Although neurotrophins have been postulated to have antidepressant properties, their effect on anxiety is not clear. We find that transgenic overexpression of the neurotrophin BDNF has an unexpected facilitatory effect on anxiety-like behavior, concomitant with increased spinogenesis in the basolateral amygdala. Moreover, anxiogenesis and amygdalar spinogenesis are also triggered by chronic stress in control mice but are occluded by BDNF overexpression, thereby suggesting a role for BDNF signaling in stressinduced plasticity in the amygdala. BDNF overexpression also causes antidepressant effects, because transgenic mice exhibit improved performance on the Porsolt forced-swim test and an absence of chronic stress-induced hippocampal atrophy. Thus, structural changes in the amygdala and hippocampus, caused by genetic manipulation of the same molecule BDNF, give rise to contrasting effects on anxiety and depressive symptoms, both of which are major behavioral correlates of stress disorders.amygdala ͉ chronic stress ͉ hippocampus ͉ morphology ͉ dendritic spines P rolonged and severe stress is associated with various cognitive and affective behavioral abnormalities. The hippocampus, which plays an important role in the formation of declarative memories, has been the primary focus of research on the cognitive effects of chronic stress (1). From a cell biological perspective, a reduction in the length and complexity of dendritic arbors of hippocampal CA3 pyramidal neurons is a well characterized morphological feature of various rodent models of repeated stress (2). This stress-induced dendritic remodeling, in turn, has been hypothesized to underlie the hippocampal volume loss (3, 4) seen in patients suffering from various stress-related disorders, including major depression, Cushing's syndrome, and posttraumatic stress disorder (5-7). Recent evidence has pointed to neurotrophins as a cause for these changes and have led to the ''neurotrophic hypothesis,'' which states that symptoms associated with depression, both pathological and behavioral, are a result of decreased neurotrophic support, and conversely, that increasing neurotrophic support would lead to the resolution of these symptoms (8, 9).Although hippocampal plasticity has, over the years, provided a useful framework for studying the cognitive effects of stress at multiple levels of neural organization, the affective aspects of stress disorders, such as increased anxiety, are likely to involve the amygdala, which plays a pivotal role in processing aversive experiences (10, 11). Interestingly, in contrast to the hippocampus, which inhibits the hypothalamic-pituitary-adrenal (HPA) axis, the amygdala stimulates it (12). In addition, pathological anxiety disorders are associated with an increase in amygdalar volume and output (13-16). Analogously, in rodents, the same chronic immobilization stress (CIS) that causes hippocampal atrophy can elicit dendritic growth in the basolateral amygdala (BLA), as well as enhanced anxiety-like behavior (17-19). These crucial diffe...

Rationale: Sleep fragmentation (SF) is one of the major characteristics of sleep apnea, and has been implicated in its morbid consequences, which encompass excessive daytime sleepiness and neurocognitive impairments. We hypothesized that absence of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is neuroprotective in SF-induced cognitive impairments. Objectives: To examine whether increased NADPH oxidase activity may play a role in SF-induced central nervous system dysfunction. Methods: The effect of chronic SF during the sleep-predominant period on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters was assessed in mice lacking NADPH oxidase activity (gp91phox-/Y ) and wild-type littermates. Measurements and Main Results: SF for 15 days was not associated with differences in sleep duration, sleep state distribution, or sleep latency in both gp91phox-/Y and control mice. However, on a standard place training task, gp91phox-/Y mice displayed normal learning and were protected from the spatial learning deficits observed in wildtype littermates exposed to SF. Moreover, anxiety levels were increased in wild-type mice exposed to SF, whereas no changes emerged in gp91phox-/Y mice. Additionally, wild-type mice, but not gp91phox-/Y mice, had significantly elevated NADPH oxidase gene expression and activity, and in malondialdehyde and 8-oxo-29-deoxyguanosine levels in cortical and hippocampal lysates after SF exposures. Conclusions: This work substantiates an important role for NADPH oxidase in hippocampal memory impairments induced by SF, modeling sleep apnea. Targeting NADPH oxidase, therefore, is expected to minimize hippocampal impairments from both intermittent hypoxia and SF associated with the disease. Keywords: NADPH oxidase; sleep fragmentation; neurocognitive impairmentsThe manifestations of obstructive sleep apnea (OSA) reflect the interactions of intermittent hypoxia (IH), intermittent hypercapnia, increased intrathoracic pressure swings, and sleep fragmentation (SF) as elicited by the episodic changes in upper airway resistance during sleep. SF is a common phenomenon among several clinical disorders, and can lead to impaired cognitive function via mechanisms that remain poorly understood (1). Indeed, uninterrupted sleep for a minimum length of time is required for optimal daytime vigilance and neurocognitive function (1-3). Preliminary studies in rodents using short-term SF paradigms have also confirmed the adverse effects of SF on learning and seem to be independent of adenosine-mediated synaptic inhibition (4-7).In clinical populations with severe SF (e.g., in OSA) total sleep time typically diminishes only slightly (8). The effects of experimentally induced SF on sleep patterns have not been critically characterized in rodents. It is likely that OSA-induced sleep perturbations are accompanied by obvious cognitive deficits because of increased levels of systemic markers of oxidative stress and inflammation, the latter leading to gray matter loss in neural...

BackgroundIn rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction.Methods and FindingsThe effect of IH during light period on two forms of spatial learning in the water maze and well as markers of oxidative stress was assessed in mice lacking NADPH oxidase activity (gp91phox _/Y) and wild-type littermates. On a standard place training task, gp91phox _/Y displayed normal learning, and were protected from the spatial learning deficits observed in wild-type littermates exposed to IH. Moreover, anxiety levels were increased in wild-type mice exposed to IH as compared to room air (RA) controls, while no changes emerged in gp91phox _/Y mice. Additionally, wild-type mice, but not gp91phox _/Y mice had significantly elevated levels of NADPH oxidase expression and activity, as well as MDA and 8-OHDG in cortical and hippocampal lysates following IH exposures.ConclusionsThe oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and thus pharmacological agents targeting NADPH oxidase may provide a therapeutic strategy in sleep-disordered breathing.

BackgroundSleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF)-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who have disrupted sleep as a result of obstructive sleep apnea, a condition associated with prominent sleep fragmentation. The aim of this study was to examine role of the TNF-α pathway after long-term sleep fragmentation in mice.MethodsThe effect of chronic sleep fragmentation during the sleep-predominant period on sleep architecture, sleep latency, cognitive function, behavior, and inflammatory markers was assessed in C57BL/6 J and in mice lacking the TNF-α receptor (double knockout mice). In addition, we also assessed the above parameters in C57BL/6 J mice after injection of a TNF-α neutralizing antibody.ResultsMice subjected to chronic sleep fragmentation had preserved sleep duration, sleep state distribution, and cumulative delta frequency power, but also exhibited excessive sleepiness, altered cognitive abilities and mood correlates, reduced cyclic AMP response element-binding protein phosphorylation and transcriptional activity, and increased phosphodiesterase-4 expression, in the absence of AMP kinase-α phosphorylation and ATP changes. Selective increases in cortical expression of TNF-α primarily circumscribed to neurons emerged. Consequently, sleepiness and cognitive dysfunction were absent in TNF-α double receptor knockout mice subjected to sleep fragmentation, and similarly, treatment with a TNF-α neutralizing antibody abrogated sleep fragmentation-induced learning deficits and increases in sleep propensity.ConclusionsTaken together, our findings show that recurrent arousals during sleep, as happens during sleep apnea, induce excessive sleepiness via activation of inflammatory mechanisms, and more specifically TNF-α-dependent pathways, despite preserved sleep duration.

Objectives Short sleep confers a higher risk of obesity in humans. Restricted sleep increases appetite, promotes higher calorie intake from fat and carbohydrate sources, and induces insulin resistance. However, the effects of fragmented sleep (SF), such as occurs in sleep apnea, on body weight, metabolic rates, and adipose tissue distribution are unknown. Design and Methods C57BL/6 mice were exposed to SF for 8 weeks. Their body weight, food consumption, and metabolic expenditure were monitored over time, and their plasma leptin levels measured after exposure to SF for 1 day as well as for 2 weeks. In addition, adipose tissue distribution was assessed at the end of the SF exposure using MRI techniques. Results Chronic SF induced obesogenic behaviors and increased weight gain in mice by promoting increased caloric intake without changing caloric expenditure. Plasma leptin levels initially decreased and subsequently increased. Furthermore, increases in both visceral and subcutaneous adipose tissue volumes occurred. Conclusions These results suggest that SF, a frequent occurrence in many disorders and more specifically in sleep apnea, is a potent inducer of obesity via activation of obesogenic behaviors and possibly leptin resistance, in the absence of global changes in energy expenditure.