Resting-State Neural Firing Rate Is Linked to Cardiac-Cycle Duration in the Human Cingulate and Parahippocampal Cortices.

Stimulation and functional imaging studies have revealed the existence of a large network of cortical regions involved in the regulation of heart rate. However, very little is known about the link between cortical neural firing and cardiac-cycle duration (CCD). Here, we analyze single-unit and multiunit data obtained in humans at rest, and show that firing rate covaries with CCD in 16.7% of the sample (25 of 150). The link between firing rate and CCD was most prevalent in the anterior medial temporal lobe (entorhinal and perirhinal cortices, anterior hippocampus, and amygdala), where 36% (18 of 50) of the units show the effect, and to a lesser extent in the mid-to-anterior cingulate cortex (11.1%, 5 of 45). The variance in firing rate explained by CCD ranged from 0.5 to 11%. Several lines of analysis indicate that neural firing influences CCD, rather than the other way around, and that neural firing affects CCD through vagally mediated mechanisms in most cases. These results show that part of the spontaneous fluctuations in firing rate can be attributed to the cortical control of the cardiac cycle. The fine tuning of the regulation of CCD represents a novel physiological factor accounting for spontaneous variance in firing rate. It remains to be determined whether the "noise" introduced in firing rate by the regulation of CCD is detrimental or beneficial to the cognitive information processing carried out in the parahippocampal and cingulate regions.SIGNIFICANCE STATEMENT Fluctuations in heart rate are known to be under the control of cortical structures, but spontaneous fluctuations in cortical firing rate, or "noise," have seldom been related to heart rate. Here, we analyze unit activity in humans at rest and show that spontaneous fluctuations in neural firing in the medial temporal lobe, as well as in the mid-to-anterior cingulate cortex, influence heart rate. This phenomenon was particularly pronounced in the entorhinal and perirhinal cortices, where it could be observed in one of three neurons. Our results show that part of spontaneous firing rate variability in regions best known for their cognitive role in spatial navigation and memory corresponds to precise physiological regulations.

Scene-selective coding by single neurons in the human parahippocampal cortex.

Imaging, electrophysiological, and lesion studies have shown a relationship between the parahippocampal cortex (PHC) and the processing of spatial scenes. Our present knowledge of PHC, however, is restricted to the macroscopic properties and dynamics of bulk tissue; the behavior and selectivity of single parahippocampal neurons remains largely unknown. In this study, we analyzed responses from 630 parahippocampal neurons in 24 neurosurgical patients during visual stimulus presentation. We found a spatially clustered subpopulation of scene-selective units with an associated event-related field potential. These units form a population code that is more distributed for scenes than for other stimulus categories, and less sparse than elsewhere in the medial temporal lobe. Our electrophysiological findings provide insight into how individual units give rise to the population response observed with functional imaging in the parahippocampal place area.

Testing the Efficacy of Single-Cell Stimulation in Biasing Presubicular Head Direction Activity.

To support navigation, the firing of head direction (HD) neurons must be tightly anchored to the external space. Indeed, inputs from external landmarks can rapidly reset the preferred direction of HD cells. Landmark stimuli have often been simulated as excitatory inputs from "visual cells" (encoding landmark information) to the HD attractor network; when excitatory visual inputs are sufficiently strong, preferred directions switch abruptly to the landmark location. In the present work, we tested whether mimicking such inputs via juxtacellular stimulation would be sufficient for shifting the tuning of individual presubicular HD cells recorded in passively rotated male rats. We recorded 81 HD cells in a cue-rich environment, and evoked spikes trains outside of their preferred direction (distance range, 11-178°). We found that HD tuning was remarkably resistant to activity manipulations. Even strong stimulations, which induced seconds-long spike trains, failed to induce a detectable shift in directional tuning. HD tuning curves before and after stimulation remained highly correlated, indicating that postsynaptic activation alone is insufficient for modifying HD output. Our data are thus consistent with the predicted stability of an HD attractor network when anchored to external landmarks. A small spiking bias at the stimulus direction could only be observed in a visually deprived environment in which both average firing rates and directional tuning were markedly reduced. Based on this evidence, we speculate that, when attractor dynamics become unstable (e.g., under disorientation), the output of HD neurons could be more efficiently controlled by strong biasing stimuli.SIGNIFICANCE STATEMENT The activity of head direction (HD) cells is thought to provide the mammalian brain with an internal sense of direction. To support navigation, the firing of HD neurons must be anchored to external landmarks, a process thought to be supported by associative plasticity within the HD system. Here, we investigated these plasticity mechanisms by juxtacellular stimulation of single HD neurons in vivo in awake rats. We found that HD coding is strongly resistant to external manipulations of spiking activity. Only in a visually deprived environment was juxtacellular stimulation able to induce a small activity bias in single presubicular neurons. We propose that juxtacellular stimulation can bias HD tuning only when competing anchoring inputs are reduced or not available.

Interspike interval analysis and spikelets in presubicular head-direction cells.

Head-direction (HD) neurons are thought to provide the mammalian brain with an internal sense of direction. These cells, which selectively increase their firing when the animal's head points in a specific direction, use the spike rate to encode HD with a high signal-to-noise ratio. In the present work, we analyzed spike train features of presubicular HD cells recorded juxtacellularly in passively rotated rats. We found that HD neurons could be classified into two groups on the basis of their propensity to fire spikes at short interspike intervals. "Bursty" neurons displayed distinct spike waveforms and were weakly but significantly more modulated by HD compared with "nonbursty" cells. In a subset of HD neurons, we observed the occurrence of spikelets, small-amplitude "spike-like" events, whose HD tuning was highly correlated to that of the co-recorded juxtacellular spikes. Bursty and nonbursty HD cells, as well as spikelets, were also observed in freely moving animals during natural behavior. We speculate that spike bursts and spikelets might contribute to presubicular HD coding by enhancing its accuracy and transmission reliability to downstream targets. NEW & NOTEWORTHY We provide evidence that presubicular head-direction (HD) cells can be classified into two classes (bursty and nonbursty) on the basis of their propensity to fire spikes at short interspike intervals. Bursty cells displayed distinct electrophysiological properties and stronger directional tuning compared with nonbursty neurons. We also provide evidence for the occurrence of spikelets in a subset of HD cells. These electrophysiological features (spike bursts and spikelets) might contribute to the precision and robustness of the presubicular HD code.

Layer-Specific Organization of Local Excitatory and Inhibitory Synaptic Connectivity in the Rat Presubiculum.

The presubiculum is part of the parahippocampal spatial navigation system and contains head direction and grid cells upstream of the medial entorhinal cortex. This position within the parahippocampal cortex renders the presubiculum uniquely suited for analyzing the circuit requirements underlying the emergence of spatially tuned neuronal activity. To identify the local circuit properties, we analyzed the topology of synaptic connections between pyramidal cells and interneurons in all layers of the presubiculum by testing 4250 potential synaptic connections using multiple whole-cell recordings of up to 8 cells simultaneously. Network topology showed layer-specific organization of microcircuits consistent with the prevailing distinction of superficial and deep layers. While connections among pyramidal cells were almost absent in superficial layers, deep layers exhibited an excitatory connectivity of 3.9%. In contrast, synaptic connectivity for inhibition was higher in superficial layers though markedly lower than in other cortical areas. Finally, synaptic amplitudes of both excitatory and inhibitory connections showed log-normal distributions suggesting a nonrandom functional connectivity. In summary, our study provides new insights into the microcircuit organization of the presubiculum by revealing area- and layer-specific connectivity rules and sets new constraints for future models of the parahippocampal navigation system.

Parahippocampal and retrosplenial connections of rat posterior parietal cortex.

The posterior parietal cortex has been implicated in spatial functions, including navigation. The hippocampal and parahippocampal region and the retrosplenial cortex are crucially involved in navigational processes and connections between the parahippocampal/retrosplenial domain and the posterior parietal cortex have been described. However, an integrated account of the organization of these connections is lacking. Here, we investigated parahippocampal connections of each posterior parietal subdivision and the neighboring secondary visual cortex using conventional retrograde and anterograde tracers as well as transsynaptic retrograde tracing with a modified rabies virus. The results show that posterior parietal as well as secondary visual cortex entertain overall sparse connections with the parahippocampal region but not with the hippocampal formation. The medial and lateral dorsal subdivisions of posterior parietal cortex receive sparse input from deep layers of all parahippocampal areas. Conversely, all posterior parietal subdivisions project moderately to dorsal presubiculum, whereas rostral perirhinal cortex, postrhinal cortex, caudal entorhinal cortex and parasubiculum all receive sparse posterior parietal input. This indicated that the presubiculum might be a major liaison between parietal and parahippocampal domains. In view of the close association of the presubiculum with the retrosplenial cortex, we included the latter in our analysis. Our data indicate that posterior parietal cortex is moderately connected with the retrosplenial cortex, particularly with rostral area 30. The relative sparseness of the connectivity with the parahippocampal and retrosplenial domains suggests that posterior parietal cortex is only a modest actor in forming spatial representations underlying navigation and spatial memory in parahippocampal and retrosplenial cortex. © 2017 Wiley Periodicals, Inc.

Head-Directional Tuning and Theta Modulation of Anatomically Identified Neurons in the Presubiculum.

The presubiculum provides a major input to the medial entorhinal cortex (MEC) and contains cells that encode for the animal's head direction (HD), as well as other cells likely to be important for navigation and memory, including grid cells. To understand the mechanisms underlying HD cell firing and its effects on other parts of the circuit, it is important to determine the anatomical identity of these functionally defined cells. Therefore, we juxtacellularly recorded single cells in the presubiculum in freely moving rats, finding two classes of cells based on firing patterns and juxtacellular labeling (of a subset). Regular-firing cells had the anatomical characteristics of pyramidal cells and included most recorded HD cells. Therefore, HD cells are likely to be excitatory pyramidal cells. For one HD cell, we could follow an axon projecting directly to the MEC. Fast-spiking (FS) cells had the anatomical characteristics of interneurons and displayed weak HD tuning. Furthermore, FS cells displayed a surprising lack of theta-rhythmic firing, in strong contrast to the FS cells that we recorded in the MEC. Overall, we show that HD cells in the presubiculum are pyramidal cells, with FS interneurons only showing weak HD tuning; therefore, MEC may receive an excitatory HD input, as previously assumed by many models. The lack of theta rhythmicity in FS interneurons suggests that different mechanisms may underlie theta in different parts of the hippocampal formation. SIGNIFICANCE STATEMENT: In freely moving rats, we recorded and labeled single neurons in the presubiculum, an area providing one of the major inputs to the medial entorhinal cortex and part of a network involved in spatial navigation and memory. Post hoc identification of labeled cells showed that (fast-spiking, FS) interneurons and pyramidal cells in the presubiculum can be distinguished based on physiological criteria. We found that both moderately and strongly tuned head-direction (HD) cells are pyramidal cells and therefore likely to provide an excitatory HD input to the entorhinal cortex. FS interneurons were weakly head directional and, surprisingly, showed no theta-rhythmic firing. Therefore, the presubiculum appears to encode HD information via excitatory pyramidal cells, possibly also involving FS interneurons, without using a theta-rhythmic temporal code.

Layer-specific modulation of entorhinal cortical excitability by presubiculum in a rat model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is often refractory to antiepileptic medications. The medial entorhinal area (MEA) is affected in TLE but mechanisms underlying hyperexcitability of MEA neurons require further elucidation. Previous studies suggest that inputs from the presubiculum (PrS) contribute to MEA pathophysiology. We assessed electrophysiologically how PrS influences MEA excitability using the rat pilocarpine model of TLE. PrS-MEA connectivity was confirmed by electrically stimulating PrS afferents while recording from neurons within superficial layers of MEA. Assessment of alterations in PrS-mediated synaptic drive to MEA neurons was made following focal application of either glutamate or NBQX to the PrS in control and epileptic animals. Here, we report that monosynaptic inputs to MEA from PrS neurons are conserved in epileptic rats, and that PrS modulation of MEA excitability is layer-specific. PrS contributes more to synaptic inhibition of LII stellate cells than excitation. Under epileptic conditions, stellate cell inhibition is significantly reduced while excitatory synaptic drive is maintained at levels similar to control. PrS contributes to both synaptic excitation and inhibition of LIII pyramidal cells in control animals. Under epileptic conditions, overall excitatory synaptic drive to these neurons is enhanced while inhibitory synaptic drive is maintained at control levels. Additionally, neither glutamate nor NBQX applied focally to PrS now affected EPSC and IPSC frequency of LIII pyramidal neurons. These layer-specific changes in PrS-MEA interactions are unexpected and of significance in unraveling pathophysiological mechanisms underlying TLE.

Regular-spiking cells in the presubiculum are hyperexcitable in a rat model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy, characterized by recurrent seizures originating in the temporal lobes. Here, we examine TLE-related changes in the presubiculum (PrS), a less-studied parahippocampal structure that both receives inputs from and projects to regions affected by TLE. We assessed the state of PrS neurons in TLE electrophysiologically to determine which of the previously identified cell types were rendered hyperexcitable in epileptic rats and whether their intrinsic and/or synaptic properties were altered. Cell types were characterized based on action potential discharge profiles followed by unsupervised hierarchical clustering. PrS neurons in epileptic animals could be divided into three major groups comprising of regular-spiking (RS), irregular-spiking (IR), and fast-adapting (FA) cells. RS cells, the predominant cell type encountered in PrS, were the only cells that were hyperexcitable in TLE. These neurons were previously identified as sending long-range axonal projections to neighboring structures including medial entorhinal area (MEA), and alterations in intrinsic properties increased their propensity for sustained firing of action potentials. Frequency and amplitude of both spontaneous excitatory and inhibitory synaptic events were reduced. Further analysis of nonaction potential-dependent miniature currents (in tetrodotoxin) indicated that reduction in excitatory drive to these neurons was mediated by decreased activity of excitatory neurons that synapse with RS cells concomitant with reduced activity of inhibitory neurons. Alterations in physiological properties of PrS neurons and their ensuing hyperexcitability could entrain parahippocampal structures downstream of PrS, including the MEA, contributing to temporal lobe epileptogenesis.

Repetition related changes in activation and functional connectivity in hippocampus predict subsequent memory.

Using fMRI, this study examined the relationship between repetition-related changes in the medial temporal lobe (MTL) activation during encoding and subsequent memory for similarity of repetitions. During scanning, subjects classified pictures of objects as natural or man-made. Each object-type was judged twice with presentations of either identical pictures or pictures of different exemplars of the same object. After scanning, a surprise recognition test required subjects to decide whether a probe word corresponded to pictures judged previously. When a subject judged the word as "old," a second judgment was made concerning the physical similarity of the two pictures. Repetition related changes in MTL activation varied depending on whether or not subjects could correctly state that pictures were different. Moreover, psychophysiological interactions analyses showed that accuracy in recalling whether the two pictures were different was predicted by repetition-related changes in the functional connectivity of MTL with frontal regions. Specifically, correct recollection was predicted by increased connectivity between the left posterior hippocampus and the right inferior frontal gyrus, and also by decreased connectivity between the left posterior hippocampus and the left precentral gyrus on the second stimulus presentation. The opposite pattern was found for trials that were incorrectly judged on the nature of the repetition. These results suggest that successful encoding is predicted by a combination of increases and decreases in both the MTL activation and functional connectivity, and not merely by increases in activation and connectivity as suggested previously.

Representation of action in occipito-temporal cortex.

A fundamental question for social cognitive neuroscience is how and where in the brain the identities and actions of others are represented. Here we present a replication and extension of a study by Kable and Chatterjee [Kable, J. W., & Chatterjee, A. Specificity of action representations in the lateral occipito-temporal cortex. Journal of Cognitive Neuroscience, 18, 1498-1517, 2006] examining the role of occipito-temporal cortex in these processes. We presented full-cue movies of actors performing whole-body actions and used fMRI to test for action- and identity-specific adaptation effects. We examined a series of functionally defined regions, including the extrastriate and fusiform body areas, the fusiform face area, the parahippocampal place area, the lateral occipital complex, the right posterior superior temporal sulcus, and motion-selective area hMT+. These regions were analyzed with both standard univariate measures as well as multivoxel pattern analyses. Additionally, we performed whole-brain tests for significant adaptation effects. We found significant action-specific adaptation in many areas, but no evidence for identity-specific adaptation. We argue that this finding could be explained by differences in the familiarity of the stimuli presented: The actions shown were familiar but the actors performing the actions were unfamiliar. However, in contrast to previous findings, we found that the action adaptation effect could not be conclusively tied to specific functionally defined regions. Instead, our results suggest that the adaptation to previously seen actions across identities is a widespread effect, evident across lateral and ventral occipito-temporal cortex.

The entorhinal cortex of the monkey: VI. Organization of projections from the hippocampus, subiculum, presubiculum, and parasubiculum.

The organization of projections from the macaque monkey hippocampus, subiculum, presubiculum, and parasubiculum to the entorhinal cortex was analyzed using anterograde and retrograde tracing techniques. Projections exclusively originate in the CA1 field of the hippocampus and in the subiculum, presubiculum, and parasubiculum. The CA1 and subicular projections terminate most densely in Layers V and VI of the entorhinal cortex, with sparser innervation of the deep portion of Layers III and II. Entorhinal projections from CA1 and the subiculum are topographically organized such that a rostrocaudal axis of origin is related to a medial-to-lateral axis of termination. A proximodistal axis of origin in CA1 and distoproximal axis in subiculum are related to a rostrocaudal axis of termination in the entorhinal cortex. The presubiculum sends a dense, bilateral projection to caudal parts of the entorhinal cortex. This projection terminates most densely in Layer III with sparser termination in Layers I, II, and V. The same parts of entorhinal cortex receive a dense projection from the parasubiculum. This projection terminates in Layers III and II. Both presubicular and parasubicular projections demonstrate the same longitudinal topographic organization as the projections from CA1 and the subiculum. These studies demonstrate that: (a) hippocampal and subicular inputs to the entorhinal cortex in the monkey are organized similar to those described in nonprimate species; (b) the topographic organization of the projections from the hippocampus and subicular areas matches that of the reciprocal projections from the entorhinal cortex to the hippocampus and the subicular areas.

Cortical efferents of the perirhinal, postrhinal, and entorhinal cortices of the rat.

We investigated the cortical efferents of the parahippocampal region by placing injections of the anterograde tracers, Phaseolus vulgaris-leuccoagglutinin, and biotinylated dextran amine, throughout the perirhinal (PER), postrhinal (POR), and entorhinal cortices of the rat brain. The resulting density of labeled fibers was evaluated in 25 subregions of the piriform, frontal, insular, temporal, cingulate, parietal, and occipital areas. The locations of labeled terminal fibers differed substantially depending on whether the location of the injection site was in PER area 35, PER area 36, POR, or the lateral or the medial entorhinal (LEA and MEA). The differences were greater for sensory regions. For example, the POR efferents preferentially target visual and spatial regions, whereas the PER efferents target all sensory modalities. The cortical efferents of each region largely reciprocate the cortical afferents, though the degree of reciprocity varied across originating and target regions. The laminar pattern of terminal fibers was consistent with the notion that the efferents are feedback projections. The density and amount of labeled fibers also differed substantially depending on the regional location of injection sites. PER area 36 and POR give rise to a greater number of heavy projections, followed by PER area 35. LEA also gives rise to widespread cortical efferents, arising mainly from a narrow band of cortex adjacent to the PER. In contrast, the remainder of the LEA and the MEA provides only weak efferents to cortical regions. Prior work has shown that nonspatial and spatial information is transmitted to the hippocampus via the PER-LEA and POR-MEA pathways, respectively. Our findings suggest that the return projections follow the same pathways, though perhaps with less segregration.

A genetic model for understanding higher order visual processing: functional interactions of the ventral visual stream in Williams syndrome.

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by a 1.6 Mb microdeletion on chromosome 7q11.23 and characterized by hypersocial personality and prominent visuospatial construction impairments. Previous WS studies have identified functional and structural abnormalities in the hippocampal formation, prefrontal regions crucial for amygdala regulation and social cognition, and the dorsal visual stream, notably the intraparietal sulcus (IPS). Although aberrant ventral stream activation has not been found in WS, object-related visual information that is processed in the ventral stream is a critical source of input into these abnormal regions. The present study, therefore, examined neural interactions of ventral stream areas in WS. Using a passive face- and house-viewing paradigm, activation and functional connectivity of stimulus-selective regions in fusiform and parahippocampal gyri, respectively, were investigated. During house viewing, significant activation differences were observed between participants with WS and a matched control group in IPS. Abnormal functional connectivity was found between parahippocampal gyrus and parietal cortex and between fusiform gyrus and a network of brain regions including amygdala and portions of prefrontal cortex. These results indicate that abnormal upstream visual object processing may contribute to the complex cognitive/behavioral phenotype in WS and provide a systems-level characterization of genetically mediated abnormalities of neural interactions.

Multiple Patterns of Axonal Collateralization of Single Layer III Neurons of the Rat Presubiculum.

The presubiculum plays a key role in processing and integrating spatial and head-directional information. Layer III neurons of the presubiculum provide strong projections to the superficial layers of the medial entorhinal cortex (MEC) in the rat. Our previous study revealed that the terminal distribution of efferents from layer III cells of the presubiculum was organized in a band-like fashion within the MEC, and the transverse axis of these zones ran parallel to the rhinal fissure. Identifying axonal branching patterns of layer III neurons of the presubiculum is important to further elucidate the functional roles of the presubiculum. In the present study, we visualized all axonal processes and terminal distributions of single presubicular layer III neurons in the rat, using in vivo injection of a viral vector expressing membrane-targeted palmitoylation site-attached green fluorescent protein (GFP). We found that layer III of the rat presubiculum comprised multiple types of neurons (n = 12) with characteristic patterns of axonal collateralization, including cortical projection neurons (n = 6) and several types of intrinsic connectional neurons (n = 6). Two of six cortical projection neurons provided two or three major axonal branches to the MEC and formed elaborate terminal arbors within the superficial layers of the MEC. The width and axis of the area of their terminal distribution resembled that of the band-like terminal field seen in our massive-scale observation. Two of the other four cortical projection neurons gave off axonal branches to the MEC and also to the subiculum, and each of the other two neurons sent axons to the subiculum or parasubiculum. Patterns of axonal arborization of six intrinsic connectional neurons were distinct from each other, with four neurons sending many axonal branches to both superficial and deep layers of the presubiculum and the other two neurons showing sparse axonal branches with terminations confined to layers III-V of the presubiculum. These data demonstrate that layer III of the rat presubiculum consists of multiple types of cortical projection neurons and interneurons, and also suggest that inputs from a single presubicular layer III neuron can directly affect a band-like zone of the MEC.

Transient suppression of progenitor cell proliferation through NMDA receptors in hippocampal dentate gyrus of mice with traumatic stress experience.

Post-traumatic stress disorder is a long-lasting psychiatric disease after the traumatic experience of severe fatal stress with the consequence of hippocampal atrophy. Freezing behaviors were more than quintupled on the fear-conditioning test in mice previously subjected to water immersion restrain stress (WIRS) with metronome tones when determined 1-28 days after WIRS, while these mice exhibited the increased immobility time on the forced swimming test with the increased spontaneous locomotion. Prior experience of WIRS led to a transient decrease in subsequent 5-bromo-2'-deoxyuridine (BrdU) incorporation into proliferating cells in the hippocampal dentate gyrus. These behavioral and neurochemical alterations were significantly prevented by the daily injection of the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluvoxamine, respectively. Moreover, WIRS significantly decreased the number of cells holding BrdU without affecting the differentiation ratio to astroglial and neuronal lineages 28 days later. Prior administration of an NMDA receptor antagonist significantly prevented the aforementioned changes by WIRS. These results suggest that NMDA receptors may play a role in mechanisms underlying the crisis of a variety of psychiatric symptoms relevant to post-traumatic stress disorder through transient suppression of neural progenitor cell proliferation in the murine hippocampal dentate gyrus.

Towards a functional organization of the medial temporal lobe memory system: role of the parahippocampal and medial entorhinal cortical areas.

Whereas substantial recent evidence has suggested to some that the medial entorhinal cortexá (MEC) plays a specialized role in spatial navigation, here we present evidence consistent with a broader role of the MEC in memory. A consideration of evidence on the anatomy and functional roles of medial temporal cortical areas and the hippocampus, and evidence from recordings from MEC neurons in rats performing a spatial memory task, suggest that the MEC may process information about both spatial and temporal context in support of episodic memory.

Cellular and subcellular localization of Kir2.1 subunits in neurons and glia in piriform cortex with implications for K+ spatial buffering.

Potassium channels of the Kir2 family are widely expressed in neurons and glia, where they form strong inwardly rectifying channels. Existing functional hypotheses for these channels in neurons are based on the weak outward conductance, whereas the leading hypothesis for glia, that they promote potassium spatial buffering, is based on inward conductance. Although the spatial buffering hypothesis has been confirmed for Müller glia in retina, many aspects of Kir2 channels that will be required for understanding their functional roles in neurons and other forms of glia have received little or no study. Particularly striking is the paucity of data regarding their cellular and subcellular localization. We address this gap for Kir2.1-containing channels by using light and electron microscopic immunocytochemistry. The analysis was of piriform cortex, a highly epileptogenic area of cerebral cortex, where pyramidal cells have K(+)-selective strong inward rectification like that observed in Müller cells, where Kir2.1 is the dominant Kir2 subunit. Pyramidal cells in adult piriform cortex also lack I(h), the mixed Na(+)-K(+) current that mediates a slower form of strong inward rectification in large pyramidal cells in neocortex and hippocampus. The experiments demonstrated surface expression of Kir2.1-containing channels in astrocytes and in multiple populations of pyramidal and nonpyramidal cells. Findings for astrocytes were not consistent with predictions for K(+) spatial buffering over substantial distance. However, findings for pyramidal cells suggest that they could be a conduit for spatially buffering K(+) when it is highly elevated during seizure.

Organization of connectivity of the rat presubiculum: II. Associational and commissural connections.

The regional, laminar, and longitudinal organization of intrinsic projections in the presubiculum was examined in the rat with the retrograde tracer horseradish peroxidase conjugated to wheat germ agglutinin and the anterograde tracer Phaseolus vulgaris-leucoagglutinin. Cells of origin of intrinsic projections in the presubiculum were distributed in layers II and V, with almost none in layers III and VI. Projections from layer II cells were bilateral and confined to layers II and V and also to the deep portion of layer I, whereas projections from layer V cells were ipsilateral and confined largely to layer V, with fewer projections to layer II. Septotemporal and proximodistal differences in both the projection and the distribution of layer II cells were found: layer II cells in the septal and mid presubiculum, especially those located in the distal part, provided long projections to the temporal presubiculum, whereas layer II cells in the temporal presubiculum provided slightly shorter projections almost entirely within the mid and temporal presubiculum. Layer II cells aggregated massively in the distal portions of the septal and mid presubiculum, but very few layer II cells were found in the most proximal part, especially in the temporal presubiculum. On the other hand, in layer V, cells of origin and their terminals were diffusely and equally distributed throughout the entire proximodistal extent of the presubiculum. Layer V cells did not project longitudinally as far as layer II cells. These longitudinal connections, in layers II and V, make it possible to merge information conveyed by parallel pathways in the presubiculum.

Spatial and temporal episodic memory retrieval recruit dissociable functional networks in the human brain.

Imaging, electrophysiological studies, and lesion work have shown that the medial temporal lobe (MTL) is important for episodic memory; however, it is unclear whether different MTL regions support the spatial, temporal, and item elements of episodic memory. In this study we used fMRI to examine retrieval performance emphasizing different aspects of episodic memory in the context of a spatial navigation paradigm. Subjects played a taxi-driver game ("yellowcab"), in which they freely searched for passengers and delivered them to specific landmark stores. Subjects then underwent fMRI scanning as they retrieved landmarks, spatial, and temporal associations from their navigational experience in three separate runs. Consistent with previous findings on item memory, perirhinal cortex activated most strongly during landmark retrieval compared with spatial or temporal source information retrieval. Both hippocampus and parahippocampal cortex activated significantly during retrieval of landmarks, spatial associations, and temporal order. We found, however, a significant dissociation between hippocampal and parahippocampal cortex activations, with spatial retrieval leading to greater parahippocampal activation compared with hippocampus and temporal order retrieval leading to greater hippocampal activation compared with parahippocampal cortex. Our results, coupled with previous findings, demonstrate that the hippocampus and parahippocampal cortex are preferentially recruited during temporal order and spatial association retrieval--key components of episodic "source" memory.