These peptides play a key role in mammalian reproductive and social behavior, including our own. For example, Thomas Baumgartner and his colleagues at the University of Zurich Selleck BKM120 found that oxytocin squirted into

a person’s nose can enhance the sense of trust (Baumgartner et al., 2008). It does so by acting on the amygdala and the midbrain, two regions involved in fear, and the dorsal striatum, a region involved in behavioral feedback. Oxytocin appears to produce a different effect when administered to people with borderline personality disorder: it impedes trust and positive social behavior. Scientists have argued that the link between oxytocin and serotonin may be different in people with this disorder, who suffer from BI 6727 nmr social anxiety and sensitivity to rejection because of early experiences with a parent, a genetic predisposition, or both (Bartz et al., 2011 and Baumgartner et al., 2008). Bargmann extended Insel’s work by identifying an amazing signaling system in C. elegans that consists of one peptide, nematocin. Nematocin, which is biochemically related to oxytocin and vasopressin, disturbs not only the worms’ reproductive behavior

but simple sensory and motor behaviors as well. From a detailed analysis of C. elegans’ behavior ( Garrison et al., 2012 and Emmons, 2012), Bargmann has concluded that oxytocin and vasopressin increase the coherence and coordinated execution of mating behavior in worms. These findings suggest that the brain has specific mechanisms designed to promote positive social behavior. These mechanisms—which appear in organisms separated by 600 million years of evolution—are remarkably well conserved. Moreover, manipulation of the mechanisms can have a profound influence on social behavior. Robert Malenka of Stanford University and his colleagues have taken a fresh look at positive group behavior (Dölen et al., 2013). They point out that even though social behavior promotes group survival in species as diverse as worms, honeybees,

and humans, before it nevertheless costs the individual effort and energy. Social behavior must provide some reward to the individual organism, they reasoned: why else would it have been conserved through evolution? They tested their idea in mice and found that oxytocin modulates the release of serotonin into the nucleus accumbens. Serotonin, a chemical that promotes feelings of well-being, rewards the mice for positive social behavior. Thus, the reinforcement of positive social interaction in mice requires the coordinated activity of both oxytocin and serotonin. Giacomo Rizzolatti and his colleagues at the University of Parma in Italy (Rizzolatti et al., 1996) discovered a network of neurons in motor areas of the cortex of monkeys that mirror the actions of others. These neurons respond similarly under two conditions: when a monkey is performing an action and when the monkey observes another monkey or a person performing the same action.

It soon appeared that the gene-targeting approach in mice, which was still in its infancy, was particularly suited to decipher the mysteries of this receptor family, because many conventional approaches proved problematic (and some, such as the development of selective anti-subunit antibodies, remain so). Knockout mice from all kainate receptor subunits produced in Steve’s laboratory finally revealed their peculiar and unexpected roles in the regulation of activity of hippocampal

circuits. The newly cloned glutamate receptors and these unique mouse models were undeniably valuable resources for many neurobiologists working on mammalian synaptic function and HDAC activity assay plasticity, and Steve Heinemann was exemplary SP600125 in his commitment to making these tools accessible to as many laboratories as possible. The myriad of acknowledgments in studies from scientific reports, originating from laboratories all over the world, make clear that his remarkable generosity greatly contributed to the swift progress in understanding neurotransmitter receptors and synaptic mechanisms over the last three decades. This undoubtedly includes many

new therapeutic avenues for pharmaceutical and biotechnological companies to search for cures in the treatment of “synaptopathies” such as stroke, epilepsy, Parkinson’s and Alzheimer’s diseases, as well as neuropsychiatric conditions. Steve’s most recent work highlights the broadness of his views and his continuous interest in the mysteries of the normal and diseased brain, from astrocytes and oscillations in recognition memory to nicotinic receptors in Alzheimer’s disease. In addition to leading his laboratory, Steve was an active member of the greater scientific community and received a number of awards and honors for his research accomplishments. Most out notably, he was elected president of the Society for Neuroscience from 2005 to 2006. He was also a member of the National Academy of Sciences, the National Institute of Medicine, and the American Academy of Arts & Sciences. He received the Bristol-Myers Squibb Distinguished Achievement in

Neuroscience Research Award and the McKnight Award for Research. In 2010, he was awarded the Julius Axelrod Prize for exceptional achievements in neuropharmacology and exemplary efforts in mentoring young scientists. In this regard, Steve leaves a wide-reaching scientific legacy that includes not only his seminal contributions to our understanding of the molecular identity and function of nicotinic cholinergic and glutamate receptors, but also shaping the course of neuroscience in the US and the world during a time of acute interest in all aspects of brain function. On a more personal level, the hundred-plus “Heinemaniacs” who comprised his laboratory over the many years of its existence were challenged by the free-wheeling nature and abundant possibilities that were intrinsic to life as a member of Steve’s team.

Other mechanisms that additionally contribute to Ca2+-dependent RRP recovery include, for example, CaM independent signaling to the priming machinery, e.g., via the C1 and C2 domains of Munc13s (Rhee et al., 2002; Shin et al., 2010), or facilitation of the release of reluctant INCB018424 cost vesicles following elevation of [Ca2+]i (Wu and Borst,

1999). The SSD levels during high-frequency synaptic activity are thought to be defined by a balance between SV release and replenishment (Dittman and Regehr, 1998; Saviane and Silver, 2006; Wang and Kaczmarek, 1998). We therefore expected that the reduction of RRP replenishment rates seen in Munc13-1W464R KI calyces (Figures 3 and 4) would result in lower SSD levels. However, a reduction of SSD levels was

only found in calyces of more mature KI animals, whereas in WT and Munc13-1W464R calyces at P9–P11 SSD was similar at all frequencies tested (Figure 6). This is surprising in view of the findings that acute application of CaM inhibitors causes lower SSD levels in the rat calyx of Held at P9–P11 (Hosoi et al., 2007; Lee et al., 2012; Sun et al., 2006) and that cultured hippocampal neurons expressing only Munc13-1W464R Selleck Imatinib from a viral rescue construct show an increased STD and lower SSD levels (Junge et al., 2004). At least four scenarios may account for this unexpected finding. First, basal, Ca2+-independent activity of Munc13-1 (Basu et al., 2005) in the Munc13-1W464R mutant might be sufficient to maintain normal SSD levels during phases of moderate to strong synaptic activity, but not upon complete RRP depletion by sustained presynaptic depolarization. Second, the priming activity of Munc13-1W464R can still be strongly potentiated via the C1 domain or the C2B domain (Rhee

et al., 2002; Shin et al., 2010). Third, it is possible that the regulation of Munc13-1 activity by CaM in the calyx of Held in vivo is mainly relevant at Dichloromethane dehalogenase rather high [Ca2+]i. Indeed, the dual pulse protocol we used to assess the replenishment of the fast and slowly releasable SV pools (Figures 3 and 4) involves long depolarizations, during which global presynaptic Ca2+-concentrations are expected to reach higher levels than during AP trains (Hosoi et al., 2007). In addition, an effect of the Munc13-1W464R mutation on the evoked synaptic responses was seen during recovery from synaptic depression after high-frequency stimulation trains, which likely cause a strong and long-lasting rise in [Ca2+]i (Figures 5A–5D). The notion that the Ca2+-CaM-Munc13-1 signaling may be only operational at rather high [Ca2+]i in intact cells is supported by a recent study on the calyx of Held (Lee et al.

We reasoned that since the vHPC and mPFC are required for and synchronize during anxiety (Adhikari et al., 2010b), mPFC single units with more robust anxiety-related firing patterns might be more strongly influenced by vHPC activity. Indeed, EPM scores were higher in units significantly phase-locked to vHPC theta (Rayleigh’s test p < 0.05) compared to other units (Figure 8C, mean score = 0.31 ± 0.07 and 0.17 ± 0.04, for phase-locked and other units, find more respectively, p < 0.05, n = 69 units). Importantly, this result is not due to differences in firing rates, as EPM scores and phase-locking to vHPC theta were correlated, even when phase-locking values were calculated on a subsample of 100 spikes

from each unit (r = +0.25, p < 0.03; Figure S2). These results demonstrate

that cells that receive vHPC input have stronger anxiety-related firing patterns. Consistent with previous results (Adhikari et al., 2010b), this effect was specific for the theta-frequency range, as EPM scores did not differ with phase-locking to vHPC delta- (1–4 Hz) VX-770 cell line or gamma-frequency (30–80 Hz) oscillations (data not shown). Furthermore, phase-locking of mPFC single units to dHPC theta oscillations was not related to EPM scores (Figure 8D), in agreement with lesion (Kjelstrup et al., 2002) and physiology (Adhikari et al., 2010b) studies suggesting that the dHPC is not required for normal anxiety-related behavior in the EPM. The above results suggest that mPFC single units with robust anxiety-related firing patterns are

preferentially recruited into a circuit involving the vHPC. The projection from the vHPC to the mPFC Amisulpride is unidirectional (Parent et al., 2010 and Verwer et al., 1997), and hippocampal theta-range activity has been shown to lead the mPFC (Adhikari et al., 2010a, Siapas et al., 2005 and Sigurdsson et al., 2010). We reasoned that if the vHPC input plays a role in the generation of anxiety-related firing patterns, mPFC single units that follow vHPC theta should have stronger paradigm-related firing patterns compared to units that do not. To find which cells follow hippocampal theta activity, MRL values were calculated after shifting the spike train of each mPFC single unit in time, relative to the vHPC theta-filtered LFP (see Experimental Procedures). Consistent with the known anatomy and previous results, the overall mean lag for maximal phase-locking was negative, indicating that on average, mPFC unit activity followed vHPC activity (mean lag = −13.8 ± 8.1 ms). However, units with positive lags relative to hippocampal theta were also found, similarly to previous reports (Adhikari et al., 2010b, Siapas et al., 2005 and Sigurdsson et al., 2010). Positive lag units may result from chance, or may be involved in polysynaptic modulation of hippocampal activity. Consistent with our prediction, cells that followed the vHPC had significantly higher EPM scores than other units (Figure 9D, mean score = 0.24 ± 0.047 and 0.07 ± 0.

, 2006). Zinc has also been reported to inhibit native and recombinant KARs. find more Zinc inhibition of KARs is subunit dependent, with KARs containing GluK4 or GluK5 subunits being more sensitive, IC50 ∼1–2 μM, than GluK1-GluK2, IC50 ∼70 μM (Mott et al., 2008). Despite the proposed presynaptic function of GluK3-containing KARs at hippocampal mossy fiber synapses, which are highly enriched in vesicular zinc, modulation of these receptors by zinc has not yet been

addressed. In this study, we show that zinc at micromolar concentrations potentiates recombinant GluK3 receptor currents evoked by glutamate. Zinc markedly slows receptor desensitization and increases apparent affinity for glutamate. By analysis of chimeric GluK2/GluK3 KARs and of GluK3 bearing selected point mutations, we mapped the zinc binding domain to the S2 segment of the LBD, in a region forming selleck kinase inhibitor the interface between two GluK3 subunits in an LBD dimer assembly. Crystallographic studies for GluK3 LBD complexes with both glutamate

and kainate revealed that zinc ions bind at multiple sites formed by aspartate, histidine, and glutamate residues, which are present in both the upper and lower lobes of the LBD. Based on these crystal structures, a GluK3 LBD dimer model was generated by superposition of GluK3 monomers on previously solved KAR LBD dimers. This identified D730 as the dimer partner component of the binding site underlying zinc potentiation, together with D759 and H762 from the adjacent subunit. Based on these structure-function first studies and on modeling of

KAR activity, we show that zinc plays a very distinct role in GluK3-KARs by stabilizing the LBD dimer assembly, thereby reducing desensitization. Given the proposed presynaptic localization of GluK3 close to zinc-containing synaptic vesicles, zinc may be an endogenous allosteric modulator for native GluK3-KARs. We tested the effect of zinc on currents activated by fast application of glutamate on lifted HEK293 cells transfected with GluK3 cDNA. Currents evoked by sustained applications (100 ms) of 10 mM glutamate, a concentration close to the EC50 value for GluK3 (Perrais et al., 2009a; Schiffer et al., 1997), were markedly enhanced with preapplication of 100 μM zinc (Figure 1A; 193% ± 38% of control amplitude, n = 17), and this potentiation was rapidly reversible upon removal of zinc. In contrast to GluK3 potentiation, and as previously reported in Xenopus oocytes ( Mott et al., 2008), zinc reversibly inhibited GluK2 currents at all concentrations tested ( Figures 1A and 1D), with an IC50 of 102 ± 11 μM and a Hill coefficient (nH) of 1.1 ± 0.1 (n = 4–9). Because a glutamate concentration of 10 mM is saturating for GluK2 ( Perrais et al., 2009a), this could mask a potentiating effect of zinc. However, currents evoked by 500 μM glutamate, a concentration below the EC50 for GluK2, were also inhibited by 100 μM zinc (48% ± 10%, n = 10; data not shown).

We speculate that these neuroanatomical changes could be the reason why spontaneous activity, which propagates through the same cortical circuits as evoked activity,

becomes more similar to previously presented evoked patterns. We also speculate that the reverbatory activity described here may relate to memory formation in behaving animals. Although the mechanisms underlying memory formation processes are still not well Selleckchem PFI-2 understood, there is a body of theoretical work going back to Hebb (1949) and Marr (1971) that predicts reverberation (Hebb) and/or reactivation (Marr) as fundamental components of memory consolidation. Such phenomena have since been observed in the hippocampus and cortex of behaving animals (Euston et al., 2007 and Wilson and McNaughton, 1994). These observations, like ours, are consistent with the theory selleck products but do not demonstrate that memory depends on this replay. However, more recent evidence suggests a direct link between replay and memory. In hippocampus, the reverberation (reactivation) is associated with SPWR events, and studies have now shown that memory is impaired when SPWRs are disrupted immediately following training (Girardeau et al.,

2009 and Ego-Stengel and Wilson, 2010). Furthermore, there are individual differences in reactivation and memory performance, and these are correlated (Gerrard et al., 2008). These data suggest that the replay of task-related activity is involved in memory processes. Note also that our experiments follow the same general design as “classic” Casein kinase 1 reactivation experiments (Wilson and McNaughton, 1994). We have a control period before an experience, a repetitive experience, followed by a test period. We show that the activity in the test period resembles the activity in the repetitive experience after controlling for any pre-existing similarity. The only difference is that the

animal is not actually behaving but rather under anesthesia. By the fundamental definition of memory as a recapitulation of neural activity evoked by an experience, this is memory. Thus, we suggest that replay of stimulus-evoked patterns observed in desynchronized brain states in urethane-anesthetized rats could be a useful model for studying mechanisms of memory. We used surgery and recording procedures that have been previously described in detail (Luczak et al., 2007 and Schjetnan and Luczak, 2011). Briefly, for somatosensory experiments, 11 Long Evans rats (400–900 g) were anesthetized with urethane (1.5g/kg intraperitoneally [i.p.]). Rats were then placed in a stereotaxic frame, and a window in the skull was prepared over primary somatosensory cortex (S1) hindlimb area (anteroposterior 1 mm; mediolateral 2 mm; dorsoventral 1.5 mm). For auditory experiments, eight Long Evans rats (250–350 g) were anesthetized with urethane (1.5g/kg i.p.) and placed in a nasal restraint that left the ears free. A window in the skull (2 × 3 mm) was prepared over the primary auditory cortex (Luczak et al.

g., Gluhbegovic, 1980) provided a few key insights about the relatively coherent trajectories of macroscopic

fiber bundles within deep white Selleckchem Palbociclib matter. However, most of what is currently known about long-distance pathways in the human brain derive from two complementary neuroimaging approaches: analyses of “structural connectivity” based on diffusion imaging (dMRI) and analyses of “functional connectivity” (fcMRI) based on resting-state fMRI (rfMRI) scans. Both approaches emerged in the 1990s and have subsequently been improved dramatically, which is greatly enhancing our understanding of human brain circuits. However, the methods also remain indirect and subject to substantial limitations that are inadequately recognized. Here, the MDV3100 datasheet focus is on results from recent efforts by the HCP to improve the acquisition and analysis of structural and functional connectivity data and to enable comparisons with other modalities, including maps of function based on task-fMRI and maps of architecture (e.g., myelin maps) in individuals and group averages. One of the most important advances has been the use of improved scanning protocols, especially “multiband” pulse sequences that acquire data many slices at a time, thereby enabling better spatial and temporal resolution (Uğurbil et al.,

2013). Diffusion MRI (dMRI) relies on the preferential diffusion of water along the length of axons in order to estimate fiber bundle orientations in each voxel. This includes not only the primary (dominant) fiber bundle, but also the secondary and even tertiary fiber orientations that can be detected in many voxels. The HCP has achieved improved dMRI data acquisition by refining the pulse sequences, using a customized 3 Tesla scanner (with a more powerful “gradient insert”), and scanning each participant for a full hour (Sotiropoulos et al., 2013 and Uğurbil et al., 2013). This yields excellent data quality Chlormezanone with high spatial resolution: 1.25 mm

voxels instead of the conventional 2 mm voxels. Data preprocessing and analysis (distortion correction, fiber orientation modeling, and probabilistic tractography) have been improved, as has the capability for visualizing the results of tractography analyses. As an example, Figure 4 illustrates state-of-the-art analysis and visualization of the probabilistic fiber trajectories, starting from a seed point on the inferior temporal gyrus (Figure 4A) and viewed in a coronal slice (Figure 4B) and as a 3D trajectory through the volume (Figure 4C). Obviously, a major strength of tractography is that it provides evidence for the 3D probabilistic trajectories within the white matter. Information about the trajectories of major tracts is of interest for a variety of reasons.

, 2003 and Lobel et al., 1998). Although the exact location of the human vestibular cortex is still under debate (for review see Guldin and Grüsser, 1998, Lopez et al., 2008 and Lopez and Blanke, 2011), fMRI work consistently identified the vestibular cortex in the parietal operculum (Eickhoff et al., 2006 and Fasold et al., 2002) and the posterior insula (Bucher et al., 1998, Fasold et al., 2002 and Vitte

et al., 1996). Earlier find more lesion work also associated vestibular deficits with damage of the posterior insula (Brandt and Dieterich, 1999). Although none of these regions were significantly activated in our fMRI study, the proximity of the present fMRI and lesion TPJ locations to vestibular cortex suggests a potential involvement of vestibular cortex or adjacent multisensory cortex (integrating visual, vestibular, and somatosensory signals) in self-location Selleck RAD001 and the first-person perspective. Our questionnaire data (Q3) show that participants from both groups self-identified more strongly with

the virtual body when the tactile stroking was applied synchronously with the visual stroking (Aspell et al., 2009 and Lenggenhager et al., 2007). Our fMRI analysis detected an activation in the right middle-inferior temporal cortex that may partly reflect changes in self-identification with the seen virtual body. This activation was found to be partially overlapping with the stereotaxic location of the right extrastriate body area (EBA). Yet, although right EBA activity showed a body-specific difference between synchronous versus asynchronous stimulation

in both groups (Supplemental Information) that are compatible with EBA’s involvement in self-identification, EBA activity in the body/synchronous conditions was not significantly different from those in the control conditions, where no self-identification occurs (Supplemental Information). Accordingly, we are cautious to interpret this activity as related to self-identification, also because related changes concerning self-attribution of a fake or virtual hand (during the rubber hand illusion) were associated with activity increases (not decreases as in our right EBA data) in Bumetanide lateral premotor and frontal opercular regions (Ehrsson et al., 2004). We note however, that this finding of a potential implication of right EBA in self-identification with a full body extends previous notions that the EBA is involved in the processing of human bodies (Downing et al., 2001, Grossman and Blake, 2002 and Astafiev et al., 2004) and human body form recognition (Urgesi et al., 2007). The synchrony-related differences in the right EBA activity during the visual presentation of a human body are also of interest as they are concordant with higher consistency (Downing et al., 2001) and selectivity (Downing et al., 2006a and Downing et al., 2006b) of the right versus left EBA. Finally, other studies have revealed the role of the EBA in the perception (Downing et al.

Theta frequency is a significant oscillatory rhythm in rodents, because it is observed during exploratory behavior and is highly effective in the induction of LTP (Frick et al., 2004, Hoffman et al., 2002, Kelso and Brown, 1986 and Watanabe et al., 2002). The facilitatory action of presynaptic NMDARs on neurotransmission offers a mechanistic rationale as to why theta frequency is effective for LTP induction. These data also resolve the paradox of how it is that synapses with low pr are able to contribute to the induction of LTP. A synapse with a pr of 0.1 might be expected

to release transmitter just twice during a train of 20 APs and might therefore be expected to fail to achieve adequate activation of the postsynaptic neuron. However, the feedback loop generated from check details Ca2+ influx via activation of NMDA autoreceptors will ensure that a low pr synapse achieves augmented release during the course of the stimulus train (Figure 10B). The relationship

between transmitter release and presynaptic NMDAR activation also has utility, because manipulations of pr also change the probability of observing presynaptic NMDAR-mediated large Ca2+ events. Manipulations that reduce pr boutons, such as adenosine, decrease the number of large Ca2+ events, whereas manipulations that increase pr increase the PD173074 number of large events. Importantly, induction of LTP, which is reported to increase pr at active synapses (Antonova et al., 2001, Bolshakov and Siegelbaum, 1995, Emptage et al., 2003, Enoki et al., 2009, Malgaroli et al., 1995 and Ward et al., 2006), increases the incidence of large Ca2+ transients. Therefore, the measurement of the number of large Ca2+ transients in the bouton provides a novel technique with which to measure pr. Whether this approach first has utility at other axon terminals will be dependent on the presence of NMDAR autoreceptors. There is an interesting correlation in the

literature that would seem to suggest that Ca2+ transient variability at the presynaptic boutons and presynaptic NMDARs is a general motif. For example, (1) modulating the frequency of mini EPSPs in the entorhinal cortex (Berretta and Jones, 1996 and Woodhall et al., 2001), layer V of the visual cortex (Sjöström et al., 2003), or CA1 pyramidal neurons of the hippocampus (Madara and Levine, 2008) or (2) enhancing long-term depression (LTD) in the visual cortex (Sjöström et al., 2003), the barrel cortex (Rodríguez-Moreno and Paulsen, 2008), and the cerebellum (Duguid and Smart, 2004) all require presynaptic NMDAR activation and each are regions known to show highly variable presynaptic Ca2+ transients (Frenguelli and Malinow, 1996, Kirischuk and Grantyn, 2002, Llano et al., 1997 and Wu and Saggau, 1994b).

“
“The prefrontal cortex (PFC), with its

abundant anatomical interconnections with numerous other cortical and subcortical areas, is thought to play a key role in the integration of information from different brain regions to support various cognitive functions (Fuster, 2001 and Miller and Cohen, 2001). In particular, the PFC is thought to be a pivotal substrate for maintaining information in the absence of changing XAV-939 solubility dmso external inputs, and neuronal activity in this brain region is assumed to be critical in working memory (Goldman-Rakic, 1995 and Baddeley, 2003). It has been suggested that the PFC works in synergy with other brain regions, including basal ganglia and the hippocampus, in order to implement memory-related activity (Fuster, 2001 and Miller and Cohen, 2001). It has been shown that recruitment of memory-active neurons in the PFC depends on task-relevant dopamine release from the ventral tegmental area (VTA) neurons (Williams and Goldman-Rakic, 1995, Watanabe et al., 1997, Lewis and O’Donnell, 2000 and Schultz, 2006). Another synergistic mechanism of the PFC that interacts with other brain regions is implied by electroencephalogram (EEG) studies in humans. These experiments have demonstrated that the

power of EEG oscillations in the 3–7 Hz band, recorded from the scalp above the PFC area (called “midline frontal theta”), correlates with working-memory performance (Gevins et al., 1997 and Sauseng et al., 2010). In human studies, it has been tacitly assumed that the midline frontal theta rhythm is generated by the hippocampus (Klimesch et al., 2001, Canolty PD-1/PD-L1 inhibitor 2 et al., 2006 and Fuentemilla et al., 2010). In support of this hypothesis, recent experiments in rodents have shown increased phase coupling between hippocampal theta oscillations (7–9 Hz) and PFC neuronal firing during the working-memory aspects of spatial tasks (Siapas et al., 2005, Jones and Wilson,

2005, Benchenane et al., 2010 and Sigurdsson et al., 2010). However, theta frequency oscillations in the PFC are conspicuously weak or absent (Siapas et al., 2005, Jones and Wilson, 2005 and Sirota et al., 2008), and it is unclear how the mesolimbic dopaminergic system is involved in hippocampal-PFC else coordination (Benchenane et al., 2010 and Lisman and Grace, 2005). Despite recent progress, the mechanisms underlying the temporal coordination of cell assemblies in the PFC-VTA-hippocampal system have remained ambiguous (Lisman and Grace, 2005). In this study, we performed simultaneous large-scale recordings of neuronal activities and local field potentials in the medial prefrontal cortex (mPFC), the VTA, and the hippocampus of the rat during a working-memory task. We found that a 4 Hz (2–5 Hz band) oscillation is dominant in PFC-VTA circuits and is phase coupled to hippocampal theta oscillations when working memory is in use. Both local gamma oscillations and neuronal firing can become phase locked to the 4 Hz oscillation.