Browsing by Author "Gursky, Zachary Henry"
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Item Damaging impact of developmental alcohol exposure on hippocampo-thalamo-prefrontal circuitry(University of Delaware, 2020) Gursky, Zachary HenryExperiences during prenatal development and early postnatal life can have significant effects on the brain and body throughout the lifespan. Exposure to teratogens such as alcohol can cause profound changes in brain structure and function, resulting in a clinical diagnosis of Fetal Alcohol Spectrum Disorders (FASD). An estimated 8% of pregnancies are impacted by alcohol exposure during late pregnancy (Umer et al., 2020), a period of development commonly known as the “brain growth spurt” (Dobbing & Sands, 1979). Alcohol exposure during development frequently leads to impairments in “executive functions”, a series of complex behaviors typically categorized by three behavioral domains: working memory, response inhibition, and set shifting (Khoury, Milligan, & Girard, 2015). ☐ Rodent models have been critical in understanding the neuroanatomical and functional correlates of executive functions. Among the structures in the brain responsible for learning and memory, executive functions are primarily subserved by interactions between the prefrontal cortex and the hippocampus. Activity in these two brain regions during working memory (and presumably other executive functions) is coordinated through a small midline thalamic nucleus, thalamic nucleus reuniens (Hallock, Wang, & Griffin, 2016; Xu & Sudhof, 2013). While hippocampal damage has been a hallmark in literature identifying neurological consequences of FASD, examination of the prefrontal cortex has only recently gained attention, and the ventral midline thalamus has been almost completely unexplored. ☐ In three previous publications, we identified thalamic damage as a with potential cause of impaired executive functions observed in diagnoses of FASD. High-dose binge alcohol exposure during the brain growth spurt reduces the number of neuron in a select ventral midline thalamic nucleus by approximately one-third (Gursky, Savage, & Klintsova, 2019; Gursky, Spillman, & Klintsova, 2020). A similar exposure paradigm resulted in deficits in set-shifting behavior and spatial working memory (Gursky, Savage, & Klintsova, under review), suggesting that damage to the thalamus may interact with the hippocampus and prefrontal cortex as one extended circuit to cause long-lasting behavioral alterations. ☐ These empirical studies led to the hypothesis that thalamus is highly sensitive to alcohol-induced damage early in life, resulting in long-lasting changes in connectivity and function of the hippocampo-thalamo-prefrontal circuit. In two related specific aims, this dissertation focuses on two components of this hypothesis to identify its relevance to diagnoses of FASD: dose-dependent sensitivity and thalamic connectivity with hippocampus and prefrontal cortex. ☐ The first specific aim examines the sensitivity of thalamic nucleus reuniens to neuron loss induced by alcohol, in both male and female rats, during the brain growth spurt (i.e., postnatal days 4-9) at either high- (5.25 g/kg/day, delivered over 2 intragastric intubations per day) or moderate-dose (3.00g/kg/day, also delivered over 2 intragastric intubations per day). The volume of nucleus reuniens, number of neurons, number of microglia (immune cells of the brain), and number of other non-glial cells were all quantified and compared to both procedural controls and typically-developing controls. Relative to both control conditions, both ethanol doses substantially decreased the volume of the region, as well as the number of neurons and “other” cells (but not microglia). Damage was present in both the moderate-dose and high-dose treatment groups, which did not differ on any neuroanatomical measures (and damage was not correlated with achieved peak blood alcohol concentration). This finding suggests that thalamic damage in FASD may be all-or-nothing after surpassing a moderate threshold of blood alcohol concentration; lower doses necessary to validate this novel hypothesis comprise a critical target of future research. ☐ The second specific aim examined the connectivity of hippocampo-thalamo-prefrontal circuitry by examining the number and proportion of efferent thalamic neurons that project to prefrontal cortex, hippocampus, or both regions collaterally. Animals were exposed to the high dose of alcohol (again, 5.25 g/kg/day over 2 intubations/day from postnatal days 4-9). Retrograde labeling of reuniens projection neurons was achieved by stereotaxic injections of AAVs expressing fluorescent labels into medial prefrontal cortex and ventral hippocampus. We did not observe any changes in total number of labeled projection neurons with any of the three projection patterns mentioned above. Secondary to this, the substantial reduction in total neuron number (replicating and expanding on previous findings) resulted in an increased representation of reuniens projection neurons that target both prefrontal cortex and hippocampus, collaterally, relative to the total number of neurons in the region. This shift in the balance of collateral projections compared to other neurons may either contribute to — or be a consequence of — altered hippocampo-thalamo-prefrontal interactions throughout life. ☐ These data provide compelling evidence that the nucleus reuniens can be similarly damaged following any number of exposure paradigms during the brain growth spurt (ranging in both dose and duration of exposure), demonstrating an identical pattern of damage among the two doses used in this experiment. Changes in the representation of different projection-classes of neurons may alter the balance of thalamic activity within the hippocampo-thalamo-prefrontal circuit, warranting future investigation into the relationship between thalamic connectivity, functional correlates throughout the hippocampo-thalamo-prefrontal circuit, and impairment of prefrontal-dependent behaviors. Identifying the difference between behavioral impairment caused by damage to prefrontal cortex versus imbalance between prefrontal afferents from thalamus and hippocampus is critical in identifying therapeutic targets for individuals diagnosed with FASD.Item Selective damage of thalamic nucleus reuniens in a rat model of fetal alcohol spectrum disorders: alterations to hippocampus- and prefrontal cortex- dependent behaviors(University of Delaware, 2018) Gursky, Zachary HenryIndividuals diagnosed with fetal alcohol spectrum disorders (FASD) often display behavioral impairments in executive functioning. Mechanistic studies have implicated coordination between prefrontal cortex and hippocampus (through thalamic nucleus reuniens) as critical for such executive functions. The current study characterized the neuroanatomical alterations to midline thalamus and alterations in executive function in a rodent model of fetal alcohol spectrum disorders. Alcohol diluted in milk formula was administered to Long Evans rat pups on postnatal days (PD) 4-9 (5.25 g/kg/day of ethanol, 11.9% v/v, intragastric intubation). Control animals were intubated without administration of liquid. In adulthood (PD72), brains of females were analyzed for total cell number and neuron number in three midline thalamic nuclei. Males from the same litters were run on a battery of behavioral assays in adulthood (postnatal day >55). This battery consisted of novel object recognition, object in place, spontaneous alternations, and behavioral flexibility tasks. Nucleus-specific damage was found in midline thalamus, resulting in long term loss of neurons as well as volume specifically in reuniens of alcohol-exposed females. Males demonstrated behavioral impairments in short-term spatial memory and rule-switching, but not object recognition or levels of activity, suggesting impairments in executive functioning. This constitutes the first investigation into the circuit-specific consequence of third trimester alcohol exposure on the midline thalamus. These specific neuroanatomical and behavioral alterations suggest that prenatal alcohol exposure results in damage to prefrontal-thalamo-hippocampal circuitry.