, 2011) Since induction of Ras in NAc by chronic cocaine and chr

, 2011). Since induction of Ras in NAc by chronic cocaine and chronic stress would be expected to activate CREB, and CREB in this region has previously been shown to oppose cocaine reward and promote depression-like BIBW2992 purchase behavior (Barrot et al., 2002, Blendy, 2006, Carlezon et al., 2005 and Pliakas et al., 2001), we focused on this protein further. We show that G9a overexpression in NAc, which represses Ras expression, also reduces levels of phospho-CREB in this brain

region. Moreover, we show that local knockdown of endogenous CREB in NAc exerts antidepressant actions in the social defeat and other behavioral assays, consistent with several prior studies of CREB action in addiction and depression models. We have also shown that genome-wide patterns of phospho-CREB binding to gene promoters in NAc of susceptible mice after chronic social defeat stress are reversed by chronic R428 molecular weight antidepressant treatment and not seen in unsusceptible animals (Wilkinson et al., 2009).

Furthermore, microarray analyses of NAc obtained from CREB-overexpressing mice revealed that CREB activity in NAc was sufficient to induce H-Ras1 expression in this brain region ( McClung and Nestler, 2003), similar to that observed here with both chronic cocaine and chronic stress. Likewise, overexpression of mCREB, a dominant-negative form of CREB, reduced H-Ras1 expression in NAc ( McClung and Nestler, 2003) and induced antidepressant-like effects in simple behavioral tests ( Barrot et al., 2002, Carlezon et al., 2005 and Pliakas et al., 2001). These data indicate a role for CREB activity in the potentiation of Ras expression, in which Ras may act, through a positive feedback loop, to increase its own expression by enhancing downstream CREB phosphorylation and activity ( Figure 8). Taken together, BDNF-TrkB-Ras-CREB signaling in NAc may be one pathway through which both drugs of abuse and stress trigger shared molecular, cellular, and behavioral adaptations ADP ribosylation factor ( Nestler et al., 2002, Pierce and Bari, 2001 and Thomas et al., 2008). The contribution of the core and shell subdivisions of NAc to the phenomena examined here remains

unknown. While the core and shell subserve distinct functions in drug and stress models (e.g., Di Ciano et al., 2008), the viral manipulations used in the current study cannot reliably distinguish these subregions, leaving the examination of this important question to future investigations. Depressive illnesses are among the most prevalent psychiatric disorders in the United States, afflicting ∼18% of the total population (Kessler et al., 2003). Only ∼40% of all individuals treated with available antidepressants experience a full remission of symptoms, underscoring the high demand for better treatments (Berton and Nestler, 2006 and Covington et al., 2010). Developing newer treatments has been limited by a scarcity of knowledge concerning the molecular biology of depression (Krishnan and Nestler, 2008).

Together, these events prevent internalized

receptors fro

Together, these events prevent internalized

receptors from recycling to the plasma membrane and promote the subsequent delivery of ubiquitin-marked receptors to lysosomes. Ubiquitin-directed sorting has been extensively demonstrated in mammalian cells for the epidermal growth factor (EGF) receptor tyrosine kinase (Raiborg and Stenmark, 2009; Eden et al., 2012) and there is increasing evidence for ubiquitin-directed sorting of various 7TMRs, as reviewed elsewhere (Marchese et al., 2008; Shenoy, 2007; Kirkin and Dikic, 2007). In some cases, specific ubiquitin ligases and hydrolases controlling 7TMR endocytic trafficking have been identified, as previously reviewed elsewhere (Hislop and von Zastrow, 2011; Marchese et al., 2008; Shenoy, 2007), but the available information on this topic is presently limited to studies of 7TMR regulation in nonneural cell types. Some selleckchem neuromodulatory 7TMRs do not require ubiquitylation to undergo efficient endocytic delivery to lysosomes, and there is evidence for additional machinery directing this process. For example, internalized delta opioid receptors can

be effectively excluded from the recycling pathway and delivered to lysosomes even when their ubiquitylation is prevented by mutation of all cytoplasmic lysine residues (Tanowitz and Von Zastrow, 2002). Receptor ubiquitylation enhances but is not required for opioid receptor localization to intralumenal vesicles, and receptors can be delivered to lysosomes for inactivating proteolytic fragmentation even when transfer www.selleckchem.com/ferroptosis.html to intralumenal vesicles is blocked (Hislop et al., 2009; Henry et al., 2011). Nevertheless, irrespective of whether or not ubiquitylation of receptors is allowed to

occur, the overall process of delta opioid receptor degradation requires the main components of the ESCRT machinery (Hislop et al., 2004). Accordingly, the present data suggest that discrete ubiquitin-independent and -dependent sorting mechanisms operate in series in the conserved ESCRT-dependent MVB pathway, with the ubiquitylation-independent oxyclozanide mechanism operating effectively upstream and having the ability to effectively “force” internalized receptors to traffic to lysosomes even when their ubiquitylation is prevented (Henry et al., 2011). Evidence for ubiquitylation-independent sorting of internalized 7TMRs to lysosomes, as for the ubiquitin-directed sorting mechanism discussed above, is presently limited primarily to studies of nonneural cell types. The biochemical basis for ubiquitylation-independent lysosomal delivery of 7TMRs remains poorly understood in any system. One possibility is that internalized receptors are guided to lysosomes simply through “piggybacking” on a ubiquitin-directed cargo, as proposed for ubiquitin-independent trafficking in yeast (Macdonald et al.

For each recording session, we verified the laminar position of t

For each recording session, we verified the laminar position of the electrode contacts by computing the evoked potential (ERP) profiles for brief visual stimulation during a passive fixation task (full-field black screen that flashed white for 100 ms,

and then returned to black). LFP responses were processed to obtain ERP traces for each contact (over 100 trials). We computed the current source density (CSD) by using the second spatial derivative of the LFP time-series across equally spaced laminar contacts using the iCSD toolbox for MATLAB (Pettersen et al., 2006). We analyzed the laminar CSD profile to verify the presence of a primary sink in the granular layer in each of the 34 recording sessions (the contact with the sink centroid served as granular layer reference at 0 μm). We then analyzed all the contacts above see more and below the reference and grouped them into one of three possible layers: supragranular, granular, and infragranular (see Supplemental Experimental Procedures). We measured spike count correlations (rSC) between Lumacaftor pairs of neurons in different layers. The calculation of rSC for a pair of neurons responding to particular stimulus orientation (θ) is as follows: equation(1) rsc(θ)=∑k=1N(rik−ri)(rjk−rj)Nσiσj=∑k=1Nrikrjk−rirjNσiσj,where

N is the number of trials, rik is the firing rate of neuron i in trial k, ri is the mean firing rate, and σi is the SD of the responses for neuron i ( Bair et al., 2001). We transformed the firing rates of neurons into Z scores, rik → zik = (rik − ri)/σi to eliminate the effect of stimulus orientation on the computation of noise correlations. To compute noise correlations for all stimulus orientations θ1, θ2,…, θn, we calculated for each neuronal pair the correlations rsc(θ1), rsc(θ2),…rsc(θn) and then averaged them in order to obtain the noise correlation coefficient for that pair:

equation(2) rSC=E[rsc(θ1),rsc(θ2),…,rsc(θn)]. To remove potential artifacts in the calculation of correlation coefficient, such as slow-wave fluctuations in responses across trials, all the neurons underwent detrending in which the spike counts for each trial were high-pass filtered using a linear-phase finite impulse response filter (Bair et al., 2001; Kohn and Smith, 2005). We thank D. Gutnisky and K. Josić for comments medroxyprogesterone on the manuscript and S. Pojoga for assistance during monkey training. This work was supported by grants from NEI, NIH EUREKA Program, Pew Scholars Program, and James S. McDonnell Foundation (V.D.), and an NIH Vision Training Grant (B.J.H). “
“To survive in an ever-changing environment, creatures must be able to predict what is going to occur next in order to plan their reactions appropriately. The natural world is not random: natural stimuli are highly redundant due to the physical properties of the world. For example, Ruderman and Bialek (1994) showed that there are strong statistical dependencies between luminance values in different pixels of natural scenes, and Nelken et al.

Although visual stimulation evoked an increase in high-frequency

Although visual stimulation evoked an increase in high-frequency power in both simple and complex cells, it did not cause a strong increase in synchrony. Finally, comparing the distribution of correlation amplitudes between complex-complex pairs and simple-complex pairs for spontaneous and visually evoked activity confirmed the lack of strong Vm correlation for paired simple and complex cells (Figure 7G). Previous literature has suggested that simple cells might be

a relatively heterogeneous group. For example, some simple cells may derive most of their excitatory input from the lateral geniculate nucleus (LGN), whereas some receive most of their input from other cortical cells (Finn et al., 2007). It then seems likely that simple cells become engaged with the complex cell circuits to different degrees. Some simple cells from previous reports, for example, have more high-frequency fluctuations than the ones analyzed here (e.g., Selleck PR 171 Cardin et al., 2005, Cardin et al., 2007 and Gray and McCormick, 1996), although it is still not known to what degree

that these fluctuations were synchronized with those in complex cells. By recording membrane potential (Vm) from pairs of V1 neurons in vivo, we have studied how visual stimulation modulates the correlation of Vm fluctuations between nearby cells. First, high-frequency Vm fluctuations induced by visual stimulation were strongly synchronized. Not only was the synchrony observed between neurons that belonged to the same functional domain, in addition, Dactolisib there was strong synchrony between neurons lying in different functional domains (e.g., Figure 1 and Figure 2). Second, visual stimulation changed the spectral structure of the Vm correlation that was present in the spontaneous state, suppressing coherence at low frequencies (0–10 Hz)

and maintaining or facilitating coherence at high frequencies (20–80 Hz; Figure 1, Figure 2, Figure 3 and Figure 4). Third, for a pair of cells, a broad range of stimuli caused comparable effects on Vm synchrony (Figure 3). Fourth, during visual stimulation, Vm synchrony secondly gave rise to a synchronous form of cross-neuron Vm STA that has an onset preceding the trigger time (Figure 6). Last, in contrast to pairs of complex cells, the high-frequency fluctuations were only weakly synchronized between simple and complex cells (Figure 7). These findings extend the former work (Lampl et al., 1999) by revealing the dependence of Vm synchrony on the stimulus properties, the cells’ stimulus specificity, and the relationship between them. Many intracellular studies in V1 have found that sensory stimulation evokes high-frequency Vm fluctuations (e.g., Anderson et al., 2000, Azouz and Gray, 2008, Bringuier et al., 1997, Cardin et al., 2005, Cardin et al., 2007, Douglas et al., 1991, Gray and McCormick, 1996, Jagadeesh et al., 1992, Priebe et al., 2004 and Volgushev et al., 2003).

During pregnancy, symptoms are an important contributor to poor h

During pregnancy, symptoms are an important contributor to poor health status, while in the postpartum period a lack of social support is the most consistent predictor of poor health outcomes

(Hueston and Kasik-Miller 1998). The recommended levels of physical activity were positively associated with one or more domains of health-related quality of life (Hueston and Kasik-Miller EPZ6438 1998). In particular, physical functioning, general health, vitality, social functioning, and mental health are critically affected by the recommended level of physical activity (Brown et al 2003). In the current study, the physical aspects of health-related quality of life, such as bodily pain and general health, seemed to be more closely associated with the amount of physical activity than the mental aspects are. This finding is consistent with several previous studies (Brown et al 2000, Ramirez-Velez 2007, Tessier et al 2007). Although the perception of vitality – measuring the degree of energy, pep, or tiredness experienced – is classified as a mental health component in the Short Form-8 and the Short Form-36 questionnaires, it has a complex construction and is moderately correlated with both mental and physical health functioning. Our data for healthy women with uncomplicated pregnancies would provide useful norms for evaluating the effect of pregnancy and its management in women with underlying health

problems or complications MycoClean Mycoplasma Removal Kit of pregnancy. Because of the changes Epigenetic inhibitor associated with gestational age in physical domains, researchers may wish to adjust the normative values of the physical domains when pregnant women are included in research studies. The long-term effects of exercise on quality of life in women after their pregnancy would best be evaluated if exercise were

adopted by these individuals as a lifestyle modification (Brown et al 2000, Ramírez-Vélez et al 2008). Studies that report long-term data from these or similar participants in subsequent years would be necessary for such an evaluation. Future studies could also aim to determine the effects of different physical exercise programs on quality of life in healthy pregnant women, eg, assessing the intensity of the exercise expressed in relative maximum oxygen uptake or relative heart rate, or through quantification of daily physical activity with accelerometers. eAddenda: Table 3 available at www.JoP.physiotherapy.asn.au Ethics: The University of Valle Research Ethics Committee approved this study (Res-022/29-UV). Informed consent was gained from all participants before data collection began. Competing interests: None declared. Support: University of Valle and Nutrition Group (Grant N. CI 1575). This work was supported by the University of Valle (Grant N. CI 1575). Robinson Ramírez-Vélez received a grant from Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología ‘Francisco José de Caldas’ to undertake doctoral study.

We observed an EGFP signal in all fibers within the CeA and in ax

We observed an EGFP signal in all fibers within the CeA and in axonal terminals in the posterior pituitary (Figure 3C). Similarly, expression of a synaptophysin-EGFP fusion protein revealed synaptic terminals in both structures (Figure 3D). Costaining of synaptophysin-EGFP puncta with antibodies against OT and vesicular glutamate transporter 2 (VGluT2), the mRNA of which was detected in OT neurons (Kawasaki et al., 2005), demonstrated overlap of EGFP, VGluT2, and OT signals (Figure 3E), confirming previous reports on magnocellular neurons enriched

by microvesicles that associate with synaptophysin (Navone et al., 1989) and contain glutamate (Meeker et al., 1991). Higher-resolution electron microscopic analysis revealed the presence of synaptic contacts between immunoreactive axon terminals and local dendrites in the CeL (Figure 3F), www.selleckchem.com/products/KU-55933.html most likely dendrites of GABAergic interneurons, of which the CeL is predominantly composed (Davis, 2000 and Huber et al., 2005). In the three cases analyzed, we encountered Vorinostat synaptic appositions bearing the features of asymmetric (Gray’s type 2) synapses, proposed to be of excitatory nature (Figure 3F). Importantly, we were unable to find synaptic contacts within the CeM (M.E., unpublished data), where fibers are traversing the region without branching and forming varicosities, as was the case in the CeL (Figure S3A). Our

collective findings strongly suggest a presence in the CeL of axonal terminals that originate from OT neurons and form glutamatergic synapses. Based on the anatomical evidence for OT-containing axonal fibers of hypothalamic origin in the CeA, we selectively expressed the blue-light (BL)-sensitive 3-mercaptopyruvate sulfurtransferase ChR2 protein (Nagel et al., 2003) fused to mCherry (Figure 4A) in

all hypothalamic OT neurons via an rAAV. Whole-cell voltage-patch-clamp recordings in vitro in coronal slices of mCherry fluorescent cells (Figures 4A and 4B, top) revealed functional ChR2 expression in PVN, SON, and AN neurons, as evident from the presence of BL induced currents with a characteristic rapidly inactivating peak followed by a stable tail (Boyden et al., 2005; Figures 4C and S4). Because high frequencies of action potentials are thought to be necessary to trigger release of neuropeptides, in contrast to release of classical neurotransmitters (Hökfelt, 1991), we quantified the effect of different BL stimulations on AP frequencies of PVN and SON neurons. Current-clamp recordings from these neurons showed that AP frequencies up to 20 Hz could be reliably induced by stimulation frequencies with short BL pulses of 10 ms applied at 30 Hz, as well as by continuous BL exposure (Figures 4C and S4A). Having shown functional ChR2 expression in the OT cell bodies, we tested whether BL could also release endogenous OT from axonal projections in horizontal slices of the CeA (Figure 4B, bottom).

A key model feature is that responses to all objects falling with

A key model feature is that responses to all objects falling within the spotlight are enhanced; thus, in our experiment it predicts that during tracking responses to the irrelevant RF stimulus would be enhanced when the translating patterns circumvented but did not enter the RF. Contrary to that, we observed that when comparing the responses during tracking versus attend-fixation INCB018424 there was either no change in attentional modulation (Pr direction of translating RDPs) or a response

decrease (AP direction) in the former relative to the latter condition. Moreover, this model also predicts that when increasing the size of the attentional spotlight, the benefits of attention should GABA inhibition decrease. We found, however, that performance in the far configuration was higher than that in the near configuration (Figures 2G and 2H) and the differences in attentional modulation between tracking and attend-RF were similar in both cases or even slightly

larger in the far configuration ( Figure 4 and Figure 5). The performance differences between the far and near configurations during tracking remained when removing the RF stimulus ( Figure 3S), ruling out that stronger distracter interference in the near condition was responsible for the effect. Furthermore, during a session we interleaved trials of the three different conditions to avoid that animals could predict in advance the difficulty of the upcoming trial. Animals show a higher performance in the

easier tasks (i.e., attend-fixation and attend-RF showed higher performance than tracking), suggesting that they could not adjust their attentional effort on a trial-by-trial basis. These findings strongly argue against the zooming spotlight hypothesis. We consider at least two Linifanib (ABT-869) possible explanations for discrepancies between our results and those of studies providing neural correlates of the zooming model (Barriopedro and Botella, 1998, Heinze et al., 1994, McCormick and Jolicoeur, 1994 and Müller et al., 2003b). First, it is possible that the coarse spatial resolution of ERPs used in those studies, does not allow measuring decreases in the activity evoked by distracters. Second, it is possible that with certain stimulus configurations and task demands the spotlight of attention zooms in/out. In fact, a recent study has provided evidence that humans can adjust the size of the attentional focus depending on task instructions (Herrmann et al., 2010). This model has been very difficult to test in studies of attention (Castiello and Umiltà, 1992 and McCormick et al., 1998; Oksama and Hyönä, 2008; Jans et al., 2010 and Cave et al., 2010). It proposes that subjects attend to multiple objects by rapidly switching a single spotlight of attention from one object to another.

0; Biodex Medical Systems, Shirley, New York, USA) The subjects

0; Biodex Medical Systems, Shirley, New York, USA). The subjects wore their own shoes to minimize any shoe-type effect by introducing discomfort or lack of adaptability due to the usage of a new shoe. Each subject was seated, with the trunk, thigh, and shank secured. Standard positioning for the ankle

inversion and eversion testing was used according to the manufacturer’s guidelines. Subjects were seated and their right leg was raised so that the shank was perpendicular to the footplate attachment. With the shank supported, the right foot was secured into the footplate in neutral position and SCH900776 zero degrees plantarflexion. Isokinetic testing of the right ankle was administered at 120°/s within a comfortable range of motion (mean ± SD) for barefoot condition (76.8° ± 12.1°) and shod condition (71.1° ± 16.7°). Three maximal repetitions were performed. A minimum of 24 h of rest was required before the subject returned to undergo testing under the second condition. Presentation of barefoot and shod conditions was randomized between subjects. Prior to each recorded performance, the subject was allowed to perform submaximal and maximal repetitions to prepare for each tested velocity. Verbal encouragement and visual feedback of the results were given in order to obtain maximal effort. After all testing was completed three subjects (subjects 2, 6, and 10) were eliminated from the analysis due to

errors in data collection. Inversion and eversion peak torque and time to peak torque was recorded for barefoot and shod conditions and the difference between conditions

was calculated. A 1210477 A positive (+) difference indicated that the barefoot condition demonstrated greater torque and a negative (−) difference indicated that the shod condition demonstrated greater torque. A difference near zero would indicate similar torque values in both the barefoot and shod conditions. For purposes of this study, either a large + or large – difference in peak torque between conditions was considered detrimental. This is because, whether or not + or −, the shoes had an affect on performance. In one case, a large + difference, because in the shoe condition the athlete was weaker and for a large – difference the shoe has made the athlete artificially stronger. Therefore, the absolute values of the differences were then ranked. The largest absolute difference between barefoot and shod conditions was ranked as a 1 and the smallest absolute difference was ranked as an 8. For time to peak torque + difference indicated that the barefoot condition demonstrated a greater amount of time to reach peak and a – difference indicated that the shod condition demonstrated a greater amount of time to reach peak torque. In addition, eversion-to-inversion peak torque percent strength ratios were also calculated for both barefoot and shod conditions.

, 2007) The alignment was inspected and edited on BioEdit – Biol

, 2007). The alignment was inspected and edited on BioEdit – Biological Sequence find more Alignment Editor (http://www.mbio.ncsu.edu/BioEdit/bioedit.html). Species-specific polymorphic regions were manually identified and primers were designed for the amplification of each one of the 11 Eimeria species. A complete list of the primers is presented in Table 1. We standardized a single PCR amplification condition for all rabbit Eimeria species, which typically consisted of 10 ng of template DNA, 1 U of AmpliTaq Gold® DNA Polymerase (Applied Biosystems,

Foster City, CA, USA), 1× GeneAmp PCR Buffer II; 1.5 mM MgCl2, 200 μM dNTP mix, and 0.4 μM of each primer ( Table 1). Cycling conditions comprised an initial denaturation step of 5 min at 95 °C, 30 cycles of 45 s at 95 °C, 45 s at 54 °C and 1 min at 72 °C, and a final extension step of 7 min at 72 °C. Amplified products were electrophoretically separated on 1.5% agarose gels and stained with 0.5 μg/mL ethidium bromide. The ITS1 sequences of the 11 Eimeria species that infect the domestic rabbit were amplified using a pair of primers common to the genus Eimeria ( Table 1). The amplification Selleck Dasatinib products varied from circa 400 bp to 600 bp (see Supplementary Material

– Fig. 1). The amplicons were fully sequenced and species-specific primers were designed for each Eimeria species ( Table 1) in order to present similar values of melting temperature (Tm). The size of the amplification targets ranged from 166 to 289 bp ( Supplementary Material – Table 1). All reactions were tested for the ability to amplify the specific targets of homologous DNA samples, and optimized for a maximum product yield. We standardized all reactions with the same PCR conditions, thus facilitating

the set up of reactions destined for the amplification of multiple Eimeria species. We conducted a series of specificity tests using the standardized PCR conditions. We tested all combinations of species-specific primer pairs and DNA samples of all Eimeria species of domestic rabbit. No cross-specific band has been observed using heterologous sets of primers and DNA samples ( Fig. 1). A full set of pictures displaying uncut versions of all gels is available ( Supplementary Rolziracetam Material – Fig. 2). We evaluated the sensitivity of the 11 species-specific reactions by serially diluting the DNA of each Eimeria species from 1 ng to 10 fg and performing the reactions under the standardized PCR conditions. As can be seen in Fig. 2, we obtained a detection limit of 500 fg for most species. In the case of E. flavescens, E. magna, E. perforans and E. piriformis, a detection limit of 1 pg has been observed. Considering a DNA content of 75 fg per sporozoite ( Cornelissen et al., 1984), the detection threshold varies from 6.7 to 13.3 sporozoites, which corresponds to approximately 0.8–1.7 sporulated oocysts, respectively.

This result is in line with the finding that local waves were usu

This result is in line with the finding that local waves were usually low amplitude, and low-amplitude waves typically occur in late NREM sleep when homeostatic sleep pressure has largely dissipated (Riedner et al., 2007). By contrast, K-complexes were mostly global and stereotypical throughout the night—that is, they did not show significant changes between early and late sleep (Figure 6B; involvement

of 54.8% ± 4.4% in early sleep versus 52.5% ± 1.9% in late sleep; p = 0.98). Interestingly, sleep spindles became slightly less local in late sleep, as sleep pressure dissipated (Figure 6C; involvement CB-839 of 44.2% ± 0.6% in early sleep versus 47.1% ± 0.5% in late sleep; p < 0.00014). This result once again supports the notion that local sleep spindles cannot be simply explained by an association with local slow waves. To examine whether slow waves propagate along typical

pathways, we checked for consistent temporal delays between brain regions in which the same wave was observed. Figure 7A provides an example of mean slow waves in depth EEG of different brain structures in one individual, revealing a propagation trend from medial frontal cortex to the MTL and hippocampus. This propagation was evident also when examining the distribution of lags for individual waves (Figure 7A, right). Despite variability in the timings LGK-974 nmr of individual waves, some regions consistently preceded scalp EEG whereas others followed it. A systematic analysis of depth EEG established that slow waves had a strong propensity to propagate from medial frontal cortex to the MTL and hippocampus. Specifically, we identified all slow waves that were detected

within ±400 ms across several brain structures (Experimental Procedures). Sorting regions according Sodium butyrate to the order in which their slow waves were detected revealed a clear tendency of slow waves to propagate from medial frontal cortex to the MTL (Figure 7B), which was highly significant statistically (Figure 7C; p < 2.3 × 10−8, unequal variance t test). In addition, this propagation tendency was consistent across individual subjects and robust to different examinations (Figure S6). Figure 7D shows an example of individual slow waves propagating across multiple brain structures. As can be seen, time offsets in OFF periods in different brain regions followed a propagation from frontal cortex to the MTL (diagonal green lines). Next, slow wave propagation was quantitatively examined in unit discharges in all 11 individuals in whom unit recordings were obtained simultaneously in frontal and MTL regions. Mean spiking activities underlying slow waves in medial frontal cortex versus MTL revealed a robust time offset (Figure 7E, left). Across individual neurons, minimal firing in frontal neurons (n = 76) was −85 ± 22 ms relative to scalp Fz negative peak, whereas minimal firing in MTL neurons (n = 155) was +102 ± 20 ms relative to the same time reference, indicating an average difference of 187 ms (Figure 7E, right).