Perirhinal Regions Research Articles

The anterior cingulate cortex and its role in controlling contextual fear memory to predatory threats

Predator exposure is a life-threatening experience and elicits learned fear responses to the context in which the predator was encountered. The anterior cingulate area (ACA) occupies a pivotal position in a cortical network responsive to predatory threats, and it exerts a critical role in processing fear memory. The experiments were made in mice and revealed that the ACA is involved in both the acquisition and expression of contextual fear to predatory threat. Overall, the ACA can provide predictive relationships between the context and the predator threat and influences fear memory acquisition through projections to the basolateral amygdala and perirhinal region and the expression of contextual fear through projections to the dorsolateral periaqueductal gray. Our results expand previous studies based on classical fear conditioning and open interesting perspectives for understanding how the ACA is involved in processing contextual fear memory to ethologic threatening conditions that entrain specific medial hypothalamic fear circuits.

Molecular mechanisms within the dentate gyrus and the perirhinal cortex interact during discrimination of similar nonspatial memories.

Differentiating between similar memories is a crucial cognitive function that enables correct episodic memory formation. The ability to separate the components of memories into distinct representations is thought to rely on a computational process known as pattern separation, by which differences are amplified to disambiguate similar events. Although pattern separation has been localized to the dentate gyrus (DG) of the hippocampus and shown to occur in a spatial domain, this cognitive function takes place also during processing of other types of information. In particular, there is some debate on whether the DG participates in pattern separation of nonspatial representations. Considering the classic role of the Prh in the acquisition and storage of object memories in general and tasks with similar features in particular, this cognitive function could rely more heavily on perirhinal regions when object-related information is processed. Here we show that two plasticity-related proteins, BDNF, and Arc, are required in the DG for nonspatial mnemonic differentiation. Moreover, we found that the crucial role of the DG is transient since activity of AMPAR is only required in the Prh but not the DG during differentiated object memory retrieval. Additionally, this memory is not modifiable by postacquisition rhBDNF infusions in the DG that are known to improve memory when given in the Prh. This highlights a differential role of Prh and DG during differentiated object memory consolidation. Additionally, we found that these molecular mechanisms actively interact in the DG and Prh for the formation of distinguishable memories, with infusions of rhBDNF in the Prh being able to rescue mnemonic deficits caused by reduced Arc expression in the DG. These results reveal a complex interaction between plasticity mechanisms in the Prh and DG for nonspatial pattern separation and posit the Prh as the key structure where unique object representations are stored.

Déjà vu and prescience in a case of severe episodic amnesia following bilateral hippocampal lesions

ABSTRACT Several studies pertaining to déjà vu have consistently made a connection with the perirhinal region, a region located below the hippocampus. This idea is strengthened by the fact that déjà vu is an erroneous sense of familiarity and that familiarity appears to largely depend on the perirhinal region in healthy subjects. In this context, the role of the hippocampus is particularly unclear as it is unknown whether or not it plays a role in the genesis of déjà vu. We report on the case of OHVR, an epileptic patient who suffers from severe episodic amnesia related to massive isolated bilateral damage to the hippocampus. In contrast, the perirhinal region is intact structurally and functionally. This patient reports frequent déjà vu but also another experiential phenomenon with a prominent feeling of prescience, which shows some of the characteristics of déjà vécu. She clearly distinguishes both. She also developed a form of synaesthesia by attributing affective valence to numbers. This study shows that déjà vu can occur in cases of amnesia with massively damaged hippocampi and confirms that the perirhinal region is a core region for déjà vu, using a different approach from previous reports. It also provides clues about a potential influence of hippocampal alterations in déjà vécu.

The relationship between clinical and pathological variables in Richardson’s syndrome

In order to determine the relationship between regional neuropathology and severity of clinical features in Richardson's syndrome (PSP-RS), the following hypotheses were tested: (1) executive dysfunction relates to prefrontal pathology; (2) language difficulties to pathology in Broca's area and/or the perirhinal cortex; and (3) visuospatial impairment to pathology in the supramarginal region. A prospectively studied case series of brain donors at a specialist clinic in Addenbrooke's Hospital Cambridge, UK, were examined. All those fulfilling postmortem criteria for PSP-RS and their last cognitive assessment within 24 months of death (N = 11/25) were included. The degree of regional neuronal loss and neuronal tau deposition across a number of cortical brain regions was performed and compared to 10 age- and sex-matched controls from the Sydney Brain Bank. Stepwise multiple linear regressions were used to determine the neuropathological correlates to cognitive scores and revealed the following. Executive dysfunction, as indexed by letter fluency, related to the degree of tau deposition in the superior frontal gyrus and supramarginal cortices (p < 0.020), language deficits related to neuron loss in the perirhinal gyrus (p < 0.001) and tau deposition in Broca's area (p = 0.020), while visuospatial dysfunction and global cognitive impairment related to tau deposition in the supramarginal gyrus (p < 0.007). The severity of cognitive deficits relate to regional cortical tau deposition in PSP-RS, although language impairment related to neuronal loss in the perirhinal region. Global cognitive dysfunction related most to the severity of tau deposition in the supramarginal gyrus warranting further research on the role of this brain region in PSP-RS.

Local and distal connections of neocortical pyramidal cells projecting to the perirhinal regions

Local and distal connections of neocortical pyramidal cells projecting to the perirhinal regions

A role for calcium‐calmodulin‐dependent protein kinase II in the consolidation of visual object recognition memory

The aim was to investigate the role of calcium-calmodulin-dependent protein kinase (CAMK)II in object recognition memory. The performance of rats in a preferential object recognition test was examined after local infusion of the CAMKII inhibitors KN-62 or autocamtide-2-related inhibitory peptide (AIP) into the perirhinal cortex. KN-62 or AIP infused after acquisition impaired memory tested at 24 h, indicating an involvement of CAMKII in the consolidation of recognition memory. Memory was impaired when KN-62 was infused at 20 min after acquisition or when AIP was infused at 20, 40, 60 or 100 min after acquisition. The time-course of CAMKII activation in rats was further examined by immunohistochemical staining for phospho-CAMKII(Thre286)alpha at 10, 40, 70 and 100 min following the viewing of novel and familiar images. At 70 min, processing novel images resulted in more phospho-CAMKII(Thre286)alpha-stained neurons in the perirhinal cortex than did the processing of familiar images, consistent with the viewing of novel images increasing the activity of CAMKII at this time. This difference was eliminated by prior infusion of AIP. These findings establish that CAMKII is active within the perirhinal region between approximately 20 and 100 min following learning and then returns to baseline. Thus, increased CAMKII activity is essential for the consolidation of long-term object recognition memory but continuation of that increased activity throughout the 24 h memory delay is not necessary for maintenance of the memory.

Learning-Related Facilitation of Rhinal Interactions by Medial Prefrontal Inputs

Much data suggests that hippocampal-medial prefrontal cortex (mPFC) interactions support memory consolidation. This process is thought to involve the gradual transfer of transient hippocampal-dependent memories to distributed neocortical sites for long-term storage. However, hippocampal projections to the neocortex involve a multisynaptic pathway that sequentially progresses through the entorhinal and perirhinal regions before reaching the neocortex. Similarly, the mPFC influences the hippocampus via the rhinal cortices, suggesting that the rhinal cortices occupy a strategic position in this network. The present study thus tested the idea that the mPFC supports memory by facilitating the transfer of hippocampal activity to the neocortex via an enhancement of entorhinal to perirhinal communication. To this end, we simultaneously recorded mPFC, perirhinal, and entorhinal neurons during the acquisition of a trace-conditioning task in which a visual conditioned stimulus (CS) was followed by a delay period after which a liquid reward was administered. At learning onset, correlated perirhinal-entorhinal firing increased in relation to mPFC activity, but with no preferential directionality, and only after reward delivery. However, as learning progressed across days, mPFC activity gradually enhanced rhinal correlations in relation to the CS as well, and did so in a specific direction: from entorhinal to perirhinal neurons. This suggests that, at late stages of learning, mPFC activity facilitates entorhinal to perirhinal communication. Because this connection is a necessary step for the transfer of hippocampal activity to the neocortex, our results suggest that the mPFC is involved in the slow iterative process supporting the integration of hippocampal-dependent memories into neocortical networks.

Differential contributions of the hippocampus and rhinal cortices to verbal memory in epilepsy

The present study explored the left mesial temporal lobe correlates of verbal memory in patients with temporal lobe epilepsy (TLE). An index of structural integrity, T2 relaxation time, was measured bilaterally in three mesial temporal regions of interest, and correlated with measures of verbal memory. The acquisition of verbal arbitrary relational material was most strongly associated with left perirhinal T2 signal. In contrast, verbal memory consolidation was related to T2 signal in the left hippocampus. Our findings suggest a key role for the left perirhinal region in the uptake of arbitrary linkages that underlie new learning. The hippocampus, on the other hand, is important for protecting newly learned information from the effects of interference. This double dissociation provides a neurocognitive account of the left mesial temporal memory syndrome.

Impaired verbal associative learning after resection of left perirhinal cortex

Some patients considered for left temporal lobectomy for epilepsy present with normal verbal learning and no MRI evidence of hippocampal pathology. In order to preserve learning function, the surgical approach in these cases often aims at sparing the hippocampus. Parahippocampal structures, including the left perirhinal region, however, also appear to contribute to some forms of verbal learning. We studied aspects of verbal learning in four patients with left temporal lobe resections that preserved the hippocampus, but which included perirhinal/entorhinal cortices in two cases. Pre- and postoperative T1-weighted MRI scans were spatially normalized and residual mesial temporal structures identified. The two patients whose resection included perirhinal and entorhinal cortices exhibited a marked decrement in the ability to acquire arbitrarily related word pairs that persisted at 12-month follow-up. Word list learning showed an early postoperative impairment, but recovered to normal levels within 12 months. In two patients, resection encompassed anterolateral and inferior temporal neocortex but spared the perirhinal and entorhinal cortices, amygdala and hippocampus. No postoperative change in verbal learning was evident. We concluded that hippocampal-sparing left temporal lobe resections result in task-specific verbal learning deficits when perirhinal/entorhinal tissue is included in the resection.

The perirhinal cortex of the rat is necessary for spatial memory retention long after but not soon after learning

Many observations in humans and experimental animals support the view that the hippocampus is critical immediately after learning in order for long-term memory formation to take place. However, exactly when the medial temporal cortices adjacent to the hippocampus are necessary for this process to occur normally is not yet well known. Using a spatial task, we studied whether the perirhinal cortex of rats is necessary to establish representations in long-term memory. Results showed that, in a spatial task sensitive to hippocampal lesions, control and perirhinal lesioned rats can both learn at the same rate (Experiment 1). Interestingly, a differential involvement of the perirhinal cortex in memory retention was observed as time passes after learning. Thus, 24 days following the end of learning, lesioned and control rats remembered the task perfectly as measured by a retraining test. In contrast, 74 days after the learning the perirhinal animals showed a profound impairment in the retention of the spatial information (Experiment 2). Taken together, these results suggest that the perirhinal region is critical for the formation of long-term spatial memory. However, its contribution to memory formation and retention is time-dependent, it being necessary only long after learning takes place and not during the phase immediately following acquisition.

Recollection of vivid memories after perirhinal region stimulations: synchronization in the theta range of spatially distributed brain areas

Electrical stimulation of the temporal cortex in patients with epilepsy sometimes elicits experiential phenomena such as recollection of vivid memories. The neurophysiological substrate of such phenomena is poorly understood. Furthermore, the relation between the site of stimulation and the type of memory elicited has only recently started to be investigated. We investigated these issues in patient FGA who had intracerebral electrodes stereotaxically implanted in the right temporal lobe for investigation of drug-resistant epilepsy. We report the results of electrical stimulations of the perirhinal region. Two stimulations elicited experiential phenomena consisting of visual memories that belonged to FGA's past, but which were not related to any particular episode. These visual memories consisted of objects or of details of objects. These two stimulations were contrasted with other stimulations in the same subhippocampal region. Cross-correlation analysis of the depth-EEG signals filtered in frequency sub-bands revealed that experiential phenomena occurred only when the various brain structures involved in the after-discharge were synchronized in the theta range. These structures included the perirhinal region, the hippocampus, other limbic structures as well as a primary visual area. Our results suggest that recollection of vivid memory after electric stimulation of the cortex may rely on wide networks of brain areas that transiently synchronize. These results also highlight the role of the perirhinal region in human memory. Experiential phenomena are rarely obtained after brain stimulation. Replication of these results is thus required due to the small number of observations reported.

Topographic organization of cortical inputs to the lateral nucleus of the macaque monkey amygdala: a retrograde tracing study.

The objective of this study was to identify cortical areas that project to the lateral nucleus of the macaque monkey amygdaloid complex. Discrete injections of the fluorescent retrograde tracers Fast blue and Diamidino yellow were placed into different locations within the lateral nucleus. Retrogradely labeled cells were mapped using a computer-aided digitizing system. In the frontal cortex, low numbers of retrogradely labeled cells were observed in medial and orbitofrontal regions (areas 10, 11, 12, 13, 13a, and 14). In the anterior cingulate cortex, low to moderate numbers of retrogradely labeled cells were located in areas 25, 24, and 32. In the insula, there were moderate to high numbers of retrogradely labeled cells in agranular and dysgranular regions. The parainsula cortex also demonstrated a moderate to high number of retrogradely labeled cells. In the temporal lobe, retrogradely labeled cells were most numerous in the rostral (polar) portion of the perirhinal cortex. Large numbers of labeled cells were also located throughout more caudal portions of the perirhinal regions as well as in the entorhinal cortex, area TE, and the superior temporal gyrus. Fewer retrogradely labeled cells were observed in the cortex along the dorsal bank of the superior temporal sulcus, in the parahippocampal cortex, and in area TEO. Although retrograde tracers can provide only limited evidence for topography, we nonetheless noted that the density of retrogradely labeled cells in a cortical area reliably depended on the location of the tracer injection in the lateral nucleus.

Arterial supply of limbic structures in the guinea pig.

This study outlines the vascular territories of the cerebral arteries that originate from the Willis circle to supply limbic structures in the guinea pig brain. The entire cerebral vascular system was visualized in four preliminary experiments by performing superselective microangiographic studies with iodine contrast medium perfusion of the whole brain after in vitro isolation according to a technique described previously (de Curtis et al. [1991] Hippocampus 1:341-354). Subsequently, the perfusion territory of the different arteries that originate from the Willis circle was characterized after cannulation and perfusion of individual arteries with a gelatin solution that contained waterproof black ink. The analysis was performed by identifying the brain regions that contained the black stain on 150-microm-thick coronal sections that were cut after brain fixation with paraformaldehyde for at least 1 week. The middle cerebral artery and the rostral and caudal posterior cerebral arteries supply the limbic cortices and some related subcortical regions. In particular, large portions of the hippocampal formation are supplied by both the rostral posterior cerebral artery and the rostral branch of the caudal posterior cerebral artery, whereas the ventral temporal part of the hippocampus is served exclusively by the rostral posterior cerebral artery. The amygdala, the periamygdaloid cortex, and the piriform cortex are served by the middle cerebral artery and in part by the perforating arteries. The entorhinal, perirhinal, and postrhinal cortices are vascularized by the posterior and middle cerebral arteries, with a very broad overlap between the distal territories of these vessels. The demonstration of an extensive superimposition between the arterial supply of the entorhinal and the perirhinal regions suggests the presence of anastomotic connections that potentially are protective against ischemic events. Such an arrangement was not observed for the arteries that supply the ventral portion of the hippocampal formation and the basolateral amygdala, which showed nonoverlapping boundaries. The pathophysiological consequences of a similar vascular organization are discussed.

Direct connection between perirhinal cortex and hippocampus is a major constituent of the lateral perforant path.

Single-pulse stimulation of the perirhinal cortex (PRC) evoked field responses in the dorsal hippocampal CA1 region in urethane-anesthetized rats. In depth profiles conducted by moving the PRC stimulating electrode, the largest amplitude hippocampal potential was generated when the stimulating electrode was located within the perirhinal region. More dorsal (temporal cortex) or more ventral (lateral entorhinal cortex) stimulating sites elicited minimal hippocampal potentials. The hippocampal response was maintained during 100 Hz stimulation of the PRC, suggesting that it was monosynaptic, and high-frequency stimulation (400 Hz) of the PRC produced a significant potentiation of hippocampal CA1 field potentials (46.73 +/- 4.14%). When the PRC and the lateral perforant path (LPP) were stimulated separately, the depth/amplitude profiles obtained from a roving recording electrode located within the dorsal hippocampus were similar. In order to determine if fibers from PRC project to the hippocampus via the LPP, the PRC-CA1 and LPP-CA1 potentials were recorded prior to and during procaine (20%, 0.5 microliter) blockade of the LPP. A simultaneous loss of both potentials was observed immediately following procaine infusion, while a commissural control potential was unaffected. Both LPP and PRC potentials returned approximately 30-40 min later. Electrolytic lesions of PRC produced a significant decrease in the amplitude of LPP-hippocampal potentials when testing was conducted 4-5 days postlesion. Lesions of lateral entorhinal cortex or temporal cortex did not produce such effects. These data suggest that a direct pathway from perirhinal cortex to the dorsal hippocampal CA1 field can undergo long-term potentiation (LTP) and that this pathway makes a major contribution to the lateral perforant path.

Brain Activation in Young and Older Adults During Implicit and Explicit Retrieval

Positron emission tomography was used to study regional cerebral blood flow (H2(15)O method) in groups of young and older adults during implicit and explicit retrieval, following a procedure devised by Squire et al. (1992). At study, subjects were exposed to four lists of words. Following list presentation, subjects were presented with three-letter word stems under four conditions: (1) silent viewing, (2) completion of word stems that could not form words from the study list, with the instruction to provide the first word that came to mind (baseline), (3) completion of word stems, half of which could form words from the study list, with the instruction to provide the first word that came to mind (priming), and (4) completion of word stems, half of which could form words from the study list, with the instruction to use the stems as cues for recall of list words (memory). The behavioral data indicated an agerelated deficit in cued recall that was reduced in priming. Both age groups showed a similar decrease of blood flow in right posterior cortex during priming relative to baseline. During cued recall, bilateral increases of blood flow were observed in prefrontal cortex and anterior cingulate gyrus for both age groups. The young adults showed selective increases of activity in left cerebellum and Wernicke's area, whereas the older adults showed a selective bilateral activation in the perirhinal region of the medial-temporal cortex during cued recall. The results suggest a simiiar biological basis of priming in both age groups: a decrease in the neural activity required to process a particular stimulus during a subsequent encounter compared with a previous one. In addition, the importance of prefrontal regions for conscious retrieval was substantiated and extended to late adulthood. Finally, the agedifferential activations observed during cued recall were discussed relative to prominent concepts in the current literature on cognitive aging (e.g., speed of processing, self-initiated operations, cross-modal recoding).

Divergent Projections from the Anterior Inferotemporal Area TE to the Perirhinal and Entorhinal Cortices in the Macaque Monkey

Area TE is located at the latter part of the ventral visual cortical pathway, which is essential for visual recognition of objects. TE projects heavily to the perirhinal region, which is important for visual recognition memory of objects. To study the organization of projections from TE to the perirhinal (areas 35 and 36) and entorhinal (area 28) cortices, we made focal injections of Phaseolus vulgaris leucoagglutinin (PHA-L) and large injections of biocytin or wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into anterior levels of TE in macaque monkeys. Injections of PHA-L into the ventral part of anterior TE (TEav) resulted in labeling of terminals distributed widely in area 36 (approximately one-half of its total extent), although the injection sites were limited to 0.7 mm in width. The labeled terminals tended to be denser in the medial part of area 36. There was less dense but definite labeling in area 35 and the lateral part of area 28. After a single injection of PHA-L or WGA-HRP into the dorsal part of anterior TE (TEad), labeled terminals were confined to a small region at the lateral part of area 36 (less than one-tenth of its total extent). The projections to areas 35 and 28 from TEad were much sparser than those from TEav. The different patterns of projections to the perirhinal and entorhinal cortices, together with previously reported differences in their afferent and other efferent connections, suggest the functional differentiation between TEav and TEad. The divergent projection from TEav to the perirhinal cortex may facilitate the association of different visual features in the perirhinal cortex.

Direct connection between perirhinal cortex and hippocampus is a major constituent of the lateral perforant path

Single-pulse stimulation of the perirhinal cortex (PRC) evoked field responses in the dorsal hippocampal CA1 region in urethane-anesthetized rats. In depth profiles conducted by moving the PRC stimulating electrode, the largest amplitude hippocampal potential was generated when the stimulating electrode was located within the perirhinal region. More dorsal (temporal cortex) or more ventral (lateral entorhinal cortex) stimulating sites elicited minimal hippocampal potentials. The hippocampal response was maintained during 100 Hz stimulation of the PRC, suggesting that it was monosynaptic, and high-frequency stimulation (400 Hz) of the PRC produced a significant potentiation of hippocampal CA1 field potentials (46.73 ± 4.14%). When the PRC and the lateral perforant path (LPP) were stimulated separately, the depth/amplitude profiles obtained from a roving recording electrode located within the dorsal hippocampus were similar. In order to determine if fibers from PRC project to the hippocampus via the LPP, the PRC-CA1 and LPP-CA1 potentials were recorded prior to and during procaine (20%, 0.5 μl) blockade of the LPP. A simultaneous loss of both potentials was observed immediately following procaine infusion, while a commissural control potential was unaffected. Both LPP and PRC potentials returned approximately 30–40 min later. Electrolytic lesions of PRC produced a significant decrease in the amplitude of LPP-hippocampal potentials when testing was conducted 4–5 days postlesion. Lesions of lateral entorhinal cortex or temporal cortex did not produce such effects. These data suggest that a direct pathway from perirhinal cortex to the dorsal hippocampal CA1 field can undergo long-term potentiation (LTP) and that this pathway makes a major contribution to the lateral perforant path. © 1996 Wiley-Liss, Inc.

Evolution of afterdischarge and seizure characteristics during electrical kindling of the guinea-pig

Interspecies comparisons may help us understand the mechanisms which underlie brain plasticity. In this study, we examined the electrical kindling phenomenon in the amygdala, piriform and perirhinal regions of the guinea-pig. The changes in afterdischarge (AD) characteristics and behavioural seizures were assessed under different stimulation intervals and parameters as well as under reduced inhibitory neurotransmitter systems. We report that the guinea-pigs displayed a number of similarities with other species, such as the progressive increases in AD characteristics and seizure behaviours, but also a number of differences, such as the behavioural manifestations of the seizures, failing to reach a fully generalized tonic-clonic seizure and an apparent insensitivity to both low-frequency stimulation and reduced GABA and catecholamine levels.

MR imaging of diseases of the limbic system.

The limbic system refers to the part of the brain that is involved in emotional expression and in cognitive and somatomotor control systems; it most likely also has a significant role in the pathogenesis of certain dementias, neuropsychiatric disturbances, and seizure disorders. This system, as originally defined, has no clear anatomic boundaries. Limbic regions of the telencephalon include a continuous medial zone of cortical regions, including the hippocampal formation; a perihippocampal zone, including the cingulate gyrus, prefrontal region, and perirhinal region; along with subcortical areas, including the septum pellucidum and the amygdala. A distinguishing characteristic of the limbic region is that it is highly interconnected and appears to form the only major route for information transfer between the neocortex and the hypothalamus. With the multiplanar capability and resolution of MR imaging, the individual parts of the limbic system and the diseases that affect them can be studied. In this review, we discuss MR imaging of the diseases that affect this system.

Zinc-containing neurons.

Zinc-containing neurons are cells that sequester zinc in their presynaptic vesicles and release it in a calcium- and impulse-dependent manner. The zinc-containing neurons are a subclass of the glutaminergic neurons: all known zinc-containing pathways are also glutaminergic pathways. With a few exceptions, zinc-containing neurons are located only in the telencephalon. The major glutaminergic systems of the brain stem, thalamus, and cerebellum, for example, all lack vesicular zinc, whereas many cerebrocortical systems are zinc containing. Within the telencephalon, the zinc-containing fiber systems form a vast associational network that reciprocally interconnects isocortical, allocortical and 'limbic' structures. Because the hippocampal, amygdalar, and perirhinal regions are prominent nodes in this network, it is presumed that vesicular zinc is involved in epileptic phenomena (in pathology) and (in normal function) in the synaptic plasticity of developmental and experiential learning. Zinc ions are potent modulators of amino acid receptors [especially the N-methyl-D-aspartate (NMDA) receptor] and corelease of zinc along with glutamate would provide a mechanism for modulating postsynaptic excitability levels. One useful hypothesis is that synaptically released zinc controls a 'window' of postsynaptic excitability, having little or no effect at physiological firing rates, but selectively depressing excitability (by NMDA receptor depression) when firing rates reach dangerous, paroxysmal levels.