Examining Risk Factors in the Cannabis-Suicide Link: Considering Trauma and Impulsivity among University Students.

Cannabis is a commonly used substance among university students that may have several negative health repercussions, including suicidal ideation (SI) and suicide attempts (SA). The factors that contribute to or help explain this relation remain uncertain. Earlier negative experiences, especially trauma encountered during early life, have been associated with the development of psychopathology upon later stressor encounters. In the current study, we examined the associations between SI and SA with problematic cannabis use among young adults and the role of earlier trauma experiences and trait impulsiveness in understanding this link. Among university students (N = 539), problematic cannabis use was moderately related to lifetime and past-12-months suicidal ideation and attempts. Impulsiveness mediated the relationship between problematic cannabis use and lifetime SI and SA. Moreover, previous life trauma moderated the relationship between problematic cannabis use and SA, such that the association between problematic cannabis use and SA was stronger among those who experienced high levels of trauma. These findings highlight behavioral and environmental factors that could predict suicide ideation and attempts among young cannabis users. Accordingly, trait impulsiveness and early trauma experiences should be considered, alongside problematic cannabis use, in suicide-risk detection and prevention strategies among young adults.

Coping With the COVID-19 Pandemic: Examining Gender Differences in Stress and Mental Health Among University Students.

The COVID-19 pandemic has imposed a wide variety of unprecedented challenges, many of which appear to be disproportionately affecting the mental health and well-being of young adults. While there is evidence to suggest university students experience high rates of mental health disorders, less is known about the specific impacts of the COVID-19 pandemic on student mental health and how they are coping with this stress. To address this gap, we conducted an online study among undergraduate students (n = 366) to examine the impact of the COVID-19 pandemic on academics, social isolation, and mental health, as well as the extent to which they have been implementing a variety of coping strategies. The pandemic had a more pronounced negative effect on female students' academics, social isolation, stress and mental health compared to male counterparts. Moreover, for females, frequent use of social media as a coping mechanism was associated with greater perceived negative impacts on their academic performance and stress levels, compared to males. However, frequent social media use related to similar negative mental health effects for both males and females. While male and female students both reported using substances to cope, for males the use of cannabis was associated with greater negative impacts on academic outcomes, stress and mental health compared to females. These findings highlight the need for adequate student support services across the post-secondary sector, and point to the importance of gender informed interventions to address the impacts of the COVID-19 pandemic.

Perinatal Exposure to Low-Dose Bisphenol-A Disrupts the Structural and Functional Development of the Hypothalamic Feeding Circuitry.

Bisphenol-A (BPA) is a component of polycarbonate and other plastics to which humans are regularly exposed at low levels. BPA is characterized as an endocrine disruptor because of observations of its estrogenic activity in various experimental models. We have previously shown evidence of disrupted hypothalamic feeding circuitry and leptin sensitivity in adult BPA-exposed animals subjected to a high-fat diet, but because these animals were already exhibiting a diet-induced obese phenotype, we could not rule out the possibility that these observations were simply consequences of the obesity, not a preexisting phenotype produced by BPA exposure. Here, we studied leptin sensitivity and hypothalamic structure in young BPA-exposed animals before the onset of a body weight or metabolic phenotype. Pregnant and lactating CD-1 mice were exposed to either BPA or diethylstilbestrol (DES) at low, environmentally relevant doses via their diet. Studies of leptin function and neurobiology were conducted on offspring at several time points. Young adult offspring from this experiment were resistant to leptin-induced suppression of food intake, body weight loss, and hypothalamic pro-opiomelanocortin (POMC) upregulation. Both male and female BPA-exposed mice showed a reduced density of POMC projections into the paraventricular nucleus of the hypothalamus (PVN). BPA- and DES-exposed pups had respectively delayed and blunted postnatal leptin surges, and POMC projections into the PVN were rescued in female BPA-exposed animals given daily injections of supplemental leptin. Our findings suggest that BPA, a putative obesogen, may exert its effects through developmental programming of the hypothalamic melanocortin circuitry, permanently altering the neurobiology of metabolic homeostasis.

Triticale Bran Alkylresorcinols Enhance Resistance to Oxidative Stress in Mice Fed a High-Fat Diet.

Triticale (× Triticosecale Whitm.) is a cereal grain with high levels of alkyresorcinols (AR) concentrated in the bran. These phenolic lipids have been shown to reduce or inhibit triglyceride accumulation and protect against oxidation; however, their biological effects have yet to be evaluated in vivo. The purpose of this study was to determine the effects of ARs extracted from triticale bran (TB) added to a high-fat diet on the development of obesity and oxidative stress. CF-1 mice were fed a standard low-fat (LF) diet, a 60% high-fat diet (HF) and HF diets containing either 0.5% AR extract (HF-AR), 10% TB (HF-TB), or 0.5% vitamin E (HF-VE). Energy intake, weight gain, glucose tolerance, fasting blood glucose (FBG) levels, and body composition were determined. Oxygen radical absorbance capacity (ORAC), superoxide dismutase (SOD) activity, and glutathione (GSH) assays were performed on mice liver and heart tissues. The findings suggest that ARs may serve as a preventative measure against risks of oxidative damage associated with high-fat diets and obesity through their application as functional foods and neutraceuticals. Future studies aim to identify the in vivo mechanisms of action of ARs and the individual homologs involved in their favorable biological effects.

Novel Regulator of Acylated Ghrelin, CF801, Reduces Weight Gain, Rebound Feeding after a Fast, and Adiposity in Mice.

Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here, we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically, they decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high-fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801, along with other compounds that regulate ghrelin secretion, may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin-based obesity treatments without altering the function of ghrelin receptors.

Rats perinatally exposed to food restriction and high-fat diet show differences in adipose tissue gene expression under chronic caloric restriction.

The aim of this study is to analyze how maternal diet during the lactational period influences the adipose tissue response to chronic caloric restriction in offspring. Lactating dams were subjected to one of three treatments: 50% food restriction (FR), ad lib standard chow (AL), or ad lib high-fat diet (HF). Juveniles were first weaned onto standard chow, then in adulthood 50% calorically restricted and maintained at 90% of normal body weight for 60 d. HF animals showed increased percent body fat compared with AL and FR animals despite equivalent body weights. HF animals showed alterations in the balance of adipose tissue lipogenic (FAS, LPL) and lipolytic (HSL) gene expression that may underlie their propensity to maintain fat stores under caloric restriction.

Interruption of ghrelin signaling in the PVN increases high-fat diet intake and body weight in stressed and non-stressed C57BL6J male mice.

Chronic social stress has been associated with increased caloric intake and adiposity. These effects have been linked to stress induced changes in the secretion of ghrelin, a hormone that targets a number of brain regions to increase food intake and energy expenditure and promote increased body fat content. One of the brain sites targeted by ghrelin is the hypothalamic paraventricular nucleus (PVN), a region critical for both the regulation of the stress response and the regulation of energy balance. Given these data, we examined the contribution of ghrelin receptors in the PVN to the metabolic and behavioral changes that are seen during chronic social stress in mice. To do this, mice were implanted with cannulae attached to osmotic minipumps and delivering either vehicle or the ghrelin receptor (growth hormone secretagogue receptor) antagonist [D-Lys-3]-GHRP-6 (20 nmol/day/mouse). Following a week of recovery, half of the animals in each group were exposed to chronic social defeat stress for a period of 3 weeks whereas the other half were left undisturbed. During this time, all animals were given ad libitum access to standard laboratory chow and presented a high-fat diet for 4 h during the day. Results showed that the ghrelin receptor antagonism did not decrease stressed induced caloric intake, but paradoxically increased the intake of the high fat diet. This would suggest that ghrelin acts on the PVN to promote the intake of carbohydrate rich diets while decreasing fat intake and blockade of ghrelin receptors in the PVN leads to more consumption of foods that are high in fat.

Stress induced obesity: lessons from rodent models of stress.

Stress was once defined as the non-specific result of the body to any demand or challenge to homeostasis. A more current view of stress is the behavioral and physiological responses generated in the face of, or in anticipation of, a perceived threat. The stress response involves activation of the sympathetic nervous system and recruitment of the hypothalamic-pituitary-adrenal (HPA) axis. When an organism encounters a stressor (social, physical, etc.), these endogenous stress systems are stimulated in order to generate a fight-or-flight response, and manage the stressful situation. As such, an organism is forced to liberate energy resources in attempt to meet the energetic demands posed by the stressor. A change in the energy homeostatic balance is thus required to exploit an appropriate resource and deliver useable energy to the target muscles and tissues involved in the stress response. Acutely, this change in energy homeostasis and the liberation of energy is considered advantageous, as it is required for the survival of the organism. However, when an organism is subjected to a prolonged stressor, as is the case during chronic stress, a continuous irregularity in energy homeostasis is considered detrimental and may lead to the development of metabolic disturbances such as cardiovascular disease, type II diabetes mellitus and obesity. This concept has been studied extensively using animal models, and the neurobiological underpinnings of stress induced metabolic disorders are beginning to surface. However, different animal models of stress continue to produce divergent metabolic phenotypes wherein some animals become anorexic and lose body mass while others increase food intake and body mass and become vulnerable to the development of metabolic disturbances. It remains unclear exactly what factors associated with stress models can be used to predict the metabolic outcome of the organism. This review will explore a variety of rodent stress models and discuss the elements that influence the metabolic outcome in order to further extend our understanding of stress-induced obesity.

Organizational effects of perinatal exposure to bisphenol-A and diethylstilbestrol on arcuate nucleus circuitry controlling food intake and energy expenditure in male and female CD-1 mice.

The endocrine disrupting compound bisphenol-A (BPA) has been reported to act as an obesogen in rodents exposed perinatally. In this study, we investigated the effects of early-life BPA exposure on adult metabolic phenotype and hypothalamic energy balance circuitry. Pregnant and lactating CD-1 dams were exposed, via specially prepared diets, to 2 environmentally relevant doses of BPA. Dams consumed an average of 0.19 and 3.49 µg/kg per day of BPA in the low and high BPA treatments prenatally and an average of 0.36 and 7.2 µg/kg per day of BPA postnatally. Offspring were weaned initially onto a normal (AIN93G) diet, then as adults exposed to either a normal or high-fat diet (HFD). Males exposed to the high dose of BPA showed impaired glucose tolerance on both diets. They also showed reduced proopiomelanocortin fiber innervation into the paraventricular nucleus of the hypothalamus, and when exposed to HFD, they demonstrated increased neuropeptide Y and Agouti-related peptide expression in the arcuate nucleus (ARC). Females exposed to the high BPA dose were heavier, ate more, and had increased adiposity and leptin concentrations with reduced proopiomelanocortin mRNA expression in the ARC when consuming a HFD. BPA-exposed females showed ARC estrogen receptor α expression patterns similar to those seen in males, suggesting a masculinizing effect of BPA. These results demonstrate that early-life exposure to the obesogen BPA leads to sexually dimorphic alterations in the structure of hypothalamic energy balance circuitry, leading to increased vulnerability for developing diet-induced obesity and metabolic impairments, such as glucose intolerance.

Understanding the neuroinflammatory response following concussion to develop treatment strategies.

Mild traumatic brain injuries (mTBI) have been associated with long-term cognitive deficits relating to trauma-induced neurodegeneration. These long-term deficits include impaired memory and attention, changes in executive function, emotional instability, and sensorimotor deficits. Furthermore, individuals with concussions show a high co-morbidity with a host of psychiatric illnesses (e.g., depression, anxiety, addiction) and dementia. The neurological damage seen in mTBI patients is the result of the impact forces and mechanical injury, followed by a delayed neuroimmune response that can last hours, days, and even months after the injury. As part of the neuroimmune response, a cascade of pro- and anti-inflammatory cytokines are released and can be detected at the site of injury as well as subcortical, and often contralateral, regions. It has been suggested that the delayed neuroinflammatory response to concussions is more damaging then the initial impact itself. However, evidence exists for favorable consequences of cytokine production following traumatic brain injuries as well. In some cases, treatments that reduce the inflammatory response will also hinder the brain's intrinsic repair mechanisms. At present, there is no evidence-based pharmacological treatment for concussions in humans. The ability to treat concussions with drug therapy requires an in-depth understanding of the pathophysiological and neuroinflammatory changes that accompany concussive injuries. The use of neurotrophic factors [e.g., nerve growth factor (NGF)] and anti-inflammatory agents as an adjunct for the management of post-concussion symptomology will be explored in this review.