on female, Long-Evans rats using a custom MRE-EPI sequence and piezoelectric actuator with a resolution of 0.25 mm isotropic and with 600 Hz vibration. NLI parameters were adjusted for brain size and frequency. The resulting shear stiffness and damping ratio maps exhibited strong contrast between different anatomical regions. These results validate the use of NLI in preclinical MRE settings.

ISMRM Annual Meeting

Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term used to identify individuals with a h... more Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term used to identify individuals with a history of prenatal alcohol exposure which results in a spectrum of diagnostic disorders. 1 in 20 infants born in the U.S. has been diagnosed with an FASD, creating a major public health crisis. Deficits in corpus callosum myelination resulting from prenatal alcohol exposure have been correlated with impairments to perceptual learning and executive function in adolescents diagnosed with FASD. This study investigates the therapeutic potential of an exercise intervention to ameliorate alcohol-induced damage to corpus callosum myelination in a rodent model of FASD.

Neurogenesis, 2017

Exposure of the embryo and fetus to alcohol can lead to abnormal physical, neuroanatomical, and b... more Exposure of the embryo and fetus to alcohol can lead to abnormal physical, neuroanatomical, and behavioral development, collectively known as Fetal Alcohol Spectrum Disorders (FASDs). This minireview focuses on the negative impact of prenatal alcohol exposure on hippocampal adult neurogenesis, an important process by which the brain adds new neurons throughout the lifespan, and hippocampal dendritic complexity through the discussion of various mammalian models of FASDs. Alcohol-induced aberrations in the outgrowth, phenotype, and stability of dendrites of neurons in the hippocampus and the prefrontal cortex will also be discussed. Timing of alcohol exposure during development (first trimester vs. third trimester-equivalent) can determine whether cell proliferation or long-term cell survival is impaired. Our work demonstrating that third trimesterequivalent exposure has a more significant impact on cell survival and dendritic morphology than rate of cell proliferation. Understanding the impact of prenatal ethanol exposure on adult neurogenesis is important as altered rates of new cell generation or successful integration of adultborn neurons could contribute to many of the hippocampal-associated deficits in memory and cognitive function observed in patients with FASDs. In addition, this commentary discusses evidence in support of aerobic exercise and environmental complexity ("enrichment") as potential therapeutic strategies for alcohol-related deficits.

Addictive Substances and Neurological Disease, 2017

Abstract A leading cause of preventable neurological and physical impairment, prenatal exposure t... more Abstract A leading cause of preventable neurological and physical impairment, prenatal exposure to alcohol is clinically diagnosable as fetal alcohol spectrum disorders (FASDs). FASD is characterized by atypical development of the brain (among other anatomical structures). In humans, alcohol exposure during the third trimester leads to cortical damage and aberrant cortical connectivity including the frontal lobe. Rodent models corroborate these findings, contributing mechanistic approaches to frontal lobe damage on cellular and subcellular levels following alcohol exposure during periods developmentally analogous to human gestation. Further research must be done to comprehensively characterize neuroanatomical damage and its relation to behaviors governed by frontal lobe (frontal cortex, or PFC) including reversal learning and behavioral flexibility (which model cognitive deficits seen in humans with FASD). Translating interventions that rescue neuroanatomical and behavioral deficits in rodents may benefit clinical treatment of FASD. Translating animal literature and identifying the mechanisms underlying damage and interventions are crucial steps in improving the quality of life in FASD-afflicted individuals.

Synapse, 2015

Developmental alcohol exposure in humans can produce a wide range of deficits collectively referr... more Developmental alcohol exposure in humans can produce a wide range of deficits collectively referred to as Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments in executive functioning later in life suggest long-term damage to the prefrontal cortex (PFC). In rodent neonates, moderate to high levels of alcohol exposure decreased frontal lobe brain size and altered medial PFC pyramidal neuron dendritic morphology. Previous research in our lab demonstrated that neonatal alcohol exposure decreased basilar dendritic complexity but did not affect spine density in Layer II/III pyramidal neurons in 26-30 day old rats. The current study adds to the literature by evaluating the effect of neonatal alcohol exposure on mPFC Layer II/III basilar dendritic morphology in adolescent male rats. Additionally, it examines the potential for voluntary exercise to mitigate alcohol-induced deficits on mPFC dendritic complexity. An animal model of binge drinking during the third trimester of pregnancy was used. Rats were intubated with alcohol (alcohol-exposed, AE; 5.25g/kg/day) on postnatal day (PD) 4-9; two control groups were included (suckle control and sham-intubated). Rats were anesthetized and perfused with heparinized saline solution on PD 42, and brains were processed for Golgi-Cox staining. Developmental alcohol exposure decreased spine density and dendritic complexity of basilar dendrites of Layer II/III neurons in the medial PFC (mPFC) compared to dendrites of control animals. Voluntary exercise increased spine density and dendritic length in AE animals resulting in elimination of the differences between AE and SH rats. Thus, voluntary exercise during early adolescence selectively rescued alcohol-induced morphological deficits in the mPFC.

Brain Research, 2011

Developmental alcohol exposure can permanently alter brain structures and produce functional impa... more Developmental alcohol exposure can permanently alter brain structures and produce functional impairments in many aspects of behavior, including learning and memory. This study evaluates the effect of neonatal alcohol exposure on adult neurogenesis in the dentate gyrus of the hippocampus and the implications of such exposure for hippocampus-dependent contextual fear conditioning. Alcohol-exposed rats (AE) received 5.25 g/kg/day of alcohol on postnatal days (PD) 4-9 (third trimester in humans), in a binge-like manner. Two control groups were included: shamintubated (SI) and suckle-control (SC). Animals were housed in social cages (3/cage) after weaning. On PD80, animals were injected with 200 mg/kg BrdU. Half of the animals were sacrificed two hours later. The remainder were sacrificed on PD114 to evaluate cell survival; separate AE, SI, and SC rats not injected with BrdU were tested for the context preexposure facilitation effect (CPFE; ∼PD117). There was no difference in the number of BrdU+ cells in AE, SI and SC groups on PD80. On PD114, cell survival was significantly decreased in AE rats, demonstrating that developmental alcohol exposure damages new cells' ability to incorporate into the network and survive. Behaviorally tested SC and SI groups preexposed to the training context 24h prior to receiving a 1.5mA 2s footshock froze significantly more during the context test than their counterparts preexposed to an alternate context. AE rats failed to show the CPFE. The current study shows the detrimental, long-lasting effects of developmental alcohol exposure on hippocampal adult neurogenesis and contextual fear conditioning.

Neuropsychology Review, Aug 12, 2020

The thalamus, a significant part of the diencephalon, is a symmetrical and bilateral central brai... more The thalamus, a significant part of the diencephalon, is a symmetrical and bilateral central brain structure. The thalamus is subdivided into three major groups of nuclei based on their function: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Anatomically, nuclei within the thalamus are described by their location, such as anterior, medial, lateral, ventral, and posterior. In this review, we summarize the role of medial and midline thalamus in cognition, ranging from learning and memory to flexible adaptation. We focus on the discoveries in animal models of alcohol-related brain damage, which identify the loss of neurons in the medial and midline thalamus as drivers of cognitive dysfunction associated with alcohol use disorders. Models of developmental ethanol exposure and models of adult alcohol-related brain damage and are compared and contrasted, and it was revealed that there are similar (anterior thalamus) and different (intralaminar [adult exposure] versus ventral midline [developmental exposure]) thalamic pathology, as well as disruptions of thalamo-hippocampal and thalamo-cortical circuits. The final part of the review summarizes approaches to recover alcohol-related brain damage and cognitive and behavioral outcomes. These approaches include pharmacological, nutritional and behavioral interventions that demonstrated the potential to mitigate alcohol-related damage. In summary, the medial/midline thalamus is a significant contributor to cognition function, which is also sensitive to alcohol-related brain damage across the life span, and plays a role in alcohol-related cognitive dysfunction.

Cells

A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurod... more A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurodevelopment and results in several disorders categorized under the umbrella term Fetal Alcohol Spectrum Disorders (FASD). Children and adolescents affected by FASD exhibit delayed maturation of cerebral white matter, which contributes to deficits in executive function, visuospatial processing, sensory integration, and interhemispheric communication. Research using animal models of FASD have uncovered that oligoglia proliferation, differentiation, and survival are vulnerable to alcohol teratogenesis in the male brain due in part to the activation of the neuroimmune system during gestation and infancy. A comprehensive investigation of prenatal alcohol exposure on white matter development in the female brain is limited. This study demonstrated that the number of mature oligodendrocytes and the production of myelin basic protein were reduced first in the female corpus callosum following alcoh...

Scientific Reports

1 in 20 live births in the United States is affected by prenatal alcohol exposure annually, creat... more 1 in 20 live births in the United States is affected by prenatal alcohol exposure annually, creating a major public health crisis. The teratogenic impact of alcohol on physical growth, neurodevelopment, and behavior is extensive, together resulting in clinical disorders which fall under the umbrella term of Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments to executive function and perceptual learning are prevalent among affected youth and are linked to disruptions to corpus callosum growth and myelination in adolescence. Targeted interventions that support neurodevelopment in FASD-affected youth are nonexistent. We evaluated the capacity of an adolescent exercise intervention, a stimulator of myelinogenesis, to upregulate corpus callosum myelination in a rat model of FASD (third trimester-equivalent alcohol exposure). This study employs in vivo diffusion tensor imaging (DTI) scanning to investigate the effects of: (1) neonatal alcohol exposure and (2) an adolescent ...

bioRxiv (Cold Spring Harbor Laboratory), Sep 28, 2023

Background Fetal Alcohol Spectrum Disorders (FASD) encompass a group of highly prevalent conditio... more Background Fetal Alcohol Spectrum Disorders (FASD) encompass a group of highly prevalent conditions resulting from prenatal alcohol exposure. Alcohol exposure during the third trimester of pregnancy overlapping with the brain growth spurt is detrimental to white matter growth and myelination, particularly in the corpus callosum, ultimately affecting tissue integrity in adolescence. Traditional neuroimaging techniques have been essential for assessing neurodevelopment in affected youth; however, these methods are limited in their capacity to track subtle microstructural alterations to white matter, thus restricting their effectiveness in monitoring therapeutic intervention. In this preliminary study we use a highly sensitive and clinically translatable Magnetic Resonance Elastography (MRE) protocol for assessing brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. Methods Rat pups were divided into two groups: alcohol-exposed (AE) pups which received alcohol in milk substitute (5.25 g/kg/day) via intragastric intubation on postnatal days (PD) four through nine during the rat brain growth spurt (Dobbing and Sands, 1979), or sham-intubated (SI) controls. In adolescence, on PD 30, half AE and SI rats were randomly assigned to either a modified home cage with free access to a running wheel or to a new home cage for 12 days (Gursky and Klintsova, 2017). Previous studies conducted in the lab have shown that 12 days of voluntary exercise intervention in adolescence immediately ameliorated callosal myelination in AE rats (Milbocker et al., 2022, 2023). MRE was used to measure longitudinal changes to mechanical properties of the whole brain and the corpus callosum at intervention termination and one-month post-intervention. Histological quantification of precursor and myelinating oligoglia in corpus callosum was performed one-month post-intervention.

Brain plasticity, Nov 16, 2023

Brain plasticity, also termed neuroplasticity, refers to the brain's lifelong ability to reorgani... more Brain plasticity, also termed neuroplasticity, refers to the brain's lifelong ability to reorganize itself in response to various changes in the environment, experiences, and learning. The brain is a dynamic organ capable of responding to stimulating or depriving environments, activities, and circumstances from changes in gene expression, release of neurotransmitters and neurotrophic factors, to cellular reorganization and reprogrammed functional connectivity. The rate of neuroplastic alteration varies across the lifespan, creating further challenges for understanding and manipulating these processes to benefit motor control, learning, memory, and neural remodeling after injury. Neuroplasticity-related research spans several decades, and hundreds of reviews have been written and published since its inception. Here we present an overview of the empirical papers published between 2017 and 2023 that address the unique effects of exercise, plasticity-stimulating activities, and the depriving effect of social isolation on brain plasticity and behavior.

Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impai... more Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impairments in executive functioning (EF). Specifically, the domains of working memory, inhibition, and set shifting are frequently impacted by prenatal alcohol exposure. Coordination between prefrontal cortex and hippocampus appear to be essential for these domains of executive functioning. The current study uses a rodent model of human third-trimester binge drinking to identify the extent of persistent executive functioning deficits following developmental alcohol by using a behavioral battery of hippocampus-and prefrontal cortex-dependent behavioral assays in adulthood. Alcohol added to milk formula was administered to Long Evans rat pups on postnatal days 4-9 (5.25 g/kg/day of ethanol; intragastric intubation), a period when rodent brain development undergoes comparable processes to human third-trimester neurodevelopment. Procedural control animals underwent sham intubation, without administration of any liquids (i.e., alcohol, milk solution). In adulthood, male rats were run on a battery of behavioral assays: novel object recognition, object-in-place associative memory, spontaneous alternation, and behavioral flexibility tasks. Alcohol-exposed rats demonstrated behavioral impairment in objectin-place preference and performed worse when the rule was switched on a plus maze task. All rats showed similar levels of novel object recognition, spontaneous alternation, discrimination learning, and reversal learning, suggesting alcohol-induced behavioral alterations are selective to executive functioning domains of spatial working memory and set-shifting in this widely-utilized rodent model. These specific behavioral alterations support the hypothesis that behavioral impairments in EF following prenatal alcohol exposure are caused by distributed damage to the prefrontal-thalamo-hippocampal circuit consisting of the medial prefrontal cortex, thalamic nucleus reuniens, and CA1 of hippocampus.

Journal of Neuroimmune Pharmacology, Dec 22, 2017

Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apo... more Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apoptosis, and synaptic pruning. Sex differences in microglia colonization of the developing brain have been reported, but have not been established following alcohol insult. Developmental alcohol exposure represents a neuroimmune challenge that may contribute to cognitive dysfunction prevalent in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. Most studies have investigated neuroimmune activation following adult alcohol exposure or following multiple exposures. The current study uses a single day binge alcohol exposure model (postnatal day [PD] 4) to examine sex differences in the neuroimmune response in the developing rat hippocampus on PD5 and 8. The neuroimmune response was evaluated through measurement of microglial number and cytokine gene expression at both time points. Male pups had higher microglial number compared to females in many hippocampal subregions on PD5, but this difference disappeared by PD8, unless exposed to alcohol. Expression of pro-inflammatory marker CD11b was higher on PD5 in alcohol-exposed (AE) females compared to AE males. After alcohol exposure, CC motif chemokine ligand 4 (CCL4) was significantly increased in female AE pups on PD5 and PD8. Tumor necrosis factor-α (TNF-α) levels were also upregulated by AE in males on PD8. The results demonstrate a clear difference between the male and female neuroimmune response to an AE challenge, which also occurs in a time-dependent manner. These findings are significant as they add to our knowledge of specific sex-dependent effects of alcohol exposure on microglia within the developing brain.

Synapse, Jun 17, 2015

Developmental alcohol exposure in humans can produce a wide range of deficits collectively referr... more Developmental alcohol exposure in humans can produce a wide range of deficits collectively referred to as Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments in executive functioning later in life suggest long-term damage to the prefrontal cortex (PFC). In rodent neonates, moderate to high levels of alcohol exposure decreased frontal lobe brain size and altered medial PFC pyramidal neuron dendritic morphology. Previous research in our lab demonstrated that neonatal alcohol exposure decreased basilar dendritic complexity but did not affect spine density in Layer II/III pyramidal neurons in 26-30 day old rats. The current study adds to the literature by evaluating the effect of neonatal alcohol exposure on mPFC Layer II/III basilar dendritic morphology in adolescent male rats. Additionally, it examines the potential for voluntary exercise to mitigate alcohol-induced deficits on mPFC dendritic complexity. An animal model of binge drinking during the third trimester of pregnancy was used. Rats were intubated with alcohol (alcohol-exposed, AE; 5.25g/kg/day) on postnatal day (PD) 4-9; two control groups were included (suckle control and sham-intubated). Rats were anesthetized and perfused with heparinized saline solution on PD 42, and brains were processed for Golgi-Cox staining. Developmental alcohol exposure decreased spine density and dendritic complexity of basilar dendrites of Layer II/III neurons in the medial PFC (mPFC) compared to dendrites of control animals. Voluntary exercise increased spine density and dendritic length in AE animals resulting in elimination of the differences between AE and SH rats. Thus, voluntary exercise during early adolescence selectively rescued alcohol-induced morphological deficits in the mPFC.

Behavioural Brain Research, May 1, 2021

Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impai... more Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impairments in executive functioning (EF). Specifically, the domains of working memory, inhibition, and set shifting are frequently impacted by prenatal alcohol exposure. Coordination between prefrontal cortex and hippocampus appear to be essential for these domains of executive functioning. The current study uses a rodent model of human third-trimester binge drinking to identify the extent of persistent executive functioning deficits following developmental alcohol by using a behavioral battery of hippocampus- and prefrontal cortex-dependent behavioral assays in adulthood. Alcohol added to milk formula was administered to Long Evans rat pups on postnatal days 4–9 (5.25 g/kg/day of ethanol; intragastric intubation), a period when rodent brain development undergoes comparable processes to human third-trimester neurodevelopment. Procedural control animals underwent sham intubation, without administration of any liquids (i.e., alcohol, milk solution). In adulthood, male rats were run on a battery of behavioral assays: novel object recognition, object-in-place associative memory, spontaneous alternation, and behavioral flexibility tasks. Alcohol-exposed rats demonstrated behavioral impairment in object-in-place preference and performed worse when the rule was switched on a plus maze task. All rats showed similar levels of novel object recognition, spontaneous alternation, discrimination learning, and reversal learning, suggesting alcohol-induced behavioral alterations are selective to executive functioning domains of spatial working memory and set-shifting in this widely-utilized rodent model. These specific behavioral alterations support the hypothesis that behavioral impairments in EF following prenatal alcohol exposure are caused by distributed damage to the prefrontal-thalamo-hippocampal circuit consisting of the medial prefrontal cortex, thalamic nucleus reuniens, and CA1 of hippocampus.

Neurotoxicology and Teratology, Mar 1, 2018

The long-term effects of developmental alcohol and stress exposure are well documented in both hu... more The long-term effects of developmental alcohol and stress exposure are well documented in both humans and non-human animal models. Damage to the brain and attendant lifelong impairments in cognition and increased risk for psychiatric disorders are debilitating consequences of developmental exposure to alcohol and/or psychosocial stress. Here we discuss evidence for a role of epigenetic mechanisms in mediating these consequences. While we highlight some of the common ways in which stress or alcohol impact the epigenome, we point out that little is understood of the epigenome's response to experiencing both stress and alcohol exposure, though stress is a contributing factor as to why women drink during pregnancy. Advancing our understanding of this relationship is of critical concern not just for the health and well-being of individuals directly exposed to these teratogens, but for generations to come.

Neuroscience, Jun 1, 2016

Aberrant activation of the developing immune system can have long-term negative consequences on c... more Aberrant activation of the developing immune system can have long-term negative consequences on cognition and behavior. Teratogens, such as alcohol, activate microglia, the brain's resident immune cells, which could contribute to the lifelong deficits in learning and memory observed in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. The current study investigates the microglial response of the brain 24 hours following neonatal alcohol exposure (postnatal days 4-9, 5.25 g/kg/day). On postnatal day 10, microglial cell counts and area of cell territory were assessed using unbiased stereology in the hippocampal subfields CA1, CA3 and dentate gyrus, and hippocampal expression of pro-and anti-inflammatory genes was analyzed. A significant decrease in microglial cell counts in CA1 and dentate gyrus was found in alcoholexposed and sham-intubated animals compared to undisturbed suckle controls, suggesting overlapping effects of alcohol exposure and intubation alone on the neuroimmune response. Cell territory was decreased in alcohol-exposed animals in CA1, CA3, and dentate gyrus compared to controls, suggesting the microglia have shifted to a more activated state following alcohol treatment. Furthermore, both alcohol-exposed and sham-intubated animals had increased levels of pro-inflammatory cytokines IL-1β, TNF-α, CD11b, and CCL4; in addition, CCL4 was significantly increased in alcohol-exposed animals compared to sham-intubated as well. Alcoholexposed animals also showed increased levels of anti-inflammatory cytokine TGF-β compared to both sham-intubated and suckle controls. In summary, the number and activation of microglia in the neonatal hippocampus are both affected in a rat model of FASD, along with increased gene expression of pro-and anti-inflammatory cytokines. This study shows that alcohol exposure during development induces a neuroimmune response, potentially contributing to long-term alcohol-related changes to cognition, behavior and immune function.

Vitamins and hormones, 2017

Fetal alcohol spectrum disorders (FASDs) are a result of the teratogenic effects of alcohol on th... more Fetal alcohol spectrum disorders (FASDs) are a result of the teratogenic effects of alcohol on the developing fetus. Decades of research examining both individuals with FASDs and animal models of developmental alcohol exposure have revealed the devastating effects of alcohol on brain structure, function, behavior, and cognition. Neurotrophic factors have an important role in guiding normal brain development and cellular plasticity in the adult brain. This chapter reviews the current literature showing that alcohol exposure during the developmental period impacts neurotrophin production and proposes avenues through which alcohol exposure and neurotrophin action might interact. These areas of overlap include formation of long-term potentiation, oxidative stress processes, neuroinflammation, apoptosis and cell loss, hippocampal adult neurogenesis, dendritic morphology and spine density, vasculogenesis and angiogenesis, and behaviors related to spatial memory, anxiety, and depression. Finally, we discuss how neurotrophins have the potential to act in a compensatory manner as neuroprotective molecules that can combat the deleterious effects of in utero alcohol exposure.

International Journal of Developmental Neuroscience, Aug 4, 2020

Developmental alcohol exposure results in altered neuroimmune function in both humans and rodents... more Developmental alcohol exposure results in altered neuroimmune function in both humans and rodents. Given the critical role for the principle neuroimmune cell, microglia, in maintaining synaptic form and function, microglial dysfunction in the cerebellum may be an important mechanism underlying the aberrant cerebellar connectivity observed in rodent models of fetal alcohol spectrum disorders. Using an established rodent model of alcohol exposure during human third-trimester fetal development, we examine the cerebellum of male and female Long Evans rats to determine the impact of early postnatal alcohol exposure on cerebellar microglia, and the potential therapeutic effects of an adolescent intervention consisting of voluntary exercise (running). All cerebelli were examined at postnatal day 42 (i.e., late adolescence), and microglia were labeled with Iba1, a microglia-specific protein. Early postnatal alcohol exposure caused an increase in microglial density throughout cerebellum and a reduction in cerebellar volume, and a reduction in the proportion of fully ramified (often called "resting state") microglia selective to lobules 1-4. In contrast, adolescent exercise decreased microglial density throughout cerebellum and increased cerebellar volume, while activating microglia (as indicated by increases in amoeboid microglia, and reductions in fully and partially ramified microglia) selectively in lobules 1-4. These results suggest that adolescent exercise may be a suitable intervention to ameliorate alcoholinduced neuroimmune dysfunction as it alters microglia density and cerebellar volume in opposite to the effects of developmental alcohol exposure. Importantly, exercise intervention can be flexibly implemented well after the time window of vulnerability to alcohol.

Neuroscience, May 1, 2020

Fetal alcohol spectrum disorders (FASD) constitute a prevalent, yet preventable, developmental di... more Fetal alcohol spectrum disorders (FASD) constitute a prevalent, yet preventable, developmental disorder worldwide. While a wealth of research demonstrates that altered function of hippocampus and prefrontal cortex may underlie behavioral impairments in FASD, only one published paper to date has examined the impact of developmental alcohol exposure on the region responsible for coordinated prefrontal-hippocampal activity: thalamic nucleus reuniens (Re). In the current study, we used a rodent model of human third trimester alcohol exposure to examine both the acute and lasting impact of a single-day alcohol exposure on Re. We administered 5.25 g/kg of ethanol to male and female Long Evans rat pups on postnatal day (PD) 7. We used unbiased stereological estimation to evaluate cell death or cell loss at three time points: 12 hours after alcohol administration; 4 days after alcohol administration (i.e., PD11); in adulthood (i.e.,postnatal day 72). Alcohol exposure on PD7 increased apoptotic cell death in Re on PD7, and caused short-term cell loss on PD11. This relationship between short-term cell death versus cell number suggests that alcohol-related cell loss is driven by induction of apoptosis. In adulthood, alcohol-exposed animals displayed permanent cell loss (mediating volume loss in the Re), which included a reduction in neuron number (relative to procedural controls). Both procedural controls and alcohol exposed animals displayed a deficit in non-neuronal cell number relative to typically-developing controls, suggesting that Re cell populations may be vulnerable to early life stress as well as alcohol exposure in an insult- and cell type-dependent manner.

ISMRM Annual Meeting

Developing preclinical MRE techniques that are comparable to human MRE is important for translati... more Developing preclinical MRE techniques that are comparable to human MRE is important for translational studies. This pilot study investigates the efficacy of the nonlinear inversion algorithm on rat brain MRE data. Whole-brain MRE scans were performed on female, Long-Evans rats using a custom MRE-EPI sequence and piezoelectric actuator with a resolution of 0.25 mm isotropic and with 600 Hz vibration. NLI parameters were adjusted for brain size and frequency. The resulting shear stiffness and damping ratio maps exhibited strong contrast between different anatomical regions. These results validate the use of NLI in preclinical MRE settings.

ISMRM Annual Meeting

Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term used to identify individuals with a h... more Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term used to identify individuals with a history of prenatal alcohol exposure which results in a spectrum of diagnostic disorders. 1 in 20 infants born in the U.S. has been diagnosed with an FASD, creating a major public health crisis. Deficits in corpus callosum myelination resulting from prenatal alcohol exposure have been correlated with impairments to perceptual learning and executive function in adolescents diagnosed with FASD. This study investigates the therapeutic potential of an exercise intervention to ameliorate alcohol-induced damage to corpus callosum myelination in a rodent model of FASD.

Neurogenesis, 2017

Exposure of the embryo and fetus to alcohol can lead to abnormal physical, neuroanatomical, and b... more Exposure of the embryo and fetus to alcohol can lead to abnormal physical, neuroanatomical, and behavioral development, collectively known as Fetal Alcohol Spectrum Disorders (FASDs). This minireview focuses on the negative impact of prenatal alcohol exposure on hippocampal adult neurogenesis, an important process by which the brain adds new neurons throughout the lifespan, and hippocampal dendritic complexity through the discussion of various mammalian models of FASDs. Alcohol-induced aberrations in the outgrowth, phenotype, and stability of dendrites of neurons in the hippocampus and the prefrontal cortex will also be discussed. Timing of alcohol exposure during development (first trimester vs. third trimester-equivalent) can determine whether cell proliferation or long-term cell survival is impaired. Our work demonstrating that third trimesterequivalent exposure has a more significant impact on cell survival and dendritic morphology than rate of cell proliferation. Understanding the impact of prenatal ethanol exposure on adult neurogenesis is important as altered rates of new cell generation or successful integration of adultborn neurons could contribute to many of the hippocampal-associated deficits in memory and cognitive function observed in patients with FASDs. In addition, this commentary discusses evidence in support of aerobic exercise and environmental complexity ("enrichment") as potential therapeutic strategies for alcohol-related deficits.

Addictive Substances and Neurological Disease, 2017

Abstract A leading cause of preventable neurological and physical impairment, prenatal exposure t... more Abstract A leading cause of preventable neurological and physical impairment, prenatal exposure to alcohol is clinically diagnosable as fetal alcohol spectrum disorders (FASDs). FASD is characterized by atypical development of the brain (among other anatomical structures). In humans, alcohol exposure during the third trimester leads to cortical damage and aberrant cortical connectivity including the frontal lobe. Rodent models corroborate these findings, contributing mechanistic approaches to frontal lobe damage on cellular and subcellular levels following alcohol exposure during periods developmentally analogous to human gestation. Further research must be done to comprehensively characterize neuroanatomical damage and its relation to behaviors governed by frontal lobe (frontal cortex, or PFC) including reversal learning and behavioral flexibility (which model cognitive deficits seen in humans with FASD). Translating interventions that rescue neuroanatomical and behavioral deficits in rodents may benefit clinical treatment of FASD. Translating animal literature and identifying the mechanisms underlying damage and interventions are crucial steps in improving the quality of life in FASD-afflicted individuals.

Synapse, 2015

Developmental alcohol exposure in humans can produce a wide range of deficits collectively referr... more Developmental alcohol exposure in humans can produce a wide range of deficits collectively referred to as Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments in executive functioning later in life suggest long-term damage to the prefrontal cortex (PFC). In rodent neonates, moderate to high levels of alcohol exposure decreased frontal lobe brain size and altered medial PFC pyramidal neuron dendritic morphology. Previous research in our lab demonstrated that neonatal alcohol exposure decreased basilar dendritic complexity but did not affect spine density in Layer II/III pyramidal neurons in 26-30 day old rats. The current study adds to the literature by evaluating the effect of neonatal alcohol exposure on mPFC Layer II/III basilar dendritic morphology in adolescent male rats. Additionally, it examines the potential for voluntary exercise to mitigate alcohol-induced deficits on mPFC dendritic complexity. An animal model of binge drinking during the third trimester of pregnancy was used. Rats were intubated with alcohol (alcohol-exposed, AE; 5.25g/kg/day) on postnatal day (PD) 4-9; two control groups were included (suckle control and sham-intubated). Rats were anesthetized and perfused with heparinized saline solution on PD 42, and brains were processed for Golgi-Cox staining. Developmental alcohol exposure decreased spine density and dendritic complexity of basilar dendrites of Layer II/III neurons in the medial PFC (mPFC) compared to dendrites of control animals. Voluntary exercise increased spine density and dendritic length in AE animals resulting in elimination of the differences between AE and SH rats. Thus, voluntary exercise during early adolescence selectively rescued alcohol-induced morphological deficits in the mPFC.

Brain Research, 2011

Developmental alcohol exposure can permanently alter brain structures and produce functional impa... more Developmental alcohol exposure can permanently alter brain structures and produce functional impairments in many aspects of behavior, including learning and memory. This study evaluates the effect of neonatal alcohol exposure on adult neurogenesis in the dentate gyrus of the hippocampus and the implications of such exposure for hippocampus-dependent contextual fear conditioning. Alcohol-exposed rats (AE) received 5.25 g/kg/day of alcohol on postnatal days (PD) 4-9 (third trimester in humans), in a binge-like manner. Two control groups were included: shamintubated (SI) and suckle-control (SC). Animals were housed in social cages (3/cage) after weaning. On PD80, animals were injected with 200 mg/kg BrdU. Half of the animals were sacrificed two hours later. The remainder were sacrificed on PD114 to evaluate cell survival; separate AE, SI, and SC rats not injected with BrdU were tested for the context preexposure facilitation effect (CPFE; ∼PD117). There was no difference in the number of BrdU+ cells in AE, SI and SC groups on PD80. On PD114, cell survival was significantly decreased in AE rats, demonstrating that developmental alcohol exposure damages new cells' ability to incorporate into the network and survive. Behaviorally tested SC and SI groups preexposed to the training context 24h prior to receiving a 1.5mA 2s footshock froze significantly more during the context test than their counterparts preexposed to an alternate context. AE rats failed to show the CPFE. The current study shows the detrimental, long-lasting effects of developmental alcohol exposure on hippocampal adult neurogenesis and contextual fear conditioning.

Neuropsychology Review, Aug 12, 2020

The thalamus, a significant part of the diencephalon, is a symmetrical and bilateral central brai... more The thalamus, a significant part of the diencephalon, is a symmetrical and bilateral central brain structure. The thalamus is subdivided into three major groups of nuclei based on their function: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Anatomically, nuclei within the thalamus are described by their location, such as anterior, medial, lateral, ventral, and posterior. In this review, we summarize the role of medial and midline thalamus in cognition, ranging from learning and memory to flexible adaptation. We focus on the discoveries in animal models of alcohol-related brain damage, which identify the loss of neurons in the medial and midline thalamus as drivers of cognitive dysfunction associated with alcohol use disorders. Models of developmental ethanol exposure and models of adult alcohol-related brain damage and are compared and contrasted, and it was revealed that there are similar (anterior thalamus) and different (intralaminar [adult exposure] versus ventral midline [developmental exposure]) thalamic pathology, as well as disruptions of thalamo-hippocampal and thalamo-cortical circuits. The final part of the review summarizes approaches to recover alcohol-related brain damage and cognitive and behavioral outcomes. These approaches include pharmacological, nutritional and behavioral interventions that demonstrated the potential to mitigate alcohol-related damage. In summary, the medial/midline thalamus is a significant contributor to cognition function, which is also sensitive to alcohol-related brain damage across the life span, and plays a role in alcohol-related cognitive dysfunction.

Cells

A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurod... more A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurodevelopment and results in several disorders categorized under the umbrella term Fetal Alcohol Spectrum Disorders (FASD). Children and adolescents affected by FASD exhibit delayed maturation of cerebral white matter, which contributes to deficits in executive function, visuospatial processing, sensory integration, and interhemispheric communication. Research using animal models of FASD have uncovered that oligoglia proliferation, differentiation, and survival are vulnerable to alcohol teratogenesis in the male brain due in part to the activation of the neuroimmune system during gestation and infancy. A comprehensive investigation of prenatal alcohol exposure on white matter development in the female brain is limited. This study demonstrated that the number of mature oligodendrocytes and the production of myelin basic protein were reduced first in the female corpus callosum following alcoh...

Scientific Reports

1 in 20 live births in the United States is affected by prenatal alcohol exposure annually, creat... more 1 in 20 live births in the United States is affected by prenatal alcohol exposure annually, creating a major public health crisis. The teratogenic impact of alcohol on physical growth, neurodevelopment, and behavior is extensive, together resulting in clinical disorders which fall under the umbrella term of Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments to executive function and perceptual learning are prevalent among affected youth and are linked to disruptions to corpus callosum growth and myelination in adolescence. Targeted interventions that support neurodevelopment in FASD-affected youth are nonexistent. We evaluated the capacity of an adolescent exercise intervention, a stimulator of myelinogenesis, to upregulate corpus callosum myelination in a rat model of FASD (third trimester-equivalent alcohol exposure). This study employs in vivo diffusion tensor imaging (DTI) scanning to investigate the effects of: (1) neonatal alcohol exposure and (2) an adolescent ...