Browsing by Author "Goodlett, Charles"
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Item Acute Alcohol and Cognition: Remembering What It Causes Us to Forget(Elsevier, 2019) Van Skike, Candice E.; Goodlett, Charles; Matthews, Douglas B.; Psychology, School of ScienceAddiction has been conceptualized as a specific form of memory that appropriates typically adaptive neural mechanisms of learning to produce the progressive spiral of drug-seeking and drug-taking behavior, perpetuating the path to addiction through aberrant processes of drug-related learning and memory. From that perspective, to understand the development of alcohol use disorders it is critical to identify how a single exposure to alcohol enters into or alters the processes of learning and memory, so that involvement of and changes in neuroplasticity processes responsible for learning and memory can be identified early on. This review characterizes the effects produced by acute alcohol intoxication as a function of brain region and memory neurocircuitry. In general, exposure to ethanol doses that produce intoxicating effects causes consistent impairments in learning and memory processes mediated by specific brain circuitry, whereas lower doses either have no effect or produce a facilitation of memory under certain task conditions. Therefore, acute ethanol does not produce a global impairment of learning and memory, and can actually facilitate particular types of memory, perhaps particular types of memory that facilitate the development of excessive alcohol use. In addition, the effects on cognition are dependent on brain region, task demands, dose received, pharmacokinetics, and tolerance. Additionally, we explore the underlying alterations in neurophysiology produced by acute alcohol exposure that help to explain these changes in cognition and highlight future directions for research. Through understanding the impact acute alcohol intoxication has on cognition, the preliminary changes potentially causing a problematic addiction memory can better be identified.Item Dyrk1a Dynamics: The Influence of Gene Copy Number on Neurodevelopment in the Ts65dn Mouse Model of Down Syndrome(2024-05) Hawley, Laura E.; Roper, Randall; Belecky-Adams, Teri; Cummins, Theodore; Goodlett, Charles; Hardy, Tabitha; Marrs, KathleenDown syndrome (DS) arises from the triplication of human chromosome 21 (Hsa21), leading to a spectrum of phenotypes characterized by neurodevelopmental and cognitive abnormalities. The Ts65Dn mouse model emulates DS by harboring three copies of genes found on Hsa21 resulting in trisomy 21 (Ts21)- like traits, including disruptions in neuronal pathways, delays in sensorimotor and behavior milestones, and deficits in learning and memory tasks. There is no cure for DS and available therapies primarily address symptoms stemming from Ts21-associated phenotypes. DYRK1A, a gene triplicated in Ts21, has a pivotal role in pathways of neurodevelopment and has been a focus of inhibition treatment research aimed at preempting abnormal brain phenotypes. This study aimed to find a point of substantial Dyrk1a expression dysregulation during a period of critical neonatal neurodevelopment and employ targeted pharmacological and genetic knockdown methods to alleviate the presence or severity of characteristically abnormal brain and behavior phenotypes. The hypothesis of this study was that administering a targeted intervention prior to a point of known overexpression in trisomic pups would ameliorate molecular, sensorimotor, and neurobehavioral deficits, redirecting growth trajectories of Ts65Dn neonatal pups towards more neurotypical outcomes. To test this hypothesis, the spatiotemporal pattern of DYRK1A expression was quantified during the first three weeks of neonatal development across the hippocampus, cerebral cortex, and cerebellum of the Ts65Dn mouse model and found to fluctuate according to the genotype, age, sex, and brain region of the subject. Dyrk1a protein and mRNA expression levels were delineated in trisomic animals by age, exploring the correlation between expression and age, sex, genotype, and brain region. Next a constitutive Dyrk1a knockdown model was integrated with the Ts65Dn model to investigate the impact of gene copy number reduction on protein and mRNA expression levels during phases of known DYRK1A dysregulation. On postnatal day 6, protein expression was rescued in all three brain regions of male animals but was rescued only in the cerebellum of females. There were no significant differences in mRNA transcript levels in either sex at this age. Finally, genetic elements were introduced into the Ts65Dn model to facilitate a spatiotemporally controlled functional reduction of Dyrk1a and discern how the timing of gene copy number reduction affects molecular and neurobehavioral development in a trisomic system. Results from these studies suggest that only functionally reducing Dyrk1a gene copy number on the day of birth is not sufficient to rescue the majority of deficits and delays present in the Ts65Dn mouse model of DS. These findings significantly enhance the understanding of trisomic Dyrk1a expression dynamics during neonatal development and shed light on tailored therapeutic approaches to modulate intrinsic DS characteristics based on age, sex, and phenotypic considerations.Item DYRK1A-Related Trabecular Defects in Male Ts65Dn Mice Emerge During a Critical Developmental Window(2021-08) LaCombe, Jonathan M.; Roper, Randall; Goodlett, Charles; Li, Jiliang; Wallace, Joseph; Meyer, JasonDown syndrome (DS) is a complex genetic disorder caused by the triplication of human chromosome 21 (Hsa21). The presence of an extra copy of an entire chromosome greatly disrupts the copy number and expression of over 350 protein coding genes. This gene dosage imbalance has far-reaching effects on normal development and aging, leading to cognitive and skeletal defects that emerge earlier in life than the general population. The present study begins by characterizing skeletal development in young male Ts65Dn mice to test the hypothesis that skeletal defects in male Ts65Dn mice are developmental in nature.Femurs from young mice ranging from postnatal day 12- to 42-days of age (P12-42) were measured and analyzed by microcomputed tomography (μCT). Cortical defects were present generally throughout development, but trabecular defects emerged at P30 and persisted until P42. The gene Dual-specificity tyrosine-regulated kinase 1a (Dyrk1a) is triplicated in both DS and in Ts65Dn mice and has been implicated as a putative cause of both cognitive and skeletal defects. To test the hypothesis that trisomic Dyrk1a is related to the emergence of trabecular defects at P30, expression of Dyrk1a in the femurs of male Ts65Dn mice was quantified by qPCR. Expression was shown to fluctuate throughout development and overexpression generally aligned with the emergence of trabecular defects at P30. The growth rate in trabecular measures between male Ts65Dn and euploid littermates was similar between P30 and P42, suggesting a closer look into cellular mechanisms at P42. Assessment of proliferation of BMSCs, differentiation and activity of osteoblasts showed no significant differences between Ts65Dn and euploid cellular activity, suggesting that the cellular microenvironment has a greater influence on cellular activity than genetic background. These data led to the hypothesis that reduction of Dyrk1a gene expression and pharmacological inhibition of DYRK1A could be executed during a critical period to prevent the emergence of trabecular defects at P30. To tests this hypothesis, doxycycline-induced cre-lox recombination to reduce Dyrk1a gene copy number or the DYRK1A inhibitor CX-4945 began at P21. The results of both genetic and pharmacological interventions suggest that trisomic Dyrk1a does not influence the emergence of trabecular defects up to P30. Instead, data suggest that the critical window for the rescue of trabecular defects lies between P30 and P42.Item Early-life trauma alters hippocampal function during an episodic memory task in adulthood(2017-05-02) Janetsian-Fritz, Sarine S.; Lapish, Christopher; Sangha, Susan; Goodlett, Charles; Neal-Beliveau, BethanyEarly life trauma is a risk factor for a number of neuropsychiatric disorders, including schizophrenia (SZ) and depression. Animal models have played a critical role in understanding how early-life trauma may evoke changes in behavior and biomarkers of altered brain function that resemble these neuropsychiatric disorders. However, since SZ is a complex condition with multifactorial etiology, it is difficult to model the breadth of this condition in a single animal model. Considering this, it is necessary to develop rodent models with clearly defined subsets of pathologies observed in the human condition and their developmental trajectory. Episodic memory is among the cognitive deficits observed in SZ. Theta (6-10 Hz), low gamma (30-50 Hz), and high gamma (50-100 Hz) frequencies in the hippocampus (HC) are critical for encoding and retrieval of memory. Also, theta-gamma comodulation, defined as correlated fluctuations in power between these frequencies, may provide a mechanism for coding episodic sequences by coordinating neuronal activity at timescales required for memory encoding and retrieval. Given that patients with SZ have impaired recognition memory, the overall objectives of these experiments were to assess local field potential (LFP) recordings in the theta and gamma range from the dorsal HC during a recognition memory task in an animal model that exhibits a subclass of symptoms that resemble SZ. In Aim 1, LFPs were recorded from the HC to assess theta and gamma power to determine whether rats that were maternally deprived (MD) for 24-hrs on postnatal day (PND 9), had altered theta and high/low gamma power compared to sham rats during novel object recognition (NOR). Brain activity was recorded while animals underwent NOR on PND 70, 74, and 78. In Aim 2, the effects of theta-low gamma comodulation and theta-high gamma comodulation in the HC were assessed during NOR between sham and MD animals. Furthermore, measures of maternal care were taken to assess if high or low licking/grooming behaviors influenced recognition memory. It was hypothesized that MD animals would have impaired recognition memory and lower theta and low/high gamma power during interaction with both objects compared to sham animals. Furthermore, it was hypothesized that sham animals would have higher theta-gamma comodulation during novel object exploration compared to the familiar object, which would be higher than the MD group. Measures of weight, locomotor activity, and thigmotaxis were also assessed. MD animals were impaired on the NOR task and had no change in theta or low/high gamma power or theta-gamma comodulation when interacting with the novel or familiar object during trials where they performed unsuccessfully or successfully. However, higher theta and gamma power and theta-gamma comodulation was observed in sham animals depending on the object they were exploring or whether it was a successful or unsuccessful trial. These data indicate altered functioning of the HC following MD and a dissociation between brain activity and behavior in this group, providing support that early life trauma can induce cognitive and physiological impairments that are long-lasting. In conclusion, these data identify a model of early life stress with a translational potential, given that there are points of contact between human studies and the MD model. Furthermore, these data provide a set of tools that could be used to further explore how these altered neural mechanisms may influence cognition and behavior.Item Eludicating triggers and neurochemical circuits underlying hot flashes in an ovariectomy model of menopause(2016-02-26) Federici, Lauren Michele; Shekhar, Anantha; Goodlett, Charles; Johnson, Philip L.; Oxford, Gerry S.; Rusyniak, Daniel E.Menopausal symptoms, primarily hot flashes, are a pressing clinical problem for both naturally menopausal women and breast and ovarian cancer patients, with a high societal and personal cost. Hot flashes are poorly understood, and animal modeling has been scarce, which has substantially hindered the development of non-hormonal treatments. An emerging factor in the hot flash experience is the role of anxiety and stress-related stimuli, which have repeatedly been shown to influence the bother, frequency, and severity of hot flashes. Causal relationships are difficult to determine in a clinical setting, and the use of animal models offers the ability to elucidate causality and mechanisms. The first part of this work details the development and validation of novel animal models of hot flashes using clinically relevant triggers (i.e., compounds or stimuli that cause hot flashes in clinical settings), which also increase anxiety symptoms. These studies revealed that these triggers elicited strong (7-9 °C) and rapid hot flash-associated increases in tail skin temperature in rats. In a surgical ovariectomy rat model of menopause, which typically exhibit anxiety-like behavior, hot flash provocation revealed an ovariectomy-dependent vulnerability, which was attenuated by estrogen replacement in tested models. An examination of the neural circuitry in response to the most robust flushing compound revealed increased cellular activity in key thermoregulatory and emotionally relevant areas. The orexin neuropeptide system was hyperactive and presented as a novel target; pretreatment with selective and dual orexin receptor antagonists significantly diminished or eliminated, respectively, the response to a hot flash provocation in ovariectomized rats. The insertion/deletion polymorphism of the serotonin transporter has been linked to increased anxiety-associated traits in humans, and subsequent studies prolonged hot flashes in SERT+/- rats, which also caused hot flashes in highly symptomatic women. These studies indicate the orexin system may be a novel non-hormonal treatment target, and future studies will determine the therapeutic importance of orexin receptor antagonists for menopausal symptoms.Item Examining Postnatal Retinal Thickness and Retinal Ganglion Cell Count in the Ts65Dn Mouse Model of Down Syndrome(2023-05) Folz, Andrew; Roper, Randall; Goodlett, Charles; Belecky-Adams, TeriDown syndrome (DS) is a genetic condition caused by the triplication of human chromosome 21 and presents with many phenotypes including decreased brain size, hypocellularity in the brain, and assorted ocular phenotypes. Some of the ocular phenotypes seen are increased risk of cataracts, accommodation difficulties, increased risk of refractive errors, and increased retinal thickness. The Ts65Dn mouse model of DS is a classically used mouse model as it presents a number of phenotypes also seen in those with DS. Some of these phenotypes include decreased brain volume, abnormal synaptic plasticity, and ocular phenotypes. These ocular phenotypes include decreased visual acuity, cataracts, and increased retinal thickness. The Ts65Dn mouse model is trisomic for Dyrk1a, a gene of interest in DS research. We hypothesize that there will be a genotypic and sex effect of retinal thickness and retinal ganglion cell (RGC) count at postnatal day 15 in the Ts65Dn mouse model of DS. Retinal slices were taken from male and female trisomic and euploid Ts65Dn mice at P15 and fluorescently labeled for RGCs and bipolar cells via immunohistochemistry. The retinas were measured for total retinal thickness and RNA-binding protein (RBPMS) positive cells in the RGC layer were counted. There was no genotypic or sex effect when comparing retinal thickness in trisomic mice as compared to euploid mice. There was a genotypic effect of RBPMS positive cell count in which the trisomic mice had a higher number of RBPMS positive cells than euploid mice. Increased retinal thickness along with increased RGC number have both been implicated with decreased apoptosis in the retina. In the Ts65Dn mouse model along with in individuals with DS, this could be due to an increase in DYRK1A protein levels reducing apoptosis. In future studies, determining DYRK1A’s influence in retinal thickness and RGC number could result in a treatment for overactive DYRK1A that could normalize retinal thickness and RGC number in those with DS.Item Externalizing Disorders : Genetics or Prenatal Alcohol Exposure?(2018-12) Wetherill, Leah; Goodlett, Charles; Grahame, Nicholas; Foroud, Tatiana; Mattson, Sarah; Neal-Beliveau, BethanyIntroduction: Externalizing disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) have a high prevalence rate in both children of alcoholics and in those with prenatal alcohol exposure (PAE). These disorders are also predictors of alcohol dependence (alcdep), heritable, and share an underlying genetic liability with alcdep. Furthermore, a mother who drinks while pregnant is likely to be alcohol dependent (AD), and vice-versa. This study incorporated these factors into one model, including as well as a measure of broad genetic risk for ADHD and alcdep to test for the contributions of these effects simultaneously. An independent sample was used to confirm the results for PAE and broad genetic risk. The hypothesis is that PAE will increase the risk to ADHD but not to CD or ODD. Methods: Each of these factors was evaluated independently to test if that effect on its own, significantly contributed to each disorder. Another model included several demographic covariates, to determine which of these environmental effects also contributed to the disorder. The final model for each disorder included environmental effects along with the primary effects of interest. Results: PAE resulted in increased risk for the inattentive (INATT) sub-type of ADHD and conduct disorder (CD) in the discovery sample and for the hyperactive-impulsive (HYPIMP), INATT and CD in the replication sample. PAE and the PAE*maternal alcohol dependence interaction increased the risk for ADHD and INATT. A broad genetic risk for ADHD was associated with all disorders except HYPIMP in the replication sample. Conclusion: This study further supports the trending evidence of a unique etiology of ADHD in those with PAE, and more specifically, that INATT and HYPIMP are affected according to two different mechanisms of action, independent of a genetic contribution due to either ADHD or alcohol dependence, both of which also were associated with a risk for INATT. The contribution of PAE to INATT and CD were the only consistent results across all definitions of alcohol exposure and in both datasets, indicating that PAE is a veritable risk for INATT and CD.Item The identification of increased Dyrk1a protein levels in Ts65Dn mice guides the targeted administration of the novel Dyrk1a inhibitor CX-4945(2018-04-27) Stringer, Megan; Goodlett, Charles; Roper, RandallDown syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability. Ts65Dn mice, the most extensively studied DS model, have three copies of ~50% of the genes on Hsa21 and display many phenotypes associated with DS, including cognitive deficits. DYRK1A is a dosage-sensitive gene found in three copies in humans with Trisomy 21 and in Ts65Dn mice and is involved in CNS development. Overexpression of DYRK1A is hypothesized to cause many of the cognitive and developmental deficits observed in DS and has been touted as a target for drug development in DS. Definitive evidence that excessive expression/activity of Dyrk1a directly contributes to specific phenotypes in DS mouse models is limited, and there is no direct evidence that verified pharmacological inhibition of Dyrk1a in vivo causes enduring improvement in DS cognitive phenotypes. In part, this reflects the remarkably limited knowledge of the temporal regulation of Dyrk1a expression and activity in different brain regions across development in DS mouse models. To establish the therapeutic potential of Dyrk1a inhibitors, the first aim of this study was to determine when and in what brain regions excessive Dyrk1a is evident and to identify developmental periods when elevated expression of Dyrk1a may be contributing to enduring aberrant functional development. This aim provided systematic quantification of Dyrk1a protein level at key postnatal (P) ages (P12, P15, P18, P24 P30, P42) in Ts65Dn mice, at ages of translational relevance to clinical applications in humans (birth, early adolescence, late adolescence, young adult). Western blot analysis showed that significant elevation of Dyrk1a with the largest effect sizes occurred in trisomic mice on P15. The second aim of this study was to test whether treating Ts65Dn with a novel Dyrk1a inhibitor (CX-4945) during the time of Dyrk1a elevation would rescue the behavioral and structural abnormalities observed. From P14-P18, Ts65Dn and euploid mice were treated with 75mg/kg CX-4945 or DMSO (vehicle) and tested on a homing task and locomotor activity in a novel arena on P17-P18, counterbalanced for order. At the cessation of treatment, hippocampal cell proliferation was assessed. While there was a lack of statistically significant improvements with CX-4945 treatment, there were modest effect sizes. In addition, several of the behavioral studies were significantly underpowered, making it difficult to conclusively ascertain the efficacy of CX-4945 on specific phenotypes. Nevertheless, this study demonstrates that Dyrk1a is dynamically expressed across development in mice, and suggests that consideration of the spatial and temporal expression of Dyrk1a may well be critical in the development of therapeutics for DS.Item Impact of Acute Ethanol Injections on Medial Prefrontal Cortex Neural Activity(2019-12) Morningstar, Mitchell D.; Lapish, Christopher; Goodlett, Charles; Linsenbardt, DavidThe medial prefrontal cortex (mPFC) is a cortical brain region involved in the evaluation and selection of motivationally relevant outcomes. mPFC-mediated cognitive functions are impaired following acute alcohol exposure. In rodent models, ethanol (EtOH) doses as low as 0.75 g/kg yield deficits in cognitive functions. These deficits following acute EtOH are thought to be mediated, at least in part, by decreases in mPFC firing rates. However, these data have been generated exclusively in anesthetized rodents. To eliminate the potentially confounding role of anesthesia on EtOH modulated mPFC activity, the present study investigated the effects of acute EtOH injections on mPFC neural activity in awake-behaving rodents. We utilized three groups: the first group received 2 saline injections during the recording. The second group received a saline injection followed 30 minutes later by a 1.0 g/kg EtOH injection. The last group received a saline injection followed 30 minutes later by a 2.0 g/kg EtOH injection. One week following the awake-behaving recording, an anesthetized recording was performed using one dose of saline followed 30 minutes later by one dose of 1.0 g/kg EtOH in order to replicate previous studies. Firing rates were normalized to a baseline period that occurred 5 minutes prior to each injection. A 5-minute time period 30 minutes following the injection was used to compare across groups. There were no significant differences across the awake-behaving saline-saline group, indicating no major effect on mPFC neural activity as a result of repeated injections. There was a significant main effect across treatment & behavioral groups in the saline-EtOH 1.0 g/kg group with reductions in the EtOH & Sleep condition. In the saline-EtOH 2.0 g/kg, mPFC neural activity was only reduced in lowered states of vigilance. This suggests that EtOH only causes gross changes on neural activity when the animal is not active and behaving. Ultimately this means that EtOH’s impact on decision making is not due to gross changes in mPFC neural activity and future work should investigate its mechanism.Item Meta-Analyses of Externalizing Disorders: Genetics or Prenatal Alcohol Exposure?(Wiley, 2017) Wetherill, Leah; Foroud, Tatiana; Goodlett, Charles; Psychology, School of ScienceBackground Externalizing disorders are heritable precursors to alcohol dependence, common in children of alcoholics (COA), and in children with prenatal alcohol exposure (PAE). Pregnancies involving alcohol exposure sufficient to affect the fetus may involve women with genetic risk for alcohol dependence. We hypothesized that known PAE will increase the odds of having an externalizing disorder compared to COA. Methods The odds ratios of 3 externalizing disorders (attention-deficit hyperactivity disorder [ADHD], conduct disorder [CD], and oppositional defiant disorder [ODD]) were obtained for 2 domains: (i) PAE and (ii) COA, by estimating the logged odds ratio (LOR) for each study. Permutation tests were implemented to compare LORs for PAE versus COA studies within each disorder, including PAE versus an alcohol dependent (AD) mother and PAE versus an AD father. Results In PAE studies, the odds of ADHD and CD were elevated. Rates of all 3 disorders were elevated in COA studies. Permutation tests revealed that the mean LOR for ADHD was significantly higher in PAE studies compared to: COA (p = 0.01), AD mother (p < 0.05), and AD father (p = 0.03). No differences were found for ODD (p = 0.09) or CD (p = 0.21). Conclusions These results provide compelling evidence of an increased risk of ADHD in those with PAE beyond that due to parental alcohol dependence or a genetic liability, consistent with a unique etiology most likely due to direct alcohol exposure during prenatal development.