Neuroregulation of nonexercise activity thermogenesis and obesity resistance

High levels of spontaneous physical activity in lean people and the nonexercise activity thermogenesis (NEAT) derived from that activity appear to protect lean people from obesity during caloric challenge, while obesity in humans is characterized by dramatically reduced spontaneous physical activity. We have similarly demonstrated that obesity-resistant rats have significantly greater spontaneous physical activity than obesity-prone rats, and that spontaneous physical activity predicts body weight gain. Although the energetic cost of activity varies between types of activity and may be regulated, individual level of spontaneous physical activity is important in determining propensity for obesity. We review the current status of knowledge about the brain mechanisms involved in controlling the level of spontaneous physical activity and the NEAT so generated. Focus is on potential neural mediators of spontaneous physical activity and NEAT, including orexin A (also known as hypocretin 1), agouti-related protein, ghrelin, and neuromedin U, in addition to brief mention of neuropeptide Y, corticotrophin releasing hormone, cholecystokinin, estrogen, leptin, and dopamine effects on spontaneous physical activity. We further review evidence that strain differences in orexin stimulation pathways for spontaneous physical activity and NEAT appear to track with the body weight phenotype, thus providing a potential mechanistic explanation for reduced activity and weight gain.     

Spontaneous brain activity observed with functional magnetic resonance imaging as a potential biomarker in neuropsychiatric disorders

As functional magnetic resonance imaging (fMRI) studies have yielded increasing amounts of information about the brain’s spontaneous activity, they have revealed fMRI’s potential to locate changes in brain hemodynamics that are associated with neuropsychiatric disorders. In this paper, we review studies that support the notion that changes in brain spontaneous activity observed by fMRI can be used as potential biomarkers for diagnosis and treatment evaluation in neuropsychiatric disorders. We first review the methods used to study spontaneous activity from the perspectives of (1) the properties of local spontaneous activity, (2) the spatial pattern of spontaneous activity, and (3) the topological properties of brain networks. We also summarize the major findings associated with major neuropsychiatric disorders obtained using these methods. Then we review the pilot studies that have used spontaneous activity to discriminate patients from normal controls. Finally, we discuss current challenges and potential research directions to further elucidate the clinical use of spontaneous brain activity in neuropsychiatric disorders.     

Low-frequency stimulation induces stable transitions in stereotypical activity in cortical networks

Reverberating spontaneous synchronized brain activity is believed to play an important role in neural information processing. Whether and how external stimuli can influence this spontaneous activity is poorly understood. Because periodic synchronized network activity is also prominent in in vitro neuronal cultures, we used cortical cultures grown on multielectrode arrays to examine how spontaneous activity is affected by external stimuli. Spontaneous network activity before and after low-frequency electrical stimulation was quantified in several ways. Our results show that the initially stable pattern of stereotypical spontaneous activity was transformed into another activity pattern that remained stable for at least 1 h. The transformations consisted of changes in single site and culture-wide network activity as well as in the spatiotemporal dynamics of network bursting. We show for the first time that low-frequency electrical stimulation can induce long-lasting alterations in spontaneous activity of cortical neuronal networks. We discuss whether the observed transformations in network activity could represent a switch in attractor state.     

Increased Ca(2+) sparks and sarcoplasmic reticulum Ca(2+) stores potentially determine the spontaneous activity of pulmonary vein cardiomyocytes

Pulmonary veins (PVs) contain cardiomyocytes with spontaneous activity that may be responsible for PV arrhythmia. Abnormal Ca(2+) regulation is known to contribute to PV arrhythmogenesis. The purpose of this study was to investigate whether PV cardiomyocytes with spontaneous activity have different intracellular Ca(2+) ([Ca(2+)](i)) transients, Ca(2+) sparks and responses to isoproterenol and ryanodine receptor modulators (magnesium and FK506) than do PV cardiomyocytes without spontaneous activity and left atrial (LA) cardiomyocytes. Through fluorescence and confocal microscopy, we evaluated the [Ca(2+)](i) transients and Ca(2+) sparks in isolated rabbit PV and LA cardiomyocytes. PV cardiomyocytes with spontaneous activity had larger [Ca(2+)](i) transients and sarcoplasmic reticulum (SR) Ca(2+) stores than PV cardiomyocytes without spontaneous activity or LA cardiomyocytes. PV cardiomyocytes with spontaneous activity also had a higher incidence and frequency of Ca(2+) sparks, and had Ca(2+) sparks with larger amplitudes than other cardiomyocytes. Magnesium (5.4 mM) reduced the [Ca(2+)](i) transient amplitude and beating rate in PV cardiomyocytes with spontaneous activity. However, in contrast with other cardiomyocytes, low doses (1.8 mM) of magnesium did not reduce the [Ca(2+)](i) transients amplitude in PV cardiomyocytes with spontaneous activity. FK506 (1 muM) diminished the SR Ca(2+) stores in PV cardiomyocytes with spontaneous activity to a lesser extent than that in other cardiomyocytes. Isoproterenol (10 nM) increased the [Ca(2+)](i) transient amplitude to a lesser extent in LA cardiomyocytes than in PV cardiomyocytes with or without spontaneous activity. In conclusion, our results suggest that enhanced [Ca(2+)](i) transients, increased Ca(2+) sparks and SR Ca(2+) stores may contribute to the spontaneous activity of PV cardiomyocytes.     

Spontaneous activity of the isolated rabbit superior cervical sympathetic ganglion

Investigation of spontaneous activity (mean amplitude of spikes 200–300 µV, frequency from 0.07 to 2.9 Hz) in the rabbit superior cervical sympathetic ganglion by the sucrose gap method showed that this activity was completely blocked by D-tubocurarine and hexamethonium; its frequency was increased in hypertonic solution, by an increase in the external potassium concentration, and by the addition of theophylline and ethanol. These observations suggest that the activity observed is due to spontaneous liberation of acetylcholine mediator from preganglionic nerve endings. However, addition of tetrodotoxin and an increase in the external calcium concentration to 10 mM block spontaneous activity in the ganglion. This suggests that the observed spontaneous activity consists of action potentials.     

BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2

Spontaneous neural activity is a basic property of the developing brain, which regulates key developmental processes, including migration, neural differentiation and formation and refinement of connections. The mechanisms regulating spontaneous activity are not known. By using transgenic embryos that overexpress BDNF under the control of the nestin promoter, we show here that BDNF controls the emergence and robustness of spontaneous activity in embryonic hippocampal slices. Further, BDNF dramatically increases spontaneous co-active network activity, which is believed to synchronize gene expression and synaptogenesis in vast numbers of neurons. In fact, BDNF raises the spontaneous activity of E18 hippocampal neurons to levels that are typical of postnatal slices. We also show that BDNF overexpression increases the number of synapses at much earlier stages (E18) than those reported previously. Most of these synapses were GABAergic, and GABAergic interneurons showed hypertrophy and a 3-fold increase in GAD expression. Interestingly, whereas BDNF does not alter the expression of GABA and glutamate ionotropic receptors, it does raise the expression of the recently cloned K(+)/Cl(-) KCC2 co-transporter, which is responsible for the conversion of GABA responses from depolarizing to inhibitory, through the control of the Cl(-) potential. Together, results indicate that both the presynaptic and postsynaptic machineries of GABAergic circuits may be essential targets of BDNF actions to control spontaneous activity. The data indicate that BDNF is a potent regulator of spontaneous activity and co-active networks, which is a new level of regulation of neurotrophins. Given that BDNF itself is regulated by neuronal activity, we suggest that BDNF acts as a homeostatic factor controlling the emergence, complexity and networking properties of spontaneous networks.     

Negative relationship between odor-induced spike activity and spontaneous oscillations in the primary olfactory system of the terrestrial slug Limax marginatus

Although primary olfactory systems in various animals display spontaneous oscillatory activity, its functional significance in olfactory processing has not been elucidated. The tentacular ganglion, the primary olfactory system of the terrestrial slug Limax marginatus, also displays spontaneous oscillatory activity at 1-2 Hz. In the present study, we examined the relationship between odor-evoked spike activity and spontaneous field potential oscillations in the tentacular nerve, representing the pathway from the primary olfactory system to the olfactory center. Neural activity was recorded from the tentacular nerve before, during and after application of various odors (garlic, carrot, and rat chow) to the sensory epithelium and the changes in firing rate and spontaneous oscillations were analyzed. We detected the baseline amplitude of the oscillations and baseline spike activity before stimulation. Odor stimulations for 20 s or 60 s evoked a transient increase in the firing rate followed by a decrease in the amplitude of spontaneous oscillations. The decrease in the amplitude was larger in the first 8 s of stimulation and subsequently showed recovery during stimulation. The amplitude of the recovered oscillations often fluctuated. Odor-evoked spikes appeared when the amplitude of the recovered oscillations was transiently small. These results suggest that the large oscillations could inhibit spike activity whereas the first transient increase in spike activity was followed by the decrease in the oscillation amplitude. Our results indicate that there is a significant negative correlation between spontaneous oscillations and odor-evoked spike activity, suggesting that the spontaneous oscillations contribute to the olfactory processing in slugs.     

The influence of day-night cycles and the additive effects of methamphetamine and illumination on the spontaneous activity in rhesus monkeys (Macaca mulatta)

The spontaneous activity of rhesus monkeys in a cage situation was measured under 12 hr. day-night cycles in Exp. I. Without exception, all the subjects (n=10) proved to be more active in the daytime than at night. In Exp. II the effect of methamphetamine upon spontaneous activity was investigated in light and dark conditions. It is supposed in the present study that methamphetamine and illumination raise the arousal level of the subjects and increase their spontaneous activity. The results show that the spontaneous activity of rhesus monkeys, which are thought to be visually dominant, greatly depends on illumination. That is, rhesus monkeys move around well in light conditions but little in dark conditions. Methamphetamine increases spontaneous activity, however, in dark as well as in light conditions. Interaction between methamphetamine and illumination effects was not significant. It would appear from these results that both internal and external factors—methamphetamine and illumination—feed into a common pool of the arousal level which controls spontaneous activity.     

Effect of human plasma proteins on spontaneous contractile activity of rat mesenteric portal vein.

This study examines the effect of various plasma proteins from man on the spontaneous contractile activity of the rat portal vein. Albumin, gamma-globulin, alpha-globulin, beta-globulin (the major plasma proteins), and immunoglobulin IgG (the major immunoglobulin present in the gamma-globulin fraction) were obtained commercially. Mesenteric portal vein strips were prepared from rats and placed in a physiological salt solution in muscle baths for the measurement of longitudinal mechanical response. Portal veins exposed to albumin or gamma-globulin showed a dose-dependent increase in the spontaneous activity, whereas those exposed to alpha-globulin or alpha- and beta-globulin together showed a dose-dependent inhibition of spontaneous activity. Immunoglobulin IgG produced a dose-dependent increase in the spontaneous activity similar to that of gamma-globulin. The increased spontaneous activity produced by albumin was not prevented by ouabain but was inhibited by phentolamine. Spontaneous contractile activity was stimulated by albumin in the chemically (6-hydroxydopamine) denervated portal vein. These findings indicate that albumin acts in a manner similar to noradrenaline. The increased spontaneous activity caused by gamma-globulin (IgG) was inhibited by ouabain or verapamil. The effect of IgG was not dependent on alpha-adrenergic, cholinergic, histaminergic, serotoninergic, or renin angiotensin systems nor was it affected by removal of the endothelium. These observations may have implications in the pathophysiology of essential hypertension.     

Comparison of spontaneous cortical unit activity in several brain areas of unanesthetized cats

Spontaneous unit activity in association area 5 and some projection areas of the cortex (first somatosensory, first and second auditory areas) were studied in cats immobilized with D-tubocurarine in which the index of specific spontaneous activity, the mean frequency, types of spontaneous activity, and statistical parameters — distribution of interspike intervals and autocorrelation function — were determined. The results showed that spontaneous unit activity in the association area differs from that in the projection areas in both intensity and character. A special feature of the spontaneous activity of the auditory areas was a well-marked volley distribution of activity. In the somatosensory area the level of spontaneous activity as reflected in all indices was the lowest. In the association cortex the largest number of neurons with spontaneous activity lay at a depth of 500–1000 µ corresponding to cortical layers III–IV. In the first auditory area neurons with spontaneous activity were concentrated at a depth of 1400 µ (layer V) and in the somatosensory area at a depth of 1000–1400 µ (alyers IV–V). The possible functional significance of these differences is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 8, No. 1, pp. 13–21, January–February, 1976.     

Dynamics of spontaneous activity in neocortical slices.

The flow of activity in the cortical microcircuitry is poorly understood. We use calcium imaging to reconstruct, with millisecond and single-cell resolution, the spontaneous activity of populations of neurons in unstimulated slices from mouse visual cortex. We find spontaneous activity correlated among networks of layer 5 pyramidal cells. Synchronous ensembles occupy overlapping territories, often share neurons, and are repeatedly activated. Sets of neurons are also sequentially activated numerous times. Network synchronization and sequential correlations are blocked by glutamatergic antagonists, even though spontaneous firing persists in many "autonomously active" neurons. This autonomous activity is periodic and depends on hyperpolarization-activated cationic (H) and persistent sodium (Na(p)) currents. We conclude that the isolated neocortical microcircuit generates spontaneous activity, mediated by a combination of intrinsic and circuit mechanisms, and that this activity can be temporally precise.     

Cortical development: the sources of spontaneous patterned activity

A recent study has found that spontaneous neural activity in the developing visual cortex has two distinct origins - local intracortical circuits and spontaneous activity in the retina.     

Spontaneous neural activity of a mechanoreceptive system is undiminished by replacement of external calcium with equimolar magnesium in the presence of EGTA

Primary afferent neurons of the lateral-line mechanosensory organs, which are believed to be closely related to the auditory and vestibular organs, exhibit "spontaneous" action potentials in the absence of mechanical stimulation of the receptor cells (hair cells). Sinusoidal mechanical stimulation of the hair cells enhances the impulse rate of the afferent neurons. The spontaneous activity is found to be a decreasing function of increasing concentration of either external magnesium or calcium, when each cation is varied in the absence of the other and bath-applied to the synaptic side of the lateral-line mechanoreceptors. One mM to 6 mM magnesium with 5 mM EGTA (the latter for chelation of remaining traces of calcium) permits undiminished spontaneous afferent activity of lateral-line neurons for as long as 3 to 4 hours. With bath-applied calcium, mechanical stimulation results in evoked incremental activity--defined as total activity with stimulation minus spontaneous activity--which significantly increases with increasing calcium concentration. However, with magnesium and EGTA in the bath, mechanical stimulation produces no increase in the neural firing rate above spontaneous rate for any magnesium concentration tested. Taken together, these results suggest that spontaneous activity, in contrast to evoked incremental activity, does not require external calcium in the bath, and production of spontaneous neural action potentials may proceed via mechanisms that are modifications of those of classical stimulus-secretion coupling.     

Spike Discharge Patterns of Spontaneous and Continuously Stimulated Activity in the Cochlear Nucleus of Anesthetized Cats

Interspike interval histograms of spontaneous and stimulated activity were computed from spike discharges of single units in the cochlear nucleus. These histograms indicate that a number of different types of spontaneous discharge patterns exist in the nucleus. The type of spontaneous activity of a given unit is related to its activity in response to continuous tones. Correlations were found between the discharge patterns of units and their anatomical locations within the nucleus.     

The suprachiasmatic nucleus exhibits diurnal variations in spontaneous excitatory postsynaptic activity

A most prominent feature of neurons in the suprachiasmatic nucleus (SCN) is the circadian rhythm in spontaneous firing frequency. To disclose synaptic mechanisms associated with the rhythmic activity, the spontaneous postsynaptic activity was studied using whole-cell, patch clamp recordings in the ventral region of the SCN in slice preparations from rats. The synaptic events were compared between two time intervals corresponding to the highest and lowest electrical activity within the SCN during subjective daytime and nighttime, respectively. The gamma-aminobutyric acid (GABA)-mediated spontaneous inhibitory activity showed no diurnal variations, but the excitatory activity was markedly higher in frequency, without differences in amplitude, during the subjective day compared to the subjective night. Spontaneous and evoked inhibitory synaptic events were blocked by the GABA(A) receptor antagonist bicuculline. The alpha-amino-hydroxy-5-methylisoxazole-4-propionic acid (AMPA/kainate) receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) blocked most of the excitatory activity. In addition, CNQX reduced the spontaneous inhibitory activity. The N-methyl-D-aspartate antagonist D-2-amino-5-phosphonopentanoic acid reduced the inhibitory activity to a lesser degree, and there was no significant difference in amplitude or frequency of synaptic events in control and Mg2+-free solutions, indicating that the AMPA receptor plays an important role in regulating the inhibitory release of GABA within the SCN. Ipsi- and contralateral stimulation of the SCN consistently evoked excitatory synaptic responses. Inhibitory synaptic responses occurred in some neurons upon increasing stimulus strength. In conclusion, this study shows that there is a substantial influence from spontaneous glutamatergic synapses on the ventral part of the SCN and that these exhibit daily variations in activity. Diurnal fluctuations in spontaneous excitatory postsynaptic activity within this network may contribute to the mechanisms for synchronization of rhythms between individual SCN neurons and may underlie the daily variations in the spontaneous firing frequency of SCN neurons.     

Failure to maintain eye-specific segregation in nob, a mutant with abnormally patterned retinal activity

Axon terminals from the two eyes initially overlap in the dorsal-lateral geniculate nucleus (dLGN) but subsequently refine to occupy nonoverlapping territories. Retinal activity is required to establish and maintain this segregation. We show that despite the presence of retinal activity, segregated projections desegregate when the structure of activity is altered. Early in development, spontaneous retinal activity in the no b-wave (nob) mouse is indistinguishable from that of wild-type mice, and eye-specific segregation proceeds normally. But, around eye-opening, spontaneous and visually evoked activity in nob retinas become abnormal, coincident with a failure to preserve precise eye-specific territories. Dark-rearing studies suggest that altered visual experience is not responsible. Transgenic rescue of the mutated protein (nyctalopin) within nob retinal interneurons, without rescuing expression in either retinal projection neurons or their postsynaptic targets in the dLGN, restores spontaneous retinal activity patterns and prevents desegregation. Thus, normally structured spontaneous retinal activity stabilizes newly refined retinogeniculate circuitry.     

The relationship between caudal differential pressure and activity of Atlantic cod: a potential method to predict oxygen consumption of free-swimming fish

This study reports the first results on telemetry of caudal differential pressure during spontaneous swimming activity in cod Gadus morhua and demonstrates that tail-beat pressure may be used as a predictor of activity and swimming costs of free-swimming cod. Tail-beat pressure was monitored using a differential pressure sensor on the caudal peduncle of cod and spontaneous swimming activity was quantified using a customized video-computer tracking programme. Tail-beat pressure was found to correlate with (1) swimming speed ( U ) and oxygen consumption during forced swimming and (2) mean U during spontaneous activity. Based on the relationship between and the integrated pressure performed by the tail during forced swimming, it should be possible to predict during spontaneous activity. To gain precise measures of activity and thus predictions of for free-swimming fish, however, individual calibrations are necessary.     

Effects of metabolic inhibitors on spontaneous and interferon-boosted human natural killer cell activity

Human natural killer (NK) cell activity can be augmented by pretreatment with partially purified preparations of human interferon (IF). Studies have now been performed to determine the metabolic processes required for and involved in spontaneous NK activity and augmentation of cytotoxicity. A 4-hr 51Cr release cellular cytotoxicity assay was used to measure the NK activity, and peripheral blood leukocyte cells (PBL) were treated with: a) x-ray or mitomycin C; b) actinomycin D; or c) emetine, cycloheximide, pactamyhcin, or puromycin to assess the roles of DNA, RNA, and protein synthesis, respectively, in spontaneous NK activity and in boosting by IF. Prolonged incubation (18 hr) of PBL after blockage of synthesis of DNA almost completely abrogated NK activity; however, NK activity could be partially or totally restored to these populations by incubation of the effector cells for 1 hr at 37 degrees C with IF. Blockage of DNA synthesis for 1 hr had no effect on spontaneous NK activity or on boosting by IF. Inhibition of RNA synthesis also had no effect on spontaneous NK activity. Treatment of PBL with actinomycin before exposure to IF prevented boosting, but treatment with the RNA synthesis inhibitor after boosting with IF for 5 to 6 hr no longer had an appreciable effect on cytotoxicity. The effect of protein synthesis inhibitors on spontaneous NK activity was dependent on the inhibitor selected. Emetine and puromycin totally abrogated spontaneous NK activity at concentrations of inhibitor that blocked 3H-leucine incorporation 90% or more. In contrast, cycloheximide and pactamycin had only minimal effects on spontaneous NK activity but totally abrogated the boosting of IF.     

Modulation of activity in starling cochlear ganglion units by middle-ear muscle contractions,perilymph movements and lagena stimuli

In the present study three groups of cochlear ganglion neurons were detected which differed in respect to their tone-evoked and spontaneous activity: auditory units which showed an irregular spontaneous discharge, non-auditory neurones with regular activity and such with an irregular spontaneous discharge pattern. Electrically-elicited contractions of the middle-ear muscle influenced the tone-evoked and/or the spontaneous activity of the auditory and the non-auditory neurones with irregular spontaneous discharge but not, however, the regularly firing units. Similar results were obtained with imposed perilymph movements in the cochlea (evoked via the vestibular system. Fractions of all three groups of cochlear ganglion neurones were responsive to direct deformations of the membraneous lagena. Several (auditory and non-auditory) units with irregular discharge were excited during a basilar membrane displacement towards scala vestibuli whereas a basilar membrane motion towards scala tympani resulted in a decrease of the discharge rate. A few units showed a different reaction. The results provide evidence that the neurones with periodic spontaneous discharge innervate the lagena and that this sense organ has no auditory significance in birds. The peripheral origin of the 'non-auditory' neurones with irregular spontaneous activity remains undecided and might be the macula lagenae or the apical portion of the basilar papilla.     

Microiontophoretic study of the effect of biogenic amines on unit activity in the rabbit visual cortex

The effect of acetylcholine, noradrenalin, and serotonin on spontaneous activity of visual cortical neurons and on their activity evoked by flashes, recorded extracellularly, was studied by microiontophoresis in unanesthetized rabbits. The ability of visual cortical neurons to respond to light does not correlate with their sensitivity to acetylcholine. This substance, which changes the spontaneous firing rate of many of the neurons tested, was less effective against their evoked activity. Noradrenalin had a powerful depressant action on both spontaneous and evoked activity of most neurons studied. Serotonin acted in different ways on the spontaneous and evoked activity of some neurons tested. It is postulated that acetylcholine mediates reticulo-cortical inputs, noradrenalin is a true inhibitory mediator in the cerebral cortex, and serotonin has a presynaptic action by preventing the liberation of natural mediators.