Temporal multiplexing of perception and memory codes in IT cortex.

A central assumption of neuroscience is that long-term memories are represented by the same brain areas that encode sensory stimuli1. Neurons in inferotemporal (IT) cortex represent the sensory percept of visual objects using a distributed axis code2-4. Whether and how the same IT neural population represents the long-term memory of visual objects remains unclear. Here we examined how familiar faces are encoded in the IT anterior medial face patch (AM), perirhinal face patch (PR) and temporal pole face patch (TP). In AM and PR we observed that the encoding axis for familiar faces is rotated relative to that for unfamiliar faces at long latency; in TP this memory-related rotation was much weaker. Contrary to previous claims, the relative response magnitude to familiar versus unfamiliar faces was not a stable indicator of familiarity in any patch5-11. The mechanism underlying the memory-related axis change is likely intrinsic to IT cortex, because inactivation of PR did not affect axis change dynamics in AM. Overall, our results suggest that memories of familiar faces are represented in AM and perirhinal cortex by a distinct long-latency code, explaining how the same cell population can encode both the percept and memory of faces.

Differences in expression of calcium binding proteins in the perirhinal and retrosplenial cortex of the rat.

The main aim was to describe interneuronal population expressing calcium binding proteins calretinin (CR) and parvalbumin (PV) in the perirhinal (PRC) and retrosplenial (RSC) cortex of the rat. These two cortical areas differ strikingly in their connectivity and function, which could be caused also by different structure of the interneuronal populations. Having a precise knowledge of the cellular composition of any cerebral area forms one of the basic input parameters and tenets for computational modelling of neuronal networks and for understanding some pathological conditions, like generating and spreading of epileptic activity. PRC possesses higher absolute and relative densities of CR+ and PV+ neurons than RSC, but the CR : PV ratio is higher in the RSC, which is similar to the neocortex. The bipolar/bitufted neurons are most common type of CR+ population, while the majority of PV+ neurons show multipolar morphology. Current results indicate that main difference between analysed areas is in density of CR+ neurons, which was significantly higher in the PRC. Our results coupled with works of other authors show that there are significant differences in the interneuronal composition and distribution of heretofore seemingly similar transitional cortical areas. These results may contribute to the better understanding of the mechanism of function of this cortical region in normal and diseased states.

Perirhinal input to neocortical layer 1 controls learning.

Hippocampal output influences memory formation in the neocortex, but this process is poorly understood because the precise anatomical location and the underlying cellular mechanisms remain elusive. Here, we show that perirhinal input, predominantly to sensory cortical layer 1 (L1), controls hippocampal-dependent associative learning in rodents. This process was marked by the emergence of distinct firing responses in defined subpopulations of layer 5 (L5) pyramidal neurons whose tuft dendrites receive perirhinal inputs in L1. Learning correlated with burst firing and the enhancement of dendritic excitability, and it was suppressed by disruption of dendritic activity. Furthermore, bursts, but not regular spike trains, were sufficient to retrieve learned behavior. We conclude that hippocampal information arriving at L5 tuft dendrites in neocortical L1 mediates memory formation in the neocortex.

Differential responsivity of neurons in perirhinal cortex, lateral entorhinal cortex, and dentate gyrus during time-bridging learning.

Many studies have focused on the function of hippocampal region CA1 as a critical site for associative memory, but much less is known about changes in the afferents to CA1. Here we report the activity of multiple single neurons from perirhinal and entorhinal cortex and from dentate gyrus during trace eyeblink conditioning as well as consolidated recall, and in pseudo-conditioned control rabbits. We also report an analysis of theta activity filtered from the local field potential (LFP). Our results show early associative changes in single-neuron firing rate as well as theta oscillations in lateral entorhinal cortex (EC) and dentate gyrus (DG), and increases in the number of responsive neurons in perirhinal cortex. In both EC and DG, a subset of neurons from conditioned animals exhibited an elevated baseline firing rate and large responses to the conditioned stimulus and trace period. A similar population of cells has been seen in DG and in medial, but not lateral, EC during spatial tasks, suggesting that lateral EC contains cells responsive to a temporal associative task. In contrast to recent studies in our laboratory that found significant CA1 contributions to long-term memory, the activity profiles of neurons within EC and DG were similar for conditioned and pseudoconditioned rabbits during post-consolidation sessions. Collectively these results demonstrate that individual subregions of medial temporal lobe differentially support new and remotely acquired memories. Neuron firing profiles were similar on training trials when conditioned responses were and were not exhibited, demonstrating that these temporal lobe regions represent the CS-US association and do not control the behavioral response. The analysis of theta activity revealed that theta power was modulated by the conditioning stimuli in both the conditioned and pseudoconditioned groups and that although both groups exhibited a resetting of phase to the corneal airpuff, only the conditioned group exhibited a resetting of phase to the whisker conditioned stimulus.

Parvalbumin interneuron mediated feedforward inhibition controls signal output in the deep layers of the perirhinal-entorhinal cortex.

The perirhinal (PER) and lateral entorhinal (LEC) cortex form an anatomical link between the neocortex and the hippocampus. However, neocortical activity is transmitted through the PER and LEC to the hippocampus with a low probability, suggesting the involvement of the inhibitory network. This study explored the role of interneuron mediated inhibition, activated by electrical stimulation in the agranular insular cortex (AiP), in the deep layers of the PER and LEC. Activated synaptic input by AiP stimulation rarely evoked action potentials in the PER-LEC deep layer excitatory principal neurons, most probably because the evoked synaptic response consisted of a small excitatory and large inhibitory conductance. Furthermore, parvalbumin positive (PV) interneurons-a subset of interneurons projecting onto the axo-somatic region of principal neurons-received synaptic input earlier than principal neurons, suggesting recruitment of feedforward inhibition. This synaptic input in PV interneurons evoked varying trains of action potentials, explaining the fast rising, long lasting synaptic inhibition received by deep layer principal neurons. Altogether, the excitatory input from the AiP onto deep layer principal neurons is overruled by strong feedforward inhibition. PV interneurons, with their fast, extensive stimulus-evoked firing, are able to deliver this fast evoked inhibition in principal neurons. This indicates an essential role for PV interneurons in the gating mechanism of the PER-LEC network.

Prefrontal connections of the perirhinal and postrhinal cortices in the rat.

Knowing how prefrontal regions interact with medial temporal lobe structures is important for understanding memory and cognition. Using anterograde and retrograde tract tracing methods in the rat, we report a detailed study of the perirhinal (PER) and postrhinal (POR) connections with the lateral, ventrolateral, and medial orbitofrontal cortices (ORBl, ORBvl, ORBm), infralimbic and prelimbic cortices (IL, PL), ventral and dorsal anterior cingulate cortices (ACAv, ACAd), and secondary motor cortex (MOs). Our analyses included the topography and laminar patterns of these connections. The PER and POR showed reciprocal connectivity with all prefrontal regions examined, but the patterns of connections differed. In general, PER areas 36 and 35 showed patterns of connectivity that were more similar to each other than to those of the POR. Analysis of anterograde tracers showed that PER areas 36 and 35 provide the strongest projections to prefrontal regions. The heaviest fiber labeling was in IL and PL, closely followed by orbital regions. Fiber labeling arising from injections in POR was weaker overall. The strongest POR efferents targeted MOs, ACAv, and ORBvl. For return projections, analysis of retrograde tracers showed that PER areas 36 and 35 receive strong inputs from orbitofrontal and medial prefrontal regions. Interestingly, PER also received substantial inputs from MOs and ACAd. The POR receives a very strong input from MOs, followed by ACAd, and ORBvl. Based on comparison of our findings with those obtained in monkeys, we argue that the rodent ACAd and MOs may be a functional homolog of the primate dorsolateral prefrontal cortex.

Conversion of object identity to object-general semantic value in the primate temporal cortex.

At the final stage of the ventral visual stream, perirhinal neurons encode the identity of memorized objects through learning. However, it remains elusive whether and how object percepts alone, or concomitantly a nonphysical attribute of the objects ("learned"), are decoded from perirhinal activities. By combining monkey psychophysics with optogenetic and electrical stimulations, we found a focal spot of memory neurons where both stimulations led monkeys to preferentially judge presented objects as "already seen." In an adjacent fringe area, where neurons did not exhibit selective responses to the learned objects, electrical stimulation induced the opposite behavioral bias toward "never seen before," whereas optogenetic stimulation still induced bias toward "already seen." These results suggest that mnemonic judgment of objects emerges via the decoding of their nonphysical attributes encoded by perirhinal neurons.

Perirhinal firing patterns are sustained across large spatial segments of the task environment.

Spatial navigation and memory depend on the neural coding of an organism's location. Fine-grained coding of location is thought to depend on the hippocampus. Likewise, animals benefit from knowledge parsing their environment into larger spatial segments, which are relevant for task performance. Here we investigate how such knowledge may be coded, and whether this occurs in structures in the temporal lobe, supplying cortical inputs to the hippocampus. We found that neurons in the perirhinal cortex of rats generate sustained firing patterns that discriminate large segments of the task environment. This contrasted to transient firing in hippocampus and sensory neocortex. These spatially extended patterns were not explained by task variables or temporally discrete sensory stimuli. Previously it has been suggested that the perirhinal cortex is part of a pathway processing object, but not spatial information. Our results indicate a greater complexity of neural coding than captured by this dichotomy.

Neural Correlates of Both Perception and Memory for Objects in the Rodent Perirhinal Cortex.

Despite its anatomical positioning as an interface between the perceptual and memory systems, the perirhinal cortex (PER) has long been considered dedicated for object recognition memory. Whether the PER is also involved in object perception has been intensely debated in recent studies, but physiological evidence has been lacking. We recorded single units from the PER while the rat made categorical responses immediately after sampling a visual object as the originally learned objects were ambiguously morphed to varying degrees. Some neurons in the PER  changed their firing rates monotonically following the gradual changes across the morphed objects as if they coded perceptual changes of the object stimuli. However, other neurons abruptly changed their firing rates according to the response categories associated with the morphed objects, seemingly responding to the learned relationships between the stimulus and its associated choice response. The gradual and abrupt changes in object-tuning properties were also found at the neural population level. Furthermore, the object-associated tuning characteristics of neurons in the PER were more readily observable in correct trials than in error trials. Our findings suggest that neurons in the PER represent perceptual details of an object in addition to its mnemonic identity.

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.

Subcortical connections of the perirhinal, postrhinal, and entorhinal cortices of the rat. I. afferents.

In this study the subcortical afferents for the rat PER areas 35 and 36, POR, and the lateral and medial entorhinal areas (LEA and MEA) were characterized. We analyzed 33 retrograde tract-tracing experiments distributed across the five regions. For each experiment, we estimated the total numbers, percentages, and densities of labeled cells in 36 subcortical structures and nuclei distributed across septum, basal ganglia, claustrum, amygdala, olfactory structures, thalamus, and hypothalamus. We found that the complement of subcortical inputs differs across the five regions, especially the PER and POR. The PER receives input from the reuniens, suprageniculate, and medial geniculate thalamic nuclei as well as the amygdala. Overall, the subcortical inputs to the PER were consistent with a role in perception, multimodal processing, and the formation of associations that include the motivational significance of individual items and objects. Subcortical inputs to the POR were dominated by the dorsal thalamus, particularly the lateral posterior nucleus, a region implicated in visuospatial attention. The complement of subcortical inputs to the POR is consistent with a role in representing and monitoring the local spatial context. We also report that, in addition to the PER, the LEA and the medial band of the MEA also receive strong amygdala input. In contrast, subcortical input to the POR and the MEA lateral band includes much less amygdala input and is dominated by dorsal thalamic nuclei, particularly nuclei involved in spatial information processing. Thus, some subcortical inputs are consistent with the view that there is functional differentiation along the septotemporal axis of the hippocampus, but others provide considerable integration. Overall, we conclude that the patterns of subcortical inputs to the PER, POR, and the entorhinal LEA and MEA provide further evidence for functional differentiation in the medial temporal lobe. © 2016 Wiley Periodicals, Inc.

Subcortical connections of the perirhinal, postrhinal, and entorhinal cortices of the rat. II. efferents.

This is the second of two studies detailing the subcortical connections of the perirhinal (PER), the postrhinal (POR) and entorhinal (EC) cortices of the rat. In the present study, we analyzed the subcortical efferents of the rat PER areas 35 and 36, POR, and the lateral and medial entorhinal areas (LEA and MEA). Anterograde tracers were injected into these five regions, and the resulting density of fiber labeling was quantified in an extensive set of subcortical structures. Density and topography of fiber labeling were quantitatively assessed in 36 subcortical areas, including olfactory structures, claustrum, amygdala nuclei, septal nuclei, basal ganglia, thalamic nuclei, and hypothalamic structures. In addition to reporting the density of labeled fibers, we incorporated a new method for quantifying the size of anterograde projections that takes into account the volume of the target subcortical structure as well as the density of fiber labeling. The PER, POR, and EC displayed unique patterns of projections to subcortical areas. Interestingly, all regions examined provided strong input to the basal ganglia, although the projections arising in the PER and LEA were stronger and more widespread. PER areas 35 and 36 exhibited similar pattern of projections with some differences. PER area 36 projects more heavily to the lateral amygdala and much more heavily to thalamic nuclei including the lateral posterior nucleus, the posterior complex, and the nucleus reuniens. Area 35 projects more heavily to olfactory structures. The LEA provides the strongest and most widespread projections to subcortical structures including all those targeted by the PER as well as the medial and posterior septal nuclei. POR shows fewer subcortical projections overall, but contributes substantial input to the lateral posterior nucleus of the thalamus. The MEA projections are even weaker. Our results suggest that the PER and LEA have greater influence over olfactory, amygdala, and septal nuclei, whereas PER area 36 and the POR have greater influence over thalamic nuclei. © 2016 Wiley Periodicals, Inc.

Topographic organization of the basal forebrain projections to the perirhinal, postrhinal, and entorhinal cortex in rats.

Previous studies have shown that the basal forebrain (BF) modulates cortical activation via its projections to the entire cortical mantle. However, the organization of these projections is only partially understood or, for certain areas, unknown. In this study, we examined the topographic organization of cholinergic and noncholinergic projections from the BF to the perirhinal, postrhinal, and entorhinal cortex by using retrograde tracing combined with choline acetyltransferase (ChAT) immunohistochemistry in rats. The perirhinal and postrhinal cortex receives major cholinergic and noncholinergic input from the caudal BF, including the caudal globus pallidus and substantia innominata and moderate input from the horizontal limb of the diagonal band, whereas the entorhinal cortex receives major input from the rostral BF, including the medial septum and the vertical and horizontal limbs of the diagonal band. In the perirhinal cases, cholinergic projection neurons are distributed more caudally in the caudal globus pallidus than noncholinergic projection neurons. Compared with the perirhinal cases, the distribution of cholinergic and noncholinergic neurons projecting to the postrhinal cortex shifts slightly caudally in the caudal globus pallidus. The distribution of cholinergic and noncholinergic neurons projecting to the lateral entorhinal cortex extends more caudally in the BF than to the medial entorhinal cortex. The ratio of ChAT-positive projection neurons to total projection neurons is higher in the perirhinal/postrhinal cases (26-48%) than in the entorhinal cases (13-30%). These results indicate that the organization of cholinergic and noncholinergic projections from the BF to the parahippocampal cortex is more complex than previously described. J. Comp. Neurol. 524:2503-2515, 2016. © 2016 Wiley Periodicals, Inc.