Cecilia J Hillard

Cecilia J Hillard
Medical College of Wisconsin | MCW · Neuroscience Research Center

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308
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Publications

Publications (308)
Article
The complexity of neuropathic pain and its associated comorbidities, including dysautonomia, make it difficult to treat. Overlap of anatomical regions and pharmacology of sympatho-sensory systems in the CNS provide targets for novel treatment strategies. The dorsal periaqueductal gray (dPAG) is an integral component of both the descending pain modu...
Article
Due to its heterogeneity, the prediction of posttraumatic stress disorder (PTSD) development after traumtic injury is difficult. Recent machine learning approaches have yielded insight into predicting PTSD symptom trajectories. Using data collected within 1 month of traumatic injury, we applied eXtreme Gradient Boosting (XGB) to classify admitted a...
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In addition to motor dysfunction, patients with Parkinson’s disease (PD) are often affected by neuropsychiatric disorders, such as anxiety and depression. In animal models, activation of the endocannabinoid (eCB) system produces anxiolytic and antidepressant-like behavioral effects. CB2 agonists have demonstrated neuroprotective effects against neu...
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Endocannabinoid signaling and the hypothalamic-pituitary-adrenal axis are activated by trauma and both stress systems regulate the transition from acute to chronic pain. This study aimed to develop a model of relationships among circulating concentrations of cortisol and endocannabinoids (eCBs) immediately after traumatic injury and the presence of...
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Inflammatory physiology has been linked to behavioral and emotional symptoms in a variety of contexts and experimental paradigms. Hematopoietic cell transplantation (HCT) represents an intersection of significant immune dysregulation and psychosocial stress, and this biobehavioral relationship can influence important clinical outcomes. For those un...
Preprint
Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonist...
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Background With the rising number of chimeric antigen receptor (CAR) T cell treated patients, it is increasingly important to understand the treatment’s impact on patient-reported outcomes (PROs) and, ideally, identify biomarkers of central nervous system (CNS) adverse effects. Methods The purpose of this exploratory study was to assess short-term...
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Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear ar...
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Despite its essential role in the (patho)physiology of several diseases, CB2R tissue expression profiles and signaling mechanisms are not yet fully understood. We report the development of a highly potent, fluorescent CB2R agonist probe employing structure-based reverse design. It commences with a highly potent, preclinically validated ligand, whic...
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The distribution and roles of the cannabinoid CB2 receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB2 receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB2 receptors in th...
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The endocannabinoid signaling system (ECSS) regulates fear and anxiety. While ECSS hypoactivity can contribute to symptoms of established post-traumatic stress disorder (PTSD), the role of the ECSS in PTSD development following trauma is unknown. A prospective, longitudinal cohort study of 170 individuals (47% non-Hispanic Caucasian and 70% male) t...
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Parkinson’s disease (PD) is a chronic neurodegenerative disorder associated with dopamine neuron loss and motor dysfunction. Neuroprotective agents that prevent dopamine neuron death hold great promise for slowing the disease’s progression. The activation of cannabinoid (CB) receptors has shown neuroprotective effects in preclinical models of neuro...
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Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prena...
Preprint
Background and purpose: Anxiety is often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear...
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Full-text available
Background: Loneliness is one of the most distressing grief symptoms and is associated with adverse mental health in bereaved older adults. The endocannabinoid signaling (ECS) system is stress-responsive and circulating endocannabinoid (eCB) concentrations are elevated following bereavement. This study examined the association between loneliness an...
Article
Background Socioeconomic Status (SES) is recognized as a major contributor to health disparities in overall disease rate, morbidity, mortality, and quality of life (QOL). Specifically, low SES, independent of race, has a negative impact on solid and haematological cancer outcomes. Chimeric antigen receptor (CAR) T-cell cancer therapy is an increasi...
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Identification of specific risk factors for posttraumatic stress disorder (PTSD) versus depression after trauma has been challenging, in part due to the high comorbidity of these disorders. As exposure to trauma triggers activation of the hypothalamic-pituitary-adrenal (HPA)-axis, examining atypical stress responses via HPA-axis hormones, namely co...
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Loneliness is associated with adverse mental health outcomes in older adults. Bereavement triggers intense feelings of loneliness. This pilot study explored the association between baseline loneliness and grief symptom trajectories in bereaved elders and explored if this association is moderated by depressive symptom changes. 56 individuals aged 50...
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CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express C...
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The cannabis-derived molecules, ∆9 tetrahydrocannabinol (THC) and cannabidiol (CBD), are both of considerable therapeutic interest for a variety of purposes, including to reduce pain and anxiety and increase sleep. In addition to their other pharmacological targets, both THC and CBD are competitive inhibitors of the equilibrative nucleoside transpo...
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Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxiou...
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Enhancing endocannabinoid signaling produces anxiolytic- and antidepressant-like effects, but the neural circuits involved remain poorly understood. The medial habenula (MHb) is a phylogenetically-conserved epithalamic structure that is a powerful modulator of anxiety- and depressive-like behavior. Here, we show that a robust endocannabinoid signal...
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Introduction We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy...
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The activation of the cannabinoid receptor type‐2 (CB2) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB2 receptor through investigating the consequences of its inactivation. TDP‐43(A315T) transgenic mice were crossed with CB2 receptor knock‐out mi...
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Background Cyclic vomiting syndrome (CVS) is a chronic functional GI disorder; a characteristic compulsive “hot-water bathing” pattern is reported to alleviate symptoms during an acute episode. There is limited data on this bathing pattern: proposed mechanisms include core temperature increase via effects on cannabinoid type 1 receptors in the brai...
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Introduction Losing a loved one often results in acute grief and depressive symptoms. The vast majority of older individuals are resilient and return to normal functioning within a year after a loss. However, a significant minority develop mental health complications, including prolonged grief disorder and bereavement-related depression. This can l...
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Biological mechanisms associated with response to trauma may impact risk for depression. One such mechanism is endocannabinoid signaling (eCB), a neuromodulatory system comprised of the CB1 subtype of cannabinoid receptors (CB1R), encoded by the CNR1 gene, and two primary endogenous ligands: 2-arachidonoylglycerol (2-AG) and N-arachidonylethanolami...
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Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depres...
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Early-life stress (ELS) is associated with later onset of depression. Early cannabis use may be a risk factor that interacts with environmental factors to increase the risk of psychopathologies. We aimed to examine the long-term effects of ELS on depression- and anxiety-like behavior, and examine whether chronic fatty acid amide hydrolase (FAAH) in...
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Introduction Chimeric antigen receptor (CAR) T cell immunotherapy represents a novel and increasingly used treatment modality for patients with relapsed and/or refractory B cell malignancies. Acute neurological toxicities of CAR-T cell therapy (e.g. immune effector cell-associated neurotoxicity syndrome) are well described, though delayed cognitive...
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Background The goals of this study were to determine whether serum concentrations of endocannabinoids (eCB) and related lipids predict disease status in patients with amyotrophic lateral sclerosis (ALS) relative to healthy controls, and whether concentrations correlate with disease duration and severity. Methods Serum concentrations of the eCBs 2‐...
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Reductions in state anxiety have been reported following an acute bout of aerobic exercise. However, less is known regarding anxiety and fear ratings to specific threatening stimuli following an acute bout of aerobic exercise in women with PTSD. Moreover, the mechanisms responsible for the anxiolytic effects of exercise are not fully understood, al...
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Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cann...
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Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous con-ditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this re-ceptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism of CB2R si...
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Early life stress (ELS) may increase predisposition to depression. Despite extensive research, there is still a lack of knowledge of how to optimally treat depression. We aimed to establish a role for the endocannabinoid (ECB) system within the hippocampal-nucleus accumbens (NAc) network as a possible effective target in combating the pathophysiolo...
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The endocannabinoid signaling system (ECSS) is altered by exposure to stress and mediates and modulates the effects of stress on the brain. Considerable preclinical data support critical roles for the endocannabinoids and their target, the CB1 cannabinoid receptor, in the adaptation of the brain to repeated stress exposure. Chronic stress exposure...
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Bereavement is one of the most intense, distressing, and traumatic events an elderly person will experience. The symptom responses to bereavement vary, particularly during the first year. However, the neurobiology underlying the symptom variance in grief is poorly understood. The endocannabinoid signaling (ECS) system is stress-responsive; mounting...
Preprint
Pharmacological modulation of cannabinoid type 2 receptor (CB<sub>2</sub>R) holds promise for the treatment of numerous conditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this receptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism o...
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Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in...
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Context The endocannabinoid (eCB) system partly controls hedonic eating, a major cause of obesity. While some studies suggested an over-activation of the eCB system in obesity, peripheral levels of eCBs across the 24-hr cycle have not been characterized in obese individuals despite the fact that in lean adults, levels of the eCB 2-arachidonoylglyce...
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Significance Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition triggered by a brief traumatic event causing delayed and prolonged changes in emotional behaviors that are accompanied by amygdalar hyperactivity. Understanding of the underlying neuronal mechanisms during stress that eventually culminate in its delayed impact...
Preprint
Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous conditions including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite its significance, researchers lack reliable tools to address questions concerning the complex mechanism of CB2R signaling and its downstream conseque...
Preprint
Cannabinoid type 2 receptor (CB<sub>2</sub>R) is a fundamental part of the endocannabinoid signaling system (eCB system), and is known to play an important role in tissue injury, inflammation, cancer and pain. In stark contrast to its significance, the underlying signaling mechanisms and tissue expression profiles are poorly understood. Due to its...
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Background: Exercise has been examined as an adjunctive treatment for substance use disorders (SUDs), yet few exercise interventions have been conducted among patients undergoing intensive outpatient (IOP) treatment, who may be the most vulnerable to relapse and for whom exercise could provide the most benefits. This study examined the effects of a...
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Neurotoxicity is an increasingly recognized complication of cancer immunotherapy occurring after allogeneic hematopoietic stem cell transplantation (HSCT), immune checkpoint inhibitor administration, and chimeric antigen receptor T cell therapy. While inflammatory cytokines are thought to play a pivotal role, the immunological and biochemical pathw...
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Background & aims: Some patients with cyclic vomiting syndrome (CVS) use cannabis to relieve stress and for its antiemetic properties. However, chronic cannabis use has been associated paradoxically with cannabinoid hyperemesis syndrome (CHS) and some patients with CVS are thought to have CHS. We sought to characterize patterns of cannabis use by...
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Introduction The endocannabinoid anandamide (AEA) signals ubiquitously throughout the body and has been shown to modulate endocrine systems and sleep/wake cycles. Previous analyses suggest a diurnal variation in plasma levels of AEA. We sought to determine the endogenous circadian profile of AEA and how this distribution may vary by body mass index...
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The endocannabinoid (eCB) system is a modulatory system that is both altered by stress and mediates the effects of acute stress, including contributing to restoration of homeostasis. Earlier studies suggest that circulating eCBs are dysregulated in adults with post-traumatic stress disorder (PTSD); however, it is not known whether circulating eCBs...
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The endocannabinoid (eCB) system is implicated in the pathophysiology of depression and is responsive to acute exercise in healthy adults. Purpose: We aimed to describe acute changes in serum eCB across a prescribed moderate (MOD) and a self-selected/preferred (PREF) intensity exercise session in women with major depressive disorder (MDD) and det...
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Introduction Hematopoietic stem cell transplantation (HCT) produces pro-inflammatory cytokines including IL-6 which can activate central nervous system (CNS) pathways to cause depressed mood, anxiety, fatigue, and sleep disturbance. Tocilizumab (toci), an IL-6 receptor antagonist, is an FDA approved treatment for cytokine release syndrome (CRS), a...
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CB2R receptors have demonstrated beneficial effects in wound healing in several models. We therefore investigated a potential role of CB2R receptors in corneal wound healing. We examined the functional contribution of CB2R receptors to the course of wound closure in an in vivo murine model. We additionally examined corneal expression of CB2R recept...
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Sickness symptoms associated with immunomodulatory treatments for cancer provided some of the first evidence for the neural and behavioral actions of cytokines. We now see a reemergence of this clinical relevance in the context of new therapeutic modalities targeting different aspects of immunity, including the IL-6 receptor antagonist tocilizumab....
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Historically, sickness symptomatology in cancer patients has been studied as aggregated phenomena arising from a similar inflammatory etiology. A parent clinical trial analyzed depression, anxiety, fatigue, sleep, and pain as separate variables in hematopoietic cell transplant (HCT) recipients experiencing cytokine blockade with an interleukin-6 re...
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Background Currently 29 states in the United States along with the District of Columbia have legalized cannabis in some forms. There is a paucity of data on the impact of legalization of cannabis use on hospitalizations due to cyclic vomiting syndrome (CVS). Aim To study the trends in CVS‐related hospitalizations and cannabis use in CVS in relatio...
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Early-life stress modulates the development of cortico-limbic circuits and increases vulnerability to adult psychopathology. Given the important stress-buffering role of endocannabinoid (eCB) signaling, we performed a comprehensive investigation of the developmental trajectory of the eCB system and the impact of exposure to early life stress induce...
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Endocannabinoid signaling regulates feeding and metabolic processes and has been linked to obesity development. Several hormonal signals, such as glucocorticoids and ghrelin, regulate feeding and metabolism by engaging the endocannabinoid system. Similarly, studies have suggested that leptin interacts with the endocannabinoid system, yet the mechan...
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Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We e...
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Background Because of their low levels of expression and the inadequacy of current research tools, CB2 cannabinoid receptors (CB2R) have been difficult to study, particularly in the brain. This receptor is especially relevant in the context of neuroinflammation, so novel tools are needed to unveil its pathophysiological role(s). Methods We have ge...
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Background: The ability to effectively cope with stress is a critical determinant of disease susceptibility. The lateral habenula (LHb) and the endocannabinoid (ECB) system have independently been shown to be involved in the selection of stress coping strategies, yet the role of ECB signaling in the LHb remains unknown. Methods: Using a battery...