A hippocampal circuit mechanism to balance memory reactivation during sleep.

Memory consolidation involves the synchronous reactivation of hippocampal cells active during recent experience in sleep sharp-wave ripples (SWRs). How this increase in firing rates and synchrony after learning is counterbalanced to preserve network stability is not understood. We discovered a network event generated by an intrahippocampal circuit formed by a subset of CA2 pyramidal cells to cholecystokinin-expressing (CCK+) basket cells, which fire a barrage of action potentials ("BARR") during non-rapid eye movement sleep. CA1 neurons and assemblies that increased their activity during learning were reactivated during SWRs but inhibited during BARRs. The initial increase in reactivation during SWRs returned to baseline through sleep. This trend was abolished by silencing CCK+ basket cells during BARRs, resulting in higher synchrony of CA1 assemblies and impaired memory consolidation.

Interictal epileptiform discharges affect memory in an Alzheimer's disease mouse model.

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multilayer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in the mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples, altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implies that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.

Hippocampo-cortical circuits for selective memory encoding, routing, and replay.

Traditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates to the different hippocampal network computations that support memory-guided behavior is not yet known. We show that the anatomical identity of pyramidal cells is a major organizing principle of CA1 assembly dynamics, the emergence of memory replay, and cortical projection patterns in rats. Segregated pyramidal cell subpopulations encoded trajectory and choice-specific information or tracked changes in reward configuration respectively, and their activity was selectively read out by different cortical targets. Furthermore, distinct hippocampo-cortical assemblies coordinated the reactivation of complementary memory representations. These findings reveal the existence of specialized hippocampo-cortical subcircuits and provide a cellular mechanism that supports the computational flexibility and memory capacities of these structures.

Interictal epileptiform discharges affect memory in an Alzheimer's Disease mouse model.

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological disease, such as Alzheimer's Disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multi-layer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples (SPW-Rs), altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implicates that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory. Significant Statement: Prevalence of neurodegenerative diseases and the number of people with dementia is increasing steadily. Therefore, novel treatment strategies for learning and memory disorders are urgently necessary. IEDs, apart from being a surrogate for epileptic brain regions, have also been linked to cognitive decline. Here we report that IEDs in human epilepsy patients and AD mouse models have similar local field potential characteristics and associated firing patterns of pyramidal cells and interneurons. Mice with more IEDs displayed fewer hippocampal SPW-Rs, poorer replay of spatial trajectories, and decreased memory performance. IED suppression is an unexplored target to treat cognitive dysfunction in neurodegenerative diseases.

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure.

Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus called place cells discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. Therefore, we tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing in vivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed, which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE.

The effects of developmental alcohol exposure on the neurobiology of spatial processing.

The consumption of alcohol during gestation is detrimental to the developing central nervous system. One functional outcome of this exposure is impaired spatial processing, defined as sensing and integrating information pertaining to spatial navigation and spatial memory. The hippocampus, entorhinal cortex, and anterior thalamus are brain regions implicated in spatial processing and are highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on spatial processing may be attributed to changes at the synaptic to circuit level. In this review, we first describe the impact of developmental alcohol exposure on spatial behavior followed by a summary of the development of brain areas involved in spatial processing. We then provide an examination of the consequences of prenatal and early postnatal alcohol exposure in rodents on hippocampal, anterior thalamus, and entorhinal cortex-dependent spatial processing from the cellular to behavioral level. We conclude by highlighting several unanswered questions which may provide a framework for future investigation.

A Comparison of Neural Decoding Methods and Population Coding Across Thalamo-Cortical Head Direction Cells.

Head direction (HD) cells, which fire action potentials whenever an animal points its head in a particular direction, are thought to subserve the animal's sense of spatial orientation. HD cells are found prominently in several thalamo-cortical regions including anterior thalamic nuclei, postsubiculum, medial entorhinal cortex, parasubiculum, and the parietal cortex. While a number of methods in neural decoding have been developed to assess the dynamics of spatial signals within thalamo-cortical regions, studies conducting a quantitative comparison of machine learning and statistical model-based decoding methods on HD cell activity are currently lacking. Here, we compare statistical model-based and machine learning approaches by assessing decoding accuracy and evaluate variables that contribute to population coding across thalamo-cortical HD cells.

Progressive impairment of directional and spatially precise trajectories by TgF344-Alzheimer's disease rats in the Morris Water Task.

Spatial navigation is impaired in early stages of Alzheimer's disease, and may be a defining behavioral marker of preclinical AD. A new rat model (TgF344-AD) of AD overcomes many limitations of other rodent models, though spatial navigation has not been comprehensively assessed. Using the hidden and cued platform variants of the Morris water task, a longitudinal assessment of spatial navigation was conducted on TgF344-AD (n = 16) and Fischer 344 (n = 12) male and female rats at three age ranges: 4 to 5 months, 7 to 8, and 10 to 11 months of age. TgF344-AD rats exhibited largely intact navigation at 4-5 months, with deficits in the hidden platform task emerging at 7-8 months and becoming significantly pronounced at 10-11 months of age. In general, TgF344-AD rats displayed less accurate swim trajectories to the platform and searched a wider area around the platform region compared to wildtype rats. Impaired navigation occurred in the absence of deficits in acquiring the procedural task demands or navigation to the cued platform location. Together, the results indicate that TgF344-AD rats exhibit comparable navigational deficits to those found in individuals with preclinical-AD.

Linear Self-Motion Cues Support the Spatial Distribution and Stability of Hippocampal Place Cells.

The vestibular system provides a crucial component of place-cell and head-direction cell activity [1-7]. Otolith signals are necessary for head-direction signal stability and associated behavior [8, 9], and the head-direction signal's contribution to parahippocampal spatial representations [10-14] suggests that place cells may also require otolithic information. Here, we demonstrate that self-movement information from the otolith organs is necessary for the development of stable place fields within and across sessions. Place cells in otoconia-deficient tilted mice showed reduced spatial coherence and formed place fields that were located closer to environmental boundaries, relative to those of control mice. These differences reveal an important otolithic contribution to place-cell functioning and provide insight into the cognitive deficits associated with otolith dysfunction.

Post-training Inactivation of the Anterior Thalamic Nuclei Impairs Spatial Performance on the Radial Arm Maze.

The limbic thalamus, specifically the anterior thalamic nuclei (ATN), contains brain signals including that of head direction cells, which fire as a function of an animal's directional orientation in an environment. Recent work has suggested that this directional orientation information stemming from the ATN contributes to the generation of hippocampal and parahippocampal spatial representations, and may contribute to the establishment of unique spatial representations in radially oriented tasks such as the radial arm maze. While previous studies have shown that ATN lesions can impair spatial working memory performance in the radial maze, little work has been done to investigate spatial reference memory in a discrimination task variant. Further, while previous studies have shown that ATN lesions can impair performance in the radial maze, these studies produced the ATN lesions prior to training. It is therefore unclear whether the ATN lesions disrupted acquisition or retention of radial maze performance. Here, we tested the role of ATN signaling in a previously learned spatial discrimination task on a radial arm maze. Rats were first trained to asymptotic levels in a task in which two maze arms were consistently baited across training. After 24 h, animals received muscimol inactivation of the ATN before a 4 trial probe test. We report impairments in post-inactivation trials, suggesting that signals from the ATN modulate the use of a previously acquired spatial discrimination in the radial-arm maze. The results are discussed in relation to the thalamo-cortical limbic circuits involved in spatial information processing, with an emphasis on the head direction signal.

Do the anterior and lateral thalamic nuclei make distinct contributions to spatial representation and memory?

The anterior and lateral thalamus has long been considered to play an important role in spatial and mnemonic cognitive functions; however, it remains unclear whether each region makes a unique contribution to spatial information processing. We begin by reviewing evidence from anatomical studies and electrophysiological recordings which suggest that at least one of the functions of the anterior thalamus is to guide spatial orientation in relation to a global or distal spatial framework, while the lateral thalamus serves to guide behavior in relation to a local or proximal framework. We conclude by reviewing experimental work using targeted manipulations (lesion or neuronal silencing) of thalamic nuclei during spatial behavior and single-unit recordings from neuronal representations of space. Our summary of this literature suggests that although the evidence strongly supports a working model of spatial information processing involving the anterior thalamus, research regarding the role of the lateral thalamus is limited and requires further attention. We therefore identify a number of major gaps in this research and suggest avenues of future study that could potentially solidify our understanding of the relative roles of anterior and lateral thalamic regions in spatial representation and memory.

Orf virus inhibits interferon stimulated gene expression and modulates the JAK/STAT signalling pathway.

Interferons (IFNs) play a critical role as a first line of defence against viral infection. Activation of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway by IFNs leads to the production of IFN stimulated genes (ISGs) that block viral replication. The Parapoxvirus, Orf virus (ORFV) induces acute pustular skin lesions of sheep and goats and is transmissible to man. The virus replicates in keratinocytes that are the immune sentinels of skin. We investigated whether or not ORFV could block the expression of ISGs. The human gene GBP1 is stimulated exclusively by type II IFN while MxA is stimulated exclusively in response to type I IFNs. We found that GBP1 and MxA were strongly inhibited in ORFV infected HeLa cells stimulated with IFN-γ or IFN-α respectively. Furthermore we showed that ORFV inhibition of ISG expression was not affected by cells pretreated with adenosine N1-oxide (ANO), a molecule that inhibits poxvirus mRNA translation. This suggested that new viral gene synthesis was not required and that a virion structural protein was involved. We next investigated whether ORFV infection affected STAT1 phosphorylation in IFN-γ or IFN-α treated HeLa cells. We found that ORFV reduced the levels of phosphorylated STAT1 in a dose-dependent manner and was specific for Tyr701 but not Ser727. Treatment of cells with sodium vanadate suggested that a tyrosine phosphatase was responsible for dephosphorylating STAT1-p. ORFV encodes a factor, ORFV057, with homology to the vaccinia virus structural protein VH1 that impairs the JAK/STAT pathway by dephosphorylating STAT1. Our findings show that ORFV has the capability to block ISG expression and modulate the JAK/STAT signalling pathway.

An unusual cause of pulmonary edema.

Primary cardiac tumors are rare malignancies. Patients may present with congestive cardiac failure due to intracavitary obstruction to blood flow, valvular dysfunction, embolic phenomena, local invasion resulting in arrhythmias, pericardial involvement, constitutional symptoms, or paraneoplastic syndromes. We describe the case of a previously fit 79-year-old woman who presented with acute pulmonary edema due to a large left atrial pleomorphic sarcoma causing severe functional mitral stenosis. She underwent palliative debulking surgery with good symptomatic relief.

Diabetic control and coronary artery bypass: effect on short-term outcomes.

AIM: To evaluate the effect of preoperative glycemic control on hospital morbidity and mortality in diabetic patients undergoing primary coronary artery bypass grafting. METHODS: Data of 3857 patients undergoing primary coronary artery bypass grafting was prospectively collected and retrospectively analyzed. There were 1109 (29%) diabetic patients, of whom 712 (64%) had hemoglobin A1c levels recorded. They were categorized by diabetic treatment: diet (179), oral hypoglycemic agent, (718) or insulin (212); and by diabetic control: hemoglobin A1c < 7 (265) or ≥7 (447). Nondiabetic patients (2,748) were used as controls. RESULTS: The preoperative risk factors of hypertension (p < 0.001), hyperlipidemia (p < 0.001), renal failure (p < 0.04), peripheral vascular disease (p < 0.001), and chronic obstructive pulmonary disease (p < 0.04) were significantly more prevalent in diabetic patients. Major complications were not significantly different between the diabetic and control groups (p = 0.33), but minor complications were less frequent in diabetic patients (p = 0.03). Major and minor complications were not significantly different among the treatment subgroups of diabetic patients (p = 0.74 and p = 0.48) or in those with hemoglobin A1c < 7 and ≥7 (p = 0.23, p = 0.41). CONCLUSIONS: Short-term outcomes were not affected by the degree of preoperative glycemic control or type of treatment used in diabetic patients undergoing primary coronary artery bypass grafting. A plausible explanation is strict protocol-driven glycemic control in the perioperative period.

Primary coronary artery bypass surgery in the presence of decreasing preoperative renal function: effect on short-term outcomes.

BACKGROUND: This study evaluated the impact of decreasing renal function on short-term outcomes in patients undergoing primary coronary artery bypass grafting (CABG). METHODS: The study period was from February 1999 to February 2009. Data on 4050 patients undergoing primary CABG were prospectively collected and analyzed retrospectively. The study population was divided into 3 groups: the CABG:N group, patients with preoperative serum creatinine levels <2 mg/dL (n = 3947); the CABG:RF group, patients with preoperative creatinine levels >2 mg/dL (n = 87); and the CABG:D group, patients on dialysis (n = 16). RESULTS: The significant differences between the groups (CABG:D > CABG:RF > CABG:N) in short-term outcomes were with respect to blood product use (P < .001), postoperative acute myocardial infarction (P < .001), pulmonary complications (P .001), infection (P < .001), and death (P < .001). The risk of short-term death (30 days) in the CABG:D group (4/16, 25%) was 25 times greater than that in the CABG:N group (38/3947, 0.96%). CONCLUSION: CABG in the presence of renal failure is associated with significant morbidity and mortality.

Management and midterm outcomes of post-infarction ventricular septal defect.

We assessed midterm outcomes, predictors of mortality, and residual defects after repair of post-infarction ventricular septal defect in 10 patients (mean age, 65.3 years; range, 50-78 years) who were operated on between 2000 and 2008. Mean time from onset of symptoms of myocardial infarction to diagnosis of ventricular septal defect was 3.5 days. Time from diagnosis to surgery ranged from 6 h to 84 days. The defects were located anteriorly in 4 patients and posteriorly in 6. Patch reconstruction of the septum was used in 6 patients and the infarct exclusion technique in 4. Hospital mortality was 60%. The only predictor of mortality was tricuspid valve competence (p = 0.048). There was no correlation between location of the defect or type of repair and operative mortality. Residual or recurrent ventricular septal defect was noted in 6 patients. Location of the defect and type of repair were not predictors of residual or recurrent defects. Residual ventricular septal defect was not associated with increased short-term mortality or reduction of functional status. Early mortality associated with post-infarction ventricular septal defect repair is significant. Discharged patients continue to have good functional capacity and quality of life, as well as favorable midterm survival.

Association between body mass index and outcome of coronary artery bypass.

Studies have shown disparate findings regarding body mass index and outcomes after coronary artery bypass. We analyzed body mass index and other clinical variables that might predict morbidity and mortality after primary isolated coronary artery bypass. Data on 4,425 patients (79% men) were reviewed retrospectively. They were classified as underweight (1.6%), normal weight (65%), obese (32%), and morbidly obese (1.4%) according to body mass index <20, 20-29, 30-39, and >40 kg·m(-2), respectively. Multiple logistic regression was used for correlates of 30-day outcome. Cox regression was used for predictors of late outcome in underweight and morbidly obese patients. There were 45 (1%) deaths and 234 (5%) cases of morbidity within 30 days. Independent correlates of 30-day morbidity were smoking, logistic EuroSCORE, blood and blood product transfusions. Correlates of 30-day mortality were logistic EuroSCORE and blood transfusion. The only independent predictor of late death in underweight and morbidly obese patients was preoperative arrhythmia. Body mass index was not a predictor of 30-day morbidity or mortality. The 1-, 3-, and 7-year survival rates were not significantly different between underweight and morbidly obese patients. Body mass index did not affect short-term outcomes after primary coronary artery bypass grafting.

Verbal autopsy: an analysis of the common causes of childhood death in the Barekese sub-district of Ghana.

The availability of mortality data for any society plays an essential role in health monitoring and evaluation, as well as in the design of health interventions. However, most resource-poor countries such as Ghana have no reliable vital registration system. In these instances, verbal autopsy (VA) may be used as an alternative method to gather mortality data. In rural Ghana, the research team utilized a VA questionnaire to interview caretakers who were present with a child under the age of five prior to death. The data was given to two physicians who independently assigned the most probable cause of death for the child. A third, blinded physician analyzed the data in the cases where the first two physicians disagreed. When there was agreement between physicians, this was assigned as the cause of death for the individual child. During the study period, we recorded 118 deaths from 92 households. Twenty-nine (24.6%) were neonatal deaths with the leading causes of death being neonatal sepsis, birth asphyxia and pneumonia. The remaining 89 (75.4%) were post-neonatal deaths with the most common causes of death being pneumonia, malaria and malnutrition. While 63/118 (53.4%) deaths occurred in the home, there is no statistically significant relationship between the location of the home and the time of travel to the nearest health facility (P=0.132). VA is an important epidemiological tool for obtaining mortality data in communities that lack reliable vital registration systems. Improvement in health care is necessary to address the large number of deaths occurring in the home.

Verbal Autopsy: an Analysis of the Common Causes of Childhood Death in the Barekese Sub-District of Ghana

The availability of mortality data for any society plays an essential role in health monitoring and evaluation; as well as in the design of health interventions. However; most resource-poor countries such as Ghana have no reliable vital registration system. In these instances; verbal autopsy (VA) may be used as an alternative method to gather mortality data. In rural Ghana; the research team utilized a VA questionnaire to interview caretakers who were present with a child under the age of five prior to death. The data was given to two physicians who independently assigned the most probable cause of death for the child. A third; blinded physician analyzed the data in the cases where the first two physicians disagreed. When there was agreement between physicians; this was assigned as the cause of death for the individual child. During the study period; we recorded 118 deaths from 92 households. Twenty-nine (24.6) were neonatal deaths with the leading causes of death being neonatal sepsis; birth asphyxia and pneumonia. The remaining 89 (75.4) were post-neonatal deaths with the most common causes of death being pneumonia; malaria and malnutrition. While 63/118 (53.4) deaths occurred in the home; there is no statistically significant relationship between the location of the home and the time of travel to the nearest health facility (P=0.132). VA is an important epidemiological tool for obtaining mortality data in communities that lack reliable vital registration systems. Improvement in health care is necessary to address the large number of deaths occurring in the home