On parsing the neural code in the prefrontal cortex of primates using principal dynamic modes.

Nonlinear modeling of multi-input multi-output (MIMO) neuronal systems using Principal Dynamic Modes (PDMs) provides a novel method for analyzing the functional connectivity between neuronal groups. This paper presents the PDM-based modeling methodology and initial results from actual multi-unit recordings in the prefrontal cortex of non-human primates. We used the PDMs to analyze the dynamic transformations of spike train activity from Layer 2 (input) to Layer 5 (output) of the prefrontal cortex in primates performing a Delayed-Match-to-Sample task. The PDM-based models reduce the complexity of representing large-scale neural MIMO systems that involve large numbers of neurons, and also offer the prospect of improved biological/physiological interpretation of the obtained models. PDM analysis of neuronal connectivity in this system revealed "input-output channels of communication" corresponding to specific bands of neural rhythms that quantify the relative importance of these frequency-specific PDMs across a variety of different tasks. We found that behavioral performance during the Delayed-Match-to-Sample task (correct vs. incorrect outcome) was associated with differential activation of frequency-specific PDMs in the prefrontal cortex.

Design of optimal stimulation patterns for neuronal ensembles based on Volterra-type hierarchical modeling.

This paper presents a general methodology for the optimal design of stimulation patterns applied to neuronal ensembles in order to elicit a desired effect. The methodology follows a variant of the hierarchical Volterra modeling approach that utilizes input-output data to construct predictive models that describe the effects of interactions among multiple input events in an ascending order of interaction complexity. The illustrative example presented in this paper concerns the multi-unit activity of CA1 neurons in the hippocampus of a rodent performing a learned delayed-nonmatch-to-sample (DNMS) task. The multi-unit activity of the hippocampal CA1 neurons is recorded via chronically implanted multi-electrode arrays during this task. The obtained model quantifies the likelihood of having correct performance of the specific task for a given multi-unit (spatiotemporal) activity pattern of a CA1 neuronal ensemble during the 'sample presentation' phase of the DNMS task. The model can be used to determine computationally (off-line) the 'optimal' multi-unit stimulation pattern that maximizes the likelihood of inducing the correct performance of the DNMS task. Our working hypothesis is that application of this optimal stimulation pattern will enhance performance of the DNMS task due to enhancement of memory formation and storage during the 'sample presentation' phase of the task.

Dynamic nonlinear modeling of interactions between neuronal ensembles using principal dynamic modes.

We present a novel methodology for modeling the interactions between neuronal ensembles that utilizes the concept of Principal Dynamic Modes (PDM) and their associated nonlinear functions (ANF). This new approach seeks to reduce the complexity of the multi-input/multi-output (MIMO) model of the interactions between neuronal ensembles--an issue of critical practical importance in scaling up the MIMO models to incorporate hundreds (or even thousands) of input-output neurons. Global PDMs were extracted from the data using estimated first-order and second-order kernels and singular value decomposition (SVD). These global PDMs represent an efficient "coordinate system" for the representation of the MIMO model. The ANFs of the PDMs are estimated from the histograms of the combinations of PDM output values that lead to output spikes. For initial testing and validation of this approach, we applied it to a set of data collected at the pre-frontal cortex of a non-human primate during a behavioral task (Delayed Match-to-Sample). Recorded spike trains from Layer-2 neurons were viewed as the "inputs" and from Layer-5 neurons as the outputs. Model prediction performance was evaluated by means of computed Receiver Operating Characteristic (ROC) curves. The results indicate that this methodology may greatly reduce the complexity of the MIMO model without significant degradation of performance.

Restorative encoding memory integrative neural device: "REMIND".

Construction and application of a neural prosthesis device that enhances existing and replaces lost memory capacity in humans is the focus of research described here in rodents. A unique approach for the analysis and application of neural population firing has been developed to decipher the pattern in which information is successfully encoded by the hippocampus where mnemonic accuracy is critical. A nonlinear dynamic multi-input multi-output (MIMO) model is utilized to extract memory relevant firing patterns in CA3 and CA1 and to predict online what the consequences of the encoded firing patterns reflect for subsequent information retrieval for successful performance of delayed-nonmatch-to-sample (DNMS) memory task in rodents. The MIMO model has been tested successfully in a number of different contexts, each of which produced improved performance by a) utilizing online predicted codes to regulate task difficulty, b) employing electrical stimulation of CA1 output areas in the same pattern as successful cell firing, c) employing electrical stimulation to recover cell firing compromised by pharmacological agents and d) transferring and improving performance in naïve animals using the same stimulation patterns that are effective in fully trained animals. The results in rodents formed the basis for extension of the MIMO model to nonhuman primates in the same type of memory task that is now being tested in the last step prior to its application in humans.

Neural correlates of fast pupil dilation in nonhuman primates: relation to behavioral performance and cognitive workload.

Pupil dilation in humans has been previously shown to correlate with cognitive workload, whereby increased frequency of dilation is associated with increased degree of difficulty of a task. It has been suggested that frontal oculomotor brain areas control cognitively related pupil dilations, but this has not been confirmed due to lack of animal models of cognitive workload and task-related pupil dilation. This is the first report of a wavelet analysis applied to continuous measures of pupil size used to detect the onset of abrupt pupil dilations and the frequency of those dilations in nonhuman primates (NHPs) performing a trial-unique delayed-match-to-sample (DMS) task. A unique finding shows that electrophysiological recordings in the same animals revealed firing of neurons in frontal cortex correlated to different components of pupil dilation during task performance. It is further demonstrated that the frequency of fast pupil dilations (but not rate of eye movements) correlated with cognitive workload during task performance. Such correlations suggest that frontal neuron encoding of pupil dilation provides critical feedback to other brain areas involved in the processing of complex visual information.

The encoding of cocaine vs. natural rewards in the striatum of nonhuman primates: categories with different activations.

The behavioral and motivational changes that result from use of abused substances depend upon activation of neuronal populations in the reward centers of the brain, located primarily in the corpus striatum in primates. To gain insight into the cellular mechanisms through which abused drugs reinforce behavior in the primate brain, changes in firing of neurons in the ventral (VStr, nucleus accumbens) and dorsal (DStr, caudate-putamen) striatum to "natural" (juice) vs. drug (i.v. cocaine) rewards were examined in four rhesus monkeys performing a visual Go-Nogo decision task. Task-related striatal neurons increased firing to one or more of the specific events that occurred within a trial represented by (1) Target stimuli (Go trials) or (2) Nogotarget stimuli (Nogo trials), and (3) Reward delivery for correct performance. These three cell populations were further subdivided into categories that reflected firing exclusively on one or the other type of signaled reward (juice or cocaine) trial (20%-30% of all cells), or, a second subpopulation that fired on both (cocaine and juice) types of rewarded trial (50%). Results show that neurons in the primate striatum encoded cocaine-rewarded trials similar to juice-rewarded trials, except for (1) increased firing on cocaine-rewarded trials, (2) prolonged activation during delivery of i.v. cocaine infusion, and (3) differential firing in ventral (VStr cells) vs. dorsal (DStr cells) striatum cocaine-rewarded trials. Reciprocal activations of antithetic subpopulations of cells during different temporal intervals within the same trial suggest a functional interaction between processes that encode drug and natural rewards in the primate brain.

Mechanisms underlying cognitive enhancement and reversal of cognitive deficits in nonhuman primates by the ampakine CX717.

RATIONALE: Performance of cognitive tasks in nonhuman primates (NHPs) requires specific brain regions to make decisions under different degrees of difficulty or "cognitive load." OBJECTIVE: Local cerebral metabolic activity ([18F]FDG PET imaging) in dorsolateral prefrontal cortex (DLPFC), medial temporal lobe (MTL), and dorsal striatum (DStr) is examined in NHPs performing a delayed-match-to-sample (DMS) task with variable degrees of cognitive load. MATERIALS AND METHODS: Correlations between cognitive load and degree of brain metabolic activity were obtained with respect to the influence of the ampakine CX717 (Cortex Pharmaceuticals), using brain imaging and recordings of neuronal activity in NHPs and measures of intracellular calcium release in rat hippocampal slices. RESULTS: Activation of DLPFC, MTL, and DStr reflected changes in performance related to cognitive load within the DMS task and were engaged primarily on high load trials. Similar increased activation patterns and improved performance were also observed following administration of CX717. Sleep deprivation in NHPs produced impaired performance and reductions in brain activation which was reversed by CX717. One potential basis for this facilitation of cognition by CX717 was increased firing of task-specific hippocampal cells. Synaptic mechanisms affected by CX717 were examined in rat hippocampal slices which showed that N-methyl-D-aspartic acid-mediated release of intracellular calcium was reduced in slices from sleep-deprived rats and reversed by application of CX717 to the bathing medium. CONCLUSIONS: The findings provide insight into how cognition is enhanced by CX717 in terms of brain, and underlying neural, processes that are activated on high vs. low cognitive load trials.

The synthetic cannabinoid HU210 induces spatial memory deficits and suppresses hippocampal firing rate in rats.

BACKGROUND AND PURPOSE: Previous work implied that the hippocampal cannabinoid system was particularly important in some forms of learning, but direct evidence for this hypothesis is scarce. We therefore assessed the effects of the synthetic cannabinoid HU210 on memory and hippocampal activity. EXPERIMENTAL APPROACH: HU210 (100 microg kg(-1)) was administered intraperitoneally to rats under three experimental conditions. One group of animals were pre-trained in spatial working memory using a delayed-matching-to-position task and effects of HU210 were assessed in a within-subject design. In another, rats were injected before acquisition learning of a spatial reference memory task with constant platform location. Finally, a separate group of animals was implanted with electrode bundles in CA1 and CA3 and single unit responses were isolated, before and after HU210 treatment. KEY RESULTS: HU210 treatment had no effect on working or short-term memory. Relative to its control Tween 80, deficits in acquisition of a reference memory version of the water maze were obtained, along with drug-related effects on anxiety, motor activity and spatial learning. Deficits were not reversed by the CB(1) receptor antagonists SR141716A (3 mg kg(-1)) or AM281 (1.5 mg kg(-1)). Single unit recordings from principal neurons in hippocampal CA3 and CA1 confirmed HU210-induced attenuation of the overall firing activity lowering both the number of complex spikes fired and the occurrence of bursts. CONCLUSIONS AND IMPLICATIONS: These data provide the first direct evidence that the underlying mechanism for the spatial memory deficits induced by HU210 in rats is the accompanying abnormality in hippocampal cell firing.

Behaviorally relevant endocannabinoid action in hippocampus: dependence on temporal summation of multiple inputs.

Endocannabinoids have been shown to mediate depolarization-induced suppression of GABAergic inhibition (DSI), possibly via release and retrograde diffusion following moderate to severe depolarization of hippocampal pyramidal neurons. However, it is not clear how hippocampal neurons, which have relatively low firing rates in vivo, achieve the degree of depolarization required to release endocannabinoids. Here it is demonstrated that DSI is not dependent on the occurrence of action potentials in the postsynaptic neuron, but is mediated by depolarization-induced calcium entry via voltage-controlled calcium channels (VCCs). The optimal level of calcium entry, and subsequent DSI, are directly related to the frequency of depolarizing pulses, which differs between immature and adult hippocampus. However, it is shown via modeled spike train inputs that the frequency dependence of DSI is overcome if two or more convergent spike trains from different neurons with normal in vivo firing rates converge and overlap in time. In these modeled circumstances, endocannabinoid-mediated DSI occurs most often when converging synaptic inputs from multiple neurons fire in synchrony to allow temporal summation of local membrane events in postsynaptic cells to exceed threshold for calcium entry. It is therefore possible that such suppression of inhibition would only occur during the time that recipient hippocampal neurons receive multiple coincident excitatory synaptic inputs.

Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) proteins in cultured hippocampal neurons.

The current study showed that potassium K current (I(K)), which is evoked at depolarizing potentials between -30 and +40 mV in cultured hippocampal neurons, was significantly reduced by exposure to the CB1 cannabinoid receptor agonist WIN 55,212-2 (WIN-2). WIN-2 (20-40 nM) produced an average 45% decrease in I(K) amplitude across all voltage steps, which was prevented by SR141716A, the CB1 receptor antagonist. The cannabinoid receptor has previously been shown to be G(i/o) protein-linked to several cellular processes; however, the decrease in I(K) was unaffected by modulators of G(i/o) proteins and agents that alter levels of protein kinase A. In contrast, CB1 receptor-mediated or direct activation of G(s) proteins with cholera toxin (CTX) produced the same decrease in I(K) amplitude as WIN-2, and the latter was blocked in CTX-treated cells. G(s) protein inhibition via GDPbetaS also eliminated the effects of WIN-2 on I(K). Consistent with this outcome, activation of protein kinase C (PKC) by arachidonic acid produced similar effects to WIN-2 and CTX. Kappa opioid receptor agonists, which also reduce I(K) amplitude via G(s) proteins, were compared with WIN-2 actions on I(K.) The kappa receptor agonist U50,488 reduced I(K) amplitude in the same manner as WIN-2, while the kappa receptor antagonist, nor-binaltorphimine, actually increased I(K) amplitude and significantly reduced the effect of co-administered WIN-2. The results indicate that CB1 and kappa receptor activation is additive with respect to I(K) amplitude, suggesting that CB1 and kappa receptors share a common G(s) protein signaling pathway involving PKC.

Differential information processing by hippocampal and subicular neurons.

It has been known for some years that hippocampal neurons are critically involved in processing of information necessary for encoding memories. What is less understood is the role of the subiculum in this process. We describe here differential response characteristics of subicular and hippocampal neurons in rats during execution of a delayed-nonmatch-to-sample short-term memory task. Subicular neurons, unlike hippocampal neurons, fire primarily in the delay interval of the task and appear to provide a temporal linkage between events encoded in hippocampus during the sample and nonmatch phases. Indeed, a large proportion of subicular neurons fire robustly for the entire duration of the delay only. Further analyses using electrical activation methods indicate that subicular neurons that receive short latency inputs from the anterior thalamus and do not project to cingulate cortex are the most responsive to stimuli with behavioral significance.

Protein kinase-dependent phosphorylation and cannabinoid receptor modulation of potassium A current (IA) in cultured rat hippocampal neurons.

The potent cannabinoid receptor agonist WIN 55,212-2 produces positive shifts in steady-state inactivation of the potassium A current (IA) in rat hippocampal neurons via an adenosine 3',5'-cyclic monophosphate (cAMP)-, protein kinase A (PKA)-dependent process. This effect is probably mediated by phosphorylation or dephosphorylation of the IA channel protein. The role of protein phosphorylation in this cascade was tested by testing cannabinoid actions in cultured hippocampal neurons (pyramidal cells) that were exposed also to either the catalytic subunit of PKA (PKAc), a PKA-specific phosphorylation inhibitor (IP-20, Walsh peptide), or a potent protein phosphatase inhibitor (okadaic acid). Cannabinoids such as WIN 55,212-2 produce a positive (rightwards) shift in the steady-state inactivation of IA, thus providing increased current at a given membrane voltage. Cells dialyzed with PKAc showed a negative shift in IA inactivation, opposite to that produced by cannabinoids, and similar to that produced by increased levels of cAMP. In addition, PKAc completely blocked the positive shift produced by WIN 55,212-2. In contrast, dialysis of cells with IP-20 produced a positive shift in steady state inactivation of IA, similar to that produced by WIN, but the effects were not additive with cannabinoid receptor activation. The phosphatase inhibitor, okadaic acid produced a small negative shift in IA steady-state inactivation when administered alone, and blocked the positive shift produced by WIN 55,212-2. Okadaic acid also enhanced the negative shift in IA inactivation when co-administered with forskolin. The effects of okadaic acid and WIN 55,212-2 were not additive, suggesting a common pathway. These results demonstrate that IA is altered by direct manipulations of the phosphorylation status of the channel protein, and that cannabinoid effects on IA are probably mediated by dephosphorylation of the IA channel.

Cannabinoid receptor activation in CA1 pyramidal cells in adult rat hippocampus.

Intracellular assessments of the physiological actions of cannabinoid receptor agonists and antagonists on adult hippocampal CA1 pyramidal cells in the in vitro slice preparation were performed using current clamp and conventional sharp-electrode intracellular recording procedures. Several manipulations were performed to delineate putative currents and conductance mechanisms affected by the cannabinoid receptor agonist WIN 55,212-2 (WIN-2). This compound produced a tonic hyperpolarization of the pyramidal cell membrane that was bicuculline sensitive, reversed by changing the chloride gradient, and abolished by the addition of TTX to the bathing medium. Instantaneous membrane input resistance, computed from hyperpolarizing current pulses (peak R(in)) was also reduced significantly in the presence of WIN-2 and was accompanied by enhancement of a superimposed slow depolarization that reduced steady-state R(in) (SSR(in)); both effects were resistant to barium. Intracellular perfusion of cesium acetate (CsAc) and the sodium/potassium channel blocker, QX314, each blocked the effect of WIN-2 on R(in) and SSR(in). WIN-2 also reduced input resistance calculated from depolarizing current injections (R(d)). This effect was also blocked by atropine, as well as media containing TTX or low Ca(2+). Each of the above effects of WIN-2 was blocked by the cannabinoid receptor antagonist SR141716A, showing a dependence on CB1 cannabinoid receptors. Several known pre- and postsynaptic processes in adult pyramidal cells are discussed which could be responsible for these cannabinoid-produced changes in membrane resistances.

Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats.

The memory-disruptive effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and the synthetic cannabinoid WIN 55,212-2 (WIN-2) were assessed in rats exposed to varying doses of each drug (Delta(9)-THC, 0.5-2.0 mg/kg; WIN-2, 0.25-0.75 mg/kg) during performance of a delayed nonmatch to sample (DNMS) task. Cannabinoids affected performance in a dose x delay-dependent manner, with WIN-2 showing a potency more than four times that of Delta(9)-THC. These effects on DNMS performance were eliminated if the cannabinoid CB1 receptor antagonist SR141617A (Sanofi Research Inc.) was preadministered, but doses of the antagonist alone had no effect on performance. Simultaneous recording from ensembles of hippocampal neurons revealed that both WIN-2 and Delta(9)-THC produced dose-dependent reductions in the frequency (i.e., "strength") of ensemble firing during the sample phase of the task to the extent that performance was at risk for errors on >70% of trials as a function of delay. This decrease in ensemble firing in the Sample phase resulted from selective interference with the activity of differentiated hippocampal functional cell types, which conjunctively encoded different combinations of task events. A reduction in ensemble firing strength did not occur in the nonmatch phase of the task. The findings indicate that activation of CB1 receptors renders animals at risk for retention of item-specific information in much the same manner as hippocampal removal.

Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain.

Chronic treatment of rats with delta9-tetrahydrocannabinol (delta9-THC) results in tolerance to its acute behavioral effects. In a previous study, 21-day delta9-THC treatment in rats decreased cannabinoid activation of G proteins in brain, as measured by in vitro autoradiography of guanosine-5'-O-(3-[35S]thiotriphosphate) ([35S]GTPgammaS) binding. The present study investigated the time course of changes in cannabinoid-stimulated [35S]GTPgammaS binding and cannabinoid receptor binding in both brain sections and membranes, following daily delta9-THC treatments for 3, 7, 14, and 21 days. Autoradiographic results showed time-dependent decreases in WIN 55212-2-stimulated [35S]GTPgammaS and [3H]WIN 55212-2 binding in cerebellum, hippocampus, caudate-putamen, and globus pallidus, with regional differences in the rate and magnitude of down-regulation and desensitization. Membrane binding assays in these regions showed qualitatively similar decreases in WIN 55212-2-stimulated [35S]GTPgammaS binding and cannabinoid receptor binding (using [3H]SR141716A), and demonstrated that decreases in ligand binding were due to decreases in maximal binding values, and not ligand affinities. These results demonstrated that chronic exposure to delta9-THC produced time-dependent and region-specific down-regulation and desensitization of brain cannabinoid receptors, which may represent underlying biochemical mechanisms of tolerance to cannabinoids.

Distribution of spatial and nonspatial information in dorsal hippocampus.

The hippocampus in the mammalian brain is required for the encoding of current and the retention of past experience. Previous studies have shown that the hippocampus contains neurons that encode information required to perform spatial and nonspatial short-term memory tasks. A more detailed understanding of the functional anatomy of the hippocampus would provide important insight into how such encoding occurs. Here we show that hippocampal neurons in the rat are distributed anatomically in distinct segments along the length of the hippocampus. Each longitudinal segment contains clusters of neurons that become active when the animal performs a task with spatial attributes. Within these same segments are ordered arrangements of neurons that encode the nonspatial aspects of the task appropriate to those spatial features. Thus, anatomical segregation of spatial information, together with the interleaved representation of nonspatial information, represents a structural framework that may help to resolve conflicting views of hippocampal function.

Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture.

Cannabinoid (CB(1)) receptor activation produced differential effects on voltage-gated outward potassium currents in whole-cell recordings from cultured (7-15 days) rat hippocampal neurons. Voltage-dependent potassium currents A (I(A)) and D (I(D)) were isolated from a composite tetraethylammonium-insensitive current (I(comp)) by blockade with either 4-aminopyridine (500 microM) or dendrotoxin (2 microM) and subtraction of the residual I(A) from I(comp) to reveal I(D). The time constants of inactivation (tau) of I(A) and I(D) as determined in this manner were found to be quite different. The CB(1) agonist WIN 55,212-2 produced a 15- to 20-mV positive shift in voltage-dependent inactivation of I(A) and a simultaneous voltage-independent reduction in the amplitude of I(D) in the same neurons. The EC(50) value for the effect of WIN 55,212-2 on I(D) amplitude (13.9 nM) was slightly lower than the EC(50) value for its effect on I(A) voltage dependence (20.6 nM). Pretreatment with either the CB(1) antagonist SR141716A or pertussis toxin completely blocked the differential effects of WIN 55,212-2 on I(A) and I(D), whereas cellular dialysis with guanosine-5'-O-(3-thio)triphosphate mimicked the action of cannabinoids but blocked the action of simultaneously administered cannabinoid receptor ligands. Finally, the differential effects of cannabinoids on I(A) and I(D) were both shown to be mediated via the well documented cannabinoid receptor inhibition of adenylyl cyclase and subsequent modulation of cAMP and protein kinase. These actions are considered in terms of cAMP-mediated phosphorylation of separate I(A) and I(D) channels and the contribution of each to composite voltage-gated potassium currents in these cells.

Anatomic model of hippocampal encoding of spatial information.

Place cells were recorded simultaneously from identified locations along the longitudinal axis of the CA3 and CA1 subregions of hippocampus with a sixteen site electrode array while rats performed a simple pellet chasing task (Deadwyler et al., J Neurosci 1996;16:354-372; Hampson et al., Hippocampus 1996;6:281-293). Cells in CA3 or CA1, separated by 100-300 microm (two electrode locations), exhibited high cross-correlations with respect to place field firing in a given location in the chamber. This pattern of co-activity changed abruptly to low cross-correlations when the longitudinal distance between recording sites increased to 400-1,000 microm. Surprisingly, cells located 1,200-1,400 microm apart again exhibited similar place fields, suggesting a repeating pattern of place field representation within hippocampus. These features were used to construct a model of hippocampal place cell activation using known anatomic connections and projections between CA3 as well as CA1 pyramidal cells. The model provides a topographic representation in hippocampus of the animals' movements around the chamber as different place cells become activated. The model utilizes key landmarks (i.e., corners and walls) to define the animals' movement trajectories through successive place fields and to construct corresponding patterns of place cell firing in hippocampus. This is accomplished via a topological transformation of the chamber's key landmarks projected onto the anatomy of the CA3 and CA1 subregions. The primary feature of the model is that it can, within limited capacity, accurately encode where the animal has been, rather than where it is going. The model, therefore, appears to be more appropriate for memory required to return to particular locations than for initial guidance into those locations.

Cannabinoids, hippocampal function and memory.

Prior studies from this laboratory have shown that the psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC), interferes with short-term memory (1-3) in both delayed match and nonmatch to sample tasks (DMS/DNMS). Recent experiments have shown that other cannabinoids such as the potent CB1 receptor agonist, WIN 55,212-2 produces a delay-dependent deficit in the DNMS task at a dose range (0.10-0.50 mg/kg) well below that of delta9-THC which was blocked by the CB11 receptor antagonist SR141716A (Sanofi Inc). The effects of WIN 55,212-2 at low doses were similar to those of isolated lesions of the hippocampus, whereas high doses (0.50 mg/kg, i.p.) produced effects similar to lesions of both hippocampus and surrounding retrohippocampal areas. The low dose effect was delay-dependent while the high dose introduced an additional deficit at short delays that was sensitive to both SR141716A and the GABA(B) receptor antagonist, phaclofen. Comparison of lesion vs. cannabinoid effects on DNMS performance suggests that CB1 receptors on hippocampal neurons interfere with the processing of DNMS task-specific information within a trial. CB1 receptors on hippocampal GABAergic interneurons and in retrohippocampal areas appear to influence the ability to maintain segregation of information between trials in the task.