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.

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.

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.

Non-rhythmic head-direction cells in the parahippocampal region are not constrained by attractor network dynamics.

Computational models postulate that head-direction (HD) cells are part of an attractor network integrating head turns. This network requires inputs from visual landmarks to anchor the HD signal to the external world. We investigated whether information about HD and visual landmarks is integrated in the medial entorhinal cortex and parasubiculum, resulting in neurons expressing a conjunctive code for HD and visual landmarks. We found that parahippocampal HD cells could be divided into two classes based on their theta-rhythmic activity: non-rhythmic and theta-rhythmic HD cells. Manipulations of the visual landmarks caused tuning curve alterations in most HD cells, with the largest visually driven changes observed in non-rhythmic HD cells. Importantly, the tuning modifications of non-rhythmic HD cells were often non-coherent across cells, refuting the notion that attractor-like dynamics control non-rhythmic HD cells. These findings reveal a new population of non-rhythmic HD cells whose malleable organization is controlled by visual landmarks.

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.

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.

Opposing and Complementary Topographic Connectivity Gradients Revealed by Quantitative Analysis of Canonical and Noncanonical Hippocampal CA1 Inputs.

Physiological studies suggest spatial representation gradients along the CA1 proximodistal axis. To determine the underlying anatomical basis, we quantitatively mapped canonical and noncanonical inputs to excitatory neurons in dorsal hippocampal CA1 along the proximal-distal axis in mice of both sexes using monosynaptic rabies tracing. Our quantitative analyses show comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Noncanonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum-CA1 input strength systematically increases but the presubiculum-CA1 input strength decreases along the proximal-distal axis. The subiculum input strength cotracks that of the lateral EC, known to be less spatially selective than the medial EC. The functional significance of this organization is verified physiologically for subiculum-to-CA1 inputs. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 representations.

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.

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.

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.

The distribution of muscarinic M1 receptors in the human hippocampus.

The muscarinic M1 receptor plays a significant role in cognition, probably by modulating information processing in key regions such as the hippocampus. To understand how the muscarinic M1 receptor achieves these functions in the hippocampus, it is critical to know the distribution of the receptor within this complex brain region. To date, there are limited data on the distribution of muscarinic M1 receptors in the human hippocampus which may also be confounded because some anti-muscarinic receptor antibodies have been shown to lack specificity. Initially, using Western blotting and immunohistochemistry, we showed the anti-muscarinic M1 receptor antibody to be used in our study bound to a single 62kDa protein that was absent in mice lacking the muscarinic M1 receptor gene. Then, using immunohistochemistry, we determined the distribution of muscarinic M1 receptors in human hippocampus from 10 subjects with no discernible history of a neurological or psychiatric disorder. Our data shows the muscarinic M1 receptor to be predominantly on pyramidal cells in the hippocampus. Muscarinic M1 receptor positive cells were most apparent in the deep polymorphic layer of the dentate gyrus, the pyramidal cell layer of cornu ammonis region 3, the cellular layers of the subiculum, layer II of the presubiculum and layer III and V of the parahippocampal gyrus. Positive cells were less numerous and less intensely stained in the pyramidal layer of cornu ammonis region 2 and were sparse in the molecular layer of the dentate gyrus as well as cornu ammonis region 1. Although immunoreactivity was present in the granular layer of the dentate gyrus, it was difficult to identity individual immunopositive cells, possibly due to the density of cells. This distribution of the muscarinic M1 receptors in human hippocampus, and its localisation on glutamatergic cells, would suggest the receptor has a significant role in modulating excitatory hippocampal neurotransmission.

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.

Diversity and overlap of parvalbumin and somatostatin expressing interneurons in mouse presubiculum.

The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre, and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labeling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for parvalbumin (PV). Immunostaining for somatostatin (SOM) revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ∼6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre, and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1). Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3). Another group (cluster 2) contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance.

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.

Topographic organization of orbitofrontal projections to the parahippocampal region in rats.

The parahippocampal region, which comprises the perirhinal, postrhinal, and entorhinal cortices, as well as the pre- and parasubiculum, receives inputs from several association cortices and provides the major cortical input to the hippocampus. This study examined the topographic organization of projections from the orbitofrontal cortex (OFC) to the parahippocampal region in rats by injecting anterograde tracers, biotinylated dextran amine (BDA) and Phaseolus vulgaris-leucoagglutinin (PHA-L), into four subdivisions of OFC. The rostral portion of the perirhinal cortex receives strong projections from the medial (MO), ventral (VO), and ventrolateral (VLO) orbitofrontal areas and the caudal portion of lateral orbitofrontal area (LO). These projections terminate in the dorsal bank and fundus of the rhinal sulcus. In contrast, the postrhinal cortex receives a strong projection specifically from VO. All four subdivisions of OFC give rise to projections to the dorsolateral parts of the lateral entorhinal cortex (LEC), preferentially distributing to more caudal levels of LEC. The medial entorhinal cortex (MEC) receives moderate input from VO and weak projections from MO, VLO, and LO. The presubiculum receives strong projections from caudal VO but only weak projections from other OFC regions. As for the laminar distribution of projections, axons originating from OFC terminate more densely in upper layers (layers I-III) than in deep layers in the parahippocampal region. These results thus show a striking topographic organization of OFC-to-parahippocampal connectivity. Whereas LO, VLO, VO, and MO interact with perirhinal-LEC circuits, the interactions with postrhinal cortex, presubiculum, and MEC are mediated predominantly through the projections of VO.

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.

Somatostatin and neuropeptide Y neurons undergo different plasticity in parahippocampal regions in kainic acid-induced epilepsy.

Parahippocampal brain areas including the subiculum, presubiculum and parasubiculum, and entorhinal cortex give rise to major input and output neurons of the hippocampus and exert increased excitability in animal models and human temporal lobe epilepsy. Using immunohistochemistry and in situ hybridization for somatostatin and neuropeptide Y, we investigated plastic morphologic and neurochemical changes in parahippocampal neurons in the kainic acid (KA) model of temporal lobe epilepsy. Although constitutively contained in similar subclasses of γ-aminobutyric acid (GABA)-ergic neurons, both neuropeptide systems undergo distinctly different changes in their expression. Somatostatin messenger RNA (mRNA) is rapidly but transiently expressed de novo in pyramidal neurons of the subiculum and entorhinal cortex 24 hours after KA. Surviving somatostatin interneurons display increased mRNA levels at late intervals (3 months) after KA and increased labeling of their terminals in the outer molecular layer of the subiculum; the labeling correlates with the number of spontaneous seizures, suggesting that the seizures may trigger somatostatin expression. In contrast, neuropeptide Y mRNA is consistently expressed in principal neurons of the proximal subiculum and the lateral entorhinal cortex and labeling for the peptide persistently increased in virtually all major excitatory pathways of the hippocampal formation. The pronounced plastic changes differentially involving both neuropeptide systems indicate marked rearrangement of parahippocampal areas, presumably aiming at endogenous seizure protection. Their receptors may be targets for anticonvulsive drug therapy.

Prefrontal cortex cytoarchitecture in normal aging and Alzheimer's disease: a relationship with IQ.

We have previously shown that the minicolumnar spacing of neurons in the cerebral cortex relates to cognitive ability, and that minicolumn thinning occurs in old age. The present study examines further the relationship between cognitive ability and cortical fine structure(minicolumn organization and neuropathology) in the dorsolateral prefrontal cortex (dlPFC) and the parahippocampal gyrus (PHG) in mild cognitive impairment (MCI)and Alzheimer's disease (AD). Premortem neuropsychological scores were related to postmortem microanatomy in 58 adults (20 normal controls, 18 MCI, and 20 confirmed AD patients). We found a correspondence between minicolumn thinning in the dlPFC and IQ decline in dementia.In mild impairment, IQ remained stable, as did dlPFC minicolumn width and dlPFC plaque load. IQ only declined as dlPFC minicolumn thinning occurred and dlPFC plaque load increased in more severe dementia. By contrast, plaque load increased and minicolumns became steadily thinner in the PHG, where minicolumn width correlated with declining mini-mental state examination score across both MCI and severe dementia. By including a further 14 younger control subjects, we found that in normal healthy aging, minicolumn width decreased in the dlPFC, whereas PHG minicolumn width did not change.AD patients in our dataset with higher IQ were older at time of death and had less pathology, which supports a neural basis for the cognitive reserve hypothesis.