Biomedical subjects

Robert E Hampson

Publications and source records attributed to Robert E Hampson.

12 recordsLinked to original sources

PubMed2006

Temporal coupling between subicular and hippocampal neurons underlies retention of trial-specific events.

The subiculum receives the majority of efferent outflow of neural information from the CA1 region of the hippocampus. As such it occupies a strategic position in which to integrate, transfer and resolve activity from the hippocampus relating to memory and performance. We have previously demonstrated that each structure has complementary ensemble firing patterns that together allow information to be represented continuously over the time course of a trial in a delayed-non-match-to-sample (DNMS) task. Here, we extend this analysis to show the precise manner in which specific neurons in both structures are coupled temporally across the delay interval on a single trial. Neurons in both structures encode position-specific information related to the sample lever press, but only subicular neurons continue to fire during the early portion of the subsequent variable delay interval. However, cross-correlation analysis of multiple spike trains showed that as the delay increased in duration other subicular neurons were temporally coupled to the subicular neurons that fired in the initial part of the delay. This latter population of subicular neurons showed strong cross-correlated firing with other initially activated subicular neurons until midway through the delay (<15s), but on longer delay intervals were coupled to a specific type of hippocampal neuron whose firing was critical for correct performance. Subicular neurons, therefore, play a critical role in bringing the hippocampus "back online" when trial delays exceed the minimum duration thus allowing both structures to cooperatively bridge relevant information across longer time intervals than would not otherwise be possible.

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PubMed2005

Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates.

The deleterious effects of prolonged sleep deprivation on behavior and cognition are a concern in modern society. Persons at risk for impaired performance and health-related issues resulting from prolonged sleep loss would benefit from agents capable of reducing these detrimental effects at the time they are sleep deprived. Agents capable of improving cognition by enhancing brain activity under normal circumstances may also have the potential to reduce the harmful or unwanted effects of sleep deprivation. The significant prevalence of excitatory alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamatergic receptors in the brain provides a basis for implementing a class of drugs that could act to alter or remove the effects of sleep deprivation. The ampakine CX717 (Cortex Pharmaceuticals), a positive allosteric modulator of AMPA receptors, was tested for its ability to enhance performance of a cognitive, delayed match-to-sample task under normal circumstances in well-trained monkeys, as well as alleviate the detrimental effects of 30-36 h of sleep deprivation. CX717 produced a dose-dependent enhancement of task performance under normal alert testing conditions. Concomitant measures of regional cerebral metabolic rates for glucose (CMRglc) during the task, utilizing positron emission tomography, revealed increased activity in prefrontal cortex, dorsal striatum, and medial temporal lobe (including hippocampus) that was significantly enhanced over normal alert conditions following administration of CX717. A single night of sleep deprivation produced severe impairments in performance in the same monkeys, accompanied by significant alterations in task-related CMRglc in these same brain regions. However, CX717 administered to sleep-deprived monkeys produced a striking removal of the behavioral impairment and returned performance to above-normal levels even though animals were sleep deprived. Consistent with this recovery, CMRglc in all but one brain region affected by sleep deprivation was also returned to the normal alert pattern by the drug. The ampakine CX717, in addition to enhancing cognitive performance under normal alert conditions, also proved effective in alleviating impairment of performance due to sleep deprivation. Therefore, the ability to activate specific brain regions under normal alert conditions and alter the deleterious effects of sleep deprivation on activity in those same regions indicate a potential role for ampakines in sustaining performance under these types of adverse conditions.

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PubMed2005

Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodine-sensitive stores.

Exogenously administered cannabinoids are neuroprotective in several different cellular and animal models. In the current study, two cannabinoid CB1 receptor ligands (WIN 55,212-2, CP 55,940) markedly reduced hippocampal cell death, in a time-dependent manner, in cultured neurons subjected to high levels of NMDA (15 microM). WIN 55,212-2 was also shown to inhibit the NMDA-induced increase in intracellular calcium concentration ([Ca2+](i)) indicated by FURA-2 fluorescence imaging in the same cultured neurons. Changes in [Ca2+](i) occurred with similar concentrations (25-100 nM) and in the same time-dependent manner (pre-exposure 1-15 min) as CB1 receptor mediated neuroprotective actions. Both effects were blocked by the CB1 receptor antagonist SR141716A. An underlying mechanism was indicated by the fact that (1) the NMDA-induced increase in [Ca2+](i) was inhibited by ryanodine, implicating a ryanodine receptor (RyR) coupled intracellular calcium channel, and (2) the cannabinoid influence involved a reduction in cAMP cAMP-dependent protein kinase (PKA) dependent phosphorylation of the same RyR levels that regulate channel. Moreover the time course of CB1 receptor mediated inhibition of PKA phosphorylation was directly related to effective pre-exposure intervals for cannabinoid neuroprotection. Control studies ruled out the involvement of inositol-trisphosphate (IP3) pathways, enhanced calcium reuptake and voltage sensitive calcium channels in the neuroprotective process. The results suggest that cannabinoids prevent cell death by initiating a time and dose dependent inhibition of adenylyl cyclase, that outlasts direct action at the CB1 receptor and is capable of reducing [Ca2+](i) via a cAMP/PKA-dependent process during the neurotoxic event.

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PubMed2004

Differential but complementary mnemonic functions of the hippocampus and subiculum.

In this study we describe how the hippocampus and subiculum act in concert to encode information in a spatial delayed-nonmatch-to-sample (DNMS) task. This encoding was functionally partitioned between neurons within subiculum and hippocampus to uniquely identify trial-specific information accounting for both spatial and temporal constraints on performance within and between trials. Encoding by subicular neurons in the task was normally accurate and specific, but only if delays were shorter than 15 s, whereas trial-specific information encoded by hippocampal neurons was subject to strong biases from prior trial sequences and was accessible only when delays exceeded 15 s. The two structures operated in a complementary manner to encode information correctly on 75% of all trials using the above strategies. The remaining 25% of trials were at risk due to inherent idiosyncrasies by which hippocampal and subicular neurons encoded information and became errors when the random sequence of trials conflicted with these constraints.

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PubMed2004

Categorization in the monkey hippocampus: a possible mechanism for encoding information into memory.

The mammalian hippocampus processes sensory information into memory. The neurobiological basis of this representation, as well as the type of information that is encoded, is central to understanding how memories are formed. Normally, there is an infinite amount of information that could be encoded for any given stimulus. Thus, the question arises as to how the hippocampus selects and encodes features of a given stimulus. Here, we show that neurons in the hippocampus of the monkey appear to categorize types of visual stimuli presented in a delayed-match-to-sample memory task. By extracting unique combinations of features, these category cells are able to encode aspects of behaviorally important images instead of encoding all visual details. The subject is then able to rapidly select an appropriate response to that stimulus when distracting stimuli are presented simultaneously, thereby facilitating performance. Moreover, across animals, this specific type of encoding differed considerably. Just as in humans, different monkeys attended to and selected different aspects of the same stimulus image, most likely reflecting different histories, strategies, and expectations residing within individual hippocampal networks.

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PubMed2004

Reward, memory and substance abuse: functional neuronal circuits in the nucleus accumbens.

The firing patterns of neurons in the nucleus accumbens (NA) are examined and discussed with respect to different types of rewards and reward conditions. Comparisons and contrasts between individually identified NA neuron responses to cocaine self-administration and water reinforcement are presented with an emphasis on the fact that the same neurons do not respond in a phasic manner to both types of rewards. However, the phasic firing patterns, even though segregated for each reinforcer, are quite similar, suggesting that the method of differentiation between rewarding stimuli in the NA is by sorting cell populations into distinct ensembles or networks for each type of reinforcer. These neural networks appear to be 'tuned' to respond to particular associative behavioral contexts that couple response execution to reward delivery, and in the process acquire a reciprocity to firing within reward contexts. This maintains the specificity of each reinforcer for the response and associated stimuli that produce it and, makes it possible to attach different NA networks to different reinforcing circumstances. Comparisons of cocaine and water reinforced NA cell firing patterns during rapid switching between these two reinforcers suggests that the networks are negatively coupled and mutually inhibit each other to maintain accurate encoding of immediately experienced, as well as expected (i.e. future) reward contingencies.

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PubMed2004

Methylmercury stimulates arachidonic acid release and cytosolic phospholipase A2 expression in primary neuronal cultures.

Cytosolic phospholipase A2 (cPLA2) plays an important role in the stimulus-dependent hydrolysis of sn-2 ester bond from membrane phospholipids, releasing arachidonic acid (AA), which along with its metabolites is involved in a number of regulatory functions. The present study examined the effect of methylmercury (MeHg; 0, 2.5, 5.0 microM) on cPLA2 activation in primary hippocampal neurons by assessing the release of 3H-AA. A significant increase in AA release was observed in cultures treated with 5 microM MeHg (10, 30, 60 and 120 min). This effect was due to neuronal cPLA2 activation, since it was completely abolished by arachidonyl trifluoromethyl ketone (AACOCF3), a specific inhibitor of cPLA2. Additional studies confirmed, by means of western blot analysis, that MeHg (5.0 and 10 microM; 16h) potently increases neuronal cPLA2 protein expression. These results suggest that cPLA2-stimulated hydrolysis and release of AA are potential mediators of MeHg-induced neurotoxicity.

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PubMed2004

Cannabinoid physiology and pharmacology: 30 years of progress.

Delta9-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB1 in the brain, and CB2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the "endocannabinoid" agonists for these receptors. CB1 receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB1 receptors couple to G(i/o) to inhibit cAMP production, decrease Ca2+ conductance, increase K+ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPgammaS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca2+ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB1 receptors. This results in suppression of gamma-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB1, CB2 and related receptors. One very important role for CB1 antagonists will be in the treatment of craving in the disease of substance abuse.

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PubMed2003

Functional significance of cannabinoid-mediated, depolarization-induced suppression of inhibition (DSI) in the hippocampus.

A number of recent studies have demonstrated that a well-known form of short-term plasticity at hippocampal GABAergic synapses, called depolarization-induced suppression of inhibition (DSI), is in fact mediated by the retrograde actions of endocannabinoids released in response to depolarization of the postsynaptic cells. These studies suggest that endogenous cannabinoids may play an important role in regulating inhibitory tone in the mammalian CNS. Despite the widespread interest and potential physiological importance of DSI, many questions regarding the physiological relevance of DSI remain. To that end, this study set out to define the specific limiting conditions that could elicit DSI at GABAergic synapses in CA1 hippocampal pyramidal neurons and to determine if DSI could be elicited with pulse trains that mimic hippocampal cell-firing patterns that occur in vivo. Whole cell recordings from hippocampal neurons under voltage-clamp configuration were made in rat hippocampal slices. Spontaneous and evoked gamma-aminobutyric acid-A (GABAA) receptor-mediated inhibitory postsynaptic currents (sIPSCs and eIPSCs, respectively) were recorded prior to and following depolarization of CA1 hippocampal pyramidal cells. Depolarizing voltage pulses were shaped to evoke currents in QX-314-treated cells similar to those accompanying single spontaneous voltage-clamped action potentials recorded from the soma. Attempts were made to elicit DSI with trains of these pulses that mimicked hippocampal cell firing patterns in vivo, for instance, when animals traverse place fields or are performing a short-term memory task. DSI could not be elicited by such pulse trains or by a number of other combinations of behaviorally specific firing parameters. The minimum duration of depolarization necessary to elicit DSI in hippocampal neurons determined by paired-pulse manipulation was 50 -75 ms at a critical interval of 20 -30 ms between pulse pairs. Under the conditions tested, the normal firing patterns of hippocampal neurons that occur in vivo do not appear to elicit DSI.

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PubMed2003

Tolerance to the memory disruptive effects of cannabinoids involves adaptation by hippocampal neurons.

The effects of chronic exposure to cannabinoids on short-term memory in rats were assessed during repeated daily injections of an initially debilitating dose (3.75 mg/kg) of the potent CB1 cannabinoid receptor ligand, WIN 55,212-2. Delayed nonmatch to sample (DNMS) performance was assessed over a 35-day exposure period in which performance was initially disrupted during the first 21 days of exposure but recovered by day 30 and was stable at pre-drug levels for 5 days thereafter. Withdrawal was precipitated by injections of the CB1 receptor antagonist SR141716A and transiently reduced performance for 2 days but was restabilized to pre-drug levels within 3-4 days. Concomitant recording from identified CA1 and CA3 hippocampal neurons demonstrated a marked correspondence in the time course of suppression of peak firing in the sample and delay phases of the task to the drug-induced performance deficits over the same days of exposure. Hippocampal encoding of task-relevant events and performance levels "tracked" each other on a daily basis throughout the chronic cannabinoid treatment and withdrawal regimen. However, hippocampal neuronal activity in the nonmatch phase of the task was unaffected by the chronic cannabinoid treatment or withdrawal, suggesting that only a select population of hippocampal neurons and synapses are involved in cannabinoid-sensitive short-term memory processes.

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PubMed2003

Temporal firing characteristics and the strategic role of subicular neurons in short-term memory.

The role of subicular neurons is explored with respect to their participation in short-term memory during performance of a spatial Delayed-Nonmatch-to-Sample (DNMS) task by well-trained rats. Subicular and CA1 neuron firing was examined in the same animals in relation to the encoding of task-relevant events during the DNMS trial. The results indicate that subicular neurons have completely different firing signatures than well-characterized hippocampal neurons in this task. Firing patterns of subicular neurons consisted of five different categories spanning all three phases of the DNMS trial, but concentrated mostly within the Sample and early portion of the Delay period. Unlike hippocampal neurons, subicular cells did not exhibit conjunctive firing correlates with respect to particular combinations of task events; rather, subicular cell firing was differentiated primarily on the basis of temporal specificity within the trial. Only two of the five subicular cell types fired differentially on correct versus error trials; however, one cell type exhibited such differential firing as an inverse function of duration of delay interval. Experiments employing gamma-aminobutyric acid GABA(B) receptor agonists and antagonists showed that both behavioral performance as well as subicular cell firing were disrupted significantly by baclofen at short delays, while performance at long delays and hippocampal cell firing were relatively immune to this effect. The relevance of subicular cell firing in the task with respect to its temporal relation to delay-dependent hippocampal neuronal activity suggests that the structures have complementary roles in the encoding and representation of items in short-term memory.

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PubMed2002

"Keeping on track": firing of hippocampal neurons during delayed-nonmatch-to-sample performance.

Hippocampal neurons that encode critical events during a delayed-nonmatch-to-sample (DNMS) task were proposed to have functional topography as demonstrated by Hampson et al. (1999b). Functional cell types (FCTs) that encode similar task features were located within alternating transverse segments along the hippocampal longitudinal axis. On this basis, Redish et al. (2001) suggested that firing of populations of CA1 neurons recorded from the same hippocampal locations in animals running on linear or curvilinear tracks should be spatially and temporally correlated; however, they failed to find such correlations. The current study addresses the issues raised by Redish et al. (2001). Initially we found that modeling of simulated place fields revealed absences in temporal correlations in the study by Redish et al. (2001) that should have been present given the reported spatial correlations. In addition, the correlation methods used by those investigators failed to detect robust but transient event-related cross-correlations between FCTs in the DNMS task. Furthermore, demonstration of such transient, short-latency correlated firing between similar CA3 and CA1 FCTs corroborated the anatomic scheme proposed by Hampson et al. (1999b) and reaffirmed the potential existence of a functional topography within hippocampus.

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