Interactions between the Orbitofrontal Cortex and the Hippocampal Memory System during the Storage of Long-Term Memory

It has been proposed that long-term declarative memories are ultimately stored through interactions between the hippocampal memory system and the neocortical association areas that initially processed the to-be-stored information. One association neocortex, the orbitofrontal cortex (OFC) is strongly and reciprocally connected with the hippocampal memory system and plays an important role in odor recognition memory in rats. We will report data from two studies: one that examined the firing of neurons in a task dependent on the parahippocampal region (PHR; including the perirhinal, postrhinal, and entrorhinal cortices), and one examined the firing of OFC neurons performing a task that is presumably dependent on the hippocampus. In the first study, we examined the role of OFC neurons in the continuous odor-guided nonmatching to sample task. While the firing of neurons in the PHR and OFC are similar in this task, there are several notable differences that are consistent with the idea that OFC is a high-order association cortex which interacts extensively with the PHR to store declarative memories. In the second study, we characterized the firing patterns of neurons in the OFC rats performing a passive, 8-odor-sequence memory task. Most interesting were neurons that fired selectively in anticipation of specific odors. We found that hippocampal lesions abolished the anticipatory firing in OFC, suggesting that these anticipatory responses (memory) were in fact dependent on the hippocampus, further supporting the view that the OFC interacts with the hippocampal memory system to store long-term, declarative memories.

SETH J. RAMUS, JENA B DAVIS, RACHEL J DONAHUE, CLAIRE B DISCENZA, and ALISSA A. WAITE.
Interactions between the Orbitofrontal Cortex and the Hippocampal Memory System during the Storage of Long-Term Memory.
Ann NY Acad Sci 2007 1121: 216-231.

http://www.annalsnyas.org/cgi/content/abstract/1121/1/216

Neural coding of reward magnitude in the orbitofrontal cortex of the rat during a five-odor olfactory discrimination task

The orbitofrontal cortex (OBFc) has been suggested to code the motivational value of environmental stimuli and to use this information for the flexible guidance of goal-directed behavior. To examine whether information regarding reward prediction is quantitatively represented in the rat OBFc, neural activity was recorded during an olfactory discrimination "go"/"no-go" task in which five different odor stimuli were predictive for various amounts of reward or an aversive reinforcer. Neural correlates related to both actual and expected reward magnitude were observed. Responses related to reward expectation occurred during the execution of the behavioral response toward the reward site and within a waiting period prior to reinforcement delivery. About one-half of these neurons demonstrated differential firing toward the different reward sizes. These data provide new and strong evidence that reward expectancy, regardless of reward magnitude, is coded by neurons of the rat OBFc, and are indicative for representation of quantitative information concerning expected reward. Moreover, neural correlates of reward expectancy appear to be distributed across both motor and nonmotor phases of the task.

van Duuren, Esther, Escamez, Francisco A. Nieto, Joosten, Ruud N.J.M.A., Visser, Rein, Mulder, Antonius B., Pennartz, Cyriel M.A.
Neural coding of reward magnitude in the orbitofrontal cortex of the rat during a five-odor olfactory discrimination task.
Learn. Mem. 2007 14: 446-456.

http://www.learnmem.org/cgi/content/abstract/14/6/446

Associative Encoding in Anterior Piriform Cortex versus Orbitofrontal Cortex during Odor Discrimination and Reversal Learning

Recent proposals have conceptualized piriform cortex as an association cortex, capable of integrating incoming olfactory information with descending input from higher order associative regions such as orbitofrontal cortex (OFC). If true, encoding in piriform cortex should reflect associative features prominent in these areas during associative learning involving olfactory cues. To test this hypothesis, we recorded from neurons in OFC and anatomically related parts of the anterior piriform cortex (APC) in rats, learning and reversing novel odor discriminations. Findings in OFC were similar to what we have reported previously, with nearly all the cue-selective neurons exhibiting substantial plasticity during learning and reversal. Also, many of the cue-selective neurons were originally responsive in anticipation of the outcomes early in learning, thereby providing a single-unit representation of the cue-outcome associations. Some of these features were also evident in firing activity in APC, including some plasticity across learning and reversal. However, APC neurons failed to reverse cue selectivity when the associated outcome was changed, and the cue-selective population did not include neurons that were active prior to outcome delivery. Thus, although representations in APC are substantially more associative than expected in a purely sensory region, they do appear to be somewhat more constrained by the sensory features of the odor cues than representations in downstream areas of OFC.

Matthew R. Roesch , Thomas A. Stalnaker , and Geoffrey Schoenbaum.
Associative Encoding in Anterior Piriform Cortex versus Orbitofrontal Cortex during Odor Discrimination and Reversal Learning.
Cerebral Cortex Advance Access published on March 1, 2007, DOI 10.1093/cercor/bhk009. Cereb. Cortex 17: 643-652.

http://cercor.oxfordjournals.org/cgi/content/abstract/17/3/643

From Rule to Response: Neuronal Processes in the Premotor and Prefrontal Cortex

The ability to use abstract rules or principles allows behavior to generalize from specific circumstances (e.g., rules learned in a specific restaurant can subsequently be applied to any dining experience). Neurons in the prefrontal cortex (PFC) encode such rules. However, to guide behavior, rules must be linked to motor responses. We investigated the neuronal mechanisms underlying this process by recording from the PFC and the premotor cortex (PMC) of monkeys trained to use two abstract rules: "same" or "different." The monkeys had to either hold or release a lever, depending on whether two successively presented pictures were the same or different, and depending on which rule was in effect. The abstract rules were represented in both regions, although they were more prevalent and were encoded earlier and more strongly in the PMC. There was a perceptual bias in the PFC, relative to the PMC, with more PFC neurons encoding the presented pictures. In contrast, neurons encoding the behavioral response were more prevalent in the PMC, and the selectivity was stronger and appeared earlier in the PMC than in the PFC.

Jonathan D. Wallis, and Earl K. Miller.
From Rule to Response: Neuronal Processes in the Premotor and Prefrontal Cortex.
Neurophysiol 90: 1790-1806, 2003. First published doi:10.1152/jn.00086.2003.

http://jn.physiology.org/cgi/content/full/90/3/1790/

Integrating Orbitofrontal Cortex into Prefrontal Theory: Common Processing Themes across Species and Subdivisions

Currently, many theories highlight either representational memory or rule representation as the hallmark of prefrontal function. Neurophysiological findings in the primate dorsolateral prefrontal cortex indicate that both features may characterize prefrontal processing. Neurons in the dorsolateral prefrontal cortex encode information in working memory, and this information is represented when relevant to the rules governing performance in a task. In this review, we discuss recent reports of encoding in primate and rat orbitofrontal regions indicating that these features also characterize activity in the orbitofrontal subdivision of the prefrontal cortex. These data indicate that (1) neural activity in the orbitofrontal cortex links the current incentive value of reinforcers to cues, rather than representing the physical features of cues or associated reinforcers; (2) this incentive-based information is represented in the orbitofrontal cortex when it is relevant to the rules guiding performance in a task; and (3) incentive information is also represented in the orbitofrontal cortex in working memory during delays when neither the cues nor reinforcers are present. Therefore, although the orbitofrontal cortex appears to be uniquely specialized to process incentive or motivational information, it may be integrated into a more global framework of prefrontal function characterized by representational encoding of performance-relevant information.

Schoenbaum, Geoffrey, Setlow, Barry
Integrating Orbitofrontal Cortex into Prefrontal Theory: Common Processing Themes across Species and Subdivisions
Learn. Mem. 2001 8: 134-147

http://www.learnmem.org/cgi/content/full/8/3/134

An attractor network in the hippocampus: Theory and neurophysiology

A quantitative computational theory of the operation of the CA3 system as an attractor or autoassociation network is described. Based on the proposal that CA3–CA3 autoassociative networks are important for episodic or event memory in which space is a component (place in rodents and spatial view in primates), it has been shown behaviorally that the CA3 supports spatial rapid one-trial learning and learning of arbitrary associations and pattern completion where space is a component. Consistent with the theory, single neurons in the primate CA3 respond to combinations of spatial view and object, and spatial view and reward. Furthermore, single CA3 neurons reflect the recall of a place from an object in a one-trial object-place event memory task. CA3 neurons also reflect in their firing a memory of spatial view that is retained and updated by idiothetic information to implement path integration when the spatial view is obscured. Based on the computational proposal that the dentate gyrus produces sparse representations by competitive learning and via the mossy fiber pathway forces new representations on the CA3 during learning (encoding), it has been shown behaviorally that the dentate gyrus supports spatial pattern separation during learning, and that the mossy fiber system to CA3 connections are involved in learning but not in recall. The perforant path input to CA3 is quantitatively appropriate to provide the cue for recall in CA3. The concept that the CA1 recodes information from CA3 and sets up associatively learned back-projections to neocortex to allow subsequent retrieval of information to neocortex provides a quantitative account of the large number of hippocampo–neocortical back-projections.

Rolls, Edmund T.
An attractor network in the hippocampus: Theory and neurophysiology
Learn. Mem. 2007 14: 714-731.

http://www.learnmem.org/cgi/content/abstract/14/11/714

Specific Involvement of Human Parietal Systems and the Amygdala in the Perception of Biological Motion

To explore the extent to which functional systems within the human posterior parietal cortex and the superior temporal sulcus are involved in the perception of action, we measured cerebral metabolic activity in human subjects by positron emission tomography during the perception of simulations of biological motion with point-light displays. The experimental design involved comparisons of activity during the perception of goal-directed hand action, whole body motion, object motion, and random motion. The results demonstrated that the perception of scripts of goal-directed hand action implicates the cortex in the intraparietal sulcus and the caudal part of the superior temporal sulcus, both in the left hemisphere. By contrast, the rostrocaudal part of the right superior temporal sulcus and adjacent temporal cortex, and limbic structures such as the amygdala, are involved in the perception of signs conveyed by expressive body movements.

Eva Bonda, Michael Petrides, David Ostry, and Alan Evans
Specific Involvement of Human Parietal Systems and the Amygdala in the Perception of Biological Motion
J. Neurosci. 16: 3737-3744; doi:

http://www.jneurosci.org/cgi/content/full/16/11/3737

Orbitofrontal Cortex Encodes Willingness to Pay in Everyday Economic Transactions

An essential component of every economic transaction is a willingness-to-pay (WTP) computation in which buyers calculate the maximum amount of financial resources that they are willing to give up in exchange for the object being sold. Despite its pervasiveness, little is known about how the brain makes this computation. We investigated the neural basis of the WTP computation by scanning hungry subjects' brains using functional magnetic resonance imaging while they placed real bids for the right to eat different foods. We found that activity in the medial orbitofrontal cortex and in the dorsolateral prefrontal cortex encodes subjects' WTP for the items. Our results support the hypothesis that the medial orbitofrontal cortex encodes the value of goals in decision making.

Hilke Plassmann, John O'Doherty, and Antonio Rangel
Orbitofrontal Cortex Encodes Willingness to Pay in Everyday Economic Transactions
J. Neurosci. 27: 9984-9988; doi:10.1523/JNEUROSCI.2131-07.2007

http://www.jneurosci.org/cgi/content/abstract/27/37/9984

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.

Rony Paz, Elizabeth P. Bauer, and Denis Paré
Learning-Related Facilitation of Rhinal Interactions by Medial Prefrontal Inputs
J. Neurosci. 27: 6542-6551; doi:10.1523/JNEUROSCI.1077-07.2007

http://www.jneurosci.org/cgi/content/full/27/24/6542

Interaction between Perirhinal and Medial Prefrontal Cortex Is Required for Temporal Order But Not Recognition Memory for Objects in Rats

The present study investigated the roles of the perirhinal cortex, medial prefrontal cortex, and intrahemispheric interactions between them in recognition and temporal order memory for objects. Experiment 1 assessed the effects of bilateral microinfusions of the sodium channel blocker lidocaine into either the anterior perirhinal or medial prefrontal cortex immediately before memory testing in a familiarity discrimination task and a recency discrimination task, both of which involved spontaneous exploration of objects. Inactivation of the perirhinal cortex disrupted performance in both tasks, whereas inactivation of the medial prefrontal cortex disrupted performance in the recency, but not the familiarity, discrimination task. In a second experiment, the importance of intrahemispheric interactions between these structures in temporal order memory were assessed by comparing the effects of unilateral inactivation of either structure alone with those of crossed unilateral inactivation of both structures on the recency discrimination task. Crossed unilateral inactivation of both structures produced a significant impairment, whereas inactivation of either structure alone produced little or no impairment. Collectively, these findings suggest that the perirhinal cortex, but not the medial prefrontal cortex, contributes to retrieval of information necessary for long-term object recognition, whereas both structures, via intrahemispheric interactions between them, contribute to retrieval of information necessary for long-term object temporal order memory. These data are consistent with models in which attributed information is stored in posterior cortical sites and supports lower-order mnemonic functions (e.g., recognition memory) but can also be retrieved and further processed via interactions with the prefrontal cortex to support higher-order mnemonic functions (e.g., temporal order memory).

Darren K. Hannesson, John G. Howland, and Anthony G.
Interaction between Perirhinal and Medial Prefrontal Cortex Is Required for Temporal Order But Not Recognition Memory for Objects in Rats.
J. Neurosci. 24: 4596-4604; doi:10.1523/JNEUROSCI.5517-03.2004

http://www.jneurosci.org/cgi/content/abstract/24/19/4596

Cytoarchitecture of the canine perirhinal and postrhinal cortex

The perirhinal cortex in the dog’s brain is composed of two traditional Brodmann’s areas: 35 and 36. Area 35 is situated along the entire rostro-caudal extent of the fundus of the posterior rhinal sulcus, whereas area 36 occupies its lateral bank. In this study, four subdivisions were distinguished in area 35 based on cytoarchitectonic differentiation. Area 36 is poorly developed in the dog’s brain and was divided into two subdivisions. The most characteristic features of area 35 are: a wide layer I, scattered cell clusters in layer II, and a prominent layer V containing a distinct population of large multiform neurons. Area 36 can be recognized by the presence of numerous cell clusters in layer II and increasing radial arrangement of neurons in deep layers of the area. Two fields of the postrhinal cortex were identified in the additional postrhinal gyrus, which is found in the fundus of the most caudal extent of the posterior rhinal sulcus.

Agnieszka WoŸnicka and Anna Kosmal
Cytoarchitecture of the canine perirhinal and postrhinal cortex.
Acta Neurobiol. Exp. 2003, 63: 197-209.

http://www.nencki.gov.pl/pdf/an/vol63/woznicka.pdf

Response Differences in Monkey TE and Perirhinal Cortex: Stimulus Association Related to Reward Schedules

Anatomic and behavioral evidence shows that TE and perirhinal cortices are two
directly connected but distinct inferior temporal areas. Despite this distinctness, physiological properties of neurons in these two areas generally have been similar with neurons in both areas showing selectivity for complex visual patterns and showing response modulations
related to behavioral context in the sequential delayed matchto-sample (DMS) trials, attention, and stimulus familiarity. Here we identify physiological differences in the neuronal activity of these two areas. We recorded single neurons from area TE and perirhinal cortex while the monkeys performed a simple behavioral task using randomly interleaved visually cued reward schedules of one, two, or three DMS trials. The monkeys used the cue’s relation to the reward schedule (indicated by the brightness) to adjust their behavioral performance. They performed most quickly and most accurately in trials in which reward was immediately forthcoming and progressively less well as more intermediate trials remained. Thus the monkeys appeared more motivated as they progressed through the trial schedule. Neurons in both TE and perirhinal cortex responded to both the visual cues related to the reward schedules and the stimulus patterns used in the DMS trials. As expected, neurons in both areas showed response selectivity to the DMS patterns, and significant, but small, modulations related to the behavioral context in the DMS trial. However, TE and perirhinal neurons showed strikingly different response properties. The latency distribution of perirhinal responses was centered 66 ms later than the distribution of TE responses, a larger difference than the 10–15 ms usually found in sequentially connected visual cortical areas. In TE, cue-related responses were related to the cue’s brightness. In perirhinal cortex, cue-related responses were related to the trial schedules independently of the cue’s brightness. For example, some perirhinal neurons responded in the first trial of any reward schedule including the one trial schedule, whereas other neurons
failed to respond in the first trial but respond in the last trial of any schedule. The majority of perirhinal neurons had more complicated relations to the schedule. The cue-related activity of TE neurons is interpreted most parsimoniously as a response to the stimulus brightness,
whereas the cue-related activity of perirhinal neurons is interpreted most parsimoniously as carrying associative information about the animal’s progress through the reward schedule. Perirhinal cortex may be part of a system gauging the relation between work schedules
and rewards.

Liu, Zheng and Barry J. Richmond.
Response differences in monkey TE and perirhinal cortex: stimulus association related to reward schedules.
J. Neurophysiol. 83: 1677–1692, 2000.

http://neuron.nimh.nih.gov/richmond/docs/TE_perirhinal_reward_schedules.pdf

Collateral projection from the amygdalo–hippocampal transition area and CA1 to the hypothalamus and medial prefrontal cortex in the rat

Amygdaloid and hippocampal neurons projecting to both the medial prefrontal cortex and hypothalamus by way of axon collaterals were examined in the rat by double labeling method using fluorescence retrograde tracers. Fluoro-gold was injected in the medial prefrontal cortex, while Fluoro-red was injected into the ventromedial and ventral premammillary nuclei of the hypothalamus. The results indicated that neurons which sent axon collaterals to both the medial prefrontal cortex and hypothalamus constituted 50 or 30% of populations of medial prefrontal cortex-projecting neurons in the amygdalo–hippocampal transition area or in CA1, respectively. Possible roles of the neurons with axon collaterals in sexually related aggressive and/or defensive behavior were discussed.

Tanemichi Chiba
Collateral projection from the amygdalo–hippocampal transition area and CA1 to the hypothalamus and medial prefrontal cortex in the rat.
Neuroscience Research Volume 38, Issue 4, December 2000, Pages 373-383.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0H-426XXND-7&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=7dfba4ddd462ea5905d7bef0ad3ecea4

Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: Combined anterograde and retrograde tracing study in the ...

A combination of anterograde and retrograde tracing techniques was used to study the projections to the nucleus accumbens from the amygdala, the hippocampal formation (including the entorhinal cortex), and the perirhinal cortex in two species of macaque monkey. To help identify possible subregions within the nucleus accumbens, the distribution of calbindin was examined in two additional monkeys. Although this revealed evidence of core- and shell-like regions within the accumbens, these different regions could not consistently be related to cytoarchitectonic features. The rostral amygdala sent nearly equivalent projections to both the medial and the lateral portions of nucleus accumbens, whereas projections arising from the middle and caudal amygdala terminated preferentially in the medial division of nucleus accumbens. The basal nucleus was the major source of these amygdala efferents, and there was a crude topography as parts of the basal and accessory basal nuclei terminated in different parts of nucleus accumbens. The subiculum was the major source of hippocampal projections to the nucleus accumbens, but some hippocampal efferents also originated in the parasubiculum, the prosubiculum, the adjacent portion of CA1, and the uncal portion of CA3. These hippocampal projections, which coursed through the fornix, showed a rostrocaudal gradient as more arose in the rostral hippocampus. Hippocampal efferents terminated most densely in the medial and ventral portions of nucleus accumbens, along with light label in the adjacent olfactory tubercle. The entorhinal projections were more evenly distributed between the medial nucleus accumbens and the olfactory tubercle, whereas the perirhinal projections were primarily to the olfactory tubercle. These cortical inputs were less reliant on the fornix. Amygdala and subicular (hippocampal) projections overlapped most completely in the medial division of nucleus accumbens.

David P. Friedman, John P. Aggleton, Richard C. Saunders.
Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: Combined anterograde and retrograde tracing study in the Macaque brain.
J. Comp. Neurol. 450:345-365, 2002.

http://www3.interscience.wiley.com/cgi-bin/abstract/97515953/

An extrahippocampal projection from the dentate gyrus to the olfactory tubercle

Background:

The dentate gyrus is well known for its mossy fiber projection to the hippocampal field 3 (CA3) and its extensive associational and commissural connections. The dentate gyrus, on the other hand, has only few projections to the CA1 and the subiculum, and none have clearly been shown to extrahippocampal target regions.

Results:

Using anterograde and retrograde tracer techniques in the Madagascan lesser hedgehog tenrec (Afrosoricidae, Afrotheria) it was shown in this study that the dentate hilar region gave rise to a faint, but distinct, bilateral projection to the most rostromedial portion of the olfactory tubercle, particularly its molecular layer. Unlike the CA1 and the subiculum the dentate gyrus did not project to the accumbens nucleus. A control injection into the medial septum-diagonal band complex also retrogradely labeled cells in the dentate hilus, but these neurons were found immediately adjacent to the heavily labeled CA3, while the tracer injections into the rostromedial tubercle did not reveal any labeling in CA3.

Conclusion:

The dentate hilar neurons projecting to the olfactory tubercle cannot be considered displaced cells of CA3 but represent true dentato-tubercular projection neurons. This projection supplements the subiculo-tubercular projection. Both terminal fields overlap among one another as well as with the fiber terminations arising in the anteromedial frontal cortex. The rostromedial olfactory tubercle might represent a distinct ventral striatal target area worth investigating in studies of the parallel processing of cortico-limbic information in tenrec as well as in cat and monkey.

Figure 3

Retrograde labeling in DtHi and HCt following tracer injections into the olfactory tubercle. Tracer injections into the rostromedial Tu (A) consistently labeled a few dentate hilar neurons (D-H; arrows point to labeled cells), but failed to label the CA3 (D-F). A-E are from Et03-58W, F-H from Et01-47W. Some labeled neurons are also noted in the ipsilateral, anterior HCt (B, C) confirming previous anterograde data [28]. Remarkably, both the HCt and the DtHi project to the rostromedial Tu, but not to the Acb. Arrow heads point to similar location. OfB, olfactory bulb; PCx, paleocortex. Scale bars = 0.8 mm in A, 0.4 mm in B and D, 0.3 mm in F, 0.2 mm in C, E and H (as G).

Heinz Künzle.
An extrahippocampal projection from the dentate gyrus to the olfactory tubercle.
BMC Neurosci. 2005; 6: 38.


http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1180450&rendertype=figure&id=F3