IU Indianapolis ScholarWorks :: Browsing by Author "Truitt, William"

Browsing by Author "Truitt, William"

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Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels
(Springer Nature, 2019-01-22) Johnson, Philip L.; Molosh, Andrei I.; Federici, Lauren M.; Bernabe, Cristian; Haggerty, David; Fitz, Stephanie D.; Nalivaiko, Eugene; Truitt, William; Shekhar, Anantha; Anatomy and Cell Biology, IU School of Medicine
Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT-/-) have increased baseline anxiety behaviors, SERT+/- rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/- model. Here we sought to determine if SERT+/- or SERT-/-, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT-/- rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/- (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/- rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT-/- and SERT+/- rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.
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.
Multisystem Effects of Mold Inhalation: A Convergence on the Central Nervous System
(2020-08) Ladd, Thatcher Bondi; Oblak, Adrian L.; Yoder, Karmen K.; Baucum, Anthony J. II; Truitt, William; Landreth, Gary
With urbanization, indoor exposure to microbial communities has changed significantly. While indoor bacterial exposure has decreased, indoor fungal exposure has increased. Along with increases in fungal species diversity, indoor air in urbanized countries is characterized by 1,000+ fold differences in mold spore density between buildings. Americans are estimated to spend ~87% of their lives in this new indoor environment, where airborne spore concentrations are unregulated. While the effects of mold exposure on certain respiratory diseases are well established, little is known about how inhaled mold affects extra-respiratory disease. Mold exposure is associated with central nervous system (CNS) symptoms in humans, but very little is known about how mold affects the CNS. Here, I show that subchronic inhalation of a common indoor mold, Aspergillus versicolor, causes neuroinflammatory gene transcription in five out of five brain regions tested, at both 1 and 2 days post inhalation. How peripheral inflammation from mold inhalation causes neuroinflammation is unknown. The mechanisms by which mold is inhaled and cleared implicate the lung, systemic circulation, and gastrointestinal tract as potential areas of immune response. After mold spores are inhaled and deposited in the lung, they are killed by antifungal immunity, cleared from the lung by the mucociliary escalator, swallowed, and excreted through the gastrointestinal tract. Molds produce many mycotoxins which enter enterohepatic recirculation with known toxic effects, including intestinal epithelial disruption. Mycotoxin concentrations in food are regulated in countries comprising ~85% of the world’s population. Inhaled molds produce these same mycotoxins, yet pulmonary exposure is unregulated. The multi-system effects of fungal exposure are poorly understood, and are part of a growing nascent field. Here, I discuss the current state of the indoor fungal environment, known health effects of mold exposure, how fungi activate the immune system, the CNS effects of a common indoor mold, how neuroinflammation from mold exposure might be occurring, future work needed for the systematic analysis of the CNS effects of mold, what is needed to determine the extent to which fungal exposure influences disease, and what might be done to mitigate those effects.
Novel Strategies for the Prevention of Post-Stroke Epilepsy and Sudden Unexpected Death in Epilepsy Patients
(2022-10) Adhikari, Yadav Prasad; Truitt, William; Witkin, Jeffrey M.; Gupta, Kunal; Brutkiewicz, Randy; Jin, Xiaoming
Stroke is the second leading cause of mortality worldwide, accounting for 5.5 million deaths annually. In addition to its high mortality rate, stroke is the most common cause of acquired epilepsy. Three to thirty percent of stroke survivors develop post-stroke epilepsy. Although currently available therapies such as thrombolytics and mechanical thrombectomy prevent immediate mortality by restoring blood flow after stroke, these treatments do not target the cellular and molecular mechanisms that lead to post-stroke epileptogenesis. With the increasing number of stroke survivors, there is an urgent need for therapies that prevent epilepsy development in this population. Here, we showed that homeostatic plasticity is involved in the development of hyperexcitability after stroke and can be targeted to prevent the development of post-stroke epilepsy. Using two-photon calcium imaging, we found that homeostatic regulation leads to cortical hyperexcitability after stroke. We also found that activity enhancement by optogenetic and pharmacological approaches can target homeostatic plasticity to prevent post-stroke epilepsy. This study demonstrates the high translational potential of activity enhancement as a novel strategy to prevent post-stroke epilepsy through regulating cortical homeostatic plasticity. Sudden premature death is a leading cause of death in patients with medically refractory epilepsy. This unanticipated death of a relatively healthy person with epilepsy in which no structural or toxicological cause of death can be identified after postmortem analysis is referred to as sudden unexpected death in epilepsy patients (SUDEP). Respiratory failure during seizures is an important underlying mechanism of SUDEP. Here, we showed that LPS-induced peripheral inflammation is protective against SUDEP. This protection is mediated at least in part via enhancing serotonergic function in the brain stem. To the best of our knowledge, this is the first study demonstrating the relationship between peripheral inflammation and SUDEP prevention.
Orbitofrontal Cortex and Social Processing in Rodent Models
(2019-05) Andrews, Katharine DiAnn; Xu, Xiao-Ming; Lamb, Bruce; McAllister, Thomas; McDonald, Brenna; Truitt, William; Wu, Yu-Chien
Social processing is the reception, interpretation, and reciprocation of social information and is critical for mental health. The neural structures, circuits, and substrates regulating these complex mechanisms are not well understood. Social processing in the form of social safety learning, as measured by a rat model of social familiarity-induced anxiolysis (SoFiA), was impaired following mild blast traumatic brain injury (mbTBI). Initial findings indicated that mbTBI altered resting state network activity in the orbitofrontal cortex (OFC) and was associated with accumulation of neurotoxin marker, acrolein, in lateral prefrontal cortex (PFC) (including OFC), indicating OFC as a brain region of interest that may contribute to social processing. Measuring GABA and Glutamate-related gene expression in OFC of mbTBI or sham-exposed rat brain revealed specific elevations of metabotropic glutamate receptor type 1 and 5 (mGluR1/5) expression in mbTBI but not sham OFC. Exposure-naïve rats intracranially injected with mGluR1/5 agonist demonstrated attenuated SoFiA, and this coincided with an impairment of social recognition (SR) behavior. Additionally, inactivation of OFC by local intracranial injection of GABAA agonist, muscimol, impaired two different measures of SR in which two conspecifics, or members of the same species, one novel and one familiar, were presented and required discrimination. Novelty seeking, decision-making, memory, and gregariousness were tested in isolation to determine OFC contributions to these specific behavioral contributions to SR test performance. OFC inactivation did not impair novelty seeking, non-social decision-making, or non-social memory as measured by novel object recognition (NOR) test, or gregariousness or social decision-making as measure by social preference (SP) test. When measuring SR behavior via consecutive presentation of two different conspecifics, OFC inactivation did not impact SR. Therefore, OFC is not directly responsible for social recognition, but rather the discrimination or ability to act upon discrimination of two simultaneously present conspecifics. These data suggest a novel role for OFC in high order processing or execution of action based on social information.
Propranolol Elicits Long Term Systemic Effects After Repetitive Mild Traumatic Brain Injury
(2023-07) Smith, Jared Andre; Obukhov, Alexander; White, Fletcher; Hato, Takashi; Naugle, Kelly; Jin, Xiaoming; Truitt, William; Grimes, Jaison
There are almost 2 million new traumatic brain injuries (TBIs) every year in the US. Of these, 80% of these can be classified as mild TBI, also known as concussions, that can lead to pronounced long term symptoms months and years after injury. The presence of post traumatic headaches (PTH) is the most common chronic side effect with prevalence of 47-95% of mTBI patients within a week of injury. Though the mechanisms after TBI leading to these headaches and other post mTBI side effects are poorly understood, recent studies have suggested the role of the immune system after injury plays a causal role in this process. Peripheral immune cells can travel to the brain after mTBI as a result of blood brain barrier dysfunction, sympathetic nervous signaling, and the release of inflammatory mediators. Recent studies have shown sympathetic activation after injury can result in IL-10 dependent systemic immunosuppressive state after mTBI. In this study we sought to limit sympathetic dependent immune alterations after injury by injecting the beta blocker propranolol directly after injury and investigating the immune changes in the blood, brain, spleen, and bone marrow of mTBI animals. Together, these data show mTBI causes immune genetic and pathway level changes at least one month after injury and that propranolol alters genes important for metabolism, cytokine signaling, epigenetic modification, innate, and adaptive immunity. We also find that propranolol reduces the presence of Ly6C+ and increases the presence of Ly6C- monocytes in the blood one month after injury; however, it leads to increased Ly6C+ monocyte presence in the spleen of mTBI mice. In conclusion, propranolol administration directly after mTBI leads to immune changes that may lead to long-term improvement in post TBI symptomology.
Spinophilin Cell Type-Specifically Mediates Metabotrophic Glutamate Receptor 5-dependent Excessive Grooming
(2022-09) Morris, Cameron W.; Truitt, William; Atwood, Brady; Baucum, Anthony J., II; Ma, Yao-Ying; McKinzie, David
Compulsive and repetitive behaviors in obsessive-compulsive spectrum disorders (OCSDs) are associated with perturbations in the sensorimotor striatum. Repetitive behaviors are associated with cell type-specific adaptations in striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs, respectively). Furthermore, preclinical models for understanding OCSDs, such as constitutive knockout of disks large associated protein 3 (SAPAP3), suggest repetitive motor dysfunction, such as excessive grooming, is associated with increased metabotropic glutamate receptor 5 (mGluR5) activity that increases dMSN function relative to iMSNs in the sensorimotor striatum. However, MSN subtype-specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Reversible phosphorylation of mGluR5’s C-terminal domain is one mechanism to regulate mGluR5 signaling, however, unlike kinases, promiscuous phosphatases require targeting proteins to shuttle them into contact with their targets. Therefore, phosphatase targeting proteins may be intimately involved in mediating mGluR5-dependent striatal adaptions underlying repetitive behaviors, such as excessive grooming in SAPAP3 deficient mice. Spinophilin, a major striatal postsynaptic phosphatase targeting protein, regulates striatal function, mGluR5 signaling, and forms a protein-protein interaction with SAPAP3 that is increased by mGluR5 co-expression. Therefore, we hypothesized that spinophilin expression in striatal medium spiny neurons mediates mGluR5-dependent excessive grooming. To test this, we used a novel conditional spinophilin mouse line combined with functional, behavioral, and molecular approaches to elucidate spinophilin's MSN subtype-specific contributions to rodent excessive grooming behavior associated with increased mGluR5 function. We found that loss of spinophilin in either MSN subtype abrogated plasticity in the sensorimotor striatum associated with increased mGluR5 function and decreased two models of excessive grooming associated with increased mGluR5 function—SAPAP3 deficient mice and global administration of a mGluR5-specific positive allosteric modulator (VU0360172). Additionally, we found that spinophilin’s protein interaction with mGluR5 correlates with grooming behavior and loss of spinophilin shifts mGluR5 interactions from lipid-raft associated proteins toward postsynaptic density proteins implicated in psychiatric disorders. Collectively, these results identify spinophilin as a novel striatal signaling hub molecule in MSNs that MSN subtype-specifically mediates striatal adaptations associated with repetitive motor dysfunction in psychiatric disorders.
Training Physician-Scientists in Social and Behavioral Science: Indiana ADRD Medical Scientist Training Program
(Oxford University Press, 2022-12-20) Fowler, Nicole; Herbert, Brittney-Shea; Callahan, Christopher; Peng, Siyun; Perry, Brea; Yoder, Karmen; Landreth, Gary; Truitt, William; Medicine, School of Medicine
There is a critical need to grow and strengthen the pipeline of physician scientists who have expertise in sociomedical and behavioral research and are dedicated to addressing the nation's challenges posed by Alzheimer's disease and related dementias (ADRD). In 2021 The Indiana ADRD Medical Scientist Training Program (IADRD MSTP) was designed to meet this need and is built on the infrastructure of a robust portfolio of ADRD research, graduate training programs in medical neurosciences and sociology, and our existing MD-PhD program at Indiana University School of Medicine. The Aims of the IADRD MSTP are: 1) To recruit and train a competitive pool of diverse students who have an interest and commitment to social and behavioral research and patient care focused on ADRD; 2) To engage MD-PhD students early in mentored sociomedical and behavioral research that integrates IUs systems-based medical training curriculum with our cutting edge ADRD research that reinforces commitment and minimizes attrition of physician-scientists ADRD; and 3) To graduate students with dual MD-PhD degrees with strong methodological training in social and behavioral science and experts in ADRD who will be successful independent investigators at the best academic medical centers nationwide. The program includes rigorous didactic training in social, behavioral, and clinical research methods, with flexibility to allow students to focus their effort on one methodological area of interest; early initiation of ADRD research experiences with multidisciplinary teams of mentors and advisors; and the provision of educational experiences that enhance students' abilities to become independent researchers.

Browsing by Author "Truitt, William"

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