Cannabinoid CB1 receptor protein expression in the rat hippocampus and entorhinal,perirhinal, postrhinal and temporal cortices: regional variations and age-related changes

Cannabinoids have been shown to disrupt memory processes and these effects occur primarily through cannabinoid CB1 receptors in the brain. The present study investigates, for the first time, the regional variations and age-related changes in CB1 protein expression in the hippocampus and its neighbouring entorhinal, perirhinal, postrhinal and temporal cortices using Western blotting. In young adult rats, CB1 protein was highly expressed in the hippocampus and within the hippocampus, the greatest density of CB1 protein was located in CA1. When a comparison was made between young (4-month-old) and aged (24-month-old) rats, CB1 protein expression was significantly increased in the aged entorhinal and temporal cortices and was significantly decreased in the aged postrhinal cortex. The present study demonstrates region-specific changes in CB1 protein expression during ageing and further suggests that cannabinoid CB1 receptors may contribute to the aging process.     

Changes in NOS protein expression and activity in the rat hippocampus,entorhinal and postrhinal cortices after unilateral electrolytic perirhinal cortex lesions

The integrity of the perirhinal cortex is critical for certain types of learning and memory. One important issue relating to the function of this region is its interaction with other brain areas that play a role in memory processing. This study investigates the time course of changes in activity and protein expression of nitric oxide synthase (NOS), which transforms L-arginine into nitric oxide (NO) and citrulline, in the hippocampus and the entorhinal and postrhinal cortices after unilateral electrolytic lesions of the perirhinal cortex. Electrolytic lesions of the perirhinal cortex resulted in long lasting changes in NOS activity and protein expression in the entorhinal and postrhinal cortices (< or = 2 weeks post-lesion). In contrast, there was a small and transient decrease in nNOS expression (with no change in NOS activity) in the dorsal portion of the hippocampus. iNOS was not expressed in any region examined at any time point. These findings provide the first evidence that electrolytic lesions of the perirhinal cortex can result in long-term neurochemical changes in its anatomically related structures. Given that NO has been implicated in neuroplasticity processes, the interpretation of memory impairments induced by electrolytic lesions of the perirhinal cortex (and possibly, therefore, other brain regions) need to be considered with regard to these findings.     

Effects of aging on agmatine levels in memory-associated brain structures

Agmatine is a metabolite of L-arginine by arginine decarboxylase. Recent evidence suggests that it exists in mammalian brain and is a novel neurotransmitter. The present study measured agmatine levels in several memory-associated brain structures in aged (24-month-old), middle-aged (12-month-old), and young (4-month-old) male Sprague Dawley rats using liquid chromatography/mass spectrometry. Agmatine levels were significantly decreased in the CA1, but increased in the CA2/3 and dentate gyrus, subregions of the hippocampus in aged and middle-aged rats relative to the young adults. In the prefrontal cortex, a dramatic decrease in agmatine level was found in aged rats as compared with middle-aged and young rats. There were significantly increased levels of agmatine in the entorhinal and perirhinal cortices in aged relative to middle-aged and young rats. In the postrhinal and temporal cortices, agmatine levels were significantly increased in aged and middle-aged rats as compared with young adults. The present findings, for the first time, demonstrate age-related changes in agmatine levels in memory-associated brain structures and raise a novel issue of the potential involvement of agmatine in the aging process.     

Glutamate receptor subunits expression in memory-associated brain structures: regional variations and effects of aging

We investigated regional variations and the effects of aging on the expression of the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor subunits in several memory-associated structures using Western blotting. In young adult rats, NR1, NR2A, and GluR2 levels varied between the hippocampus and parahippocampal region and between the subregions of the hippocampus. When a comparison was made between young (4-month-old) and aged (24-month-old) rats, significant decreases in NR1 expression were found in the aged ventral hippocampus and the entorhinal and postrhinal cortices. There were significant decreases in NR2A expression in the aged parahippocampal region, but not in the hippocampus. The expression of the GluR2 subunit was significantly reduced in the ventral hippocampus and the postrhinal cortex. A dramatic decrease in NR1 and GluR2 expression was found in the aged CA2/3 and CA1, respectively, but there were no significant age-related changes in NR2A expression. All three subunits were expressed at a similar level in the two age groups in the prefrontal cortex. These results suggest differential expression and effects of aging on NMDA and AMPA receptor subunits in memory-associated brain structures.     

Cortical afferents of the perirhinal,postrhinal, and entorhinal cortices of the rat

We have divided the cortical regions surrounding the rat hippocampus into three cytoarchitectonically discrete cortical regions, the perirhinal, the postrhinal, and the entorhinal cortices. These regions appear to be homologous to the monkey perirhinal, parahippocampal, and entorhinal cortices, respectively. The origin of cortical afferents to these regions is well-documented in the monkey but less is known about them in the rat. The present study investigated the origins of cortical input to the rat perirhinal (areas 35 and 36) and postrhinal cortices and the lateral and medial subdivisions of the entorhinal cortex (LEA and MEA) by placing injections of retrograde tracers at several locations within each region. For each experiment, the total numbers of retrogradely labeled cells (and cell densities) were estimated for 34 cortical regions. We found that the complement of cortical inputs differs for each of the five regions. Area 35 receives its heaviest input from entorhinal, piriform, and insular areas. Area 36 receives its heaviest projections from other temporal cortical regions such as ventral temporal association cortex. Area 36 also receives substantial input from insular and entorhinal areas. Whereas area 36 receives similar magnitudes of input from cortices subserving all sensory modalities, the heaviest projections to the postrhinal cortex originate in visual associational cortex and visuospatial areas such as the posterior parietal cortex. The cortical projections to the LEA are heavier than to the MEA and differ in origin. The LEA is primarily innervated by the perirhinal, insular, piriform, and postrhinal cortices. The MEA is primarily innervated by the piriform and postrhinal cortices, but also receives minor projections from retrosplenial, posterior parietal, and visual association areas. J. Comp. Neurol. 398:179–205, 1998. © 1998 Wiley-Liss, Inc.     

Hippocampal nitric oxide synthase and arginase and age-associated behavioral deficits

The present study investigated age-related changes in nitric oxide synthase (NOS) and arginase in the subregions of the hippocampus and their correlations with animals' performance in the open field, T-maze, and water maze tasks. Aged rats (24 months old) showed reduced exploratory activity and poorer spatial learning relative to the young adults (4 months old). Significant increases in total NOS activity were found in the aged dentate gyrus and a dramatic decrease in endothelial NOS expression was observed in the aged CA2/3. Activity or protein expression of inducible NOS was not detected in any subregion of the hippocampus. There were no age-related changes in total arginase activity or arginase I and arginase II protein expression. Correlation analysis revealed that animals' motor ability was associated with CA1 NOS and arginase, as well as hippocampal function. The present findings provide further support for the involvement of NOS/NO and arginase in the normal aging process. A strong positive correlation between CA1 eNOS protein expression and swimming speed in the water maze task may reflect a relationship between the local cerebral blood flow and neuronal activity.     

Neurons and networks in the entorhinal cortex: A reappraisal of the lateral and medial entorhinal subdivisions mediating parallel cortical pathways

In this review, we aim to reappraise the organization of intrinsic and extrinsic networks of the entorhinal cortex with a focus on the concept of parallel cortical connectivity streams. The concept of two entorhinal areas, the lateral and medial entorhinal cortex, belonging to two parallel input–output streams mediating the encoding and storage of respectively what and where information hinges on the claim that a major component of their cortical connections is with the perirhinal cortex and postrhinal or parahippocampal cortex in, respectively, rodents or primates. In this scenario, the lateral entorhinal cortex and the perirhinal cortex are connectionally associated and likewise the postrhinal/parahippocampal cortex and the medial entorhinal cortex are partners. In contrast, here we argue that the connectivity matrix emphasizes the potential of substantial integration of cortical information through interactions between the two entorhinal subdivisions and between the perirhinal and postrhinal/parahippocampal cortices, but most importantly through a new observation that the postrhinal/parahippocampal cortex projects to both lateral and medial entorhinal cortex. We suggest that entorhinal inputs provide the hippocampus with high‐order complex representations of the external environment, its stability, as well as apparent changes either as an inherent feature of a biological environment or as the result of navigating the environment. This thus indicates that the current connectional model of the parahippocampal region as part of the medial temporal lobe memory system needs to be revised.     

Identifying cortical inputs to the rat hippocampus that subserve allocentric spatial processes: a simple problem with a complex answer

A consideration of the cortical projections to the hippocampus provides a number of candidate regions that might provide distal sensory information needed for allocentric processing. Prominent among the input regions are the entorhinal cortex, the perirhinal cortex, the postrhinal cortex, and the retrosplenial cortex. A review of these sites reveals the surprising fact that in spite of their anatomical connections, removal of the perirhinal and postrhinal cortices has little or no effect on spatial tasks and hence does not functionally disconnect the hippocampus. Extensive retrosplenial lesions have only mild effects, and even lesions of the entorhinal cortex only partially mimic the effects of hippocampal lesions upon tests of spatial memory. In contrast, studies using c-fos imaging support the involvement of the entorhinal, postrhinal, and retrosplenial cortices, but not the perirhinal cortex. It is argued that there exist multiple aspects of spatial memory, and this is reflected in the multiple routes by which cortical information can reach the hippocampus. One consequence is that lesions in a single site often have surprisingly mild effects on standard spatial tests.     

Perirhinal and postrhinal cortices of the rat: Interconnectivity and connections with the entorhinal cortex

The cortical regions dorsally adjacent to the posterior rhinal sulcus in the rat can be divided into a rostral region, the perirhinal cortex, which shares features of the monkey perirhinal cortex, and a caudal region, the postrhinal cortex, which has connectional attributes similar to the monkey parahippocampal cortex. We examined the connectivity among the rat perirhinal (areas 35 and 36), postrhinal, and entorhinal cortices by placing anterograde and retrograde tracers in all three regions. There is a dorsal-to-ventral cascade of connections in the perirhinal and entorhinal cortices. Dorsal area 36 projects strongly to ventral area 36, and ventral area 36 projects strongly to area 35. The return projections are substantially weaker. The cascade continues with the perirhinal to entorhinal connections. Area 35 is more strongly interconnected with the entorhinal cortex, ventral area 36 somewhat less strongly, and dorsal area 36 projects only weakly to the entorhinal cortex. The postrhinal-to-perirhinal connections also follow this general pattern. The postrhinal cortex is more heavily connected with dorsal area 36 than with ventral area 36 and is more heavily connected with area 36 than with area 35. The rostral portion of the postrhinal cortex has the strongest connections with the perirhinal cortex. Like in the monkey, the perirhinal and postrhinal cortices have different patterns of projections to the entorhinal cortex. The perirhinal cortex is preferentially connected with the rostrolateral portion of the entorhinal cortex. The postrhinal cortex projects to a part of this same region but is also connected to caudal and medial portions of the entorhinal cortex. The perirhinal and postrhinal projections to the entorhinal cortex originate in layers III and V and terminate preferentially in layers II and III. J. Comp. Neurol. 391:293–321, 1998. © 1998 Wiley-Liss, Inc.     

Reduced nicotinamide adenine dinucleotide phosphate-diaphorase/nitric oxide synthase profiles in the human hippocampal formation and perirhinal cortex

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-stained profiles were evaluated throughout the human hippocampal formation (i. e., dentate gyrus, Ammon's horn, subicular complex, entorhinal cortex) and perirhinal cortex. NADPH-d staining revealed pleomorphic cells, fibers, and blood vessels. Within the entorhinal and the perirhinal cortices, darkly stained (type 1) NADPH-d pyramidal, fusiform, bipolar, and multipolar neurons with extensive dendrites were scattered mainly within deep layers and subjacent white matter. Moderately stained (type 2) NADPH-d round or oval neurons were seen mainly in layers II and III of the entorhinal and perirhinal cortices, in the dentate gyrus polymorphic layer, in the CA fields stratum pyramidal and radiatum, and in the subicular complex. The distribution of type 2 cells was more abundant in the perirhinal cortex compared to the hippocampal formation. Lightly stained (type 3) NADPH-d pyramidal and oval neurons were distributed in CA4, the entorhinal cortex medial subfields, and the amygdalohippocampal transition area. Sections concurrently stained for NADPH-d and nitric oxide synthase (NOS) revealed that all type 1 neurons coexpressed NOS, whereas types 2 and 3 were NOS immunonegative. NADPH-d fibers were heterogeneously distributed within the different regions examined and were frequently in close apposition to reactive blood vessels. The greatest concentration of fibers was in layers III and V–VI of the entorhinal and perirhinal cortices, dentate gyrus polymorphic and molecular layers, and CA1 and CA4. A band of fibers coursing within CA1 divided into dorsal and ventral bundles to reach the presubiculum and entorhinal cortex, respectively. Although the distribution of NADPH-d fibers was conserved across all ages examined (28–98 years), we observed an increase in the density of fiber staining in the aged cases. These results may be relevant to our understanding of selective vulnerability of neuronal systems within the human hippocampal formation in aging and in neurodegenerative diseases. © 1995 Wiley-Liss, Inc.     

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. J. Comp. Neurol. 522:772–793, 2014. © 2013 Wiley Periodicals, Inc.     

Evidence for a direct projection from the postrhinal cortex to the subiculum in the rat

Behavioral data indicate that three of the areas which form the parahippocampal region in the rat, i.e., the entorhinal, perirhinal, and postrhinal cortices, have different, although related functions that also differ from those of the hippocampal formation. These functional differences might be related to differences in connectivity, on the one hand with parts of the association cortex, and on the other with the hippocampal formation. In a previous study, we showed the existence of both a direct and an indirect projection from the perirhinal cortex to areas CA1 and subiculum of the hippocampus. Here we present the result of a second study, demonstrating a similarly organized projection from the postrhinal cortex to the subiculum, comprising both a direct and an indirect route. Electrical stimulation of the postrhinal cortex in vivo evoked field potentials throughout the subiculum and the dentate gyrus. Current source density analysis in both the subiculum and dentate gyrus revealed the presence of sink-source pairs, indicative of a synaptic termination. Based on comparison with the sink-source pairs found after stimulation of the medial entorhinal cortex, we conclude that the connection between the postrhinal cortex and the dentate gyrus most likely is formed by a polysynaptic pathway mediated via the medial entorhinal cortex, while the pathway from the postrhinal cortex to the subiculum is likely monosynaptic. In order to substantiate these findings, we carried out several tracer experiments. Anterograde tracer injections in the postrhinal cortex resulted in labeled fibers in limited parts of the subiculum, but no anatomical evidence for a projection of the postrhinal cortex to the dentate gyrus was found. Additional retrograde tracer injections in the subiculum also showed evidence for a direct postrhinal-to-subiculum projection with a strong topological organization. Based on these combined anatomical and electrophysiological data, we conclude that the postrhinal cortex indeed can reach the subiculum via both a direct and an indirect pathway.     

Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. I. Temporal lobe afferents.

In this investigation the efferent projections from ventral temporal neocortical and limbic cortical areas to the entorhinal and perirhinal cortices have been investigated in the rhesus monkey using silver impregnation methods. It was observed that virtually all ventral temporal neocortical areas contribute some afferents to the transitional zones of periallocortex (perirhinal and prorhinal cortices) forming the walls of the rhinal sulcus. These areas in turn project medially to the entorhinal cortex and hippocampus. Additional direct sources of afferent input to the entorhinal cortex were found to originate in Brodmann's areas 51, 49 and 27, and Bonin and Bailey's areas TF and TH. These connections have been characterized as final relays in multisynaptic cortico-cortical pathways linking the entorhinal cortex and, ultimately, hippocampus to the association areas of the frontal, parietal, temporal, and occipital lobes.     

Memory‐related changes in L‐citrulline and agmatine in the rat brain

L ‐citrulline, L ‐ornithine, and agmatine are the metabolites of L ‐arginine by nitric oxide synthase (NOS), arginase, and arginine decarboxylase (ADC), respectively. In contrast to the NOS and arginase pathways, the role of the ADC‐agmatine pathway in learning and memory has only been paid attention lately. Recent evidence suggests a potential involvement of agmatine in learning and memory processing. The present study further addressed this issue by comparing the levels of agmatine, as well as L ‐arginine, L ‐citrulline, and L ‐ornithine, in the hippocampus, parahippocampal region, prefrontal cortex, vestibular nucleus, and cerebellum in rats that were trained in the delayed nonmatch to position task in the T‐maze with their yoked controls. There were significantly increased agmatine levels in the prefrontal, entorhinal, and perirhinal cortices and increased L ‐citrulline concentrations in the dentate gyrus (DG) and prefrontal cortex in the T‐maze training group relative to the control one. L ‐arginine and L ‐ornithine levels were not significantly different between groups in the brain regions examined. These results demonstrate T‐maze training‐induced region‐specific increases in L ‐citrulline and agmatine. Significant positive correlations between prefrontal and perirhinal agmatine levels and animals' performance in the T‐maze further suggest the direct involvement of agmatine in learning and memory processing. © 2009 Wiley‐Liss, Inc.     

Novel temporal configurations of stimuli produce discrete changes in immediate-early gene expression in the rat hippocampus

Changes in limbic brain activity in response to novel configurations of visual stimuli were assessed by quantifying two immediate-early genes, c-fos and zif268. Rats were first trained to use distal, visual cues to support radial-arm maze performance. Two separate sets of visual cues were used, one in the morning (Set A) and the other in the afternoon (Set B). On the final day the experimental group was tested with a novel configuration created by combining four of the eight visual cues from Set A with four of the eight visual cues from Set B. Although each individual cue was in a familiar location, the combination of cues was novel. Comparisons with a control group revealed discrete decreases in Fos centred in the hippocampus and retrosplenial cortex. The hippocampal c-fos findings produced a dissociation with the perirhinal cortex, where no change was observed. Other regions seemingly unaffected by the novel stimulus configuration included the postrhinal, entorhinal and parietal cortices. Zif268 levels in the experimental group increased in the anterior ventral thalamic nucleus. Although previous studies have shown how the rat hippocampus is involved in responding to the spatial rearrangement of visual stimuli, the present study examined temporal rearrangement. The selective immediate-early gene changes in the hippocampus and two closely related sites (retrosplenial cortex and anterior ventral thalamic nucleus) when processing the new stimulus configuration support the notion that the hippocampus is important for learning the 'relational' or 'structural' features of arrays of elements, be they spatial or temporal.     

Topographical and laminar organization of subicular projections to the parahippocampal region of the rat

In this study, we analyzed in detail the topographic organization of the subiculoparahippocampal projection in the rat. The anterograde tracers Phaseolus vulgaris leucoagglutinin-L and biotinylated dextran amine were injected into the subiculum at different septotemporal and transverse levels. Deep layers of the ento-, peri-, and postrhinal cortices are the main recipients of subicular projections, but in all cases we noted that a small fraction of the projections also terminates in the superficial layers II and III. Analysis of the fiber patterns in the parahippocampal region revealed a topographic organization, depending on the location of the cells of origin along both the transverse and the septotemporal axes of the subiculum. Projections originating from subicular cells close to CA1, i.e., proximal part of subiculum, terminate exclusively in the lateral entorhinal cortex and in the perirhinal cortex. In contrast, projections from cells closer to the subiculum-presubiculum border, i.e., distal part of subiculum, terminate in the medial entorhinal cortex and in the postrhinal cortex. In addition, cells in septal portions of the subiculum project to a lateral band of entorhinal cortex parallel to the rhinal sulcus and to peri- or postrhinal cortices, whereas cells in more temporal portions project to more medial parts of the entorhinal cortex. These results indicate that subicular projections to the parahippocampal region precisely reciprocate the known inputs from this region to the hippocampal formation. We thus suggest that the reciprocal connectivity between the subiculum and the parahippocampal region is organized as parallel pathways that serve to segregate information flow and thus maintain the identity of processed information. Although this parallel organization is comparable to that of the CA1-parahippocampal projections, differences exist with respect to the degree of collateralization.     

Age-related changes of the nitric oxide system in the rat brain

This work examines the age-related changes of the NO pathway in the central nervous system (CNS), analyzing nitric oxide synthase (NOS) isoform expression, the level of nitrotyrosine-modified proteins, and the NOS activity in the cerebral cortex, decorticated brain (basal ganglia, thalamus, hypothalamus, tegtum and tegmentum) and cerebellum of young, adult and aged rats. Our data demonstrate that the different NOS isoforms are not uniformly expressed across the CNS. In this sense, the nNOS and eNOS isoenzymes are expressed mainly in the cerebellum and decorticated brain, respectively, while the iNOS isoenzyme shows the highest level in cerebellum. Concerning age, in the cerebral cortex nNOS significantly increased its expression only in adult animals; meanwhile, in the cerebellum the eNOS expression decreased whereas iNOS increased in adult and aged rats. No age-related changes in any isoform were found in decorticated brain. NOS activity, determined by nitrate plus nitrite quantification, registered the highest levels in the cerebellum, where the significant increase detected with aging was probably related to iNOS activity. The number of nitrotyrosine-modified immunoreactive bands differed among regions; thus, the highest number was detected in the decorticated brain while the cerebellum showed the least number of bands. Finally, bulk protein nitration increased in cerebral cortex only in adult animal. No changes were found in the decorticated brain, and the decrease detected in the cerebellum of aged animals was not significant. According to these results, the NO pathway is differently modified with age in the three CNS regions analyzed.     

Projections from the periamygdaloid cortex to the amygdaloid complex, the hippocampal formation, and the parahippocampal region: a PHA-L study in the rat

The periamygdaloid cortex, an amygdaloid region that processes olfactory information, projects to the hippocampal formation and parahippocampal region. To elucidate the topographic details of these projections, pathways were anterogradely traced using Phaseolus vulgaris leukoagglutinin (PHA-L) in 14 rats. First, we investigated the intradivisional, interdivisional, and intra-amygdaloid connections of various subfields [periamygdaloid subfield (PAC), medial subfield (PACm), sulcal subfield (PACs)] of the periamygdaloid cortex. Thereafter, we focused on projections to the hippocampal formation (dentate gyrus, hippocampus proper, subiculum) and to the parahippocampal region (presubiculum, parasubiculum, entorhinal, and perirhinal and postrhinal cortices). The PACm had the heaviest intradivisional projections and it also originated light interdivisional projections to other periamygdaloid subfields. Projections from the other subfields converged in the PACs. All subfields provided substantial intra-amygdaloid projections to the medial and posterior cortical nuclei. In addition, the PAC subfield projected to the ventrolateral and medial divisions of the lateral nucleus. The heaviest periamygdalohippocampal projections originated in the PACm and PACs, which projected moderately to the temporal end of the stratum lacunosum moleculare of the CA1 subfield and to the molecular layer of the ventral subiculum. The PACm also projected moderately to the temporal CA3 subfield. The heaviest projections to the entorhinal cortex originated in the PACs and terminated in the amygdalo-entorhinal, ventral intermediate, and medial subfields. Area 35 of the perirhinal cortex was lightly innervated by the PAC subfield. Thus, these connections might allow for olfactory information entering the amygdala to become associated with signals from other sensory modalities that enter the amygdala via other nuclei. Further, the periamygdalohippocampal pathways might form one route by which the amygdala modulates memory formation and retrieval in the medial temporal lobe memory system. These pathways can also facilitate the spread of seizure activity from the amygdala to the hippocampal and parahippocampal regions in temporal lobe epilepsy.