Browsing by Author "Lapish, Christopher"

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    Assessing Motivational and Associative Learning Mechanisms Underlying Compulsive Drinking
    (2021-08) Carron, Claire R.; Grahame, Nicholas; Czachowski, Cristine; Lapish, Christopher; Hopf, Fredric
    Continued consumption of alcohol despite the knowledge of negative consequences is a hallmark of alcohol use disorder (AUD), yet much remains unknown about what motivates these behaviors. Compulsive drinking may require motivational resources that are not necessary when drinking in unchallenged conditions in order to counteract the addition of these negative consequences. Increased sensitivity to drug-paired stimuli via associative learning processes may provide this additional motivation. To evaluate if alcohol-paired stimuli enhance alcohol seeking, selectively bred crossed High Alcohol Preferring mice experienced Pavlovian conditioning procedures with an alcohol unconditioned stimulus. We hypothesized that after repeated pairings, alcohol cues would elicit seeking conditioned responses. Then, to determine if the motivation provided by these cues influenced responding, mice were trained to respond for alcohol and tested in the presence of alcohol cues. Finally, to test if alcohol-paired cues influence compulsive drinking, this same test was repeated with the addition of response-contingent footshock. We hypothesized the cue paired with alcohol would increase responding for alcohol in unchallenged conditions, but especially in challenged conditions, contributing to compulsivity. An auditory stimulus paired with alcohol did elicit enhanced seeking responses, but contrary to hypothesis, we observed no effect of these same cues on instrumental responding. To validate these findings, training and testing procedures must be optimized to ensure conditioning has properly occurred and compulsivity is being appropriately measured.
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    Circuit-level Mechanisms of EtOH-dependent dopamine release.
    (2017-06-30) DiVolo, Matteo; Morozova, Ekaterina; Lapish, Christopher; Kuznetsov, Alexey; Gutkin, Boris; Mathematical Sciences, School of Science
    Alcoholism is the third leading cause of preventable mortality in the world. In the last decades a large body of experimental data has paved the way to a clearer knowledge of the specific molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms play together to result in a dysregulated dopamine (DA) release under alcohol influence remains unclear. In this manuscript, we delineate potential circuit-level mechanisms responsible for EtOH-dependent increase and dysregulation of DA release from the ventral tegmental area (VTA) into nucleus accumbens (Nac). For this purpose, we build a circuit model of the VTA composed of DA and GABAergic neurons, that integrate external Glutamatergic (Glu) inputs to result in DA release. In particular, we reproduced a non-monotonic dose dependence of DA neurons firing activity on EtOH: an increase in firing at small to intermediate doses and a drop below baseline (alcohol-free) levels at high EtOH concentrations. Our simulations predict that a certain level of synchrony is necessary for the firing rate increase produced by EtOH. Moreover, EtOH effect on the DA neuron firing rate and, consequently, DA release can reverse depending on the average activity level of the Glu afferents to VTA. Further, we propose a mechanism for emergence of transient (phasic) DA peaks and the increase in their frequency in EtOH. Phasic DA transients result from DA neuron population bursts, and these bursts are enhanced in EtOH. These results suggest the role of synchrony and average activity level of Glu afferents to VTA in shaping the phasic and tonic DA release under the acute influence of EtOH and in normal conditions.
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    De-Mixing Decision Representations in Rodent dmPFC to Investigate Strategy Change During Delay Discounting
    (2023-05) White, Shelby M.; Lapish, Christopher; Czachowski, Cristine; Oberlin, Brandon; Seamans, Jeremy
    Several pathological disorders are characterized by maladaptive decision-making (Dalley & Robbins, 2017). Decision-making tasks, such as Delay Discounting (DD), are used to assess the behavioral manifestations of maladaptive decision-making in both clinical and preclinical settings (de Wit, Flory, Acheson, Mccloskey, & Manuck, 2007). DD measures cognitive impulsivity and broadly refers to the inability to delay gratification (Hamilton et al., 2015). How decisions are made in tasks that measure DD can be understood by assessing patterns of behavior that are observable in the sequences of choices or the statistics that accompany each choice (e.g. response latency). These measures have led to insights that suggest strategies that are used by the agent to facilitate the decision (Linsenbardt, Smoker, Janetsian-Fritz, & Lapish, 2016). The current set of analyses aims to use individual trial data to identify the neural underpinnings associated with strategy transition during DD. A greater understanding of how strategy change occurs at a neural level will be useful for developing cognitive and behavioral strategies aimed at reducing impulsive choice. The rat dorso-medial prefrontal cortex (dmPFC) has been implicated as an important brain region for recognizing the need to change strategy during DD (Powell & Redish, 2016). Using advanced statistical techniques, such as demixed principal component analysis (dPCA), we can then begin to understand how decision representations evolve over the decision- making process to impact behaviors such as strategy change. This study was the first known attempt at using dPCA applied to individual sessions to accurately model how decision representations evolve across individual trials. Evidence exists that representations follow a breakdown and remapping at the individual trial level (Karlsson, Tervo, & Karpova, 2012; Powell & Redish, 2016). Furthermore, these representational changes across individual trials have previously been proposed to act as a signal to change strategies (Powell & Redish, 2016). This study aimed to test the hypothesis that a ‘breakdown’ followed by a ‘remapping’ of the decision representation would act as a signal to change strategy that is observable in the behavior of the animal. To investigate the relationship between trials surrounding the breakdown and/or subsequent remapping of the decision representation and trials surrounding strategy changes, sequences of trials surrounding the breakdown and/or remapping were compared to sequences of 9 trials surrounding the strategy-change trial. Strategy types consisted of either exploiting the immediate lever (IM-Exploit), delay lever (DEL-Exploit), or exploring between the two lever options (Explore). Contrary to the hypothesis, an overall relationship between breakdown and remapping trial sequences were not associated with change-trial sequences. In partial support of the hypothesis however, at the 4-sec delay when the subjective value of the immediate reward was high, a relationship between breakdown sequence and strategy change sequence was detected for when the animal was exploiting the delay lever (e.g. DEL-Exploit strategy). This result suggests that a breakdown in decision representation may act as a signal to prompt strategy change under certain contexts. One notable finding of this study was that the decision representation was much more robust at the 4-sec delay compared to the 8-sec delay, suggesting that decisions at the 4-sec delay contain more context that differentiate the two choice options (immediate or delay). In other words, the encoding of the two choice options was more dissociable at the 4-sec delay compared to the 8-sec delay, which was quantified by measuring the average distance between the two representations (immediate and delay) on a given trial. Given that Wistar rats are equally likely to choose between the immediate and delay choice alternatives at the 8-sec delay (Linsenbardt et al., 2016), this finding provides further support for current prevalent theories of how animals use a cognitive search process to mentally imagine choice alternatives during deliberation. If context which differentiates choice options at the 8-sec delay is less dissociable, it is likely that the cognitive search process would be equally likely to find either choice option. If the choice options are equally likely to be found, it would be assumed that the choice alternatives would also be equally likely to be chosen, which is what has been observed in Wistar rats at the 8-sec delay.
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    Delay Discounting in At-Risk Preadolescents: Brain Mechanisms and Behavior
    (2021-12) Butcher, Tarah J; Oberlin, Brandon; Lapish, Christopher; Hulvershorn, Leslie
    It is well documented that adolescent substance use is associated with deficits in brain function and behavior. However, possible deficits that predate substance use initiation remain poorly characterized in preadolescents at-risk for developing substance use disorder (SUD). To characterize potential brain and behavioral differences that predate substance use, substance naïve preadolescents, ages 11–12, were recruited into three groups to complete functional magnetic resonance imaging delay discounting: (1) High-risk youth (n=35) with a family history of SUD and externalizing psychiatric disorders, (2) psychiatric controls (n=35) with no family history of SUD, but equivalent externalizing psychiatric disorders as high-risk youth, and (3) healthy controls (n=29) with no family history of SUD and minimal psychopathology. While no behavioral differences between groups were identified, there were group differences in posterior cingulate cortex (PCC) function during decision making. Specifically, the high-risk group showed stronger deactivation of the PCC than healthy controls. These results suggest that high-risk preadolescents may need to suppress activity of key nodes of the default mode network (a task negative network) to a greater extent to properly allocate attention to the task.
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    Determining the Impact of Repeated Binge Drinking on Corticostriatal Theta Synchrony
    (2020-12) Ardinger, Cherish; Lapish, Christopher; Grahame, Nicholas; Linsenbardt, David
    The development of alcohol use disorder (AUD) is believed to involve functional adaptations in corticostriatal projections which regulate the reinforcing properties of ethanol (EtOH). To further our understanding of how repeated EtOH consumption impacts the corticostriatal circuit, extracellular electrophysiological recordings (local field potentials; LFPs) were gathered from the nucleus accumbens and prefrontal cortex of female and male C57BL/6J mice voluntarily consuming EtOH or water using ‘drinking-in-the-dark’ (DID) procedures. Mice were given 15 consecutive days of two-hours of access to EtOH (20% v/v), three hours into the dark cycle while LFPs were recorded. To determine the impact of repeated EtOH consumption on neural activity between these brain regions, theta phase-locking value (PLV, a measure of synchrony) was calculated. Specifically, theta PLV was calculated during active drinking periods (bouts) and average PLV during the first bout was compared to the last bout to determine within session changes in synchrony. Results indicated significantly lower PLV during the last bout than the first bout. Additionally, longer bouts predicted lower PLV during the last bout, but not the first bout when mice were consuming EtOH. These results may suggest that alcohol intoxication decreases corticostriatal synchrony over a drinking period. Results considering changes in theta power spectral density (PSD) indicated an increase in PSD when mice were given access to water during the typical EtOH access time following the 15-day EtOH drinking history. This effect was not seen when mice were drinking water prior to EtOH access and may be indicative of a successive negative contrast effect. This work identifies unique functional characteristics of corticostriatal communication associated with binge-like EtOH intake and sets the stage for identifying the biological mechanisms subserving them.
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    Development, validation, and characterization of a novel preclinical animal model of social familiarity-induced anxiolysis
    (2017-09-29) Lungwitz, Elizabeth Ann; Shekhar, Anantha; Truitt, William; Oxford, Gerry; Rodd, Zachary; Lapish, Christopher
    Social support is a powerful therapeutic against fear and anxiety and is utilized in many psychotherapies. The concept that a familiar or friendly presence helps a person learn to overcome anxiety has been well-known for decades, yet, the basic neural mechanisms that regulate this psychosocial learning remain unknown. A first step towards elucidating these basic mechanisms is the development of a valid preclinical animal model. However, preclinical behavioral models exploring the use of a social presence in reducing anxiety have not been fully characterized. Therefore, it was our goal to identify a useful way in which to study the mechanisms of how a social presence can induce anxiolysis (the reduction of anxiety). We accomplished this goal by characterizing and validating a preclinical model, as well as demonstrating that the model was capable of measuring deficits in rats given a mild traumatic brain injury. To this end, we identified an existing, but uncharacterized model, the social interaction-habituation model, as an effective model of social familiarity-induced anxiolysis (SoFiA), which demonstrates socially enhanced safety learning, or psychosocial learning. We find that as social familiarity develops across time, anxiolysis develops. We identified that the use of a Bright Light Challenge is a useful anxiogenic stimulus to use during SI-habituation training. The anxiolysis acquired following SI-habituation testing is partner specific, and can be blocked by an inhibition of the medical prefrontal cortex, while it can be enhanced by D-cycloserine. We found that this model identified deficits in SoFiA acquisition in rodents exposed to a mild traumatic brain injury, which, in humans, has been linked to psychosocial deficits. This work is a step in creating ways in which we can study and better understand the regulatory processes of emotions mediated by social behavior.
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    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, Bethany
    Early 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.
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    Effect of Drinking History on Reinforced and Extinction Responding in Crossed High Alcohol-Preferring Mice
    (2022-12) Winkler, Garrett; Grahame, Nicholas; Lapish, Christopher; Logrip, Marian
    Tolerance is a diagnostic criterion for alcohol use disorder (AUD) and dependence and is often measured metabolically or behaviorally by comparing blood ethanol concentrations (BEC) or locomotor performance to an ethanol (EtOH) challenge before and after a drinking history, respectively. To explore another aspect of chronic behavioral tolerance in a family history positive (FH+) model of AUD, crossed High Alcohol Preferring (cHAP) mice were allowed to respond instrumentally for an EtOH reinforcer after either a five-week history of continuous home cage two-bottle choice (2BC) drinking or a concurrent five-week water-drinking period. Additionally, some of these animals were placed back into the operant box after home cage drinking histories to respond in extinction, allowing for the quantification of alcohol-motivated seeking alone in the absence of EtOH taking and its intoxicating effects. The results demonstrate that an alcohol history does not lead to a subsequent increase in active lever responding or inactive lever responding when compared to water-drinking controls. However, female cHAP mice with an EtOH-drinking history respond more on the inactive lever in extinction compared to water controls, suggesting that home cage EtOH history potentiates variation in responding in extinction. Overall, female mice responded more on the active lever and drank more alcohol in the reinforced condition, but again, there was not an effect of drinking history on this sex-specific effect. Together these results suggest that while female cHAPs, regardless of drinking history, are more motivated to work to drink EtOH, reinforced and non-reinforced instrumental responding are not reliable readouts for tolerance in cHAP mice compared to other endpoints such as drinking in the dark (DID) assays.
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    The Effects of Early-Life Lead Exposure on Adult Delta9-Tetrahydrocannabinol Sensitivity, Self-administration, and Tolerance
    (2022-08) Garcy, Daniel; Boehm, Stephen; Lapish, Christopher; Logrip, Marian
    Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (main psychoactive component delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3rd most widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. This thesis sets out to establish whether there is a link between early life Pb exposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The first aim seeks to answer whether Pb exposure affects physiological THC sensitivity (as measured by the cannabinoid-induced tetrad). The second aim seeks to answer whether Pb exposure affects edible THC self-administration and the development of THC tolerance (also measured by the tetrad). It was hypothesized that Pb exposure would decrease THC sensitivity (Aim 1), would enhance THC self-administration (Aim 2), enhance the development of THC tolerance (Aim 2), and finally that sex-dependent effects of Pb-exposure and THC would be observed (Aims 1 & 2). These hypotheses ended up not being supported, but Aim 1 produced findings indicating that THC sensitivity was increased by Pb exposure, but only in female mice. Future research will hopefully be able to fully explore the implications of these findings.
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    Enhancing Our Genetic Knowledge of Human Iris Pigmentation and Facial Morphology
    (2019-12) Eller, Ryan; Walsh, Susan; Berbari, Nicolas; Lapish, Christopher; Picard, Christine; Roper, Randall
    The biological underpinnings that control iris pigmentation and facial morphology are two areas of research that over the last decade are becoming more thoroughly investigated due to the increased affordability of genotyping and advances in technology allowing for more advanced analysis techniques. Despite the ease of access to the data and the tools required to perform iris pigmentation and facial morphological studies, there are still numerous challenges researchers must overcome when exploring the genetics of these complex phenotypes. Some of these challenges include difficulty in working with the bioinformatic programs designed to analyze genetic associations, the inability to define a phenotype that captures the true nature of these traits, and analysis techniques that fail to model complex gene-gene interactions and their effect on a phenotype or phenotypes of interest. In this body of work, I attempted to address these challenges by designing a bioinformatic pipeline, Odyssey, that bridges the communication gaps between various data preparation programs and the programs that analyze genomic data. With this program, genome-wide association studies (GWAS) could be conducted in a quicker, more efficient, and easier manner. I also redefined iris color as a quantitative measurement of pre-defined color classes. In this way it is possible to define and quantify the unique and intricate mixtures of color, which allows for the identification of known and novel variants that affect individual iris color. I also improved upon current prediction models by developing a neural network model capable of predicting a quantitative output to four pre-defined classes; blue/grey, light brown (hazel), perceived green, and dark brown. I examined the effects of defining a simple facial morphology phenotype that more accurately captures the lower face and jaw shape. I then analyzed this phenotype via a GWAS and found several novel variants that may be associated with a square and diamond shaped face. Lastly, I demonstrated that structural equation modeling can be used in combination with traditional GWAS to examine interactions amongst associated variants, which unearths potential biological relationships that impact the multifaceted phenotype of facial morphology.