Perirhinal and Postrhinal Damage Have Different Consequences on Attention as Assessed in the Five-Choice Serial Reaction Time Task.

The perirhinal (PER) and postrhinal (POR) cortices, structures in the medial temporal lobe, are implicated in learning and memory. The PER is understood to process object information and the POR to process spatial or contextual information. Whether the medial temporal lobe is dedicated to memory, however, is under debate. In this study, we addressed the hypothesis that the PER and POR are also involved in non-mnemonic cognitive functions. Rats with PER or POR damage and SHAM surgical controls were shaped, trained, and tested on the five-choice serial reaction time (5CSRT) task, which assesses attention and executive function. Rats with PER damage were impaired in acquiring the task and at asymptote, although processing information about objects was not relevant to the task. When confronted with attentional challenges, rats with PER damage showed a pattern consistent with decreased attentional capacity, increased response errors, and increased impulsive behavior. Rats with POR damage showed intact acquisition and normal asymptotic performance. They also exhibited faster latencies in the absence of speed accuracy trade-off suggesting enhanced response readiness. We suggest this increased response readiness results from decreased automatic monitoring of the local environment, which might normally compete with response readiness. Our findings are consistent with a role for PER in controlled attention and a role for POR in stimulus-driven attention providing evidence that the PER and POR cortices have functions that go beyond memory for objects and memory for scenes and contexts, respectively. These findings provide new evidence for functional specialization in the medial temporal lobe.

Activation of a Habenulo-Raphe Circuit Is Critical for the Behavioral and Neurochemical Consequences of Uncontrollable Stress in the Male Rat.

Exposure to uncontrollable stress [inescapable tailshock (IS)] produces behavioral changes that do not occur if the stressor is controllable [escapable tailshock (ES)] an outcome that is mediated by greater IS-induced dorsal raphe nucleus (DRN) serotonin [5-hydroxytryptamine (5-HT)] activation. It has been proposed that this differential activation occurs because the presence of control leads to top-down inhibition of the DRN from medial prefrontal cortex (mPFC), not because uncontrollability produces greater excitatory input. Although mPFC inhibitory regulation over DRN 5-HT activation has received considerable attention, the relevant excitatory inputs that drive DRN 5-HT during stress have not. The lateral habenula (LHb) provides a major excitatory input to the DRN, but very little is known about the role of the LHb in regulating DRN-dependent behaviors. Here, optogenetic silencing of the LHb during IS blocked the typical anxiety-like behaviors produced by IS in male rats. Moreover, LHb silencing blocked the increase in extracellular basolateral amygdala 5-HT during IS and, surprisingly, during behavioral testing the following day. We also provide evidence that LHb-DRN pathway activation is not sensitive to the dimension of behavioral control. Overall, these experiments highlight a critical role for LHb in driving DRN activation and 5-HT release into downstream circuits that mediate anxiety-like behavioral outcomes of IS and further support the idea that behavioral control does not modulate excitatory inputs to the DRN.

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.

Reversal of social deficits by subchronic oxytocin in two autism mouse models.

Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-d-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia-like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders.

Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats.

Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct sub-regions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. This article is part of a Special Issue entitled SI: Noradrenergic System.

Facilitation of serotonin signaling by SSRIs is attenuated by social isolation.

Hypofunction of the serotonergic system is often associated with major depression and obsessive compulsive disorder (OCD). Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to treat these disorders, and require 3-6 weeks of chronic treatment before improvements in the symptoms are observed. SSRIs inhibit serotonin's transporter, and in doing so, increase extracellular serotonin concentrations. Thus, efficacy of SSRIs likely depends upon the brain's adaptive response to sustained increases in serotonin levels. Individual responsiveness to SSRI treatment may depend on a variety of factors that influence these changes, including ongoing stress. Social isolation is a passive, naturalistic form of chronic mild stress that can model depression in rodents. In this study, we examined how 20-day treatment with the SSRI citalopram (CIT) alters marble-burying (MB), open field behavior, and serotonin signaling in single- vs pair-housed animals. We used in vivo voltammetry to measure electrically evoked serotonin, comparing release rate, net overflow, and clearance. Pair-housed mice were significantly more responsive to CIT treatment, exhibiting reduced MB and facilitation of serotonin release that positively correlated with the frequency of electrical stimulation. These effects of CIT treatment were attenuated in single-housed mice. Notably, although CIT treatment enhanced serotonin release in pair-housed mice, it did not significantly alter uptake rate. In summary, we report that chronic SSRI treatment facilitates serotonin release in a frequency-dependent manner, and this effect is blocked by social isolation. These findings suggest that the efficacy of SSRIs in treating depression and OCD may depend on ongoing stressors during treatment.

Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism.

Restricted repetitive behaviors are core symptoms of autism spectrum disorders (ASDs). The range of symptoms encompassed by the repetitive behavior domain includes lower-order stereotypy and self-injury, and higher-order indices of circumscribed interests and cognitive rigidity. Heterogeneity in clinical ASD profiles suggests that specific manifestations of repetitive behavior reflect differential neuropathology. The present studies utilized a set of phenotyping tasks to determine a repetitive behavior profile for the C58/J mouse strain, a model of ASD core symptoms. In an observational screen, C58/J demonstrated overt motor stereotypy, but not over-grooming, a commonly-used measure for mouse repetitive behavior. Amphetamine did not exacerbate motor stereotypy, but had enhanced stimulant effects on locomotion and rearing in C58/J, compared to C57BL/6J. Both C58/J and Grin1 knockdown mice, another model of ASD-like behavior, had marked deficits in marble-burying. In a nose poke task for higher-order repetitive behavior, C58/J had reduced holeboard exploration and preference for non-social, versus social, olfactory stimuli, but did not demonstrate cognitive rigidity following familiarization to an appetitive stimulus. Analysis of available high-density genotype data indicated specific regions of divergence between C58/J and two highly-sociable strains with common genetic lineage. Strain genome comparisons identified autism candidate genes, including Cntnap2 and Slc6a4, located within regions divergent in C58/J. However, Grin1, Nlgn1, Sapap3, and Slitrk5, genes linked to repetitive over-grooming, were not in regions of divergence. These studies suggest that specific repetitive phenotypes can be used to distinguish ASD mouse models, with implications for divergent underlying mechanisms for different repetitive behavior profiles.

Hippocampal and subicular efferents and afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat.

Available evidence suggests there is functional differentiation among hippocampal and parahippocampal subregions and along the dorsoventral (septotemporal) axis of the hippocampus. The aim of this study was to characterize and compare the efferent and afferent connections of perirhinal areas 35 and 36, postrhinal cortex, and the lateral and medial entorhinal areas (LEA and MEA) with dorsal and ventral components of the hippocampal formation (dentate gyrus, hippocampus cornu ammonis fields, and subiculum) as well as the presubiculum, and the parasubiculum. The entorhinal connections were also characterized with respect to the LEA and MEA dentate gyrus-projecting bands. In general, the entorhinal connections with the hippocampal formation are much stronger than the perirhinal and postrhinal connections. The entorhinal cortex projects strongly to all components of the hippocampal formation, whereas the perirhinal and postrhinal cortices project weakly and only to CA1 and the subiculum. In addition, the postrhinal cortex preferentially targets the dorsal CA1 and subiculum, whereas the perirhinal cortex targets ventral subiculum. Similarly, the perirhinal cortex receives more input from ventral hippocampal formation structures and the postrhinal cortex receives more input from dorsal hippocampal structures. The LEA and the MEA medial band are more strongly interconnected with ventral hippocampal structures, whereas the MEA lateral band is more interconnected with dorsal hippocampal structures. With regard to the presubiculum and parasubiculum, the postrhinal cortex and the MEA lateral band receive stronger input from the dorsal presubiculum and caudal parasubiculum. In contrast, the LEA and MEA medial bands receive stronger input from the ventral presubiculum and rostral parasubiculum.

Prosocial effects of oxytocin in two mouse models of autism spectrum disorders.

Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin.

Borders and comparative cytoarchitecture of the perirhinal and postrhinal cortices in an F1 hybrid mouse.

We examined the cytoarchitectonic and chemoarchitectonic organization of the cortical regions associated with the posterior rhinal fissure in the mouse brain, within the framework of what is known about these regions in the rat. Primary observations were in a first-generation hybrid mouse line, B6129PF/J1. The F1 hybrid was chosen because of the many advantages afforded in the study of the molecular and cellular bases of learning and memory. Comparisons with the parent strains, the C57BL6/J and 129P3/J are also reported. Mouse brain tissue was processed for visualization of Nissl material, myelin, acetyl cholinesterase, parvalbumin, and heavy metals. Tissue stained for heavy metals by the Timm's method was particularly useful in the assignment of borders and in the comparative analyses because the patterns of staining were similar across species and strains. As in the rat, the areas examined were parcellated into 2 regions, the perirhinal and the postrhinal cortices. The perirhinal cortex was divided into areas 35 and 36, and the postrhinal cortex was divided into dorsal (PORd) and ventral (PORv) subregions. In addition to identifying the borders of the perirhinal cortex, we were able to identify a region in the mouse brain that shares signature features with the rat postrhinal cortex.

Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice.

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.

Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex.

The brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)-containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density, may contribute to the regulation of NE efflux. Quantification of dopamine ß-hydroxylase (DßH)-immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus by using unbiased sampling methods. The density of DßH varicosities is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in the VPM than in the somatosensory cortex. Our results provide anatomical evidence for non-uniform release of NE across functionally discrete cortical regions. This morphology may account for a differential, region-specific, impact of LC output on different cortical areas.

Experimental strategies for investigating psychostimulant drug actions and prefrontal cortical function in ADHD and related attention disorders.

Amphetamine-like psychostimulant drugs have been used for decades to treat a variety of clinical conditions. Methylphenidate (MPH)-Ritalin(R) , a compound that blocks reuptake of synaptically released norepinephrine (NE) and dopamine (DA) in the brain, has been used for more than 30 years in low dose, long-term regimens to treat attention deficit-hyperactive disorder (ADHD) in juveniles, adolescents, and adults. Now, these agents are also becoming increasingly popular among healthy individuals from all walks of life (e.g., military, students) and age groups (teenagers thru senior citizens) to promote wakefulness and improve attention. Although there is agreement regarding the primary biochemical action of MPH, the physiological basis for its efficacy in normal individuals and ADHD patients is lacking. Study of the behavioral and physiological actions of clinically and behaviorally relevant doses of MPH in normal animals provides an opportunity to explore the role of catecholamine transmitters in prefrontal cortical function and attentional processes as they relate to normal operation of brain circuits and ADHD pathology. The goal of ongoing studies has been to: (1) assess the effects of low dose MPH on rodent performance in a well characterized sensory-guided sustained attention task, (2) examine the effects of the same low-dose chronic MPH administration on task-related discharge of prefrontal cortical (PFC) neurons, and (3) investigate the effects of NE and DA on membrane response properties and synaptic transmission in identified subsets of PFC neurons. Combinations of these approaches can be used in adolescent, adult, and aged animals to identify the parameters of cell and neural circuit function that are regulated by MPH and to establish an overarching explanation of how MPH impacts PFC operations from cellular through behavioral functional domains.

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

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

Functional neuroanatomy of the parahippocampal region: the lateral and medial entorhinal areas.

The entorhinal cortex (EC) serves a pivotal role in corticohippocampal interactions, but a complete description of its extrinsic connections has not been presented. Here, we have summarized the cortical, subcortical, and hippocampal connections of the lateral entorhinal area (LEA) and the medial entorhinal area (MEA) in the rat. We found that the targets and relative strengths of the entorhinal connections are strikingly different for the LEA and MEA. For example, the LEA receives considerably heavier input from the piriform and insular cortices, whereas the MEA is more heavily targeted by the visual, posterior parietal, and retrosplenial cortices. Regarding subcortical connections, the LEA receives heavy input from the amygdala and olfactory structures, whereas the MEA is targeted by the dorsal thalamus, primarily the midline nuclei and also the dorsolateral and dorsoanterior thalamic nuclei. Differences in the LEA and MEA connections with hippocampal and parahippocampal structures are also described. In addition, because the EC is characterized by bands of intrinsic connectivity that span the LEA and MEA and project to different septotemporal levels of the dentate gyrus, special attention was paid to the efferents and afferents of those bands. Finally, we summarized the connections of the dorsocaudal MEA, the region in which the entorhinal "grid cells" were discovered. The subregional differences in entorhinal connectivity described here provide further evidence for functional diversity within the EC. It is hoped that these findings will inform future studies of the role of the EC in learning and memory.

Functional neuroanatomy of the parahippocampal region in the rat: the perirhinal and postrhinal cortices.

The parahippocampal region in the rodent brain includes the perirhinal, postrhinal, and entorhinal cortices, the presubiculum, and the parasubiculum. In recent years, the perirhinal and postrhinal cortices have been a focus in memory research because they supply highly processed, polymodal sensory information to the hippocampus, both directly and via the entorhinal cortex. Available evidence indicates that these cortices receive different complements of cortical information, which are then forwarded to the hippocampus via parallel pathways. Here we have summarized the cortical, subcortical, and hippocampal connections of the perirhinal and postrhinal cortices in order to provide further insight into the nature of the information that is processed by these regions prior to arriving in the hippocampus. As has been previously described, the cortical afferents of the rodent postrhinal cortex are dominated by structures known to be involved in the processing of visual and spatial information, whereas the cortical afferents of the perirhinal cortex result in remarkable convergence of polymodal sensory information. The two regions are also differentiated by their cortical efferents. The perirhinal cortex projects more strongly to piriform, frontal, and insular regions, whereas the postrhinal cortex projects preferentially to visual and visuospatial regions. The subcortical connections of the two regions provide further evidence that they have different functions. For example, the perirhinal cortex has strong reciprocal connections with the amygdala, which suggest involvement in processing affective stimuli. Subcortical input to the postrhinal cortex is dominated by projections from dorsal thalamic structures, particularly the lateral posterior nucleus. Although the perirhinal and postrhinal cortices are considered to contribute to the episodic memory system, many questions remain about their particular roles. A detailed description of the anatomical connections of the perirhinal and postrhinal cortices will permit the generation of new, anatomically guided, hypotheses about their role in episodic memory and other cognitive processes.

The hippocampus and disambiguation of overlapping sequences.

Recent models of hippocampal function emphasize its potential role in disambiguating sequences of events that compose distinct episodic memories. In this study, rats were trained to distinguish two overlapping sequences of odor choices. The capacity to disambiguate the sequences was measured by the critical odor choice after the overlapping elements of the sequences. When the sequences were presented in rapid alternation, damage to the hippocampus, produced either by infusions of the neurotoxin ibotenic acid or by radiofrequency current, produced a severe deficit, although animals with radiofrequency lesions relearned the task. When the sequences were presented spaced apart and in random order, animals with radiofrequency hippocampal lesions could perform the task. However, they failed when a memory delay was imposed before the critical choice. These findings support the hypothesis that the hippocampus is involved in representing sequences of nonspatial events, particularly when interference between the sequences is high or when animals must remember across a substantial delay preceding items in a current sequence.

Critical role of the hippocampus in memory for sequences of events.

Recent models of hippocampal function emphasize the potential role of this brain structure in encoding and retrieving sequences of events that compose episodic memories. Here we show that hippocampal lesions produce a severe and selective impairment in the capacity of rats to remember the sequential ordering of a series of odors, despite an intact capacity to recognize odors that recently occurred. These findings support the hypothesis that hippocampal networks mediate associations between sequential events that constitute elements of an episodic memory.