a. (Blumberg, Seelke et al. 2005) pdf

b. (Buchanan and Richerson 2010) pdf

c. (Carter, Yizhar et al. 2010) pdf

d. (Greene 2013) pdf

e. (Lee, Song et al. 2013) pdf

f. (Lo, Chou et al. 2004) pdf

g. (McGregor and Siegel 2010) pdf

h. (Millman, Mihalas et al. 2010) pdf

i. (Rose, Ahmad et al. 2009) pdf

j. (Sterman, Howe et al. 1970) pdf

k. (Suzuki, Sinton et al. 2013) pdf

l. (Ueno, Tomita et al. 2012) pdf


Blumberg, M. S., A. M. Seelke, et al. (2005). "Dynamics of sleep-wake cyclicity in developing rats." Proc Natl Acad Sci U S A 102(41): 14860-4.

                Adult mammals cycle between periods of sleep and wakefulness. Recent assessments of these cycles in humans and other mammals indicate that sleep bout durations exhibit an exponential distribution, whereas wake bout durations exhibit a power-law distribution. Moreover, it was found that wake bout distributions, but not sleep bout distributions, exhibit scale invariance across mammals of different body sizes. Here we test the generalizability of these findings by examining the distributions of sleep and wake bout durations in infant rats between 2 and 21 days of age. In agreement with Lo et al., we find that sleep bout durations exhibit exponential distributions at all ages examined. In contrast, however, wake bout durations also exhibit exponential distributions at the younger ages, with a clear power-law distribution only emerging at the older ages. Further analyses failed to find substantial evidence either of short- or long-term correlations in the data, thus suggesting that the durations of current sleep and wake bouts evolve through time without memory of the durations of preceding bouts. These findings further support the notion that bouts of sleep and wakefulness are regulated independently. Moreover, in light of recent evidence that developmental changes in sleep and wake bouts can be attributed in part to increasing forebrain influences, these findings suggest the possibility of identifying specific neural circuits that modulate the changing complexity of sleep and wake dynamics during development.


Buchanan, G. F. and G. B. Richerson (2010). "Central serotonin neurons are required for arousal to CO2." Proceedings of the National Academy of Sciences 107(37): 16354-16359.

                There is a long-standing controversy about the role of serotonin in sleep/wake control, with competing theories that it either promotes sleep or causes arousal. Here, we show that there is a marked increase in wakefulness when all serotonin neurons are genetically deleted in mice hemizygous for ePet1-Cre and homozygous for floxed Lmx1b (Lmx1bf/f/p). However, this only occurs at cool ambient temperatures and can be explained by a thermoregulatory defect that leads to an increase in motor activity to generate heat. Because some serotonin neurons are stimulated by CO2, and serotonin activates thalamocortical networks, we hypothesized that serotonin neurons cause arousal in response to hypercapnia. We found that Lmx1bf/f/p mice completely lacked any arousal response to inhalation of 10% CO2 (with 21% O2 in balance N2) but had normal arousal responses to hypoxia, sound, and air puff. We propose that serotonin neurons mediate the potentially life-saving arousal response to hypercapnia. Impairment of this response may contribute to sudden unexpected death in epilepsy, sudden infant death syndrome, and sleep apnea.


Carter, M. E., O. Yizhar, et al. (2010). "Tuning arousal with optogenetic modulation of locus coeruleus neurons." Nat Neurosci 13(12): 1526-33.

                Neural activity in the noradrenergic locus coeruleus correlates with periods of wakefulness and arousal. However, it is unclear whether tonic or phasic activity in these neurons is necessary or sufficient to induce transitions between behavioral states and to promote long-term arousal. Using optogenetic tools in mice, we found that there is a frequency-dependent, causal relationship among locus coeruleus firing, cortical activity, sleep-to-wake transitions and general locomotor arousal. We also found that sustained, high-frequency stimulation of the locus coeruleus at frequencies of 5 Hz and above caused reversible behavioral arrests. These results suggest that the locus coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic overexcitation cause behavioral attacks that resemble those seen in people with neuropsychiatric disorders.


Greene, R. W. (2013). "Role for neuronal nitric oxide synthase in sleep homeostasis and arousal." Proc Natl Acad Sci U S A 110(50): 19982-3.


Konvalinka, I., D. Xygalatas, et al. (2011). "Synchronized arousal between performers and related spectators in a fire-walking ritual." Proc Natl Acad Sci U S A 108(20): 8514-9.

                Collective rituals are present in all known societies, but their function is a matter of long-standing debates. Field observations suggest that they may enhance social cohesion and that their effects are not limited to those actively performing but affect the audience as well. Here we show physiological effects of synchronized arousal in a Spanish fire-walking ritual, between active participants and related spectators, but not participants and other members of the audience. We assessed arousal by heart rate dynamics and applied nonlinear mathematical analysis to heart rate data obtained from 38 participants. We compared synchronized arousal between fire-walkers and spectators. For this comparison, we used recurrence quantification analysis on individual data and cross-recurrence quantification analysis on pairs of participants' data. These methods identified fine-grained commonalities of arousal during the 30-min ritual between fire-walkers and related spectators but not unrelated spectators. This indicates that the mediating mechanism may be informational, because participants and related observers had very different bodily behavior. This study demonstrates that a collective ritual may evoke synchronized arousal over time between active participants and bystanders. It links field observations to a physiological basis and offers a unique approach for the quantification of social effects on human physiology during real-world interactions.


Lee, J., K. Song, et al. (2013). "Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons." Proceedings of the National Academy of Sciences 110(50): 20266-20271.

                T-type Ca2+ channels in thalamocortical (TC) neurons have long been considered to play a critical role in the genesis of sleep spindles, one of several TC oscillations. A classical model for TC oscillations states that reciprocal interaction between synaptically connected GABAergic thalamic reticular nucleus (TRN) neurons and glutamatergic TC neurons generates oscillations through T-type channel-mediated low-threshold burst firings of neurons in the two nuclei. These oscillations are then transmitted from TC neurons to cortical neurons, contributing to the network of TC oscillations. Unexpectedly, however, we found that both WT and KO mice for CaV3.1, the gene for T-type Ca2+ channels in TC neurons, exhibit typical waxing-and-waning sleep spindle waves at a similar occurrence and with similar amplitudes and episode durations during non-rapid eye movement sleep. Single-unit recording in parallel with electroencephalography in vivo confirmed a complete lack of burst firing in the mutant TC neurons. Of particular interest, the tonic spike frequency in TC neurons was significantly increased during spindle periods compared with nonspindle periods in both genotypes. In contrast, no significant change in burst firing frequency between spindle and nonspindle periods was noted in the WT mice. Furthermore, spindle-like oscillations were readily generated within intrathalamic circuits composed solely of TRN and TC neurons in vitro in both the KO mutant and WT mice. Our findings call into question the essential role of low-threshold burst firings in TC neurons and suggest that tonic firing is important for the generation and propagation of spindle oscillations in the TC circuit.


Lo, C. C., T. Chou, et al. (2004). "Common scale-invariant patterns of sleep-wake transitions across mammalian species." Proc Natl Acad Sci U S A 101(50): 17545-8.

                Although mammals of different species have different sleep patterns, brief sleep-wake transitions commonly are observed across species and appear to occur randomly throughout the sleeping period. The dynamical patterns and functions of these brief awakenings from sleep are not well understood, and they often are viewed as disruptions (random or pathologic) of the sleep process. In this article, we hypothesize that brief awakenings from sleep may reflect aspects of the endogenous sleep control mechanism and thus may exhibit certain robust dynamical patterns across species. We analyze sleep recordings from mice, rats, cats, and humans, and we compare the distributions of sleep and wake episode durations. For all four species, we find that durations of brief wake episodes during the sleep period exhibit a scale-free power-law behavior with an exponent alpha that remains the same for all species (alpha approximately equal to 2.2). In contrast, sleep episode durations for all four species follow exponential distributions with characteristic time scales, which change across species in relation to body mass and metabolic rate. Our findings suggest common dynamical features of brief awakenings and sleep durations across species and may provide insights into the dynamics of the neural circuits controlling sleep.


McGregor, R. and J. M. Siegel (2010). "Illuminating the locus coeruleus: control of posture and arousal." Nat Neurosci 13(12): 1448-9.


Millman, D., S. Mihalas, et al. (2010). "Self-organized criticality occurs in non-conservative neuronal networks during Up states." Nat Phys 6(10): 801-805.

                During sleep, under anesthesia and in vitro, cortical neurons in sensory, motor, association and executive areas fluctuate between Up and Down states (UDS) characterized by distinct membrane potentials and spike rates [1, 2, 3, 4, 5]. Another phenomenon observed in preparations similar to those that exhibit UDS, such as anesthetized rats [6], brain slices and cultures devoid of sensory input [7], as well as awake monkey cortex [8] is self-organized criticality (SOC). This is characterized by activity "avalanches" whose size distributions obey a power law with critical exponent of about [Formula: see text] and branching parameter near unity. Recent work has demonstrated SOC in conservative neuronal network models [9, 10], however critical behavior breaks down when biologically realistic non-conservatism is introduced [9]. We here report robust SOC behavior in networks of non-conservative leaky integrate-and-fire neurons with short-term synaptic depression. We show analytically and numerically that these networks typically have 2 stable activity levels corresponding to Up and Down states, that the networks switch spontaneously between them, and that Up states are critical and Down states are subcritical.


Nassar, M. R., K. M. Rumsey, et al. (2012). "Rational regulation of learning dynamics by pupil-linked arousal systems." Nat Neurosci 15(7): 1040-6.

                The ability to make inferences about the current state of a dynamic process requires ongoing assessments of the stability and reliability of data generated by that process. We found that these assessments, as defined by a normative model, were reflected in nonluminance-mediated changes in pupil diameter of human subjects performing a predictive-inference task. Brief changes in pupil diameter reflected assessed instabilities in a process that generated noisy data. Baseline pupil diameter reflected the reliability with which recent data indicate the current state of the data-generating process and individual differences in expectations about the rate of instabilities. Together these pupil metrics predicted the influence of new data on subsequent inferences. Moreover, a task- and luminance-independent manipulation of pupil diameter predictably altered the influence of new data. Thus, pupil-linked arousal systems can help to regulate the influence of incoming data on existing beliefs in a dynamic environment.


Quinkert, A. W., V. Vimal, et al. (2011). "Quantitative descriptions of generalized arousal, an elementary function of the vertebrate brain." Proc Natl Acad Sci U S A 108 Suppl 3: 15617-23.

                We review a concept of the most primitive, fundamental function of the vertebrate CNS, generalized arousal (GA). Three independent lines of evidence indicate the existence of GA: statistical, genetic, and mechanistic. Here we ask, is this concept amenable to quantitative analysis? Answering in the affirmative, four quantitative approaches have proven useful: (i) factor analysis, (ii) information theory, (iii) deterministic chaos, and (iv) application of a Gaussian equation. It strikes us that, to date, not just one but at least four different quantitative approaches seem necessary for describing different aspects of scientific work on GA.


Rose, M. F., K. A. Ahmad, et al. (2009). "Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1." Proc Natl Acad Sci U S A 106(52): 22462-7.

                Hindbrain networks important for sensation and arousal contain diverse neuronal populations with distinct projections, yet share specific characteristics such as neurotransmitter expression. The relationship between the function of these neurons, their developmental origin, and the timing of their migration remains unclear. Mice lacking the proneural transcription factor Math1 (Atoh1) lose neurons essential for hearing, balance, and unconscious proprioception. By using a new, inducible Math1(Cre*PR) allele, we found that Math1 is also required for the conscious proprioceptive system, including excitatory projection neurons of the dorsal column nuclei and for vital components of the interoceptive system, such as Barrington's nucleus, that is closely associated with arousal. In addition to specific networks, Math1 lineages shared specific neurotransmitter expression, including glutamate, acetylcholine, somatostatin, corticotropin releasing hormone, and nitric oxide. These findings identify twenty novel Math1 lineages and indicate that the Math1 network functions partly as an interface for conscious (early-born) and unconscious (late-born) proprioceptive inputs to the cortex and cerebellum, respectively. In addition, these data provide previously unsuspected genetic and developmental links between proprioception, interoception, hearing, and arousal.


Shabel, S. J. and P. H. Janak (2009). "Substantial similarity in amygdala neuronal activity during conditioned appetitive and aversive emotional arousal." Proc Natl Acad Sci U S A 106(35): 15031-6.

                The amygdala is important for determining the emotional significance of environmental stimuli. However, the degree to which appetitive and aversive stimuli are processed by the same or different neuronal circuits within the amygdala remains unclear. Here we show that neuronal activity during the expression of classically conditioned appetitive and aversive emotional responses is more similar than expected by chance, despite the different sensory modalities of the eliciting stimuli. We also found that the activity of a large number of cells (> 43%) was correlated with blood pressure, a measure of emotional arousal. Together, our results suggest that a substantial proportion of neuronal circuits within the amygdala can contribute to both appetitive and aversive emotional arousal.


Sterman, M. B., R. C. Howe, et al. (1970). "Facilitation of spindle-burst sleep by conditioning of electroencephalographic activity while awake." Science 167(3921): 1146-8.

                A slow-wave electroencephalographic rhythm recorded from the sensorimotor cortex of the waking cat has been correlated behaviorally with the suppression of movement. Facilitation of this rhythm through conditioning selectively enhances a similar pattern recorded during sleep, the familiar spindle burst. The training also produced longer epochs of undisturbed sleep. The specific neural mechanism manipulated during wakefulness appears to function also in sleep and to be involved with the regulation of phasic motor behavior.


Suzuki, A., C. M. Sinton, et al. (2013). "Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice." Proc Natl Acad Sci U S A 110(25): 10288-93.

                Sleep is regulated by homeostatic mechanisms, and the low-frequency power in the electroencephalogram (delta power) during non-rapid eye movement sleep reflects homeostatic sleep need. Additionally, sleep is limited by circadian and environmentally influenced arousal. Little is known, however, about the underlying neural substrates for sleep homeostasis and arousal and about the potential link between them. Here, we subjected C57BL/6 mice to 6 h of sleep deprivation using two different methods: gentle handling and continual cage change. Both groups were deprived of sleep to a similar extent (>99%), and, as expected, the delta power increase during recovery sleep was quantitatively similar in both groups. However, in a multiple sleep latency test, the cage change group showed significantly longer sleep latencies than the gentle handling group, indicating that the cage change group had a higher level of arousal despite the similar sleep loss. To investigate the possible biochemical correlates of these behavioral changes, we screened for arousal-related and sleep need-related phosphoprotein markers from the diencephalon. We found that the abundance of highly phosphorylated forms of dynamin 1, a presynaptic neuronal protein, was associated with sleep latency in the multiple sleep latency test. In contrast, the abundance of highly phosphorylated forms of N-myc downstream regulated gene 2, a glial protein, was increased in parallel with delta power. The changes of these protein species disappeared after 2 h of recovery sleep. These results suggest that homeostatic sleep need and arousal can be dissociated behaviorally and biochemically and that phosphorylated N-myc downstream regulated gene 2 and dynamin 1 may serve as markers of homeostatic sleep need and arousal, respectively.


Ueno, T., J. Tomita, et al. (2012). "Identification of a dopamine pathway that regulates sleep and arousal in Drosophila." Nat Neurosci 15(11): 1516-23.

                Sleep is required to maintain physiological functions, including memory, and is regulated by monoamines across species. Enhancement of dopamine signals by a mutation in the dopamine transporter (DAT) decreases sleep, but the underlying dopamine circuit responsible for this remains unknown. We found that the D1 dopamine receptor (DA1) in the dorsal fan-shaped body (dFSB) mediates the arousal effect of dopamine in Drosophila. The short sleep phenotype of the DAT mutant was completely rescued by an additional mutation in the DA1 (also known as DopR) gene, but expression of wild-type DA1 in the dFSB restored the short sleep phenotype. We found anatomical and physiological connections between dopamine neurons and the dFSB neuron. Finally, we used mosaic analysis with a repressive marker and found that a single dopamine neuron projecting to the FSB activated arousal. These results suggest that a local dopamine pathway regulates sleep.