Biomedical subjects

Giulio Tononi

Publications and source records attributed to Giulio Tononi.

At least 19 recordsLinked to original sources

PubMed2005

Sleep and wakefulness modulate gene expression in Drosophila.

In the mammalian brain, sleep and wakefulness are associated with widespread changes in gene expression. Sleep in fruit flies shares many features with mammalian sleep, but it is currently unknown to what extent behavioral states affect gene expression in Drosophila. To find out, we performed a comprehensive microarray analysis of gene expression in spontaneously awake, sleep-deprived and sleeping flies. Fly heads were collected at 4 am, after 8 h of spontaneous sleep or sleep deprivation, and at 4 pm, after 8 h of spontaneous wakefulness. As in rats, we found that behavioral state and time of day affect Drosophila gene expression to a comparable extent. As in rats, transcripts with higher expression in wakefulness and in sleep belong to different functional categories, and in several cases these groups overlap with those previously identified in rats. Wakefulness-related genes code for transcription factors and for proteins involved in the stress response, immune response, glutamatergic transmission, and carbohydrate metabolism. Sleep-related transcripts include the glial gene anachronism and several genes involved in lipid metabolism. Finally, the expression of many wakefulness-related and sleep-related Drosophila transcripts is also modulated by the time of day, suggesting an interaction at the molecular level between circadian and homeostatic mechanism of sleep regulation.

Animals↗

PubMed2005

Locus ceruleus control of slow-wave homeostasis.

Sleep intensity is regulated by the duration of previous wakefulness, suggesting that waking results in the progressive accumulation of sleep need (Borbely and Achermann, 2000). In mammals, sleep intensity is reflected by slow-wave activity (SWA) in the nonrapid eye movement (NREM) sleep electroencephalogram, which increases in proportion to the time spent awake. However, the mechanisms responsible for the increase of NREM SWA after wakefulness remain unclear. According to a recent hypothesis (Tononi and Cirelli, 2003), the increase in SWA occurs because during wakefulness, many cortical circuits undergo synaptic potentiation, as evidenced by the widespread induction of long-term potentiation (LTP)-related genes in the brain of awake animals. A direct prediction of this hypothesis is that manipulations interfering with the induction of LTP-related genes should result in a blunted SWA response. Here, we examined SWA response in rats in which cortical norepinephrine (NA) was depleted, a manipulation that greatly reduces the induction of LTP-related genes during wakefulness (Cirelli and Tononi, 2004). We found that the homeostatic response of the lower-range SWA was markedly and specifically reduced after NA depletion. These data suggest that the wake-dependent accumulation of sleep need is causally related to cellular changes dependent on NA release, such as the induction of LTP-related genes, and support the hypothesis that sleep SWA homeostasis may be related to synaptic potentiation during wakefulness.

Analysis of Variance↗

PubMed2005

Reduced sleep in Drosophila Shaker mutants.

Most of us sleep 7-8 h per night, and if we are deprived of sleep our performance suffers greatly; however, a few do well with just 3-4 h of sleep-a trait that seems to run in families. Determining which genes underlie this phenotype could shed light on the mechanisms and functions of sleep. To do so, we performed mutagenesis in Drosophila melanogaster, because flies also sleep for many hours and, when sleep deprived, show sleep rebound and performance impairments. By screening 9,000 mutant lines, we found minisleep (mns), a line that sleeps for one-third of the wild-type amount. We show that mns flies perform normally in a number of tasks, have preserved sleep homeostasis, but are not impaired by sleep deprivation. We then show that mns flies carry a point mutation in a conserved domain of the Shaker gene. Moreover, after crossing out genetic modifiers accumulated over many generations, other Shaker alleles also become short sleepers and fail to complement the mns phenotype. Finally, we show that short-sleeping Shaker flies have a reduced lifespan. Shaker, which encodes a voltage-dependent potassium channel controlling membrane repolarization and transmitter release, may thus regulate sleep need or efficiency.

Amino Acid Sequence↗

PubMed2005

Modeling the effects of transcranial magnetic stimulation on cortical circuits.

Transcranial magnetic stimulation (TMS) is commonly used to activate or inactivate specific cortical areas in a noninvasive manner. Because of technical constraints, the precise effects of TMS on cortical circuits are difficult to assess experimentally. Here, this issue is investigated by constructing a detailed model of a portion of the thalamocortical system and examining the effects of the simulated delivery of a TMS pulse. The model, which incorporates a large number of physiological and anatomical constraints, includes 33,000 spiking neurons arranged in a 3-layered motor cortex and over 5 million intra- and interlayer synaptic connections. The model was validated by reproducing several results from the experimental literature. These include the frequency, timing, dose response, and pharmacological modulation of epidurally recorded responses to TMS (the so-called I-waves), as well as paired-pulse response curves consistent with data from several experimental studies. The modeled responses to simulated TMS pulses in different experimental paradigms provide a detailed, self-consistent account of the neural and synaptic activities evoked by TMS within prototypical cortical circuits.

Animals↗

PubMed2004

Modeling sleep and wakefulness in the thalamocortical system.

When the brain goes from wakefulness to sleep, cortical neurons begin to undergo slow oscillations in their membrane potential that are synchronized by thalamocortical circuits and reflected in EEG slow waves. To provide a self-consistent account of the transition from wakefulness to sleep and of the generation of sleep slow waves, we have constructed a large-scale computer model that encompasses portions of two visual areas and associated thalamic and reticular thalamic nuclei. Thousands of model neurons, incorporating several intrinsic currents, are interconnected with millions of thalamocortical, corticothalamic, and both intra- and interareal corticocortical connections. In the waking mode, the model exhibits irregular spontaneous firing and selective responses to visual stimuli. In the sleep mode, neuromodulatory changes lead to slow oscillations that closely resemble those observed in vivo and in vitro. A systematic exploration of the effects of intrinsic currents and network parameters on the initiation, maintenance, and termination of slow oscillations shows the following. 1) An increase in potassium leak conductances is sufficient to trigger the transition from wakefulness to sleep. 2) The activation of persistent sodium currents is sufficient to initiate the up-state of the slow oscillation. 3) A combination of intrinsic and synaptic currents is sufficient to maintain the up-state. 4) Depolarization-activated potassium currents and synaptic depression terminate the up-state. 5) Corticocortical connections synchronize the slow oscillation. The model is the first to integrate intrinsic neuronal properties with detailed thalamocortical anatomy and reproduce neural activity patterns in both wakefulness and sleep, thereby providing a powerful tool to investigate the role of sleep in information transmission and plasticity.

Afferent Pathways↗

PubMed2004

An information integration theory of consciousness.

BACKGROUND: Consciousness poses two main problems. The first is understanding the conditions that determine to what extent a system has conscious experience. For instance, why is our consciousness generated by certain parts of our brain, such as the thalamocortical system, and not by other parts, such as the cerebellum? And why are we conscious during wakefulness and much less so during dreamless sleep? The second problem is understanding the conditions that determine what kind of consciousness a system has. For example, why do specific parts of the brain contribute specific qualities to our conscious experience, such as vision and audition? PRESENTATION OF THE HYPOTHESIS: This paper presents a theory about what consciousness is and how it can be measured. According to the theory, consciousness corresponds to the capacity of a system to integrate information. This claim is motivated by two key phenomenological properties of consciousness: differentiation - the availability of a very large number of conscious experiences; and integration - the unity of each such experience. The theory states that the quantity of consciousness available to a system can be measured as the Phi value of a complex of elements. Phi is the amount of causally effective information that can be integrated across the informational weakest link of a subset of elements. A complex is a subset of elements with Phi>0 that is not part of a subset of higher Phi. The theory also claims that the quality of consciousness is determined by the informational relationships among the elements of a complex, which are specified by the values of effective information among them. Finally, each particular conscious experience is specified by the value, at any given time, of the variables mediating informational interactions among the elements of a complex. TESTING THE HYPOTHESIS: The information integration theory accounts, in a principled manner, for several neurobiological observations concerning consciousness. As shown here, these include the association of consciousness with certain neural systems rather than with others; the fact that neural processes underlying consciousness can influence or be influenced by neural processes that remain unconscious; the reduction of consciousness during dreamless sleep and generalized seizures; and the time requirements on neural interactions that support consciousness. IMPLICATIONS OF THE HYPOTHESIS: The theory entails that consciousness is a fundamental quantity, that it is graded, that it is present in infants and animals, and that it should be possible to build conscious artifacts.

Afferent Pathways↗

PubMed2004

Transcranial Magnetic Stimulation in the investigation and treatment of schizophrenia: a review.

Transcranial Magnetic Stimulation (TMS) is a non-invasive method of stimulating the brain that is increasingly being used in neuropsychiatric research and clinical psychiatry. This review examines the role of TMS in schizophrenia research as a diagnostic and a therapeutic resource. After a brief overview of TMS, we describe the application of TMS to schizophrenia in studies of cortical excitability and inhibition, and we discuss the potential confounding role of neuroleptic medications. Based on these studies, it appears that some impairment of cortical inhibition may be present in schizophrenic subjects. We then review attempts to employ TMS for treating different symptoms of schizophrenia. Some encouraging results have been obtained, such as the reduction of auditory hallucinations after slow TMS over auditory cortex and an improvement of psychotic symptoms after high frequency TMS over left prefrontal cortex. However, these results need to be confirmed using better placebo conditions. Future studies are likely to employ TMS in combination with functional brain imaging to examine the effects produced by the stimulated area on activity in other brain regions. Such studies may reveal impaired effective connectivity between specific brain areas, which could identify these regions as targets for selective stimulation with therapeutic doses of TMS.

Auditory Cortex↗

PubMed2004

A [17F]-fluoromethane PET/TMS study of effective connectivity.

We used transcranial magnetic stimulation (TMS) in combination with positron emission tomography (PET) to investigate the effective connectivity of four cortical regions within the same study. By employing [17F]-[CH3F] ([17F]-fluoromethane) as a radiotracer of blood-flow, we were able to obtain increased sensitivity compared to [15O]-H2O for both cortical and subcortical structures. The brain areas investigated were left primary motor cortex, right primary visual cortex, and left and right prefrontal areas. We found that each site of stimulation yielded a different pattern of activation/deactivation consistent with its anatomical connectivity. Moreover, we found that TMS of prefrontal and motor cortical areas gave rise to trans-synaptic activation of subcortical circuits.

Adult↗

PubMed2004

The sleep slow oscillation as a traveling wave.

During much of sleep, virtually all cortical neurons undergo a slow oscillation (<1 Hz) in membrane potential, cycling from a hyperpolarized state of silence to a depolarized state of intense firing. This slow oscillation is the fundamental cellular phenomenon that organizes other sleep rhythms such as spindles and slow waves. Using high-density electroencephalogram recordings in humans, we show here that each cycle of the slow oscillation is a traveling wave. Each wave originates at a definite site and travels over the scalp at an estimated speed of 1.2-7.0 m/sec. Waves originate more frequently in prefrontal-orbitofrontal regions and propagate in an anteroposterior direction. Their rate of occurrence increases progressively reaching almost once per second as sleep deepens. The pattern of origin and propagation of sleep slow oscillations is reproducible across nights and subjects and provides a blueprint of cortical excitability and connectivity. The orderly propagation of correlated activity along connected pathways may play a role in spike timing-dependent synaptic plasticity during sleep.

Adult↗

PubMed2004

Chlorotoxin-mediated disinhibition of noradrenergic locus coeruleus neurons using a conditional transgenic approach.

The noradrenergic locus coeruleus (LC) has been implicated in the promotion of arousal, in focused attention and learning, and in the regulation of the sleep/waking cycle. The complex biological functions of the central noradrenergic system have been investigated largely through electrophysiological recordings and neurotoxic lesions of LC neurons. Activation of LC neurons through electrical or chemical stimulation has also led to important insights, although these techniques have limited cellular specificity and short-term effects. Here, we describe a novel method aimed at stimulating the central noradrenergic system in a highly selective manner for prolonged periods of time. This was achieved through the conditional expression of a transgene for chlorotoxin (Cltx) in the LC of adult mice. Chlorotoxin is a component of scorpion venom that partially blocks small conductance chloride channels. In this manner, the influence of GABAergic and glycinergic inhibitory inputs on LC cells is greatly reduced, while their ability to respond to excitatory inputs is unaffected. We demonstrate that the unilateral induction of Cltx expression in the LC is associated with a concomitant ipsilateral increase in the expression of markers of noradrenergic activity in LC neurons. Moreover, LC disinhibition is associated with the ipsilateral induction of the immediate early gene NGFI-A in cortical and subcortical target areas. Unlike previous gain of function approaches, transgenic disinhibition of LC cells is highly selective and persists for at least several weeks. This method represents a powerful new tool to assess the long-term effects of LC activation and is potentially applicable to other neuronal systems.

Adenoviridae↗

PubMed2004

Sleep homeostasis in Drosophila melanogaster.

STUDY OBJECTIVES: The fruit fly Drosophila melanogaster is emerging as a promising model system for the genetic dissection of sleep. As in mammals, sleep in the fruit fly is a reversible state of reduced responsiveness to the external world and has been defined using an array of behavioral, pharmacologic, molecular, and electrophysiologic criteria. A central feature of mammalian sleep is its homeostatic regulation by the amount of previous wakefulness. Dissecting the mechanisms of homeostatic regulation is likely to provide key insights into the functions of sleep. Thus, it is important to establish to what extent sleep homeostasis is similar between mammals and flies. This study was designed to determine whether in flies, as in mammals, (1) sleep rebound is dependent on prior time awake; (2) sleep deprivation affects the intensity, in addition to the duration, of sleep rebound; (3) sleep loss impairs vigilance and performance; (4) the sleep homeostatic response is conserved among different wild-type lines, and between female and male flies of the same line. DESIGN: Motor activity of individual flies was recorded at 1-minute intervals using the infrared Drosophila Activity Monitoring System during 2 baseline days; during 6, 12, and 24 hours of sleep deprivation; and during 2 days of recovery. Sleep was defined as any period of uninterrupted behavioral immobility lasting > 5 minutes. Sleep continuity was measured by calculating the number of brief awakenings, the number and duration of sleep episodes, and a sleep continuity score. Vigilance before and after sleep deprivation was assessed by measuring the escape response triggered by 2 different aversive stimuli. SETTING: Fly sleep research laboratory at UW-Madison. PARTICIPANTS AND INTERVENTIONS: Adult flies of the Canton-S (CS) strain and 116 other wild-type lines (> or = 16 female and > or = 16 male flies per line). MEASUREMENTS AND RESULTS: In wild-type CS flies, as in mammals, the amount of sleep recovered after sleep deprivation was dependent on prior time awake. Relative to baseline sleep, recovery sleep in CS flies was less fragmented, with longer sleep episodes, and was associated with a higher arousal threshold. Sleep deprivation in CS flies also reduced performance. Sleep duration and continuity increased after 24 hour of sleep deprivation in all the other wild-type lines tested. CONCLUSION: The sleep homeostatic response in fruit flies is a stable phenotype and shares most of, if not all, the major features of mammalian sleep homeostasis, thus supporting the use of Drosophila as a model system for the genetic dissection of sleep mechanisms and functions.

Animals↗

PubMed2004

Locus ceruleus control of state-dependent gene expression.

Wakefulness and sleep are accompanied by changes in behavior and neural activity, as well as by the upregulation of different functional categories of genes. However, the mechanisms responsible for such state-dependent changes in gene expression are unknown. Here we investigate to what extent state-dependent changes in gene expression depend on the central noradrenergic (NA) system, which is active in wakefulness and reduces its firing during sleep. We measured the levels of approximately 5000 transcripts expressed in the cerebral cortex of control rats and in rats pretreated with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a neurotoxin that removes the noradrenergic innervation of the cortex. We found that NA depletion reduces the expression of approximately 20% of known wakefulness-related transcripts. Most of these transcripts are involved in synaptic plasticity and in the cellular response to stress. In contrast, NA depletion increased the expression of the sleep-related gene encoding the translation elongation factor 2. These results indicate that the activity of the central NA system during wakefulness modulates neuronal transcription to favor synaptic potentiation and counteract cellular stress, whereas its inactivity during sleep may play a permissive role to enhance brain protein synthesis.

Animals↗

PubMed2004

Local sleep and learning.

Human sleep is a global state whose functions remain unclear. During much of sleep, cortical neurons undergo slow oscillations in membrane potential, which appear in electroencephalograms as slow wave activity (SWA) of <4 Hz. The amount of SWA is homeostatically regulated, increasing after wakefulness and returning to baseline during sleep. It has been suggested that SWA homeostasis may reflect synaptic changes underlying a cellular need for sleep. If this were so, inducing local synaptic changes should induce local SWA changes, and these should benefit neural function. Here we show that sleep homeostasis indeed has a local component, which can be triggered by a learning task involving specific brain regions. Furthermore, we show that the local increase in SWA after learning correlates with improved performance of the task after sleep. Thus, sleep homeostasis can be induced on a local level and can benefit performance.

Brain↗

PubMed2004

Extensive and divergent effects of sleep and wakefulness on brain gene expression.

Sleep is present in all species where it has been studied, but its functions remain unknown. To investigate what benefits sleep may bring at the cellular level, we profiled gene expression in awake and sleeping rats by using high-density microarrays. We find that approximately 10% of the transcripts in the cerebral cortex change their expression between day and night and demonstrate that half of them are modulated by sleep and wakefulness independent of time of day. We also show that molecular correlates of sleep are found in the cerebellum, a structure not known for generating sleep rhythms. Finally, we show that different functional categories of genes are selectively associated with sleep and wakefulness. The approximately 100 known genes whose expression increases during sleep provide molecular support for the proposed involvement of sleep in protein synthesis and neural plasticity and point to a novel role for sleep in membrane trafficking and maintenance.

Animals↗

PubMed2003

Sleep and synaptic homeostasis: a hypothesis.

During much of sleep, the cerebral cortex is rippled by slow waves, which appear in the electroencephalogram as oscillations between 0.5 and 4.5 Hz. Slow waves are regulated as a function of previous wakefulness, being maximal at the beginning of sleep and then progressively returning to a baseline level. This paper discusses a hypothesis about the significance of slow-wave activity and its homeostatic regulation. The hypothesis is as follows: 1. Wakefulness is associated with synaptic potentiation in several cortical circuits; 2. Synaptic potentiation is tied to the homeostatic regulation of slow-wave activity; 3. Slow-wave activity is associated with synaptic downscaling; 4. Synaptic downscaling is tied to the beneficial effects of sleep on performance. The hypothesized link between sleep and synaptic homeostasis is supported by several lines of evidence and leads to testable predictions.

Animals↗

PubMed2003

Measuring information integration.

BACKGROUND: To understand the functioning of distributed networks such as the brain, it is important to characterize their ability to integrate information. The paper considers a measure based on effective information, a quantity capturing all causal interactions that can occur between two parts of a system. RESULTS: The capacity to integrate information, or Phi, is given by the minimum amount of effective information that can be exchanged between two complementary parts of a subset. It is shown that this measure can be used to identify the subsets of a system that can integrate information, or complexes. The analysis is applied to idealized neural systems that differ in the organization of their connections. The results indicate that Phi is maximized by having each element develop a different connection pattern with the rest of the complex (functional specialization) while ensuring that a large amount of information can be exchanged across any bipartition of the network (functional integration). CONCLUSION: Based on this analysis, the connectional organization of certain neural architectures, such as the thalamocortical system, are well suited to information integration, while that of others, such as the cerebellum, are not, with significant functional consequences. The proposed analysis of information integration should be applicable to other systems and networks.

Brain↗

PubMed2002

Electrophysiological correlates of rest and activity in Drosophila melanogaster.

Extended periods of rest in Drosophila melanogaster resemble mammalian sleep states in that they are characterized by heightened arousal thresholds and specific alterations in gene expression. Defined as inactivity periods spanning 5 or more min, amounts of this sleep-like state are, as in mammals, sensitive to prior amounts of waking activity, time of day, and pharmacological intervention. Clearly recognizable changes in the pattern and amount of brain electrical activity accompany changes in motor activity and arousal thresholds originally used to identify mammalian sleeping behavior. Electroencephalograms (EEGs) and/or local field potentials (LFPs) are now widely used to quantify sleep state amounts and define types of sleep. Thus, slow-wave sleep (SWS) is characterized by EEG spindles and large-amplitude delta-frequency (0-3.5 Hz) waves. Rapid-eye movement (REM) sleep is characterized by irregular gamma-frequency cortical EEG patterns and rhythmic theta-frequency (5-9 Hz) hippocampal EEG activity. It is unknown whether rest and activity in Drosophila are associated with distinct electrophysiological correlates. To address this issue, we monitored motor activity levels and recorded LFPs in the medial brain between the mushroom bodies, structures implicated in the modulation of locomotor activity, of Drosophila. The results indicate that LFPs can be reliably recorded from the brains of awake, moving fruit flies, that targeted genetic manipulations can be used to localize sources of LFP activity, and that brain electrical activity of Drosophila is reliably correlated with activity state.

Acclimatization↗

PubMed2002

Tonic rhythmic activity of rat cerebellar neurons.

Simultaneous recordings of multiple single unit activity in both cerebral and cerebellar cortex, cortical EEG, and both nuchal and vibrissal EMG were obtained in nine unrestrained rats. Putative Purkinje cells of the deep vermal cerebellar cortex exhibited rhythmic discharge of simple spikes with extremely low variability in interspike intervals for several hours. The highly rhythmic nature of spike discharge was remarkably stable across all states of sleep (both slow-wave and rapid eye movement sleep) and wake including quiet waking, grooming, eating, running in a familiar environment, and exploring a novel environment. The frequencies at which oscillatory discharges took place varied, among different cells, between 16 and 142 Hz; however, 75% of the recorded cells discharged at frequencies between 20 and 50 Hz. From recordings in which two to four such cells were recorded simultaneously, evidence was found for multiple cells firing at the same frequency as well as for multiple cells firing at different frequencies. The precise timing of spike discharge in these cells makes them potential candidates to participate in timing functions thought to depend on the cerebellum

Action Potentials↗