Sleep fragmentation, a feature of sleep apnea as well as other sleep and medical/psychiatric disorders, is thought to lead to excessive daytime sleepiness. A rodent model of sleep fragmentation was developed (termed sleep interruption, SI), where rats were awakened every 2 min by the movement of an automated treadmill for either 6 or 24 h of exposure. The sleep pattern of rats exposed to 24h of SI resembled sleep of the apneic patient in the following ways: sleep was fragmented (up to 30 awakening/h), total REM sleep time was greatly reduced, NREM sleep episode duration was reduced (from 2 min, 5 s baseline to 58 s during SI), whereas the total amount of NREM sleep time per 24h approached basal levels. Both 6 and 24 h of SI made rats more sleepy, as indicated by a reduced latency to fall asleep upon SI termination. Electrographic measures in the recovery sleep period following either 6 or 24 h of SI also indicated an elevation of homeostatic sleep drive; specifically, the average NREM episode duration increased (e.g., for 24 h SI, from 2 min, 5 s baseline to 3 min, 19 s following SI), as did the NREM delta power during recovery sleep. Basal forebrain (BF) levels of extracellular adenosine (AD) were also measured with microdialysis sample collection and HPLC detection, as previous work suggests that increasing concentrations of BF AD are related to sleepiness. BF AD levels were significantly elevated during SI, peaking at 220% of baseline during 30 h of SI exposure. These combined findings imply an elevation of the homeostatic sleep drive following either 6 or 24 h of SI, and BF AD levels appear to correlate more with sleepiness than with the cumulative amount of prior wakefulness, since total NREM sleep time declined only slightly. SI may be partially responsible for the symptom of daytime sleepiness observed in a number of clinical disorders, and this may be mediated by mechanisms involving BF AD. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2007 December 27. Published in final edited form as:Neuroscience. Obstructive sleep apnea (OSA) affects 2-4% of the general population (Young et al., 1993), and is characterized by apneic moments during sleep, which are terminated by brief arousals and a reestablishment of the upper airway patency. Thus, sleep fragmentation is a primary physiological disturbance, and may be responsible for some of the symptoms/signs associated with OSA, including excessive daytime sleepiness, which is a principal presenting complaint of patients (Roth et a...

Granule neurons generated in the adult mammalian hippocampus synaptically integrate to facilitate cognitive function and antidepressant efficacy. Here, we investigated the role of BDNF in facilitating their maturation in vivo. We found that depletion of central BDNF in mice elicited an increase in hippocampal cell proliferation without affecting cell survival or fate specification. However, new mutant neurons failed to fully mature as indicated by their lack of calbindin, reduced dendritic differentiation and an accumulation of calretinin + immature neurons in the BDNF mutant dentate gyrus. Furthermore, the facilitating effects of GABA A receptor stimulation on neurogenesis were absent in the mutants, suggesting that defects might be due to alterations in GABA signaling. Transcriptional analysis of the mutant hippocampal neurogenic region revealed increases in markers for immature neurons and decreases in neuronal differentiation facilitators. These findings demonstrate that BDNF is required for the terminal differentiation of new neurons in the adult hippocampus.

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, play prominent roles in food intake regulation through central mechanisms. However, the neural circuits underlying their anorexigenic effects remain largely unknown. We showed previously that selective BDNF depletion in the ventromedial hypothalamus (VMH) of mice resulted in hyperphagic behavior and obesity. Here, we sought to ascertain whether its regulatory effects involved the mesolimbic dopamine system, which mediates motivated and reward-seeking behaviors including consumption of palatable food. We found that expression of BDNF and TrkB mRNA in the ventral tegmental area (VTA) of wild-type mice was influenced by consumption of palatable, high-fat food (HFF). Moreover, amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core. Mutant mice also exhibited dramatic increases in HFF consumption, which were exacerbated when access to HFF was restricted. However, mutants displayed enhanced responses to D 1 receptor agonist administration, which normalized their intake of HFF in a 4 h food intake test. Finally, in contrast to deletion of Bdnf in the VMH of mice, which resulted in increased intake of standard chow, BDNF depletion in the VTA elicited excessive intake of HFF but not of standard chow and increased body weights under HFF conditions. Our findings indicate that the effects of BDNF on eating behavior are neural substratedependent and that BDNF influences hedonic feeding via positive modulation of the mesolimbic dopamine system.

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3β (GSK3β). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

Sleep deprivation alters mood and anxiety in man. In rats, 24 h of treadmill-induced total sleep deprivation or sleep fragmentation increased exploratory behavior in an open field test of anxiety compared to cage or exercise controls. Plasma corticosterone (CORT) levels of sleep disturbed and exercise control rats were elevated compared to cage controls, suggesting that the increased exploration observed in the sleep disturbed rats was not due to a hypothalamic-pituitary-adrenal (HPA) stress response. KeywordsSleep deprivation; Sleep fragmentation; Anxiety; Corticosterone; Rat It has been well documented that loss of sleep in man results in changes in emotional behavior, personality and psychopathology [28]. For example, sleep deprivation has been shown to relieve symptoms of depression [30], trigger manic episodes [3,8], and cause temporary states of paranoid schizophrenic-like behavior [27]. In addition, both sleep deprivation and sleep fragmentation have been shown to adversely affect subjective measures of mood such as vigor and fatigue [4,5,21]. There is also a strong relationship between sleep loss and anxiety in that sleep loss is a complaint in up to 70% of people suffering from generalized anxiety disorder and nocturnal panic attacks occur in up to 45% of panic episodes [28]. In humans, experimental sleep deprivation is reported to contribute to, or exacerbate anxiety [14,20] To manipulate sleep, the rats lived in a treadmill cage (l × w × h = 50.8 cm × 16.51 cm × 30.48 cm) in which the floor is a horizontal belt automatically programmed to move slowly at a rate of 0.02 m/s as previously described [26]. To induce sleep fragmentation, the treadmill ran at this slow speed for 30 s, followed by no treadmill movement for 90 s. To induce total sleep deprivation, the treadmill ran for 4 s followed by no treadmill movement for 12 s. These schedules ran continuously for 24 h starting at 0700 h. In order to habituate the rats to the treadmill movement, the treadmills were turned on (5 min treadmill on followed by 5 min off) for one hour on each of the 2 days prior to the experiment. There were two control groups, an untreated cage control group, and an exercise control group. To control for the non-specific effects of locomotor activity, the exercise control group obtained an equivalent amount of treadmill movement/exercise, but with a treadmill schedule of 10 min on/30 min off, allowing for longer periods of undisturbed sleep. The use of treadmills to disturb the sleep of rats in this laboratory has been characterized previously [12,13,26].Plasma CORT levels were measured in a group of rats (cage control n = 7, exercise control n = 6, sleep fragmentation n = 6, sleep deprivation n = 6) to determine if the treadmill procedures altered this endocrinological measure of stress, and, to determine if the sleep loss induced increase in open field exploration correlated with corticosterone levels. Rats were rapidly decapitated immediately after 24 h of sleep fragmentation, sleep deprivation, or exercise control...

The prevalence of obesity and its associated medical complications, including type 2 diabetes and cardiovascular disease, continues to rise globally. Lifestyle changes in the last decades have greatly contributed to the current obesity trends. However, inheritable biological factors that disrupt the tightly regulated equilibrium between caloric intake and energy expenditure also appear to play a critical part. Mounting evidence obtained from human and rodent studies suggests that perturbed brain-derived neurotrophic factor (BDNF) signaling in appetite-regulating centers in the brain might be a culprit. Here we review findings that inform the critical roles of BDNF and its receptor TrkB in energy balance and reward centers of the brain impacting feeding behavior and body weight.

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are critical components of the neural circuitry controlling appetite and body weight. Diminished BDNF signaling in mice results in severe hyperphagia and obesity. In humans, BDNF haploinsufficiency and the functional Bdnf Val66Met polymorphism have been linked to elevated food intake and body weight. The mechanisms underlying this dysfunction are poorly defined. We demonstrate a chief role of ␣2␦-1, a calcium channel subunit and thrombospondin receptor, in triggering overeating in mice with central BDNF depletion. We show reduced ␣2␦-1 cell-surface expression in the BDNF mutant ventromedial hypothalamus (VMH), an energy balance-regulating center. This deficit contributes to the hyperphagia exhibited by BDNF mutant mice because selective inhibition of ␣2␦-1 by gabapentin infusion into wild-type VMH significantly increases feeding and body weight gain. Importantly, viral-mediated ␣2␦-1 rescue in BDNF mutant VMH significantly mitigates their hyperphagia, obesity, and liver steatosis and normalizes deficits in glucose homeostasis. Whole-cell recordings in BDNF mutant VMH neurons revealed normal calcium currents but reduced frequency of EPSCs. These results suggest calcium channel-independent effects of ␣2␦-1 on feeding and implicate ␣2␦-1-thrombospondin interactions known to facilitate excitatory synapse assembly. Our findings identify a central mechanism mediating the inhibitory effects of BDNF on feeding. They also demonstrate a novel and critical role for ␣2␦-1 in appetite control and suggest a mechanism underlying weight gain in humans treated with gabapentinoid drugs.

Brief arousals from sleep in patients with sleep apnea and other disorders prevent restful sleep, and contribute to cognitive, metabolic and physiologic dysfunction. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system. These inputs include the brainstem parabrachial neurons which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia, but which cell types within the BF mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here using optogenetic techniques in mice, we show that BF parvalbumin (PV) neurons fulfill several criteria for a system mediating brief arousals from sleep.Optical stimulation of BF PV neurons during the light period, when mice normally sleep, caused rapid transitions to wakefulness and increased wake bout durations. Unlike many other ascending arousal systems, arousals induced by stimulation of BF PV neurons were brief, resulting in only a small (13.6%) increase in the total amount of wakefulness. Bilateral optical inhibition of BF PV neurons increased the latency to arousal produced by hypercarbia or auditory stimuli. Thus, BF PV neurons are an important component of the brain circuitry which generates brief arousals from sleep in response to internal and external sensory stimuli.