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Introduction In typically developing youth, increases in body mass index (BMI) and rates of obesity accompany treatment of obstructive sleep apnea syndrome (OSAS) with adenotonsillectomy regardless of baseline BMI and OSAS severity. Residual OSAS following adenotonsillectomy and overweight/obesity are common in Down syndrome (DS). We sought to examine the impact of positive airway pressure (PAP) on BMIZ in youth with DS and OSAS. Methods Baseline, 6, and 12 month height/length and weight as well as pre-PAP PSG data were abstracted from the Children’s Hospital of Philadelphia Sleep Center for patients with DS and OSAS initiated on PAP between 01/01/2014-07/11/01/2017 (N=73; Median age=6.6y IQR: 3.6-12.1; 52% White, 29% Black; 42% Male). BMIZ was calculated. Longitudinal mixed effects models adjusted for adherence from 0-6 months, baseline BMIZ, and baseline SpO2 nadir were used to evaluate change in BMIZ at months 6 and 12 and the impact of baseline BMIZ on trajectories. Results OAHI (median; IQR) at initiation was 15.9 (8.1-28.9) events/hour, SpO2 nadir was 83% (77-88), and BMIZ was 1.50 (0.94-2.34). No differences in BMIZ at 6 and 12 months compared to baseline BMIZ were found (p>0.2 for both). Baseline BMIZ was associated with BMIZ at 6- and 12 months (β-coefficient=0.99; p Conclusion Initiation of PAP has a beneficial impact on nutritional status in youth with DS and OSAS. In youth who are at the lower end of BMIZ, BMIZ increases to a healthier status following the initiation of PAP, and in youth who are at the higher side of BMIZ, BMIZ decreases to a healthier status. Prospective studies are needed to elaborate on these associations. Support None

Dopamine and glutamate serve crucial functions in neural plasticity, learning and memory, and addiction. Contemporary theories contend that these two, widely-distributed neurotransmitter systems play an integrative role in motivational and associative information processing. Combined signaling of these systems, particularly through the dopamine (DA) D1 and glutamate (Glu) N-methyl-d-aspartate receptors (NMDAR), triggers critical intracellular signaling cascades that lead to changes in chromatin structure, gene expression, synaptic plasticity, and ultimately behavior. Addictive drugs also induce long-term neuroadaptations at the molecular and genomic levels causing structural changes that alter basic connectivity. Indeed, evidence that drugs of abuse engage D1- and NMDA-mediated neuronal cascades shared with normal reward learning provides one of the most important insights from contemporary studies on the neurobiology of addiction. Such drug-induced neuroadaptations likely contribute to abnormal information processing and behavior, resulting in the poor decision-making, loss of control, and compulsivity that characterize addiction. Such features are also common to many other neuropsychiatric disorders. Behavior problems, construed as difficulties associated with operant learning and behavior, present compelling challenges and unique opportunities for their treatment that require further study. The present review highlights the integrative work of Ann E. Kelley and colleagues, demonstrating a critical role not only for NMDAR, D1 receptors (D1R), and their associated signaling cascades, but also for other Glu receptors and protein synthesis in operant learning throughout a cortico-striatal-limbic network. Recent work has extended the impact of appetitive learning to epigenetic processes. A better understanding of these processes will likely assist in discovering therapeutics to engage neural plasticity-related processes and promote functional behavioral adaptations.

Background Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of the maternal copy of UBE3A gene, which encodes the enzyme ubiquitin ligase E3A, also termed E6-AP. A mouse model of AS has been generated and these mice exhibit many of the observed neurological alterations in humans. Because of clinical and neuroanatomical similarities between AS and schizophrenia, we examined AS model mice for alterations in the neuregulin-ErbB4 pathway, which has been implicated in the pathophysiology of schizophrenia. We focused our studies on the hippocampus, one of the major brain loci impaired in AS mice. Methods We determined the expression of neuregulin 1 and ErbB4 receptors in AS mice and wild-type littermates (ages 10–16 weeks) and studied the effects of ErbB inhibition on long-term potentiation in hippocampal area cornu ammonis 1 and on hippocampus-dependent contextual fear memory. Results We observed enhanced neuregulin-ErbB4 signaling in the hippocampus of AS model mice and found that ErbB inhibitors could reverse deficits in long-term potentiation, a cellular substrate for learning and memory. In addition, we found that an ErbB inhibitor enhanced long-term contextual fear memory in AS model mice. Conclusions Our findings suggest that neuregulin-ErbB4 signaling is involved in synaptic plasticity and memory impairments in AS model mice, suggesting that ErbB inhibitors have therapeutic potential for the treatment of AS.

The “sleep-for-memory” hypothesis has gained considerable momentum in response to a growing body of literature detailing the beneficial effects of sleep on memory function. Indeed, memory function from humans to flies appears to benefit from, if not depend on, some core property of sleep. Over time, sleep has been proposed to serve a variety of functions 120. However, it has been argued that the core function of sleep is likely cellular since the function of proteins from membrane receptors to transcription factors are remarkably consistent across phylogenetic lines, as is the need for sleep, regardless of differences in sleep architecture and brain complexity 21. The sleep-for-memory hypothesis posits that a primary cellular function of sleep is memory consolidation, the process by which newly acquired information is stabilized and stored. Like the need for sleep, the molecular mechanisms that mediate memory consolidation are also conserved across species. Although little is known about the molecular mechanisms mediating sleep-dependent memory processing, there is evidence to suggest that wakeful experience is recapitulated during sleep, suggesting, by extension, that the same molecular processes that promote memory consolidation might be re-engaged during sleep to further stabilize and improve memory. Here we present several key concepts and molecular processes that are known to underlie learning and memory consolidation. We then give an overview of some the electrophysiological events specific to various sleep states that might serve to modulate activity within these signaling pathways. We address recent progress, questions still unanswered, and the challenges and limitations associated with the methodologies used to study sleep-memory interactions on a molecular level.

Genetic manipulation of cAMP-dependent protein kinase A (PKA) in Drosophila has implicated an important role for PKA in sleeplwake state regulation. Here, we characterize the role of this signaling pathway in the regulation of sleep using electroencephalographic (EEG) and electromyographic (EMG) recordings in R(AB) transgenic mice that express a dominant negative form of the regulatory subunit of PKA in neurons within cortex and hippocampus. Previous studies have revealed that these mutant mice have reduced PKA activity that results in the impairment of hippocampus-dependent long-term memory and long-lasting forms of hippocampal synaptic plasticity.PKA assays, in situ hybridization, immunoblots, and sleep studies were performed in R(AB) transgenic mice and wild-type control mice.We have found that R(AB) transgenic mice have reduced PKA activity within cortex and reduced Ser845 phosphorylation of the glutamate receptor subunit GluR1. R(AB) transgenic mice exhibit non-rapid eye movement (NREM) sleep fragmentation and increased amounts of rapid eye movement (REM) sleep relative to wild-type mice. Further, R(AB) transgenic mice have more delta power but less sigma power during NREM sleep relative to wild-type mice. After sleep deprivation, the amounts of NREM and REM sleep were comparable between wild-type and R(AB) transgenic mice. However, the homeostatic rebound of sigma power in R(AB) transgenic mice was reduced.Alterations in cortical synaptic receptors, impairments in sleep continuity, and alterations in sleep oscillations in R(AB) mice imply that PKA is involved not only in synaptic plasticity and memory storage but also in the regulation of sleep/wake states.

One of the greatest challenges in the understanding and treatment of addiction is cue-elicited relapse to drug use. The present findings of Miller and Marshall and Lee et al. reported in this issue of Neuron demonstrate that retrieved drug-related memories undergo reconsolidation and thus suggest that these maladaptive associations may be more labile than previously thought.

Little is known about how memories of new voluntary motor actions, also known as procedural memory, are formed at the molecular level. Our work examining acquisition of lever-pressing for food in rats has shown that activation of glutamate NMDA receptors, within broadly distributed but interconnected regions (e.g., nucleus accumbens core, prefrontal cortex, basolateral amygdala), is critical for such learning to occur. This receptor stimulation triggers intracellular cascades that involve protein phosphorylation and new protein synthesis. In support of this idea, we have found that posttrial inhibition of protein synthesis in the ventral striatum impairs learning, whereas posttrial NMDA receptor blockade does not. More recent data show extension of this network to the central amygdala, where infusions of NMDA antagonists also impair learning. We hypothesize that activity in this distributed network (including dopaminergic activity and perhaps muscarinic cholinergic activity) computes coincident events and thus enhances the probability that temporally related actions and events (e.g., lever pressing and delivery of reward) become associated. Such basic mechanisms of plasticity within this reinforcement learning network also appear to be profoundly affected in addiction.

It is widely held that long-term memories are established by consolidation of newly acquired information into stable neural representations, a process that requires protein synthesis and synaptic plasticity. Plasticity within the nucleus accumbens (NAc), a major component of the ventral striatum, is thought to mediate instrumental learning processes and many aspects of drug addiction. Here we show that the inhibition of protein synthesis within the NAc disrupts consolidation of an appetitive instrumental learning task (lever-pressing for food) in rats. Post-trial infusions of anisomycin immediately after the first several training sessions prevented consolidation, whereas infusions delayed by 2 or 4 hours had no effect. However, if the rats were allowed to learn the task, the behavior was not sensitive to disruption by intra-accumbens anisomycin. Control infusions into the medial NAc shell or the dorsolateral striatum did not impair learning; in fact, an enhancement was observed in the latter case. These results show that de novo protein synthesis within the NAc is necessary for the consolidation, but not reconsolidation, of appetitive instrumental memories.

Sleep deprivation is a common problem of considerable health and economic impact in today's society. Sleep loss is associated with deleterious effects on cognitive functions such as memory and has a high comorbidity with many neurodegenerative and neuropsychiatric disorders. Therefore, it is crucial to understand the molecular basis of the effect of sleep deprivation in the brain. In this study, we combined genome-wide and traditional molecular biological approaches to determine the cellular and molecular impacts of sleep deprivation in the mouse hippocampus, a brain area crucial for many forms of memory. Microarray analysis examining the effects of 5 h of sleep deprivation on gene expression in the mouse hippocampus found 533 genes with altered expression. Bioinformatic analysis revealed that a prominent effect of sleep deprivation was to downregulate translation, potentially mediated through components of the insulin signaling pathway such as the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. Consistent with this analysis, sleep deprivation reduced levels of total and phosphorylated mTOR, and levels returned to baseline after 2.5 h of recovery sleep. Our findings represent the first genome-wide analysis of the effects of sleep deprivation on the mouse hippocampus, and they suggest that the detrimental effects of sleep deprivation may be mediated by reductions in protein synthesis via downregulation of mTOR. Because protein synthesis and mTOR activation are required for long-term memory formation, our study improves our understanding of the molecular mechanisms underlying the memory impairments induced by sleep deprivation.

It is well established that cAMP signaling within neurons plays a major role in the formation of long-term memories—signaling thought to proceed through protein kinase A (PKA). However, here we show that exchange protein activated by cAMP (Epac) is able to enhance the formation of long-term memory in the hippocampus and appears to do so independent of PKA, thus demonstrating the importance of Epac-mediated signaling in memory consolidation.

In order to survive in changing environments, animals must be able to acquire, consolidate, and retrieve pertinent information regarding a given stimulus situation. The ability to learn associations between various stimuli and events, including motor actions, is the basis of instrumental learning (Rescorla 1991; Dickinson and Balleine 1994). Appetitive instrumental learning occurs when an animal associates its behavior with a favorable outcome such as food, sex, or the avoidance of pain. For instance, in a common experimental model of instrumental learning, a hungry rat learns to press a lever to obtain a food reward. The nucleus accumbens (NAc) and its associated circuitry have been linked to the acquisition of adaptive motor responses and the control of behaviors related to natural reinforcers (Setlow 1997; Parkinson et al. 2000; Corbit et al. 2001). Because of the rich glutamatergic and dopaminergic innervation of the NAc from regions associated with motivational, cognitive, and sensory processes, many studies have focused on the role of these neurotransmitter systems with respect to instrumental and incentive learning (Berridge and Robinson 1998; Cardinal et al. 2002; Beninger and Gerdjikov 2004; Kelley 2004). For example, blockade of glutamate (N-methyl-d-aspartate, NMDA) or dopamine D1 receptors within the NAc core potently impairs instrumental learning, and coinfusion of low, individually ineffective doses of AP-5 and SCH23390 also prevents learning, suggesting that convergence of both systems on post-synaptic neurons is required (Smith-Roe and Kelley 2000). The coincident detection of glutamate and dopamine signals has been shown to be required for long-term potentiation (Wickens et al. 1996; Arbuthnott et al. 2000; Floresco et al. 2001; Kerr and Wickens 2001) by regulating the transcription and translation of plasticity-related immediate-early genes through various second messenger systems (Sharp et al. 1995; Sutton and Beninger 1999; Berke and Hyman 2000; Horvitz 2002; Reynolds and Wickens 2002; Steward and Worley 2002; Kelley 2004). Indeed, post-training inhibition of cAMP-dependent protein kinase (PKA) (Baldwin et al. 2002a) or inhibition of de novo protein synthesis within the NAc core (Hernandez et al. 2002) prevents the consolidation, or long-term stabilization, of memory for response-outcome contingencies. In the aforementioned studies, pre-trial blockade of NMDA and D1 receptors appeared to prevent the encoding (or acquisition) of information; however, it is possible that disruption of the consolidation phase of learning or retrieval could have contributed to the observed impairments. Thus, it remains unclear as to whether glutamate and dopamine are required only to initiate plasticity or whether these neurotransmitters also modulate consolidation. As such, post-trial infusions are often used to temporally dissociate encoding from consolidation (Breen and McGaugh 1961). Therefore, the present study compared the effects of pre- and post-trial infusions of antagonists specific for NMDA or D1 receptors in the NAc core of male Sprague-Dawley rats in the same task. In addition, we investigated the effects of an antagonist specific for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) receptors, since their role in instrumental learning has not yet been described. Lastly, we used a time-stamp behavioral analysis program that records the temporal relationship of task-related events and behaviors during training in order to gain insight into which behaviors are critical for instrumental learning.

Little is known about how memories of new voluntary motor actions, also known as procedural memory, are formed at the molecular level. Our work examining acquisition of lever-pressing for food in rats has shown that activation of glutamate NMDA receptors, within broadly distributed but interconnected regions (e.g., nucleus accumbens core, prefrontal cortex, basolateral amygdala), is critical for such learning to occur. This receptor stimulation triggers intracellular cascades that involve protein phosphorylation and new protein synthesis. In support of this idea, we have found that posttrial inhibition of protein synthesis in the ventral striatum impairs learning, whereas posttrial NMDA receptor blockade does not. More recent data show extension of this network to the central amygdala, where infusions of NMDA antagonists also impair learning. We hypothesize that activity in this distributed network (including dopaminergic activity and perhaps muscarinic cholinergic activity) computes coincident events and thus enhances the probability that temporally related actions and events (e.g., lever pressing and delivery of reward) become associated. Such basic mechanisms of plasticity within this reinforcement learning network also appear to be profoundly affected in addiction.

MuStDO 5 is a multivalent plasmid DNA vaccine for malaria comprised of five plasmid DNAs encoding five proteins from Plasmodium falciparum and one plasmid DNA encoding human GM-CSF. To evaluate the safety of MuStDO 5, a series of pre-clinical studies were conducted in mice and rabbits. In pharmacology studies in mice, GM-CSF could not be detected in the serum following either intramuscular or a combined intramuscular/intradermal administration of the vaccine, but was readily detected in the muscle following intramuscular administration. In a tissue distribution study in mice, MuStDO 5 plasmid DNA was detected by PCR initially in highly vascularized tissues, while at later time-points the plasmid DNA was detected primarily at the site(s) of injection. In GLP safety studies in mice and rabbits, repeated intramuscular/intradermal administration of the MuStDO 5 vaccine was found to be safe and well tolerated without any evidence of autoimmune pathology.

Several findings indicate that adipose tissue and bone have a complex reciprocal relationship. The two cells lineages share a common progenitor, and adipocyte endocrine activity may influence bone metabolism. Recent evidence from animal models suggests that bone cells may contribute regulating energy metabolism.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, particularly frequent in post-menopausal women. It is characterized by hypercalcemia with inappropriately high spontaneous plasma PTH. Singlegland adenoma is the most common cause (75- 85%). PHPT is usually a sporadic disease but in approximately5% of cases, a familial hyperparathyroid syndrome is diagnosed. Familial hyperparathyroidism is a clinically and genetically heterogeneous group of disorders including: multiple endocrine neoplasia (MEN) type 1, MEN type 2A, MEN4, benign familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism. These syndromes show mendelian inheritance patterns and the main genes for most of them have been defined. The classic form of PHPT, which presents with hypercalcemia, kidney stones, and bone disease, is no longer common. Currently, there is an increasing interest in the subtle manifestations of PHPT, particularly the cardiovascular and neuropsychiatric manifestations. Parathyroidectomy is the definitive cure for PHPT even though patients with the asymptomatic form of the disease can be followed conservatively.

Purpose To investigate the effect of 18 months' parathyroid hormone 1-84 (PTH 1-84) treatment on serum levels of bone morphogenetic protein 4 (BMP4) and vascular endothelial growth factor (VEGF), in postmenopausal women with established osteoporosis.Methods Thirty-seven postmenopausal women with osteoporosis (mean age 72.9 +/- 8.1 years old) and 23 healthy controls (mean age 68.9 +/- 9.9 years old) were enrolled. Patients were treated with daily subcutaneous injections of PTH (1-84) 100 mcg for 18 months, plus calcium 1 gr and vitamin D 800 IU per os daily. Blood samples were taken every 6 months during the study.Results At baseline, there were no differences considering anthropometric parameters, co-morbidities, current medications used between patients and controls. Mean serum VEGF levels were significantly higher in osteoporotic patients compared to controls (436.7 +/- 259.7 vs. 260.3 +/- 184.3 pg/ml, p = 0.006), while there were no differences in mean serum values of BMP4 (5.3 +/- 1.7 vs. 5.7 +/- 1.6 pg/ml, p = 0.40). Serum VEGF levels increased by approximately 20% after 12 months of PTH (1-84) treatment compared to baseline (p = 0.03) and by 22% after 18 months (p = 0.01). A significant increase of 10% in mean serum BMP4 levels was observed after 18 months of PTH (1-84) treatment compared to baseline (p = 0.02). In the control group we found no differences after 18 months compared to baseline in BMP4 (5.7 +/- 1.6 vs. 6.0 +/- 1.5 pg/ml, p = 0.53) and VEGF (260.3 +/- 184.3 vs. 257.4 +/- 107.1 pg/ ml, p = 0.94).Conclusions PTH (1-84) treatment increased serum levels of VEGF and BMP4 in postmenopausal women with severe osteoporosis.

Background: Hypercalcemia induces arrhythmias and shortening of QT. The aim of this study was to investigate risk factors for occurrence of arrhythmias in patients with primary hyperparathyroidism (PHPT) during bicycle ergometer exercise test (ET). Methods: Thirty PHPT postmenopausal women (mean age, 60·9 ± 8·0 years) and 30, sex and age-matched, controls underwent ET, echocardiogram and mineral metabolism biochemical evaluation. The following stages were considered during ET: rest, peak exercise, recovery (early recovery, 2 and 10 min after peak exercise). QT was corrected with Bazett's formula (QTc). Results: Compared with controls, PHPT patients showed an increased occurrence of ventricular premature beats (VPBs) during ET (26·6% vs. 6·6%, P = 0·03). Being affected by PHPT predicted the onset of VPBs at peak exercise (P = 0·04) and recovery (P = 0·03), as shown by logistic regression analysis. In PHPT patients, serum calcium level was a predictor of VPBs at peak exercise (P = 0·05). QTc in patients with PHPT was in the normal range. Serum calcium level showed a negative correlation with QTc (P = 0·01) in whole sample. Compared with controls, PHTP patients had QTc significantly shorter for every stage of ET, except at peak exercise. Physiological reduction of QTc interval from rest to peak exercise was not seen in patients with PHPT, QTc at rest being the only predictor of QTc in every stage, as shown by multivariate regression analysis. Conclusions: In patients with PHPT, an increased occurrence of VPBs and a different QTc adaptation during ET were observed and may represent risk factors for major arrhythmias. © 2012 Stichting European Society for Clinical Investigation Journal Foundation.