Lateral habenula integration of proactive and retroactive information mediates behavioral flexibility.

The lateral habenula (LHb) is known to play an important role in signaling aversive or adverse events that have happened or are predicted by cues under Pavlovian conditions. In rodents, it is also required for behavioral flexibility when changes in reward outcomes signal that strategies should be changed. It is not known whether the LHb also controls appetitive behaviors when an animal is able to utilize external cues proactively to guide upcoming decisions. In order to test this, male Long-Evans rats were trained to switch between two arms of a figure eight maze based on the tone presented prior to the choice. Importantly, the tones were switched every three to six trials so rats were able establish a response pattern before being required to switch. This caused rats to rely on both proactive (tones) and retroactive information (reward feedback) to guide behavior. Inactivation of the LHb with the GABA agonists baclofen and muscimol impaired overall performance by increasing both errors when the tones are switched (switch errors) as well as on subsequent trials (perseverative errors) indicating that both proactive and retroactive information are utilized by the LHb to guide behavioral flexibility. Once a correct choice was made in a given block, LHb inactivated rats did not make more errors than controls. A control study revealed that the LHb is not required for tone or reward magnitude discrimination per se. These results demonstrate for the first time that the LHb contributes to behavioral flexibility through utilizing both proactive and retroactive information when performing appetitive tasks.

Temporary inactivation of the retrosplenial cortex causes a transient reorganization of spatial coding in the hippocampus.

The ability to navigate accurately is dependent on the integration of visual and movement-related cues. Navigation based on metrics derived from movement is referred to as path integration. Recent theories of navigation have suggested that posterior cortical areas, the retrosplenial and posterior parietal cortex, are involved in path integration during navigation. In support of this hypothesis, we have found previously that temporary inactivation of retrosplenial cortex results in dark-selective impairments on the radial maze (Cooper and Mizumori, 1999). To understand further the role of the retrosplenial cortex in navigation, we combined temporary inactivation of retrosplenial cortex with recording of complex spike cells in the hippocampus. Thus, behavioral performance during spatial memory testing could be compared with place-field responses before, and during, inactivation of retrosplenial cortex. In the first experiment, behavioral results confirmed that inactivation of retrosplenial cortex only impairs radial maze performance in darkness when animals are at asymptote levels of performance. A second experiment revealed that retrosplenial cortex inactivation impaired spatial learning during initial light training. In both experiments, the normal location of hippocampal "place fields" was changed by temporary inactivation of retrosplenial cortex, whereas other electrophysiological properties of the cells were not affected. The changes in place coding occurred in the presence, and absence, of behavioral impairments. We suggest that the retrosplenial cortex provides mnemonic spatial information for updating location codes in the hippocampus, thereby facilitating accurate path integration. In this way, the retrosplenial cortex and hippocampus may be part of an interactive neural system that mediates navigation.

Age and experience-dependent representational reorganization during spatial learning.

Previously, we found that aged rats showed a significant enhancement of hippocampal CA1 place cell spatial specificity, as well as a reduction of hilar place cell spatial specificity, during asymptote performance of a spatial memory task. Because such an age effect was not observed when animals performed a nonspatial task, the present study tested the hypothesis that the different patterns of spatial selectivity observed in memory and nonmemory tests reflected a redistribution of spatial representations that occurred in response to changing task demands. In the present experiment, after animals became familiar with the test environment and motor demands of performance on a radial maze, CA1 and hilar place cells were recorded as they learned a spatial memory task. CA1 place cells recorded from unimpaired old, but not impaired old or young, animals became more spatially selective as animals learned the task. Hilar spatial selectivity for both age groups was not significantly related to choice accuracy. These data support the hypothesis that at least a subpopulation of aged rats may benefit from reorganization of spatial representations in such a way that the normal age-related spatial learning deficit is attenuated.

Differential effects of age on subpopulations of hippocampal theta cells.

The possible contribution of age-related changes in the firing properties of hippocampal theta cells to spatial learning deficits was addressed in the present study. The behavioral correlates of theta cells in strata oriens, pyramidale, and granulosum were compared as young and old rats performed a radial maze spatial working memory task. Behaviorally, the old animals made significantly more errors on the maze and required more time to solve the task than did young animals. Firing rates were compared in four different locomotion states: still, running radially inward and radially outward, and forward motion. The discharge rates of theta cells in strata pyramidale and granulosum were significantly modulated by these movements in both age groups. Stratum oriens theta cells recorded from young animals, on the other hand, were not movement-sensitive, while similar cells from old animals demonstrated exaggerated responses to movement. In old animals, the mean discharge rates were higher in stratum granulosum and lower in stratum oriens than in the young rats. The discharge rates of cells in stratum pyramidale did not differ between age groups. These region specific changes in the firing characteristics of hippocampal theta cells are likely to have important consequences for information processing in this structure.

Selective decline in protein F1 phosphorylation in hippocampus of senescent rats.

Certain forms of neuronal plasticity have been found to be expressed through alterations in brain protein phosphorylation, and its regulation by protein kinase activity. Of interest in this regard is the possibility that the decline in neuronal plasticity and cognitive function that occurs in advanced age may result in part from altered phosphorylation of specific proteins. As a first attempt to identify age-related changes in phosphoproteins, we assayed in vitro phosphorylation of proteins in hippocampus, cerebellum, entorhinal cortex, and frontal cortex from Fischer-344 rats of 5 months, 11 months, and 25 months of age. Compared to the middle-aged animals, the aged rats showed a selective 46% decline in phosphorylation of the 47 kDa protein (F1) in hippocampus, with no change in the phosphorylation of other proteins measured in this structure. Aged animals also showed decreased phosphorylation relative to young animals. No age-related change was observed in any protein band for the other brain areas examined. Since protein F1 is phosphorylated by protein kinase C (PKC), the cytosolic and membrane distribution of this enzyme was compared across age groups. The activity of PKC in hippocampus did not change across age. The explanation of this age-related decline in protein F1 phosphorylation is likely to be a decline in the substrate protein itself. The results are discussed in terms of protein F1's possible role in age-related decline of hippocampal synaptic plasticity.

Effects of dietary choline on memory and brain chemistry in aged mice.

The purpose of this study was to investigate in more detail the characteristics of the age-related extension of the retrograde amnesia gradient previously demonstrated in a passive avoidance task [6]. In Experiment 1, it was found that while 2-3 month old mice were susceptible to the amnesic effects of anisomycin (ANI) only when given prior to 15 min post-training, memory of 14-16 month old mice was susceptible to disruption when ANI was given as late as 20 min post-training, and retention of 17-20 month old mice was impaired when ANI was injected even as late as 30 min after training. Experiment 2 examined whether the age-related change in susceptibility to the effects of ANI could be ameliorated by chronic pretreatment with a choline-enriched diet. Results showed that ANI injected 20 min after training did not induce amnesia in choline treated mice (14.5 month old), but did induce amnesia when injected 15 min post training. Subsequent assay of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) activity showed that choline treatment significantly reduced ChAT activity but did not affect TH activity. It appears that dietary choline treatment can render new long-term memories less susceptible to disruption following training.

A neural systems analysis of adaptive navigation.

In the field of the neurobiology of learning, significant emphasis has been placed on understanding neural plasticity within a single structure (or synapse type) as it relates to a particular type of learning mediated by a particular brain area. To appreciate fully the breadth of the plasticity responsible for complex learning phenomena, it is imperative that we also examine the neural mechanisms of the behavioral instantiation of learned information, how motivational systems interact, and how past memories affect the learning process. To address this issue, we describe a model of complex learning (rodent adaptive navigation) that could be used to study dynamically interactive neural systems. Adaptive navigation depends on the efficient integration of external and internal sensory information with motivational systems to arrive at the most effective cognitive and/or behavioral strategies. We present evidence consistent with the view that during navigation: 1) the limbic thalamus and limbic cortex is primarily responsible for the integration of current and expected sensory information, 2) the hippocampal-septal-hypothalamic system provides a mechanism whereby motivational perspectives bias sensory processing, and 3) the amygdala-prefrontal-striatal circuit allows animals to evaluate the expected reinforcement consequences of context-dependent behavioral responses. Although much remains to be determined regarding the nature of the interactions among neural systems, new insights have emerged regarding the mechanisms that underlie flexible and adaptive behavioral responses.

Directing place representation in the hippocampus.

Theoretical models of rodent navigation consider location information and directional heading to be essential. Indeed, the existence of location-selective 'place cells' and orientation-selective 'head direction cells' is well documented. Different models suggest different forms of interaction between information about location and heading direction. However, until recently, there were no clear empirical data that could be used to distinguish the different models in terms of the nature of the integration of location and directional heading information. Recently, Leutgeb et al. provided evidence that head direction and place signals coexist within the CA1 region of hippocampus, and that the head direction signals are likely to be generated by a subpopulation of interneurons. This finding opens up new possibilities for clarifying current models and for developing biologically plausible theories of synaptic interactions between location and head direction codes. In this paper, we first present the issue concerning the nature of the interaction between location and head direction signals, followed by a selective review of place and head direction cell research. The finding of Leutgeb et al. is then summarized, and its implications for current models are discussed. Finally, a view is presented that considers place fields to be a product not only of (external and internal) sensory input, but also of non-spatial variables such as motivation and responses. The finding of Leutgeb et al. and many earlier anatomical studies suggest that hippocampal head direction, motivation and response information may be represented by the interneuron population. Thus, these factors may have strong impact on the location codes of hippocampal pyramidal neurons. Their influence may further define the behavioral context of the current spatial environment.

Context-specific spatial representations by lateral septal cells.

To test whether the location coding of lateral septal cells is dependent on cue constellations, we examined single units in two different recording arenas on alternating days. Repeated recordings of lateral septal neurons in the same arena revealed that matching locations are encoded on separate days by about one third of the cells. The cells typically showed location-selective firing in only one of the two recording arenas and initially showed unrelated patterns when tested in a different recording arena. When tested for a second time in each recording arena, the initially dissimilar patterns were modified towards increased similarity between arenas. Simultaneously recorded hippocampal principal cells showed distinct place fields for each recording arena throughout the recording sequence. These results indicate that the initial reorganization of the lateral septal location coding may occur as a direct consequence of the hippocampal reorganization. Further septal reorganization is then partially independent of established place fields in the CA1 and CA3 area.Location-selective cells in cortical areas that receive projections from hippocampus proper (i.e. the subiculum and the entorhinal cortex) have not been shown to encode differences between recording arenas. Although some characteristics of this generalized coding scheme have also been found for location-selective lateral septal cells, the encoding of context information was generally preserved in the subcortical target cells of projections from the CA1 and CA3 area.

Convergence of head direction and place information in the CA1 region of hippocampus.

The hippocampus has long been considered critical for spatial learning and navigation. Recent theoretical models of the rodent and primate hippocampus consider spatial processing a special case of a more general memory function. These non-spatial theories of hippocampus differ from navigational theories with respect to the role of self-motion representations. The present study presents evidence for a new cell type in the CA1 area of the rat hippocampus that codes for directional heading independent of location information (i.e. the angular component of self-motion). These hippocampal head direction cells are controlled by external and idiothetic cues in a similar way as head direction cells in other brain areas and hippocampal place cells. Convergent head direction information and location information may be an essential component of a neural system that monitors behavioral sequences during navigation. Conflicts between internally generated and external cues have previously been shown to result in new hippocampal place representations, suggesting that head direction information may participate in synaptic interactions when new location codes are formed. Combined hippocampal representations of self-motion and external cues may therefore contribute to path integration as well as spatial memory processing.

Comparison of spatial and temporal characteristics of neuronal activity in sequential stages of hippocampal processing.

The activity of individual pyramidal cells in the CA1 and CA3 subfields of the rodent hippocampus exhibits a remarkable selectivity for specific locations and orientations of the rat within spatially-extended environments. These cells exhibit high rates of activity when the animal is present within restricted regions of space, referred to as place fields, and are extremely quiet when it is elsewhere. Although this phenomenon has been well studied in the CA fields of the hippocampus, relatively little is known about the spatial and temporal firing characteristics either of the entorhinal cortical inputs to the hippocampus, or of the subicular recipients of the output of hippocampal place cells. We report here on a comparison of spatial and temporal discharge characteristics among entorhinal cortex, CA3 and CA1, and the subiculum. CA3 complex spike cells were significantly more spatially specific than their CA1 counterparts. Neither entorhinal cortex nor subiculum exhibited the highly localized patterns of spatial firing observed in the CA fields. In addition, average discharge rates in these areas were substantially higher. However, particularly in subiculum, there was evidence for spatially consistent, but dispersed, firing in some cells, suggestive of the convergence of a number of CA1 place cells. The patterns observed are not consistent with the hypothesis that spatial selectivity is progressively refined at the various levels of hippocampal processing. Rather, hippocampal output appears to be expressed as a much more highly distributed spatial code than activity within the hippocampus proper. We suggest that the sparse coding used within the hippocampus itself represents a mechanism for increasing the storage capacity of a network whose function is to form associations rapidly.

Characteristics of basolateral amygdala neuronal firing on a spatial memory task involving differential reward.

Previous research has shown that spatial, movement, and reward information is integrated within the ventral striatum (VS). The present study examined the possible contribution of the basolateral nuclei of the amygdala (BLA) to this interaction by examining behavioral correlates of BLA neurons while rats performed multiple memory trials on an 8-arm radial maze. Alternate arms consistently held 1 of 2 different amounts of reward. Recorded cells were correlated with motion, auditory input, space, and reward acquisition. Reward-related units were found that anticipated reward encounter, that responded during reward consumption, and that differentiated between high and low reward magnitude. This is consistent with the hypothesis that BLA neurons may provide the VS with reward-related information that could then be integrated with spatial information to ultimately affect goal-directed behavior.

Redistribution of spatial representation in the hippocampus of aged rats performing a spatial memory task.

Young and old rats performed on a maze according to a forced-choice and then a spatial memory procedure either in the same or a different environment. Aged rats were slower to learn the spatial memory task when tested in the same, but not in a different, room. One interpretation of this pattern of results is that although old rats learn new rules as quickly as young rats, they show less flexibility with old rules and familiar spatial information. Impaired choice accuracy during asymptote performance suggests poor processing of trial-unique information by old rats. Spatial correlates of hippocampal CA1 and hilar cells varied with task demand: CA1 cells of aged rats showed more spatially selective place fields, whereas hilar cells showed more diffuse location coding during spatial memory, and not forced-choice, tests. Such representational reorganization may reflect a compensatory response to age-related neurobiological changes in hippocampus.

Short- and long-term components of working memory in the rat.

Previous experiments suggested that working memory of rats trained on a radial maze can be discussed in terms of its short- and long-term temporal components. For example, in Mizumori, Channon, Rosenzweig, and Bennett's (1985) study, long-term working memory was found to be susceptible to disruption by the protein synthesis inhibitor anisomycin (ANI). In Experiment 1 of this report, we examined the neuropharmacological nature of short-term working memory of rats trained to retrieve food from all arms of a 12-arm radial maze. Delay intervals of varying length were placed between Choices 6 and 7. Lanthanum (LaCl3) and glutamate (GLU) injected bilaterally into the hippocampus effectively impaired retention over short delay intervals, which suggests a possible role for calcium and/or potassium and for glutamate in working memory. However, another equally likely explanation for the amnesic effects of LaCl3 and GLU is that these drugs impaired reference memory. To test more directly the hypothesis that LaCl3, GLU, or ANI might differentially affect working and reference memory, we tested the effects of these drugs on performance of rats trained to retrieve food from only 8 arms of the 12-arm maze in Experiment 2. The remaining 4 arms were never baited, in order to test reference memory function. We predicted that rats would make errors only in baited arms (i.e., errors of working memory). Instead, results of Experiment 2 showed that LaCl3, GLU, or ANI injection produced errors in unbaited arms even before a 120-min delay. If rats were injected with LaCl3 or GLU, baited-arm errors were observed only after the delay period.(ABSTRACT TRUNCATED AT 250 WORDS)

Finding your way in the dark: the retrosplenial cortex contributes to spatial memory and navigation without visual cues.

Path integration is presumed to rely on self-motion cues to identify locations in space and is subject to cumulative error. The authors tested the hypothesis that rats use memory to reduce such errors and that the retrosplenial cortex contributes to this process. Rats were trained for 1 week to hoard food in an arena after beginning a trial from a fixed starting location; probe trials were then conducted in which they began a trial from a novel place in light or darkness. After control injections, rats searched around the training location, showing normal spatial memory. Inactivation of the retrosplenial cortex disrupted this search preference. To assess accuracy during navigation, rats were then trained to perform multiple trials daily, with a fixed or a different starting location in light or darkness. Retrosplenial cortex inactivation impaired accuracy in darkness. The retrosplenial cortex may provide mnemonic information, which decreases errors when navigating in the dark.

Long-term working memory in the rat: effects of hippocampally applied anisomycin.

The extent to which protein synthesis is involved in working memory was investigated with the protein synthesis inhibitor anisomycin (ANI). Rats were trained to perform accurately on a 12-arm radial maze when delays of 240 min were interposed between choice 6 and choice 7. Bilateral hippocampal cannulas were then implanted. Accuracy on choices 7-12 was studied when ANI or saline was injected either 30 min before choice 1 or 5-10 min after choice 6 (Experiment 1). Pretrial injection of ANI significantly impaired performance following the 240-min delay, whereas ANI injected during the delay had no such effect. In Experiments 2 and 3, the ANI-induced amnesia was replicated, and the temporal course of development of the amnesia was determined. Pretrial administration of ANI did not significantly affect retention after a 2-min delay but did produce amnesia after delays of 15 min or longer. These data suggest that protein synthesis is important for the formation of temporary memories, provided the retention interval is long enough. It is suggested that working memory includes both short-term and long-term components. Protein synthesis appears to be important for formation of the long-term component, but not the short-term component, of working memory.

Spatial- and locomotion-related neural representation in rat hippocampus following long-term survival from ischemia.

Spatial and locomotion-related behavioral correlates of hippocampal cell discharge were compared between ischemic and sham-control rats performing a spatial maze. Ischemic rats showed impaired choice accuracy during maze acquisition, but not during asymptote performance. Single-unit correlates during asymptote performance revealed enhanced spatial selectivity of CA2/3 complex-spike cells coincident with attenuated place-specific firing by hilar complex-spike or subicular cells. Responsivity to locomotion state by stratum granulosum interneurons was exaggerated, and locomotion-induced changes in firing of hilar and subicular interneurons was reduced. Ischemic rats showed recovered spatial learning abilities as evidenced by the fact that acquisition of the spatial task in a second environment was not impaired. Because representational reorganization was also observed in ischemic, maze-naive rats, brain injury per se appears to change information coding schemes.

Retrosplenial cortex inactivation selectively impairs navigation in darkness.

There is an emerging consensus that retrosplenial and posterior parietal cortex importantly contribute to navigation. Several theories of navigation have argued that these cortical areas, particularly retrosplenial cortex, are involved in path integration. In an effort to characterize the role of retrosplenial cortex in active navigation, the effects of temporary inactivation of retrosplenial cortex on spatial memory performance were evaluated in light and dark testing conditions. Inactivation of retrosplenial cortex selectively resulted in behavioral impairments when animals were tested in darkness. These data support the hypothesis that retrosplenial cortex contributes to navigation in darkness, perhaps by providing mnemonic associations of the visual and nonvisual environment that can be used to correct for cumulative errors that occur during path integration.

Neurons in rat medial prefrontal cortex show anticipatory rate changes to predictable differential rewards in a spatial memory task.

The present study electrophysiologically examined the contribution of prelimbic and infralimbic neurons in the medial prefrontal cortex (mPFC) to integration of reward and spatial information while rats performed multiple memory trials on a differentially rewarded eight arm radial maze. Alternate arms consistently held one of two different reward amounts. Similar to previous examinations of the rat mPFC, few cells showed discrete place fields or altered firing during a delay period. The most common behavioral correlate was a change in neuronal firing rate prior to reward acquisition at arm ends. A small number of reward-related cells differentiated between high and low reward arms. The presence of neurons that anticipate expected reward consequences based on information about the spatial environment is consistent with the hypothesis that the mPFC is part of a neural system which merges spatial information with its motivational significance.

Investigations into the neuropharmacological basis of temporal stages of memory formation in mice trained in an active avoidance task.

The memorial effects of glutamate, LaCl3, ouabain, or anisomycin injection around the time of active avoidance training in mice were assessed in this study. Based on the Gibbs and Ng hypothesis of memory formation in chicks (Biobehav. Rev., 1 [1977] 113-136), it was predicted that these pharmacological agents would not only induce significant amnesia but, more specifically, short duration memory should be selectively impaired by glutamate and LaCl3, intermediate duration memory should be impaired by ouabain, and anisomycin should affect only long-lasting memories. Results of the experiments described below indicate these drugs are potent inhibitors of memory formation in rodents. In addition, LaCl3-induced amnesia was fully prevented by CaCl2. However, the mechanism by which glutamate and ouabain affected memory may not be exactly as described by Gibbs and Ng: gamma-D-glutamylglycine and diphenylhydantoin did not completely prevent glutamate- and ouabain-induced amnesias, respectively. Finally, all amnestic agents induced amnesia that developed within minutes of training, and the time course of development of amnesia for each drug could not be distinguished from one another. These data are discussed in terms of their implications for the Gibbs and Ng model of memory formation.