Modulatory Effects of GABA(B) Receptor Facilitation in a Model of Chronic Inflammation

Inflammation within the brain (neuroinflammation) has been associated with a number of neurodegenerative diseases, including Alzheimerʼs disease (AD) (Solito et al., 2012). Within the brain, inflammation is defined broadly as prolonged activation of the brainʼs immune cells, known as glial cells. Excessive activation of glial cells within the brains of AD patients is a hallmark of the disease, however the mechanism by which this contributes to disease pathology is relatively unclear (Jo et al., 2014). Recently, studies have shown that glial cells, known as astrocytes, are able to synthesize and release the inhibitory neurotransmitter GABA (Charles et al., 2003). Further, microglia cells, the primary immunocompetent cells of the brain, have been shown to be GABAceptive cells, which express GABA (B) type receptors (Kuhn et al., 2004). Early characterizations of AD first described alterations in astrocyte location and activation in the disease and interestingly, differences in the total abundance of GABA within the brains of AD patients have recently been reported. Combined, these data provide support for the hypothesis that astrocytes regulate microglia activity through the release of GABA acting at GABA(B) type receptors. The activation of GABA(B) on microglia may serve to reduce the activation status of these microglia, thereby reducing the number of pro-inflammatory cytokines present within the brain (Streit et al., 2002). In the present study, we examined the effects of the GABA(B) agonist baclofen on chronic inflammation in rodents administered lipopolysaccharide (LPS). LPS is a bacterial endotoxin derived from the cell wall of gram-negative bacteria and is capable of mounting an immune response through the activation of toll-like receptor 4 (TLR4). Our data indicate that the administration of baclofen initially attenuated the pyrogenic effects of LPS administration, though this effect was lost after two weeks of injections. The administration of baclofen also rescued deficits in spatial learning and memory seen in animals chronically administered LPS. Furthermore, a significant increase in the total abundance of AB oligomers, believed to play a role in the pathology of AD, was seen in the brains of animals chronically administered LPS. Together, these data provide evidence that the modulation of GABA(B) receptor function altered the immune response evoked by activation of TLR4. These data also provide support for a potential role of GABA(B) in modulating aberrant immune activity seen in AD populations

Ketamine Induced Deficits in Working Memory with Relevance to Schizophrenia

Schizophrenia is a chronic debilitating brain disorder, which affects approximately one per­cent of the adult population worldwide. The symptoms of schizophrenia are commonly divided into three broad classes: positive symptoms, negative symptoms, and cognitive disturbances (Kay, et al., 1987). The positive symptoms of schizophrenia include hallucinations, delusions, and dis­organized thinking, while the negative symptoms include affective flattening, social withdrawal, and an inability to plan and carry out future activities. The cognitive disturbances exhibited in schizophrenia include deficits in spatial reference and working memory as well as difficulties with focus and attention (Lewis et. al., 2007). Several models have been proposed as to the etiology of schizophrenia, one of which proposes the hypofunction of a discrete class of excitatory receptors (NMDA) on primarily inhibitory circuits in the brain. This change in signaling is argued to give rise to a loss of coordinated network activity throughout the brain resulting in deficits observed in schizophrenia (Figure 1). Data for this model is based on postmortem alterations in inhibitory cir­cuits and the ability of drugs that block the function of the NMDA receptor (NMDA antagonists) to produce deficits similar to those seen in schizophrenia populations (Coyle, 2012). The ability of these NMDA antagonists to produce psychosis similar to what is observed in schizophrenia has led to their extensive use in studying the mechanisms responsible for the disorder. Previous studies in our laboratory have demonstrated the ability of ketamine, an NMDA receptor antago­nist, to produce deficits in rodent’s spatial and emotional learning and memory consistent with observations in schizophrenia populations (Bolton et al., 2012; Sabbagh et al., 2012). In these investigations, it was also shown that ketamine administration was sufficient to induce alterations in inhibitory circuits in the brain that are commonly implicated in schizophrenia (Sabbagh et al., 2013). In the present study, we examined the extent to which the same administration of ketamine produced deficits in rodent’s spatial reference and working memory performance in the radial arm maze task. As working memory deficits are a core pathological feature of schizophrenia, these in­vestigations seek to further the validity of the ketamine model as it relates to the etiological origin of schizophrenia

An Acute Inflammatory Response in a Diabetic Alzheimer’s Disease Model

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 50 to 80 percent of all dementia cases. This neurodegenerative disease leads to neuronal death and tissue loss in the brain, resulting in the slow deterioration of memory, thinking skills, and eventually even the ability perform daily tasks. While it is not a normal part of aging, AD is mostly diagnosed in people over the age of 65; thus, the main risk factor for Alzheimer’s disease is increased age, though it is most likely other additional factors also contribute (Heese & Akatsu, 2006). Neuropathological hallmarks of AD include neurofibrillary tangles (NFTs) formed by the aggregation of hyperphosphorylated tau proteins, and amyloid plaques formed by the accumulation of β-amyloid (Aβ) proteins (Cvetkovic-Dozic et al., 2001). To date, the etiology of AD remains unknown but several models investigating multiple pathways have been used to better understand the disease. In this experiment, two specific AD risk factors, Type 2 diabetes mellitus (DM) and inflammation of the brain, are of interest. Recent evidence has indicated a connection between Alzheimer’s disease and Type 2 DM. The use of the DM model to investigate AD represents a useful tool to examine AD pathologies. In Type 2 DM, cells fail to use insulin properly, resulting in insulin resistance. This resistance consequently affects the metabolism of tau and Aβ proteins, potentially leading to formation or acceleration of NFTs and amyloid plaques characteristically seen in AD (Gasparini et al., 2002). Chronic brain inflammation, commonly referred to as neuroinflammation, induces a neurotoxic effect by increasing Aβ proteins, senile plaques, and neuronal damage, leading to exacerbated symptoms and a more rapid disease progression. Alternatively, acute inflammatory responses have been suggested to serve a protective role in degenerative disorders (Frank-Cannon et al., 2009). A critical question in AD research is what aspects of chronic neuroinflammation exacerbate pathological features, as well as if an acute inflammatory response may play a neuroprotective role by reducing the aggregation of Aβ, and thus lowering the likelihood of cell loss. The purpose of this study was to investigate the role that acute brain inflammation plays in a diabetic model of AD. In order to examine this, we investigated if an acute immune response induced by lipopolysaccharide (LPS) would alter AD related behavioral or pathological features using the streptozotocin (STZ) diabetic model of AD

A Computational Perspective of Schizophrenia

The etiology of schizophrenia remains largely elusive, thus dampening the effectiveness of current treatment strategies. Abnormal neural migration and neurogenesis in the hippocampus have been suggested to be involved in schizophrenia (Jakob & Beckmann, 1994). A few approaches, including computational modeling, have investigated schizophrenia as a network disorder. Computational modeling uses mathematics to predict the behavior of biological systems based on the input of a set of parameters collected from laboratory experiments. In this study, we constructed a computational model to explore the ramifications of additional PV neurons migrating to an aberrant location in the hippocampus and interfering with a closed-loop circuit between a preexisting PV neuron and 10 pyramidal neurons. Evidence suggests that PV neurons provide GABAergic input and oscillating gamma rhythmicity (30-80 Hz) to pyramidal neurons in the CA1 region of the hippocampus (Tukker et al., 2007). We predict that asynchronous release of action potentials from a migratory PV neuron will decrease the level of excitation and reduce the gamma-band activity in our closed-loop computational circuit. If this computational model can make an accurate prediction, it may serve to be a reliable tool to probe the direction of future research in not only schizophrenia, but in a wide range of mental afflictions

Analysis of Morris Water Maze data with Bayesian statistical methods

Neuroscientists commonly use a Morris Water Maze to assess learning in rodents. In his kind of a maze, the subjects learn to swim toward a platform hidden in opaque water as they orient themselves according to the cues on the walls. This protocol presents a challenge to statistical analysis, because an artificial cut-off must be set for those experimental subjects that do not reach the platform so as they do not drown from exhaustion. This fact leads to the data being right censored. In our experimental data, which compares learning in rodents that have chemically induced symptoms of schizophrenia to a control group of rodents a cut-off of 60 seconds was used, and is the mode of the distribution. Utilizing Bayesian inferential procedures, we account for the censoring in the data and compare the results of learning between the treatment and control group

Inflammation as a Central Mechanism in Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain\u27s resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms

Diabetes Mellitus Affects Working Memory

Alzheimer’s disease (AD) degrades the brain’s ability to remember, think, and carry out tasks. The exact cause is not known, but several risk factors have been identified, including diabetes mellitus (DM). DM causes elevated blood sugar levels due to reduced insulin production in the pancreas. The linkage between elevated glucose levels and the behavioral impairments are not fully understood, which was the focus of this study. Rats were trained to alternate directions in a maze to receive a reward on consecutive trials. After training, five rats were injected with streptozotocin (STZ), which induces hyperglycemia by injuring pancreatic beta cells. Three control animals received benign vehicle injections. All eight rats then underwent implant surgery and received an implant with 128 recording probes attached to an electronic interface board. The recording electrodes targeted the hippocampus and the anterior cingulate cortex (ACC), which are both associated with learning and memory processes. We found that STZ rats had reduced accuracy after long delay periods compared to the control rats. During task performance, there was a decrease in the power of theta activity and an increase in delta activity moments before starting a new trial. This was the opposite of control animals, who before starting new trials had higher theta power and less delta power as they focused. These findings imply that the STZ rats were impaired on longer delay periods. These findings are like reports from animal models of AD and may help explain why DM is a risk factor for AD

Rasagiline Effects on Glucose Metabolism, Cognition, and Tau in Alzheimer’s Dementia

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer\u27s disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P \u3c 0.025), anterior cingulate (P \u3c 0.041), and striatal (P \u3c 0.023) regions. Clinical measures showed benefit in quality of life (P \u3c 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response

Dietary Strawberries Improve Cardiometabolic Risks in Adults With Obesity and Elevated Serum Ldl Cholesterol in a Randomized Controlled Crossover Trial

Background and aims: Dietary berries, such as strawberries, are rich in bioactive compounds and have been shown to lower cardiometabolic risk. We examined the effects of two dietary achievable doses of strawberries on glycemic control and lipid profiles in obese adults with elevated serum LDL cholesterol (LDL-C). Methods: In this 14-week randomized controlled crossover study, participants were assigned to one of the three arms for four weeks separated by a one-week washout period: control powder, one serving (low dose: 13 g strawberry powder/day), or two-and-a-half servings (high dose: 32 g strawberry powder/day). Participants were instructed to follow their usual diet and lifestyle while refraining from consuming other berries and related products throughout the study interval. Blood samples, anthropometric measures, blood pressure, and dietary and physical activity data were collected at baseline and at the end of each four-week phase of intervention. Results: In total, 33 participants completed all three phases of the trial [(mean ± SD): Age: 53 ± 13 y; BMI: 33 ± 3.0 kg/m ). Findings revealed significant reductions in fasting insulin (p = 0.0002) and homeostatic model of assessment of insulin resistance (p = 0.0003) following the high dose strawberry phase when compared to the low dose strawberry and control phases. Glucose and conventional lipid profiles did not differ among the phases. Nuclear magnetic resonance-determined particle concentrations of total VLDL and chylomicrons, small VLDL, and total and small LDL were significantly decreased after the high dose strawberry phase, compared to control and low dose phases (all p \u3c 0.0001). Among the biomarkers of inflammation and adipokines measured, only serum PAI-1 showed a decrease after the high dose strawberry phase (p = 0.002). Conclusions: These data suggest that consuming strawberries at two-and-a-half servings for four weeks significantly improves insulin resistance, lipid particle profiles, and serum PAI-1 in obese adults with elevated serum LDL-C.

Altered Theta Rhythm and Hippocampal-Cortical Interactions Underlie Working Memory Deficits in a Hyperglycemia Risk Factor Model of Alzheimer’s Disease

Diabetes mellitus is a metabolic disease associated with dysregulated glucose and insulin levels and an increased risk of developing Alzheimer’s disease (AD) later in life. It is thought that chronic hyperglycemia leads to neuroinflammation and tau hyperphosphorylation in the hippocampus leading to cognitive decline, but effects on hippocampal network activity are unknown. A sustained hyperglycemic state was induced in otherwise healthy animals and subjects were then tested on a spatial delayed alternation task while recording from the hippocampus and anterior cingulate cortex (ACC). Hyperglycemic animals performed worse on long delay trials and had multiple electrophysiological differences throughout the task. We found increased delta power and decreased theta power in the hippocampus, which led to altered theta/delta ratios at the end of the delay period. Cross frequency coupling was significantly higher in multiple bands and delay period hippocampus-ACC theta coherence was elevated, revealing hypersynchrony. The highest coherence values appeared long delays on error trials for STZ animals, the opposite of what was observed in controls, where lower delay period coherence was associated with errors. Consistent with previous investigations, we found increases in phosphorylated tau in STZ animals’ hippocampus and cortex, which might account for the observed oscillatory and cognitive changes. To investigate the effects of chronic hyperglycemia on hippocampal network activity Wirt et al induced sustained hyperglycemia in rats and tested them in a spatial delayed alternation task while recording from the hippocampus and anterior cingulate cortex. They demonstrated that hyperglycemia impaired task performance and altered theta rhythm as well as increasing tau phosphorylation, which suggest there is potentially a direct link between chronic hyperglycemia and Alzheimer’s disease