Browsing by Author "Leasure, J. Leigh"
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Item A Translational Animal Model Of Radiation-Induced Effects On Cognitive Functions: A Feasibility Study(2013-05) Trevino, Melissa 1985-; Leasure, J. Leigh; Hernandez, Arturo E.; Yoshida, HanakoNeurocognitive late-effects are commonly reported among survivors of pediatric brain cancer. Radiation therapy has been linked to these neurocognitive deficits in attention, working memory, and processing speed. The current feasibility study was conducted in order to establish whether it is possible to model these deficits in the rodent. Using the 5-Choice Serial Reaction Time Task (5-CSRTT), prefrontal cognitive processes, which are reported to be among the most affected in the pediatric cancer population, can be assessed in the rodent. Irradiated and control animals were trained to perform the 5-CSRTT and tested at four separate time points. Irradiated animals showed significant impairments compared with control animals at 5, 7, and 12 months post-irradiation. These results show that deficits in prefrontal-mediated cognitive processes induced by radiation therapy can be successfully modeled in the rodent.Item An Investigation of the Effect of Chronic Unpredictable Stress on Hippocampal Integrity and Spatial Learning(2012-05) Hawley, Darby; Leasure, J. Leigh; Hiscock, Merrill; Eriksen, Jason; Alkadhi, Karim A.Chronic stress has been shown to induce neuroplastic changes in the hippocampus, decrease the survival of progenitor cells in the hippocampus, and impair hippocampal-dependent learning and memory. Recent evidence suggests that the hippocampus has two functionally distinct subregions. The dorsal portion appears to be primarily associated with spatial navigation, while the ventral region has been linked to anxiety-related functions. Regionally-specific neuroplastic changes in the dorsal and ventral subregions of the hippocampus suggest that the hippocampus may play a dual role in the stress response. We previously demonstrated that following chronic unpredictable stress (CUS), markers of neuroplasticity were preserved specifically in the dorsal dentate gyrus (DG) of the hippocampus. Considering that hippocampal integrity is imperative for learning and memory, we hypothesized that the increased markers of neuroplasticity observed in the dorsal DG of CUS-exposed animals would enhance performance on tests of spatial navigation ability. In the present investigation, spatial navigation on the radial arm water maze (RAWM) was assessed in rats following exposure to CUS, as well as neurogenesis, neuroprotective proteins, and synaptic plasticity in the dorsal and ventral DG of the hippocampus. Despite similarly elevated levels of corticosterone, stressed animals found the hidden platform faster and with fewer errors on the RAWM long-term memory trial compared to control animals. Furthermore, elevated coriticosterone in control and stressed animals exposed to the RAWM had decreased cell proliferation (CldU) and neurogenesis (DCX) in the ventral DG. Stressed animals also had decreased cell survival (IdU) in the ventral DG. Proteins proBDNF and PSD-95, which promote LTP and synaptic plasticity, were increased in the dorsal DG. Stressed animals had increased neuroprotective proteins and preserved neuroplasticity in the dorsal DG, which may have contributed to the improved spatial navigation abilities on the RAWM. These regionally-specific neuroplastic changes suggest that the hippocampus does, in fact, play a dual role in response to chronic stress, and chronic stress does not impair spatial learning and memory.Item Bilingual language control: Bottom-up versus top-down(2021-05) Bodet, Tres P.; Hernandez, Arturo E.; Tamber-Rosenau, Benjamin J.; Leasure, J. LeighBilinguals’ language control mechanisms are well-researched and modelled. An overlooked aspect of their environment, however, is the language context. This research study asks whether context (bottom-up influence) may impact effortful language control mechanisms (top-down control). The present research tests the hypothesis that context can affect top-down language control, and that the extent of these effects are context-dependent, by manipulating auditory language distractors in a picture-naming paradigm with no cued language-switching. This was a departure from the norm of cueing a bilingual to switch languages in order to evidence a proposed language control mechanism. In short, participants heard brief, trial-length audio distractors while engaged in English-only picture-naming. The distractor languages varied per block and were Hungarian, English, Spanish, and Mixed (English and Spanish distractor trials randomly dispersed throughout the block). By removing any cued language-switching (topdown switching) and only changing the context (using auditory distractors), the results yielded can be attributed to the impact of changing bottom-up influence. In the end, the results did not support the hypotheses presented—image-naming response times did not differ significantly between contexts. However, results may suggest that while the immediate effects of a change in context are consistent, the lasting effects may differ from context to context. A number of measures of individual differences significantly influenced these results as well, including cognitive control abilities and English proficiency. While these results do support the view that context matters, future studies are needed to better elucidate the way in which it does or does not matter.Item Binge Alcohol Effects on the Prefrontal Cortex(2016-12) West, Rebecca K.; Leasure, J. Leigh; Kosten, Therese A.; Cirino, Paul T.Approximately 92% of U.S. adults who drink excessively report binge drinking in the past 30 days. Increased alcohol marketing in recent years has particularly targeted women, causing a 36% increase in the last 10 years in the number of women who are engaging in binge alcohol consumption. Since women appear to be more vulnerable to the harmful neurological effects of alcohol, this increase is of particular concern. One of the brain regions most affected by binge alcohol consumption is the frontal cortex, an area important for many functions and decision making of daily life. Loss of prefrontal grey matter resulting from heavy alcohol consumption has been documented, however this volume loss does not appear to be caused by a decrease in the number of prefrontal cortex neurons. This study aimed to determine whether the medial prefrontal cortex (mPFC) in female rats is more vulnerable to alcohol induced damage (compared to males), by examining neuronal volume and quantity as well as prefrontal- dependent behavioral tasks following binge alcohol exposure. To assess this, adult male and female Long-Evans rats were assigned to binge or control groups and exposed to ethanol using a well-established 4-day model of alcohol-induced neurodegeneration. Both male and female binged animals had significantly smaller average neuronal volumes than their respective control groups, as well as spatial working memory deficits detected during behavioral testing. No differences were found between binged male and binged female rats on neuronal volume, population or behavioral outcomes. These results support prior research indicating that frontal regions are vulnerable to binge alcohol damage.Item Brain Structure and Age of Acquisition in Bilinguals and Monolinguals(2018-12) Claussenius-Kalman, Hannah; Hernandez, Arturo E.; Leasure, J. Leigh; Tamber-Rosenau, Benjamin J.Researchers debate whether the age of second language acquisition (AoA) plays any role in determining brain structure. Whereas some studies suggest that bilinguals handle both languages via a single set of cognitive control regions regardless of AoA, others suggest that each language depends on different sets of brain regions for late (but not early/simultaneous) bilinguals. Likewise, structural neuroimaging studies have come to contrasting conclusions: either AoA does not affect structure, or later AoA relates to gray matter expansion in cognitive control and language processing regions. These differing results may occur for two main reasons: 1) low power caused by small group sizes, and 2) a lack of consistency in measures (of brain structure and of AoA) used across studies. This study aimed to address both of these gaps. MRI scans were used to measure cortical thickness, volume, and density via whole-brain analyses of 216 bilingual and 145 monolingual human adults (male and female). Results showed that the neuroanatomical correlates of AoA differ in terms of cortical thickness, volume, and density. Specifically: 1) late bilinguals had thicker cortex than monolinguals, simultaneous bilinguals, and early bilinguals in left and right frontal, temporal, parietal, and occipital regions; 2) no volume differences were found, and 3) compared to monolinguals, late bilinguals had greater density in the left middle frontal gyrus and right pars opercularis and postcentral gyrus, whereas early bilinguals had greater density in the bilateral temporal pole, right middle frontal gyrus, and right postcentral gyrus. The one similar finding across all brain structure measures was that monolinguals and simultaneous bilinguals did not differ. Results suggest that, relative to simultaneous bilinguals and monolinguals, late bilinguals handle language via structural increases in language processing and cognitive control areas. The present results demonstrate that it is important to use multiple measures of brain structure in order to clarify our understanding of bilingual language acquisition, as well as the importance of obtaining sufficient power to test hypotheses using whole-brain analyses.Item Can Exercise Reverse Binge Alcohol-Induced Brain Damage?(2013-05) Maynard, Mark E.; Leasure, J. Leigh; Hernandez, Arturo E.; Yoshida, HanakoBinge pattern drinking is characterized by excessive alcohol intake, combined with multiple periods of intoxication and withdrawal. This excessive consumption produces gray and white matter cell loss and cognitive impairments, leading to a cycle of further alcohol consumption. Animal models implicate the hippocampus, important for learning and memory, as being particularly sensitive to alcohol induced-neurodegeneration. Furthermore, binge alcohol has been shown to induce cell death and inhibit adult neurogenesis. Voluntary running-wheel exercise has been shown to increase hippocampal neurogenesis and promote overall brain health. The current study investigates the effects of repeated binge alcohol exposure and the potential of voluntary exercise to aid in recovery during abstinence. Female Long Evans rats were exposed to 1 or 2 four-day binge alcohol exposures before exercising voluntarily for four weeks. Rats were sacrificed 35 days after their last dose of alcohol and examined for histological markers of neurogenesis (doublecortin (DCX+)) and cell survival, (number of remaining granule cells) in the dentate gyrus. Binge exposure resulted in a decrease in granule cells, an effect that was reversed by exercise. A single binge had no effect on DCX+ cells; however, a second binge significantly reduced the number of DCX+ cells. Exercise increased the number of DCX+ cells in controls, however there was no increase in single binge animals demonstrating a binge induced suppression of the neurogenic effect of exercise. We conclude that while exercise can restore binge alcohol induced loss of granule cells, repeated binge alcohol exposure decreases neuronal differentiation in the hippocampus after 5 weeks of abstinence. Exercise, which promotes neurogenesis in the alcohol-naïve brain, may have limited ability to do so in the binge-exposed brain.Item Can the brain benefits of exercise be enhanced without additional exercise?(Journal of Neurology and Neuromedicine, 2016-07) Leasure, J. Leigh; West, RebeccaExercise is increasingly becoming accepted as "medicine" for diseases of both brain and body. For the brain, exercise offers chemical, cellular and structural benefits, including enhanced generation of new neurons, glia and blood vessels, increased expression of neurotrophins (such as brain-derived neurotrophic factor (BDNF), dendritic remodeling and stabilization of stress responses and inflammatory signaling. These mechanisms of action directly counteract those present in disease states. For example, the depressed brain is characterized by decreased synaptic plasticity, hippocampal neurogenesis and BDNF, all of which can be reversed by exercise.Item Cognitive Control: Good Bilinguals, Bad Bilinguals, and Monolinguals(2013-12) Ravid, Maya 1989-; Hernandez, Arturo E.; Hiscock, Merrill; Leasure, J. LeighThe purpose of this study was to investigate how differences within the bilingual population affect the discovery of a bilingual advantage. One-hundred and one Spanish-English bilinguals and 53 English monolinguals participated in three different tasks. In a verbal picture-naming task bilinguals were required to switch between English and Spanish while naming pictures in quick succession. Errors of interference (EI), in which bilinguals named a picture in the uncued language, were used to divide the bilingual group into non-switchers (few EI) and switchers (many EI). The two bilingual groups were then compared with monolinguals in two non-verbal tasks of cognitive control, a shape-color switching task and a Simon task. In the shape-color switching task participants were required to respond to either the shape or the color of a stimulus, and the rule for response changed following a number of trials by the presentation of a non-verbal cue. In the Simon task, participants were presented with different colored circles in different locations on the screen and were required to disregard location and respond to the color of the circle. Results revealed that monolinguals responded faster than both bilinguals in the shape-color task. In the Simon task, monolinguals responded faster than switcher bilinguals, with the non-switcher bilinguals not significantly different from the monolinguals or the switcher bilinguals. Non-switcher bilinguals were more accurate on the shape-color task than switcher bilinguals, with the monolinguals not significantly different from either bilingual group. These results suggest that bilinguals and monolinguals approach these tasks differently, with bilinguals focused on response selection and accuracy to the detriment of their reaction time. This may be due to the salience of response selection (i.e. language selection) in the bilinguals’ daily lives. Additionally, it was found that some bilinguals (non-switchers) outperformed other bilinguals (switchers), indicating that better performance on a verbal switching task is related to better performance on a non-verbal switching task, but no bilingual advantage was discovered in comparisons of bilinguals and monolinguals.Item Combined Effects of Binge Alcohol and Exercise on Intensity of Perineuronal Nets(2021-04-01) Popson, Pierce; Met-Hoxha, Erisa; Rodgers, ShaefaliPerineuronal Nets (PNNs) are lattice-like protein structures that surround the soma and processes of neurons in the extracellular matrix. PNNs have been known to exist for over a century and regulate two main functions: neuroplasticity and neuroprotection. The roles of neuroplasticity and protection are deeply involved with everyday life but are of key importance concerning specific behaviors such as alcohol consumption and exercise. While many people can consume alcohol without experiencing negative consequences that outweigh the positive experiences, there is still a necessity to understand the underlying neurological consequences of consuming alcohol regularly. Limited research indicates that the expression of PNNs increases after alcohol exposure and decreases with physical exercise in cortical regions (Chen et al., 2015; Reichelt et al., 2019; Smith et al., 2015). This increased expression of PNNs seems to indicate a restriction of plasticity from specific behaviors such as binge drinking and a possible neuroprotective effect against the immunological effects of alcohol. Comparatively, the reduction in expression of PNNs in the presence of exercise suggests an increase in neuroplasticity. However, research surrounding perineuronal nets has been sporadic in the methods for the analysis of these structures. This lack of clarity has led to difficulty in the interpretation of data from existing sources. Through the use of fluorescent staining, ImageJ, and PIPSQUEAK AI, a standardized methodological approach for the quantification of PNNs was further developed to analyze the interaction between variables such as binge alcohol consumption and exercise.Item Computational Image Analysis of Glial Morphology Following Binge-induced Damage and Exercise-driven Recovery(2014-08) Barton, Emily Avalon; Leasure, J. Leigh; Hernandez, Arturo E.; Roysam, BadrinathNeuronal health is dependent upon proper functioning of glial cells. When this support system fails, neurons cannot function properly. Therefore, a more complete understanding of the role of glia in brain health and pathology is vital. Exercise augments the supportive capabilities of glia, which may account for the overall beneficial effect of exercise on brain health. Conversely, binge drinking damages vulnerable corticolimbic structures and causes cognitive impairments. In the present study, we used computational image analysis to examine the effects of binge alcohol consumption and exercise on the glia in the medial prefrontal cortex (mPFC). Twenty-four female Long Evans rats were exposed to a four-day binge before exercising voluntarily for four weeks. Rats were sacrificed 35 days after their last dose of alcohol. The tissue was stained for microglia (Iba1), neurons (NeuN), astrocytes (GFAP) and cell nuclei (DAPI). Fluorescent confocal microscope images were analyzed using FARSIGHT, a computational image analysis toolkit. We found that exercise increased the number of microglia and the amount of GFAP signal surrounding microglia. However, exercise following binge exposure resulted in a reduced number of microglia and stopped the increase of GFAP surrounding microglia. Additionally, the microglia arbors in binged animals did not fan out in all directions, but instead stayed closer together and extended out further; suggesting binge exposure caused a lasting change in microglia reactivity. Together, our results demonstrate enduring changes of binge alcohol consumption in the frontal cortex 35 days after a single binge episode. Furthermore, previous binge exposure appears to reduce the available plastic response of microglia and astrocytes.Item Controlling Febrile Seizures in a Model of Dravet Syndrome(2013-08) Gu, Feng 1978-; Ziburkus, Jokubas; Dauwalder, Brigitte; Leasure, J. Leigh; Rea, Michael A.Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is one of the most devastating types of childhood epilepsies. Children with SMEI suffer from febrile and afebrile seizures (FS and aFS), ataxia, and social and cognitive dysfunctions. SMEI is pharmacologically intractable and can be fatal in 10-20% of patients. 70%-80% of SMEI patients are found to have SCN1A gene mutations. Recent studies of mouse models of SMEI (mSMEI) with SCN1A gene mutations have elucidated molecular and cellular mechanisms that may account for the epileptogenesis. There remains, however, a critical need to further elucidate how SCN1A gene mutation impacts neuronal activity in key anatomical circuits, and to develop new strategies for controlling seizures in SMEI. This dissertation aims to analyze and control neural circuit excitability and hyperthermia-induced FS both in vitro and in vivo using mSMEI carrying a SCN1A gene mutation. Using a combination of electrophysiology and fast voltage-sensitive dye imaging (VSDI) we studied synaptic excitatory/inhibitory balance, characteristics of neural activity propagation, and hyperthermia-induced FS-like events (FSLEs) in the hippocampus of mSMEI in vitro. Our in vitro studies reveal significant excitation and inhibition (E/I) imbalance in mSMEI, showing decreased inhibition, increased excitation, evoked neural activity that is abnormally wide-spread, and a decrease in FSLE threshold in the hippocampal circuits. To control hyperthermia-induced hyperexcitability and seizure activity (also referred to as febrile seizures), we used adenosine A1 receptor (AIR) agonist N6-cyclopentyladenosine (CPA). We found that in vitro, low concentration (50nM) of CPA significantly reduced hippocampal circuit hyperexcitability and blocked hyperthermia-induced FSLEs without blocking excitatory synaptic transmission. Furthermore, we tested whether CPA would have an equivalent effect on hyperthermia-induced FS in vivo. We found that SMEI transgenic animals had significantly lower FS threshold than their wild-type littermates. Acute injection of CPA prior to hyperthermia exposure effectively suppressed FS. In addition to the acute effect of CPA, we also tested if chronic treatment of SMEI mice with CPA during early postnatal development (postnatal days P11-20) can have a long-lasting anti-convulsant effect. We discovered that 24 hours and even 10 days after the last drug treatment (at P20), FS threshold in vivo was still significantly reduced. Our follow-up studies in vitro, following the chronic treatment in vivo, showed that following 10 days of treatment, synaptic excitation was decreased while the inhibitory responses were unaltered. Our findings suggest that A1R agonist CPA may serve as an effective compound to recover the E/I balance and control or prevent epileptogenesis in SMEI.Item Cortical area size dictates performance at modality-specific behaviors(Proceedings of the National Academy of Sciences, 2007-03) Leingärtner, Axel; Thuret, Sandrine; Kroll, Todd T.; Chou, Shen-Ju; Leasure, J. Leigh; Gage, Fred H.; O'Leary, Dennis D. M.The mammalian neocortex is organized into unique areas that serve functions such as sensory perception and modality-specific behaviors. The sizes of primary cortical areas vary across species, and also within a species, raising the question of whether area size dictates behavioral performance. We show that adult mice genetically engineered to overexpress the transcription factor EMX2 in embryonic cortical progenitor cells, resulting in reductions in sizes of somatosensory and motor areas, exhibit significant deficiencies at tactile and motor behaviors. Even increasing the size of sensorimotor areas by decreasing cortical EMX2 levels can lead to diminished sensorimotor behaviors. Genetic crosses that retain ectopic Emx2 transgene expression subcortically but restore cortical Emx2 expression to wild-type levels also restore cortical areas to wild-type sizes and in parallel restore tactile and motor behaviors to wild-type performance. These findings show that area size can dictate performance at modality-specific behaviors and suggest that areas have an optimal size, influenced by parameters of its neural system, for maximum behavioral performance. This study underscores the importance of establishing during embryonic development appropriate levels of regulatory proteins that determine area sizes, thereby influencing behavior later in life.Item Cortical Thickness in the Cognitive Control Network, Task Switching, and Bilingualism(2015-08) Vaughn, Kelly A.; Hernandez, Arturo E.; Leasure, J. Leigh; Yoshida, HanakoPrevious research involving patients with brain damage, children with ADHD, aging adults, Alzheimer’s patients, and normal monolingual children and adults suggests that cortical thickness in certain regions of the brain, specifically the dorsolateral prefrontal cortex, anterior cingulate cortex, inferior parietal lobule, and inferior frontal gyrus, is related to cognitive control abilities. For each of these groups, greater cortical thickness in these regions is associated with better cognitive control, and lesser cortical thickness is associated with poorer cognitive control. Surprisingly, researchers have not yet examined this relationship within the bilingual population, although bilinguals have sometimes demonstrated enhanced cognitive control abilities. Additionally, previous research by Della Rosa et al. (2013) and Mechelli et al. (2004) suggests that greater grey matter density in one of these regions, the inferior parietal lobule, is related to earlier age of second language acquisition, higher second language proficiency, and better overall language skills. Therefore, in order to fully understand the relationship between cortical thickness and cognitive control, it is important to examine the relationship between cortical thickness in the aforementioned regions and performance by bilinguals on a cognitive control task. This study measured cognitive control using a non-verbal switching task in which participants switched between sorting images by color and sorting images by shape as indicated by a symbolic cue. Results indicate that, in this bilingual sample, cortical thickness of the right and left inferior parietal lobules differentially correlate with response time costs and accuracy costs as a result of switching tasks. These findings shed light on the relationship between cognitive control and language in the brain.Item Data-Driven, Label Consistent, Dictionary Learning Methods for Analysis of Biological Datasets(2016-08) Megjhani, Murad; Roysam, Badrinath; Contreras-Vidal, Jose L.; Shih, Wei-Chuan; Mayerich, David; Leasure, J. Leigh; Burks, JaredThe goal of this thesis is to develop a data-driven, label consistent, and dictionary learning based framework that can be applied on a variety of signal analysis problems. Current methods based on analytical models do not adequately take the variability within and across datasets into consideration when designing signal analysis algorithms. This variability can be added as a morphological constraint to improve the signal analysis algorithms. In particular, this work focuses on three different applications: 1) we present a method for large-scale automated three-dimensional (3-D) reconstruction and profiling of microglia populations in extended regions of brain tissue for quantifying arbor morphology, sensing activation states, and analyzing the spatial distributions of cell activation patterns in tissue; this work provided an opportunity to profile the distribution of microglia in the controlled and device implanted brain. 2) we present a novel morphological constrained spectral unmixing (MCSU) algorithm that combines the spectral and morphological cues in the multispectral image data cube to improve the unmixing quality, this work provided an opportunity to identify new therapeutic opportunities for pancreatic ductal adenocarcinoma (PDAC) from the images collected from humans; and finally, 3) we developed a framework to analyze neuronal response from electroencephalography (EEG) datasets acquired from the infants ranging from 6-24 months. We demonstrated that combining different frequency bands from different spatial locations, yields better classification results, instead of the traditional approach where either one or two frequency bands are used. Using an adaptation of Tibshirani’s Sparse Group LASSO algorithm, we uncovered different spatial and bio markers for understanding a human infant’s brain. These bio-markers can be used for developmental stages of infants and further analysis is required to study the clinical aspects of infant’s social and cognitive development. This work establishes the fundamental mathematical basis for the next generation of algorithms that can leverage the morphological cues from the biological datasets. The algorithm has been embedded into the open source FARSIGHT toolkit with an intuitive graphical user interface.Item Developmental Exercise Effects on Adult Brain and Behavior(2020-12) Perez, Emma Claudia; Leasure, J. Leigh; Kosten, Therese A.; Fletcher, Jack M.; Eriksen, JasonAmong affluent populations, sedentary behavior is an increasing concern, particularly for children and adolescents who require daily exercise. Exercise results in a myriad of positive effects on brain and behavior, but whether these effects during development carry over into adulthood is largely unknown. Environmental enrichment research demonstrates the impact of early life experiences on adult brain and behavior, and emerging evidence on early life exercise follows a similar pattern, particularly for cognition. The hippocampus, which continues to develop in adolescence, is part of the stress circuitry and plays a role in emotion. Exercise conditions this circuitry without psychological stress. The hippocampus can also generate new neurons through quiescent (idling) stem cells in the dentate gyrus (DG), a pool of cells available to proliferate (eg. after a stimulus) and thus represent a form of structural plasticity. The present study examines the lasting effects of developmental exercise on adulthood brain and behavior. Specifically, it was hypothesized that adolescent exercise history would buffer chronic stress effects (and thus enhance stress resilience) in measures of affective behavior and structural plasticity in the DG in adulthood. Behavioral assessment of anxiety- and depressive-like behaviors demonstrated stress increased these behaviors and that exercise may promote partial stress resilience in males. Females demonstrated little to no behavioral changes in affect due to stress or exercise. There were also no long-term effects of exercise on quiescent stem cell populations in the DG, nor any protective effect from stress in the number of proliferating, quiescent stem cells. Proliferating stem cells were reduced by stress in males. However, exercise increased brain size in adulthood. Given that the results suggest that developmental exercise promotes stress resilience in depressive-like behavior in males, further research on coping strategies may elucidate how exercise promotes specific stress resilient behaviors in adulthood. The lack of structural plasticity effects but increase in brain size point towards examining other brain structural elements, such as glial cells. The lack of overall effects on females suggest that further research is necessary to understand how female brain and behavior is altered by chronic stress prior to examining carry-over effects of developmental exercise.Item Differential response of hippocampal subregions to stress and learning(PLoS ONE, 2012) Hawley, Darby F.; Morch, Kristin; Christie, Brian R.; Leasure, J. LeighThe hippocampus has two functionally distinct subregions–the dorsal portion, primarily associated with spatial navigation, and the ventral portion, primarily associated with anxiety. In a prior study of chronic unpredictable stress (CUS) in rodents, we found that it selectively enhanced cellular plasticity in the dorsal hippocampal subregion while negatively impacting it in the ventral. In the present study, we determined whether this adaptive plasticity in the dorsal subregion would confer CUS rats an advantage in a spatial task–the radial arm water maze (RAWM). RAWM exposure is both stressful and requires spatial navigation, and therefore places demands simultaneously upon both hippocampal subregions. Therefore, we used Western blotting to investigate differential expression of plasticity-associated proteins (brain derived neurotrophic factor [BDNF], proBDNF and postsynaptic density-95 [PSD-95]) in the dorsal and ventral subregions following RAWM exposure. Lastly, we used unbiased stereology to compare the effects of CUS on proliferation, survival and neuronal differentiation of cells in the dorsal and ventral hippocampal subregions. We found that CUS and exposure to the RAWM both increased corticosterone, indicating that both are stressful; nevertheless, CUS animals had significantly better long-term spatial memory. We also observed a subregion-specific pattern of protein expression following RAWM, with proBDNF increased in the dorsal and decreased in the ventral subregion, while PSD-95 was selectively upregulated in the ventral. Finally, consistent with our previous study, we found that CUS most negatively affected neurogenesis in the ventral (compared to the dorsal) subregion. Taken together, our data support a dual role for the hippocampus in stressful experiences, with the more resilient dorsal portion undergoing adaptive plasticity (perhaps to facilitate escape from or neutralization of the stressor), and the ventral portion involved in affective responses.Item Do Circulating Sex Hormones Influence Neuronal Susceptibility to Binge Alcohol?(2023-05-15) Beck, Alaska Lynn; Leasure, J. Leigh; Alward, Beau A.; Williams, Michael W.Circulating sex-hormones influence various functions throughout the body, including neuroprotection and neurodegeneration across types of brain injury. Limited evidence exists to suggest whether sex hormones influence neuronal susceptibility to binge alcohol induced brain damage too. Stimulation of the stress response, microglial activation, and loss of neurons in the hippocampus are known outcomes of alcohol exposure. Alcohol injury is a stressor that results in neuroimmune activation and stimulates the hypothalamic-pituitary-adrenal-axis (HPA-axis) responsible for the body’s stress response. Sex hormones organize the HPA-axis during development, creating sex-based responses to stress, and are highly influential for activation of this axis throughout adulthood. Females produce a more robust response of cortisol (CORT) from the HPA than males under stressful conditions, this may be linked to increased risk of alcohol injury. Existing studies of gonad- (GDX) and ovariectomy (OVX) at adulthood report alterations in CORT secretion profiles, switching to patterns similar to the opposite intact sex. The removal of circulating estrogens may afford females protection from binge damage but males may lose their testosterone buffer, raising their response to alcohol. To study the relationship between circulating sex hormones and binge-induced brain damage, we performed GDX and OVX in adult rats. Quantification of neuron loss, neuroimmune response, and CORT levels were used to observe the influence of circulating sex hormones on binge alcohol-induced neuronal damage in males and females. We hypothesized binge exposure would produce greater neuron loss, more neuroimmune activation, and higher CORT levels in all binge groups compared to controls. We expected OVX females and intact males 3 to show similar damage profiles, and that GDX males and intact females would show similar damage profiles. Specifically, we expected higher CORT secretion in GDX males and intact females, compared to OVX females and intact males, accompanied by greater decrement in neurons and an increased neuroimmune response. Examination of the impact of removing circulating sex hormones did not support a role for circulating sex hormones in modulating the HPA-axis and CORT output. Binge exposure led to granule neuron loss in the hippocampus but no effect of removing circulating sex hormones was found in males or females. No effect of binge exposure or circulating sex hormones was found for the neuroimmune response in the hippocampus for either sex, but binge exposure and sex hormones influenced outcomes in the mPFC for males. Neuroimmune response, quantified by number of total, ramified, and activated microglia, was increased in the mPFC from binge exposure in sham males. GDX males showed a decrease in overall neuroimmune response, characterized by loss of ramified microglia, with exposure to binge alcohol. Our findings support the loss of granule neurons from binge exposure and an influence of circulating sex hormones on the mediation of the neuroimmune response to binge alcohol in males but not females.Item Effects of Regulating Rac1 in a Mouse Model of Fragile X Syndrome(2016-08) Martinez, Luis A.; Tejada-Simon, Maria V.; Eriksen, Jason; Salim, Samina; Leasure, J. Leigh; Ziburkus, JokubasAutism is a complex neurodevelopmental disorder characterized by social deficits, communication and language impairments, and restricted or stereotyped patterns of behavior. Intellectual disability (ID), reported in nearly 70% of those with autism, is a pervasive co-morbidity that exacerbates cognitive functions and impedes behavioral development. The most effective treatment for autism and ID are behavior-based interventions such as Applied Behavior Analysis (ABA) that require rigorous training methodologies. Furthermore, treatment must be started early and must be continuous and consistent for optimal efficiency. The high cost of behavior therapies and demanding schedule often precludes a successful outcome. Over the years, studies have revealed structural and functional synaptic impairments in autism and ID in areas important for cognitive functions such as learning and memory formation. The observation in these learning disabilities that repeated training can overcome cognitive deficiencies suggests that mechanisms of learning and memory are not entirely defective. Autism and ID have been found to share dysregulation of molecular signaling cascades involved in synaptogenesis, spinogenesis and synaptic plasticity. The structural integrity of synapses and dendritic spines within those synapses relies on the underlying actin cytoskeleton. Examination of post-mortem brain tissue of autistic individuals reveals not just an unusually high number of dendritic spines but a high density of immature spines. Post-mortem brain tissue also exhibits high levels of the small Rho GTPase Rac1, a well-recognized regulator of actin dynamics at the synapse. The integral role of Rac1 in dendritic spine development, synaptic plasticity, and learning and memory has been extensively studied. Together these studies present Rac1 as an intriguing target in the treatment of cognitive deficits associated with autism and ID. Herein, we studied whether regulation of Rac1 might represent a promising treatment for cognitive impairment in autism, using Fragile X syndrome (FXS) as a model. FXS is the leading single gene cause of autism and ID. Neurons express a high density of underdeveloped dendritic spines in FXS humans and animal models. Synaptic plasticity deficits are prevalent throughout the brains of FXS mouse models including the cortex and hippocampus, areas critical for various forms of learning and memory. Moderate to severe learning deficiencies are also characteristic in FXS patients and is paralleled in mouse models. Therefore, FXS is an ideal model in the clinical and laboratory setting to investigate therapies aimed at autism and ID. In FXS mouse models, hyperactive Rac1 has been demonstrated in hippocampus and cortex where dendritic spine abnormalities are a common feature. Our results show that in the Fmr1 KO mice (an animal model of FXS) deficits in memory and synaptic plasticity are associated with the presence and localization of Rac1. Furthermore, treatment of Fmr1 KO mice with a specific Rac1 inhibitor improves memory and increases hippocampal LTP. Taken together these observations show that Rac1 may contribute to FXS related learning and memory impairments in humans. Importantly, this study suggests that targeting Rac1 in FXS may rescue cognitive impairments. Such a therapy may be translated into broader applications in autism and ID.Item Exercise and Alcohol Consumption: Implicit Associations, Joint Motives, and Actual Behaviors of Both(2016-08) Najjar, Laian Z.; Leasure, J. Leigh; Neighbors, Clayton; Henderson, Craig E.Physical activity has been suggested as a potential intervention for alcohol use disorders (AUD), however, there is conflicting evidence as to its efficacy. This may be due, in part, to the well-established positive relationship between physical activity and alcohol intake, in that drinkers tend to be more active than non-drinkers. Prior studies have focused mainly on the explicit relationship between physical activity (PA) and alcohol consumption (AC); however, potential implicit links between alcohol use and exercise have not been investigated, thus, the overarching objective of this study was to determine whether there is an implicit association between PA and AC. A second objective was to evaluate potential joint motives underlying exercise and drinking (such as celebration), as that may further clarify the alcohol consumption-physical activity relationship. Male and female participants (N=391; 77% female) aged eighteen and above were recruited from two large southwestern universities. Participants completed self-report measures of alcohol frequency and quantity, drinking motives and enjoyment, exercise frequency and intensity, exercise motives and enjoyment, and religious perceptions pertaining to alcohol consumption. To evaluate implicit attitudes, participants took three Implicit Association Tests (IATs). IAT1 tested implicit attitudes toward alcohol consumption and exercise, with targets alcohol/water and attributes exercise/inactivity. IAT2 evaluated implicit drinking identity attitudes, with targets drinker/non-drinker and attributes me/not me. IAT3 examined implicit attitudes towards exercise importance, with targets exercise/rest and attributes important/unimportant. I expected to find a stronger implicit association between exercise and alcohol intake in participants who drink more in quantity and frequency, and those who exercise more intensely and frequently; I also expected the implicit link to be strongest in those who enjoy doing both. Additionally, I hypothesized that the more motivated individuals are to drink, the stronger their implicit drinking identity; and individuals with joint motives for exercise and drinking will have a stronger implicit association between both, and will drink and exercise more. Because religious adherence can affect alcohol perceptions and behaviors, I predicted that non-religious individuals drink and exercise more than religious individuals, and non-religious individuals have a stronger implicit drinking identity than religious individuals. I also hypothesized that non-religious participants’ perceptions toward alcohol use will be more positive than that of religious participants’. Contrary to my central hypotheses, my results yielded no association between implicit attitudes toward physical activity and alcohol use and actual behaviors for both. However, I did find that the more motivated participants are to drink, the stronger their implicit drinking identity; and participants who expressed joint motivation to exercise and drink have a stronger implicit association between exercise and drinking, and tend to consume more alcohol. Interestingly, there were no significant differences between non-religious and religious individuals’ amount and frequency of alcohol consumption, exercise frequency and intensity, or implicit drinking identity, although non-religious individuals’ perceptions toward alcohol use were more positive than those of religious people. Taken together, these findings provide preliminary evidence linking implicit attitudes, joint motives for exercise and drinking, religious perceptions toward alcohol use, and the actual behaviors of exercise and drinking. Having a better understanding of these relationships may help in the development of appropriate exercise-based interventions for AUDs.Item Exercise and alcohol consumption: What we know, what we need to know, and why it is important(Frontiers in Psychiatry, 2015-11) Leasure, J. Leigh; Neighbors, Clayton; Henderson, Craig E.; Young, Chelsie M.Exercise provides a wealth of benefits to brain and body, and is regarded as a protective factor against disease. Protective factors tend to cluster together – that is, people who engage in one healthy behavior, such as exercise, also engage in other healthy behaviors, such as maintaining a nutritious diet and getting sufficient sleep. In contrast to exercise, alcohol consumption is not typically regarded as a health-promoting behavior, although moderate intake has been associated with a lower risk of cardiovascular disease. Surprisingly, several large, population-based studies have shown a positive association between physical activity and alcohol intake. The present review focuses on what is known about this relationship, including potential neural bases as well as moderating factors, and discusses important directions for further study, such as a more thorough characterization of people who both drink and exercise. We focus on ramifications for intervening with people who have alcohol use disorders, as exercise has been assessed as both a treatment and preventive measure, with mixed results. We believe that, in order for such interventions to be effective, clinical trials must distinguish treatment-seeking populations from non-treatment-seeking ones, as well as ensure that the use of exercise as a tool to decrease alcohol consumption is made explicit. We posit that a better understanding of the relationship between physical activity and alcohol intake will maximize intervention efforts by informing the design of clinical trials and research-driven prevention strategies, as well as enable individuals to make educated decisions about their health behaviors.
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