TLRs can act alone or heterodimerize to create specific responses to a given stimuli. All TLRs except TLR3 signal through the adaptive protein Myd88, which leads to the induction of NF-κB and the release of cytokines, such as IL-1β, TNF-α, and IL-12. Conversely, TLR3 cannot activate Myd88 but signals through a TRIF-dependent pathway, Ipatasertib manufacturer leading to the induction of IRF3 and the production of other cytokines, such as IFNβ. TLR4 can also signal through TRIF with the help of the adaptor protein TRAM. Both Myd88 and TRIF-dependent signaling pathways can also engage

mitogen-associated protein kinase (MAPK) pathways, including ERK1/2, p38, and JNK, which lead to the stimulation of cell growth and

the induction of inflammatory cytokine production (Brown et al., 2011). For an in-depth review of TLR pathways, the reader can consult Hanke and Kielian (2011) and Rivest (2009). A function for NLRs in neuroinflammation is a rather recent discovery. Mostly known for their functions in the spleen and lymph nodes, there is much still to learn of their roles in the CNS. Among the 21 members of the NLR family, NLRP1-3, NLRP6, NLRP10, NOD1, Bioactive Compound Library and NOD2 show the highest level of expression in the CNS, mostly in microglia but also in astrocytes, oligodendrocytes, neurons, and endothelial cells for some subtypes (Rosenzweig et al., 2011). almost Among these, NLRP3 and NOD2 have been the most studied so far because of their implication in autoinflammatory diseases of the CNS (Deane et al., 2012). NOD2 can respond to muramyl dipeptide (MDP, a PAMP from bacterial cell walls) and viral ssRNA (Ribes et al., 2012). NOD2 activates NF-κB transcription through the adaptor protein RICK, which leads to the production of proinflammatory cytokines in response to MDP (Ribes et al., 2012). In response to viral ssRNA, NOD2 activates the IRF3 transcription factor with the MAVS

adaptor protein, leading to the release of type 1 interferons (Strober and Watanabe, 2011). NLRP3 is normally in a repressed state, bound to specific chaperone proteins. The presence of an array of different signals can liberate and therefore activate NLRP3. Such signals include PAMPs, DAMPs, and intact pathogens (Zambetti et al., 2012). Upon its release, NLRP3 activates the inflammasome, a complex of proteins that includes caspase-1, leading to the release of active IL-1β from a precursor (Zambetti et al., 2012). The final type of pattern recognition receptors, RIG-1-like receptors, is geared toward the recognition of viral nucleic acids in the cytoplasm (Creagh and O’Neill, 2006). Three members of this family have been described so far: retinoic acid-induced gene 1 (RIG-1), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2).

To

more accurately address peptide mobility in brain tissue, two-photon sensitive caging groups must be employed so that release will be restricted to μm3-scale volumes. Here, we have described photoactivatable tools for the study of opioid signaling within the mammalian brain. By caging both LE and Dyn-8, we provide reagents that can be used to study mu, delta, and kappa receptors. Using UV-mediated photolysis of caged LE in brain slices, we demonstrated that somatic mu receptors in the LC generate an outward current mediated primarily by K+ channels. These reagents allowed us to probe the mechanisms that regulate the spread click here of opioid signaling in brain tissue and revealed that with graded, temporally precise, and spatially confined release, neuropeptides are capable of subtle and relatively short-lasting

modulation of neuronal function. This approach represents a general strategy for probing the spatiotemporal dynamics of neuropeptides and should be applicable to other peptide transmitters. These reagents are expected to interface well with two-photon Ca2+ and voltage imaging methods, as the CNB chromophore exhibits poor sensitivity to two-photon excitation. Similarly, one-photon excitation, with the visible wavelengths used to image fluorophores such as GFP and activate light-sensitive ion channels such as channelrhodopsin, is MK 8776 also compatible with our probes. However, the intense UV light used for uncaging can photobleach fluorophores and partially activate channelrhodopsin, so care must be taken to control the area of illumination and minimize the requisite UV

light intensity in these contexts. Extension to in vivo studies, including amperometry to measure the effects of opioids on monoamine release, should be possible by equipping optrodes and fiberoptic coupled carbon fibers with perfusion lines for peptide delivery and may thus enable spatiotemporal studies into opioidergic modulation of behavior with unprecedented precision. Custom chemical synthesis was carried out by Peptech Corporation (Burlington, MA) using standard Fmoc-based solid-phase peptide synthesis. The carboxynitrobenzyl-modified tyrosine was prepared by modifying established protocols (Sreekumar et al., 1998). most After arrival, CYLE and CYD8 were typically handled under lighting filtered using Rosculux #312 Canary optical filter paper to remove any traces of UV light that could lead to unintentional photolysis. It was essential to further purify the synthetic material by semipreparative reverse-phase high-pressure liquid chromatography (RP-HPLC, Agilent) to remove contaminating photolysis products, which typically included ∼1% LE or Dyn-8. Crucially, the UV (and VIS) lamps on the detector were turned off during the purification to prevent photolysis of the purified material.

Regular-spiking neurons responded with single spikes early in the train and bursts later, whereas bursting neurons fired bursts early in the train and single spikes later (Figures 4A and 4B). As both types of neurons can

and do elicit bursts, the present nomenclature for the observed physiological heterogeneity is misleading. Therefore, we introduce a new nomenclature: late-bursting (previously “regular-spiking”) and early-bursting (previously “bursting”) pyramidal neurons. Although we chose names based on their bursting patterns in response to trains of inputs, there are many additional differences between the two cell types (summarized in Table 2). We studied the long-lasting modulation of pyramidal cell firing patterns using synaptic theta-burst stimulation (TBS)—a commonly used plasticity-induction

protocol that mimics hippocampal activity in vivo during spatial exploration and other learning tasks. To establish a normative baseline prior to plasticity Dolutegravir in vivo induction, we adjusted the somatic current injection amplitude to elicit on average four bursts out of ten inputs per train during the baseline period and held this amplitude constant for the duration of the experiment. After measuring neuronal output by counting the number of bursts elicited by each train during a 10 min baseline period, we delivered TBS (see Experimental Procedures) and measured the ensuing changes in bursting. Because neuronal output in response to somatic current injection is controlled by activation of intrinsic voltage-gated or Ca2+-activated ion channels, changes in the those number of burst responses were a measure of altered intrinsic click here postsynaptic excitability.

Expanding on previous work focusing on early-bursting cells (Moore et al., 2009), we found that both types of neurons throughout CA1 and the subiculum displayed a long-lasting increase in bursting after synaptic TBS in normal artificial cerebrospinal fluid (ACSF) (Figures 4C–4E and Figure S3). As shown for a representative late-bursting neuron in CA1 and an early-bursting neuron in the subiculum, four bursts were elicited during the baseline period (Figure 4A) and nine bursts were elicited by the same stimulus after TBS (Figure 4C). This plasticity of bursting (“burst plasticity”) was activity dependent—in the absence of synaptic TBS, the level of bursting did not change over the course of 50 min (Figure S3A). We investigated the pharmacology of burst plasticity induction in the two cell types throughout CA1 and the subiculum. We found that the induction of burst plasticity in both cell types did not require activation of ionotropic glutamate receptors or GABAA and GABAB receptors (Figures S3B and S3C). Rather, plasticity induction depended on selective activation of metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors (mAChRs). Interestingly, the two types of neurons differed strikingly in their response to the activation of specific subtypes of receptors (Figure 4F and Figures S3D–S3K).

J.J.F.R.-F. was supported by the Fundação para a Ciência e Tecnologia, scholarship SFRH/BD/33273/2007, A.S. by an INRSA Training Grant in Quantitative Neuroscience

2 T32 MH065214, A.G.B. by AFOSR Grant FA9550-08-1-041, Y.N. by a Sloan Research Fellowship, and M.M.B. by the National Institute of Mental Health Grant P50 MH062196 and a Collaborative Activity Award from the James S. McDonnell Foundation. “
“For almost 50 years, we have known that nuclear histones are modified by reversible acetylation (Allfrey et al., 1964). Histone acetyl transferases (HATs) acetylate lysines in these proteins and thereby neutralize their positive charge, reduce their affinity for negatively charged DNA, and make DNA more accessible for transcription and transcriptional control (Figure 1). Histone acetylation FG4592 and deacetylation also play important this website roles in the nervous system, where acetylation is implicated in synaptic plasticity and memory formation. For instance, in Aplysia, the neurotransmitter serotonin activates histone acetylation in the promoter region of the immediate early gene C/EBP, which is necessary for synaptic facilitation ( Guan et al., 2002).

This effect can be enhanced by inhibitors of deacetylases (HDACs, Figure 1). In rodents, HDAC inhibitors induce sprouting of dendrites, an increased synapse number, and improved performance in memory tasks ( Fischer et al., 2007). Not surprisingly,

HDAC inhibitors are neuroprotective, and HDACs are candidate drug targets for the treatment of memory dysfunction and neurodegenerative diseases, such as Alzheimer’s disease. Recent studies suggest that HATs are also cytosolic, that many cytosolic proteins are also acetylated, and that this affects a wide range of cellular functions such as cytoskeletal dynamics, cellular transport, protein folding, and receptor signaling (Choudhary et al., 2009 and Sadoul et al., 2011). Elongator protein 3 (ELP3) is one such cytosolic HAT. It is the catalytic subunit of the six-subunit Elongator complex first described in yeast as a component of RNA polymerase II involved in transcription elongation Mannose-binding protein-associated serine protease in the nucleus (Otero et al., 1999). ELP3 contains a histone acetyl transferase motif, and the Elongator complex indeed acetylates histones. However, most ELP3 is present in the cytosol, where it was implicated in tRNA modification (Svejstrup, 2007). Using forward genetic screens in Drosophila, elp3 recently surfaced in relation to synaptic function ( Simpson et al., 2009). In this issue of Neuron, Miśkiewicz et al. (2011) now present the first direct evidence for such a synaptic function at the fly neuromuscular junction (NMJ).

(2012) extend these findings to implicate mTOR in age-induced deterioration of POMC neurons leading to hyperphagic obesity. Nevertheless, it remains unclear how hypertrophy of POMC neurons leads to dysregulation of neuronal projections and neurotransmitter release and what the intracellular and extracellular triggers of this process are. An intriguing recent finding was the observation of peroxisome proliferation in POMC neurons associated with diet-induced obesity ( Diano et al., 2011). This process is related to glucose and lipid overload to POMC neurons ( Diano et al., 2011), which is also a fundamental prerequisite of cellular growth. In that case, reversal of peroxisome proliferation resulted in restoration of POMC

neuronal firing by enhancing generation of reactive oxygen species ( Diano et al., VX-770 cost 2011). Thus, it is possible that mTOR-related cellular growth of POMC neurons may also impair cellular metabolism and ROS control. Yang et al. (2012)

explored whether constant Imatinib concentration elevation of mTOR signaling in either POMC neurons or NPY/AgRP neurons may lead to obesity or weight loss using an elegantly designed mouse model. To accomplish cell-selective upregulation of mTOR signaling in either of these cell populations, they crossed POMC-Cre or AgRP-Cre mice with floxed TSC1 mice. TSC1 is a negative regulator of mTOR; hence, its cell-specific knockdown in either POMC or AgRP neurons would lead to chronically elevated mTOR signaling in these cells. They confirmed the findings of Mori

et al. (2009), showing that elevation of mTOR signaling induced by deletion of the Tsc1 gene in POMC neurons silenced POMC neuron activity and resulted in hyperphagic obesity even in young mice. Intriguingly, however, deletion of the Tsc1 gene in NPY/AgRP neurons had no effect on the firing rate and soma size of these neurons. They further corroborated these findings by investigating the effect of intracerebral infusion of rapamycin, an inhibitor of mTOR signaling, on metabolic phenotype and neuronal activity. Rapamycin has been proposed as a putative promoter of longevity and suppressor of metabolic disorders and neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Central administration of rapamycin rescued silencing and hypertrophy of POMC neurons during chronological aging and suppressed STK38 age-dependent obesity. On the other hand, consistent with patterns of the conditional KO mice deleting Tsc1 gene in NPY/AgRP neurons, rapamycin had no effect on NPY/AgRP neuronal activity. One possible explanation for the “insensitivity” of NPY/AgRP neurons to rapamycin is that NPY/AgRP neurons may be more reliant on other intracellular pathways for their firing, such as fatty acid metabolism ( Andrews et al., 2008). To elucidate an underlying mechanism for the observed phenomenon, Yang et al. (2012) revealed a contribution of KATP channel activity in the age-related silencing of POMC neurons.

Fig. 1B indicates

that the addition of ALDO at 10−12 M to the bath increased the pHirr. However, Fig. 1C shows that the addition of ALDO at 10−6 M Navitoclax price decreased the pHirr, and pHi recovery was not complete. Fig. 2A shows a representative experiment to indicate that with ANP (10−6 M) alone, the pHirr and the final pHi were not different from the control value. However, Fig. 2B and C shows that ANP impaired both the stimulatory and inhibitory effects of ALDO on the pHirr (and during both situations, the final pHi was not different from the basal value). Fig. 3 shows that in the control situation (140 mM Na+e) the mean pHirr was 0.195 ± 0.012 pH units/min (16/96), and the superfusion of tubules with HOE 694 alone inhibited the pHirr, indicating that the pHirr

is mostly due to the basolateral NHE1 in S3 segments. In addition, Fig. 3 shows that in the absence of Na+e (a condition that inhibits the activity of Na+/H+ exchanger), there was a significantly lower pHirr, indicating that a Na+-independent H+ extrusion mechanism exists in the S3 segment of normal rats. This small pHirr was abolished by concanamycin, showing that the H+-ATPase is the only mechanism responsible for this Na+-independent click here H+ transport. However, this mechanism of cellular extrusion of H+ initiates about 2.5 min after cellular acidification with the NH4Cl pulse. Fig. 4 indicates that 10−12 M ALDO increased the pHirr by approximately 59% of the control value, and 10−6 M ALDO decreased it by approximately 49% heptaminol of the control value. Spironolactone alone

did not alter the pHirr and did not prevent the stimulatory and the inhibitory effects of ALDO on the Na+/H+ exchanger, demonstrating that this rapid biphasic effect of ALDO is independent of binding with the MR receptor. RU 486 alone decreased the pHirr (approximately 39% of control value); in addition, RU 486 abolished the stimulatory effect of ALDO but did not alter its inhibitory effect on the Na+/H+ exchanger. These results suggest that the GR antagonism interferes with the nongenomic stimulatory effect of ALDO on the Na+/H+ exchanger. Fig. 4 also shows that, compared to the control, ANP or BAPTA alone did not significantly alter the pHirr; however, ANP or BAPTA significantly abolished both stimulatory and inhibitory effects of ALDO on the pHirr. Table 2 summarizes the mean values of pHi and pHirr responses found in all experimental groups studied. Fig. 5 gives the cell calcium fluorescent signal tracing during 3 min in one representative experiment from each of 6 experimental groups. The images were continuously acquired (at time intervals of 2 s) before and after the addition of different drug solutions to the bath. The baseline value did not significantly change. However, approximately 0.4 min after the addition of ALDO (10−12 M or 10−6 M), there was a transient (approximately 1.

, 2005, 2006; Doi et al., 2011). VIP and, to a lesser extent, vasopressin and gastrin releasing peptide have been shown to mediate rhythm stability in and synchrony among circadian cells (Maywood et al., 2011). In contrast, we have found GABA to destabilize and desynchronize circadian cells. Synchronization and desynchronization are thus both

active processes that can be differentially modulated. It is interesting to speculate that developmental and seasonal changes may alter the balance between fast neurotransmission and slower neuropeptide signaling to adjust the timing among SCN neurons. It is possible that GABA plays an important role within this setting to actively drive networks of oscillators to new phase relationships. Additionally, recent work suggests that a hierarchy

of neuropeptidergic signals may differentially promote or sustain rhythmicity and synchrony among SCN cells (Maywood et al., 2011). In light of our results, we must place GABAA Sunitinib mouse signaling within this hierarchy and classify potential synchronizing agents by their ability to overcome the destabilizing effects of GABA. Our data suggest that VIP may be the only agent capable of overcoming this destabilizing effect since it is only after VIP signaling is eliminated that the desynchronizing effects this website of GABA are unmasked. Given that VIP signaling diminishes during aging (Cayetanot et al., 2005), increasingly unopposed GABAergic signaling may weaken SCN neuronal synchrony and contribute Cytidine deaminase to sleep/wake cycle fragmentation in the elderly. See a detailed description in the Supplemental Experimental Procedures. All animal procedures complied with National Institutes of Health (NIH) guidelines and were approved by the Washington University Animal Care and Use Committee. Spike trains from SCN neurons were recorded using MEAs and the Z score and strength of each interaction was measured. We graphed functional connections with GUESS software and analyzed network architecture with NodeXL software. We developed an empirical method to discriminate correlated activity that derived from real versus coincidental neuronal interactions. We reasoned

that correlations between spike trains recorded from neurons in physically distinct culture dishes do not signify connectivity. Using this logic, we iteratively cross-correlated spike trains from all neurons across 10 cultures (samples) over 1 hr to determine the distribution of Z scores associated with inherently false across-sample correlations. Using the full distribution of false across-sample correlations, we determined Z score magnitude thresholds that corresponded with likelihoods of discovering false-positive across-array correlations. To determine if connection strength systematically changed with time of day, we fit the strength versus time data with linear and cosine functions and estimated the resultant p value using the F test. PER2::LUC expression from SCN explants was measured using photomultiplier tubes or a CCD camera.

, 1996). In addition, the charged residues in the S4s, especially of domains III and IV, are also important for Nav inactivation (Cha et al., 1999). However, difference in the S4s alone may not explain why NALCN

is voltage insensitive and doesn’t have inactivation. Indeed, a mutant tetrameric K+ channel can still be voltage-gated even when artificially engineered to have only one 6-TM subunit (equivalent to one of the four domains in the 24-TM channels) with an intact S4 but the other three without any charged residues in their S4s (Gagnon and Bezanilla, 2009). On the other hand, cyclic-nucleotide-gated (CNG) channels made of tetramers of 6-TM proteins are only weakly voltage-sensitive despite having charged residues in their S4s. Indeed, when the S4 of CNGA2 is used to replace Ku-0059436 cell line that of the EAG (KCNH2) Kv channel, it is fully functional in sensing voltage changes and in supporting a voltage-gated K+ channel (Tang and Papazian, 1997). It therefore remains possible that NALCN’s voltage insensitivity lies in regions besides the S4s, such as the C-terminal part of S3 and the S3-S4 linker that together MK-8776 in vivo with S4 form the voltage-sensor paddle as shown in the crystal structure of Kv channels (Jiang et al., 2003). Alternatively, NALCN’s

VSDs may be functional but there is “defect” in the coupling between voltage-sensing and channel gating. The functionality of NALCN’s four VSDs can be tested by transferring each Casein kinase 1 of them into homotetrameric Kv channels (Bosmans et al., 2008 and Xu et al., 2010). The second unique feature of NALCN is its pore filter (Figure 3B). The selectivity filter in CaV, NaV, and KV is surrounded by the VSDs and is formed by the S5-S6 pore (P) loops that are contributed by each 6-TM domain (Doyle et al., 1998, Jiang et al., 2003, MacKinnon, 1995, Miller, 1995 and Payandeh et al., 2011). In CaVs, the Ca2+ selectivity requires one glutamate (E) or aspartate (D) residue contributed

from each of the four homologous repeats (EEEE motif) in the pore filter (Heinemann et al., 1992 and Yang et al., 1993). NaVs have a DEKA motif in the analogous position (Figure 3B). NALCN has an EEKE motif, a combination of the EEEE (CaV) and DEKA (NaV) motifs. The EEKE motif is conserved in NALCN homologs in mammals, D. melanogaster and C. elegans. NALCN from the fresh water snail Lymnaea stagnalis has an EKEE motif ( Lu and Feng, 2011). In Nav, mutating the DEKA motif into DEKE converts the Na+ selective channel into a channel conducting primarily Na+ but also some K+ and Ca2+ ( Schlief et al., 1996). Likewise, mutating the EEEE motif of CaVs into EEKE enables the otherwise highly Ca2+-selective channels permeable to monovalent ions ( Parent and Gopalakrishnan, 1995, Tang et al., 1993 and Yang et al., 1993).

, 2007 and Spassky et al., 2005). Lineage tracing of radial glia by neonatal viral infection

also shows that they give rise to multiciliated Obeticholic Acid mw ependymal cells, striatal astrocytes, and oligodendrocytes, indicating that radial glia are the developmental predecessors of the adult VZ-SVZ. Type B1 cells have several characteristics that are reminiscent of their radial glial progenitors—a thin apical process with a primary cilium extending into the ventricular lumen, a basal process that extends to reach blood vessels, and behavior that is reminiscent of the interkinetic nuclear migration observed in the embryo (Doetsch et al., 1997, Mirzadeh et al., 2008, Shen et al., 2008 and Tavazoie et al., 2008). Therefore, this periventricular germinal niche, previously referred to as the SVZ, also includes a compartment that directly contacts the ventricle, reminiscent of the ventricular zone (VZ) in the embryo. Multiple lines of evidence suggest that signals arising from the ciliated ependymal cells and the cerebrospinal fluid (CSF) in the ventricle may influence the activity of cells in the adult VZ-SVZ. The walls of the lateral ventricles exhibit a specific planar organization: the small apical processes of one or more type B1 cells are surrounded by a rosette of ependymal cells, forming pinwheel

structures on this surface (Figure 1; Mirzadeh et al., 2008). This organization is unique to regions of the ventricular wall where neurogenesis continues throughout life. Interestingly, B1 cells establish symmetric adherens junctions with

other adjoining B1 cells in the center of pinwheels and asymmetric contacts check details with surrounding ependymal cells, highlighting a possible mechanism for affecting stem cell state via direct adhesive contacts. Mapping of the numbers of ventricle-contacting type B1 cells along the ventricular surface reveals “hotspots” where large numbers of these cells are observed, suggesting a possible correlation with sites of stem cell activation or increased division (Mirzadeh et al., 2008). While it is clear from lineage tracing experiments that ventricle-contacting astrocytes are neurogenic, it is not yet known whether ventricular contact, or specialized contact with the ependyma, is a requirement for neurogenesis. In fact, neurogenic stem cells are the present all along the RMS, where there is no apparent open ventricle (Vicario-Abejón et al., 2003, Merkle et al., 2007 and Alonso et al., 2008). Specifically, the role of CSF components in the regulation of the proliferation and differentiation of B1 cells remains unknown. The unique location of the type B1 cell primary cilium contacting the CSF raises several intriguing possibilities for the regulation of stem cell activity. The primary cilium can have a mechanosensory function, suggesting that the force of CSF flow itself may exert an influence on the proliferative state of the stem cell (Singla and Reiter, 2006).

Fukushima et al. (2012) are inclined toward the position that the signal arises primarily

from neuronal spiking in the superficial layers of auditory cortex, based on a proximity argument and on a prior study in rodent auditory cortex. This seems to us to be unlikely, given that in the auditory cortices selleck of the awake monkey, the massive weight of both stimulus-evoked and spontaneous firing is in the granular layers compared to the relatively sparse firing seen in the more superficial layers (see e.g., Kajikawa and Schroeder, 2011). Assuming, as the authors do, that high-gamma power is related to multiunit firing, high gamma generated by high-volume firing in the middle layers is likely to overwhelm any generated by the much more sparse firing in supragranular sites. Fukushima et al. (2012) raise a number of logical possibilities regarding underlying causes of structure in ongoing auditory cortical activity, based on a detailed consideration of the relevant anatomical connectivity

patterns between core and higher-order high throughput screening cortices and between auditory core and thalamic regions. They also discuss a provocative idea that ongoing activity in auditory cortex represents a playback of recently experienced stimulation. Continuing down this path to longer time scales, it is noteworthy that the dynamical structure of spontaneous activity across the spectrum in auditory cortex bears a remarkable, and likely noncoincidental, resemblance to the 1/f statistics of the natural auditory environment (Garcia-Lazaro et al., 2006). This fits with the idea that the

blueprint for macaque auditory cortex evolved under the pressures of this natural environment and that in ontogeny, individuals’ auditory Isotretinoin cortices further tune to the statistics of that same environment (Berkes et al., 2011). It will be interesting to investigate these relationships further and to see how nature and nurture collaborate in this arena. Needless to say, the causes of “spontaneous order” in auditory as well as other cortices are a prime area for future research, as currently there are many more questions than answers. For example, the authors note work by Raichle and colleagues on so-called “resting state” fMRI as evidence that the brain is constantly active, a line of work that has virtually exploded as a means of mapping large-scale brain functional connectivity networks using graph theoretic analyses (Bullmore and Sporns, 2009). To connect the dots, it is interesting to note that this approach is in principle applicable at smaller scales such as those dealt with here, which would in effect represent subsets or nodes in a larger network. This in turn underscores the point (see also below) that it will be important to relate high-gamma to lower-frequency dynamics, extending down to the infraslow ranges that approximate the time frame of hemodynamic oscillations.