Non-competitive metabotropic glutamate 1 receptor antagonists block activity of slowly adapting type I mechanoreceptor units in the rat sinus hair follicle.

Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechanotransduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (YM-298198) had an IC(50) of 8.7 muM (95% CI 5.7 to 13.2 microM), representing the most potent known blocker of type I mechanoreceptors. The derivative 6-amino-N-cyclohexyl-3-methylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (desmethyl YM-298198) had a comparable potency. Another compound 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) had a similar depressant effect, although it was less potent with an approximate IC(50) of 100 microM. Between three and seven times the concentration of CPCCOEt and YM-298198 respectively was required to produce similar depressions in slowly adapting type II units. No depression, and some weak excitatory effects, were observed using the following ligands: the competitive mGlu1 receptor antagonist alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) (300 microM), the phosphoserine phosphatase inhibitor dl-2-amino-3-phosphonopropionic acid (dl-AP3) (2 mM), non-competitive mGlu5 receptor antagonists 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine (MTEP) (10 microM) and 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) (100 microM), the mGlu1 receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) (500 microM), and the mGlu5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) (1 mM). The results suggest that the non-competitive mGlu1 receptor antagonists are not acting at conventional mGlu1 receptors but at other binding sites, possibly those directly associated with mechanogated channels or on any of a number of indirect biochemical pathways. YM-298198 and related compounds may prove to be useful ligands to identify mechanosensitive channel proteins. The selective interference of type I units may provide further evidence that Merkel cells are mechanotransducers. Finally such compounds may deliver insights or treatments for Merkel cell carcinoma.

A pharmacological study of slowly adapting mechanoreceptors responsive to cold thermal stimulation.

Weber's silver Thaler illusion is the perception that cold objects appear heavier than warm objects. We were interested in studying the pharmacology of mechanoreceptor units that displayed increased spontaneous firing to cold stimuli. An isolated rat sinus hair preparation with intact nerve terminals was used to record the activity of two types of slowly adapting mechanoreceptors (St I and St II) during temperature ramps (0.91-1.73 degrees C/min) from normal bath temperature of 31+/-2 degrees C, cold to 14.5 degrees C and heat to 46 degrees C. Twenty-seven of the 43 mechanoreceptor units displayed marked increases in their spontaneous firing to cold or cooling thermal gradients, and were classified as cold mechanoreceptors. A high proportion (3:1) of St II units were responsive to cold than not, while the ratio was reversed for St I units (1:2). Most cold mechanoreceptor units showed decreases in mechanical responses to cold thermal gradients. Similar to specific cold thermoreceptors, many of the cold mechanoreceptor units briefly displayed increased spontaneous firing at higher (>41 degrees C) temperatures. The spontaneous firing of cold mechanoreceptor units was increased by the transient receptor potential (TRP) channel agonist icilin (30-100 microM) in a dose-dependent manner. Responses to mechanical stimulation were generally unaffected by icilin in these units, although their evoked response latencies were significantly reduced (similar to the effect of K+ channel blocker tetraethylammonium in St II units). TRPM8 channel agonist, (-) menthol 200 microM, had mixed effects on spontaneous firing but consistently enhanced cold responses. Other TRP agonists, cinnamaldehyde 1-2 mM and camphor 0.5-2 microM, reduced spontaneous and evoked responses. TRPA1 agonist allyl isothiocyanate (mustard oil) 50-100 microM and TRPV1 agonist capsaicin 1-3 microM had no effect. A broad spectrum TRP antagonist, Ruthenium Red 30 microM, had no effect. The TRPM8 antagonist, capsazepine 100-200 microM, blocked cold-evoked responses. Although these data generally provide support for the possibility that cooling responses are mediated by TRPM8 channels, the detailed profile of results suggests that another, as yet unidentified TRP channel, is involved. Multiplex coding of mechanical and thermal information by slowly adapting mechanoreceptors may play a functional role in thermal perception, and may explain Weber's silver Thaler illusion.

Group II metabotropic glutamate receptors reduce excitatory but not inhibitory neurotransmission in rat barrel cortex in vivo.

Group II metabotropic (mGlu) receptors are known to play an important role in regulating the release of excitatory transmitter in a number of brain areas. Previous experiments demonstrated that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) depressed excitatory transmission in the adult rat barrel cortex. Here we show, using in vivo extracellular single unit recordings and iontophoretic application of drugs, that selective activation of Group II mGlu receptors depresses excitatory but not inhibitory transmission. The selective Group II receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) had similar depressant effects to 1S,3R-ACPD on tactile evoked responses of rapidly adapting neurons. The depressant effects were seen on shorter latency (<12 ms) responses, were most pronounced in layers 3-4 (and 5b for 2R,4R-APDC only), and were reversibly antagonized by the Group II receptor antagonist (2S)-alpha-ethylglutamic acid (EGLU) relative to depressions produced by iontophoretic GABA. Where 1S,3R-ACPD and 2R,4R-APDC depressed excitatory transmission, there was little or no effect on postsynaptic excitations produced by iontophoretic AMPA--a result that supports a presynaptic location of Group II receptors on excitatory terminals. To assess the possible involvement of Group II mGlu receptors in the modulation of inhibition, we studied the effect of iontophoretic 1S,3R-ACPD in a condition-test protocol. The results contrasted markedly from those previously observed using the Group III agonist L(+)-2-amino-4-phosphonobutyric acid in that activation of Group II receptors using 1S,3R-ACPD did not modulate inhibition. Therefore our results show that Group II mGlu receptors play an important role in modulating excitatory, but not inhibitory, transmission. We propose that the Group II mGlu receptors are located on excitatory terminals, and act as autoreceptors. Their role appears to be important in the early stages of cortical processing, by keeping excitatory inputs within specified physiological limits, and possibly by mediating depression evidenced during synaptic plasticity.

Are unconventional NMDA receptors involved in slowly adapting type I mechanoreceptor responses?

Specific immunohistochemical staining for NMDA receptor NR2A/B subunits was found in the outer root sheath layer of rat sinus hair (whisker) follicle. Co-localization with CK 20 confirmed that Merkel cells were stained. The NR2A/B staining seen on Merkel cells was pericellular. In addition it appeared that NF70-positive staining was in close proximity to, but did not colocalise with NR2A/B immunoreactivity, indicating that NR2A/B was only expressed by Merkel cells and not their adjacent nerve terminals. Merkel cells and the nerve terminals have previously been associated with electrophysiological recordings from slowly adapting type I (St I) mechanoreceptor unit activity. Pharmacological experiments with isolated sinus hairs using a wide range of ionotropic glutamate receptor antagonists found that only certain NMDA receptor blockers depressed St I unit responses to mechanical stimuli. AMPA/kainate receptor antagonists (CNQX and NBQX, 100 microM) had no effect, nor did classical competitive NMDA receptor antagonists, D-AP5 (600 microM) and R-CPP (100 microM), nor the NMDA glycine site antagonist 5,7-dichlorokynurenic acid (100 microM). The only effective NMDA receptor blockers were those selective for the polyamine site: ifenprodil (IC50 20 microM) and Ro 25-6981 (IC50 approximately 50 microM), and the associated ion channel: MK 801, ketamine and (+/-)-1-(1,2-diphenylethyl)piperidine (IC50 < 100 microM). The two enantiomers of MK 801 were equipotent. All effects were long lasting, consistent with their non-/uncompetitive actions. The most potent drug tested, ifenprodil, at an effective dose of 30 microM, had a mean recovery time of 74 min. A three-fold increase in drug concentration was required to depress St II units (associated with non-synaptic lanceolate endings). Changes in Zn2+ did not affect St I unit responses. These data suggest that unconventional NMDA receptors are involved in St I unit responses, but question the notion of a glutamatergic synapse between the Merkel cell and nerve terminal.

Evidence for glutamate receptor mediated transmission at mechanoreceptors in the skin.

The functional role of Merkel cells in the mechanosensitivity of the slowly adapting type I responses has been a controversial issue for many years. Here we show, for the first time, that glutamate receptor-mediated transmission is largely responsible for the static component of the slowly adapting type I response. An isolated sinus hair preparation was used to study the two types (I and II) of slowly adapting units. A broad spectrum ionotropic glutamate receptor antagonist kynurenate (1-10 mM) caused reliable and dose-dependent reductions in the static component of type I unit responses to mechanical stimulation. In addition, an amino acid transmitter candidate aspartate applied to the preparation selectively increased responses in type I units but not responses in type II units. This evidence establishes that the Merkel cell is a mechano-electric transducer, and challenges prevailing views that the Merkel cell acts merely as a support or target cell in the epidermis.

Right-sided asymmetry in sensitivity to tickle.

A standard tickle apparatus was used to apply stimuli to the soles of left and right feet of subjects. Subject ratings of the strength of the tickle sensation felt after each stimulus revealed that the right foot was significantly more sensitive than the left. This effect was independent of both hand and foot preference. The results are discussed in relation to other findings on lateralisation, and it is suggested that they are consistent with evidence that the left hemisphere is more involved in positive emotions.

Electrophysiological evidence against a neurotransmitter role of corticotropin-releasing hormone (CRH) in primary somatosensory cortex.

The possible neurotransmitter role of corticotropin-releasing hormone (CRH) was studied in the primary somatosensory cortex of the rat. Electrical activity of single neurones was recorded in layers II-VI of cortex, and in the region of the locus coeruleus. Iontophoresis and pressure ejection were employed to locally apply CRH, and changes in spontaneous, synaptically driven and iontophoretically driven firing were examined. In the cortex, of 62 neurones recorded most (51) were completely unaffected by high and prolonged current/pressure ejections of CRH. Depression of firing was occasionally seen (8 of 62), while a very few (3) were weakly excited. Of 25 cells studied with vibrissal stimulation to evoke excitatory synaptic responses, responses in two cells were depressed and in two they were enhanced. Activity that was evoked by iontophoretic ejection of excitatory amino acids, such as glutamate, was depressed in 6 of 40 cells (none were enhanced). Such effects as were seen were weak and often difficult to reproduce. The effect of CRH on depressions produced by GABA was also tested in four experiments. No effects on the amplitude or duration of the depressions were observed. In contrast recordings made in the midbrain, in the region of the locus coeruleus, resulted in over half the neurones (11 of 20) showing clear reproducible excitatory responses to CRH applications. Solutions used in the experiments were analysed using chromatography, radioimmunoassay and bioassay, and no significant degradation of the peptide was found compared with the synthetic standard (CRH (1-41)). The data provide evidence against CRH acting as a neurotransmitter or modulator in primary cortex, suggesting that the CRH which is localized in certain types of cortical cells is involved in other processes.

Differential effect of whisker trimming on excitatory and inhibitory transmission in primary somatosensory cortex of the adult rat in vivo.

The effects of sensory deprivation on excitatory and inhibitory activity in the primary somatosensory cortex were studied in the adult rat. Excitatory and inhibitory transmission generated by whisker stimulation, and neuronal responsiveness to iontophoretically applied excitatory amino acids were recorded. Whisker input deprivation, through whisker trimming for a median of 24 days, resulted in a significant decrease in excitatory transmission to surround whisker stimulation. In contrast, the response magnitude to principal whisker stimulation remained unchanged. However, the response latencies to principal whisker and surround whisker stimulation were significantly reduced, which led to altered temporal response distributions in deprived cells. Neurons deprived of sensory input were significantly less responsive to glutamate, N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate and kainate. Following deprivation, no change was observed in cortical inhibitory transmission measured 30-200 ms post-stimulus. These results show that excitatory transmission (including excitatory amino acid receptor function) is altered by adult whisker deprivation.

A pharmacological study of the modulation of neuronal and behavioural nociceptive responses in the rat trigeminal region.

Electrical stimulation of the brain, particularly in the periventricular grey areas, caused long-lasting increases in behavioural escape thresholds to heating and mechanical stimuli applied to the facial region of the rat. The brain stimulation selectively suppressed responses to noxious stimuli. Responses to non-noxious stimuli, evoked by low threshold brush, were unaffected. The same animals that were studied in the behavioural tests were then anaesthetized with urethane and the inhibitory effect of the same brain stimulation was studied in single neurones recorded in the caudal trigeminal nucleus. A clear correlation (rs = 0.63) emerged between degree of behavioural antinociception and the amount of inhibition seen in nociceptive neurones. In addition the mean duration of the inhibition (6 min) was similar to the mean duration of the antinociceptive effect (7.3 min). Other classes of non-nociceptive neurones were unaffected by the stimulation. The neurones were also studied using iontophoretically applied monoamine candidates for the inhibitory neurotransmitter noradrenaline (NA) and 5-hydroxytryptamine (5-HT). The profile of the effects of NA most closely fitted that of the inhibitory neurotransmitter. This profile was expressed in terms of depression and excitation of different classes of neurones, and by the duration of effects. The depressants effects could be antagonized by iontophoretic idazoxan. In addition clonidine induced long-lasting depression of firing. 5-HT was more likely than NA to excite nociceptive neurones and to depress non-nociceptive neurons. Only NA consistently elevated thermal response thresholds in a similar manner to that produced by brain stimulation. These results provide some support for the hypothesis that selective descending inhibition of nociceptive responses in neurones of the rat caudal trigeminal nucleus is mediated by NA, possibly by an action at alpha2-adrenoceptors.

The effects of L-AP4 and L-serine-O-phosphate on inhibition in primary somatosensory cortex of the adult rat in vivo.

The effects of two iontophoretically applied Group III mGluR agonists were studied on the inhibition in neocortex produced by natural stimulation of vibrissae. The agonists L-AP4 and L-serine-O-phosphate (L-SOP) were shown to produce qualitatively similar effects on the inhibition. Forty-four percent of neurones (total n = 57) displayed disinhibition during application of the agonists. The disinhibitory effects often outlasted the offset of the agonist application by at least 10 min. Concurrent application of the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG) appeared to reverse the disinhibitory effects of L-AP4 and L-SOP in 3 out of 5 neurones tested. However (+)-MCPG itself was found to have disinhibitory effects in some neurones. Some neurones (n = 7) showed increases in inhibition during either L-AP4 or L-SOP application. These appeared most pronounced in those neurones where the initial (pre-drug) inhibition was minimal, perhaps suggesting that the agonists were disinhibiting a local disinhibition. The data obtained in the experiments suggest that the disinhibitory effects are mediated by a heteroreceptor on inhibitory terminals, action at which depresses the release of inhibitory transmitter. The possible role of the modulation of inhibition by presynaptic mGluRs is discussed.

Synaptic plasticity induced in single neurones of the primary somatosensory cortex in vivo.

Experiments carried out in urethane-anaesthetized rats in which single neurones were recorded extracellularly from primary somatosensory (SI) cortex employed a procedure in which one of two vibrissal inputs was temporally paired with iontophoretic applications of glutamate. Following the pairing procedure. 31% of 49 neurones studied displayed some form of synaptic plasticity, in that responses to one or both vibrissal stimuli were altered. Homosynaptic potentiation occurred in 4 neurones, and these were recorded in layers II/III only. Homosynaptic depression occurred in 6 neurones and were mainly recorded in layer IV. Heterosynaptic depression was observed in 3 neurones. Non-selective depression was observed in 2 neurones. The duration of the induced plastic changes typically exceeded 15 min, and often lasted as long as stable recordings continued. The results from experiments in which repeated glutamate applications were given alone (without synaptic input) confirmed that the non-selective changes were due to repeated glutamate applications and not the temporal pairing with synaptic responses per se. Dual recordings confirmed that plasticity was restricted to the neurone at which pairings were made, and (at the other neurone) that synaptic responses remained stable over the course of study. In some neurones homosynaptic potentiation and depression were shown to occur to the early response component (< 10 ms), suggesting that direct thalamocortical synapses are modifiable.

Cortical layer-specific effects of the metabotropic glutamate receptor agonist 1S,3R-ACPD in rat primary somatosensory cortex in vivo.

The effects of iontophoretically applied (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a metabotropic glutamate receptor (mGluR) agonist, were studied on extracellularly recorded neurons throughout the depth of the primary somatosensory cortex in the anaesthetized adult rat. Distinct excitatory effects were found almost exclusively in neurons recorded in layer V. Postsynaptic depressant effects dominated neurons recorded in layers I-IV. In layer VI, neurons were equally divided as to excitation and depression. Both the excitatory and postsynaptic depressant effects could be antagonized by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG). Experiments using bicuculline and several lines of analysis suggested that the postsynaptic depressant effects were mediated directly, rather than through disfacilitation. In a proportion of neurons 1S,3R-ACPD selectively depressed synaptically evoked responses (produced by vibrissa deflections), with little or no effect on the postsynaptic level of firing. Comparing the depressant effects of 1S,3R-ACPD with those of GABA supported a presynaptic mGluR site. Responses to centre and surround receptive field stimulation were depressed to the same extent, suggesting that thalamocortical and intracortical axon terminals are equally endowed with presynaptic receptors. In contrast to previous studies, the actions of L-2-amino-4-phosphonobutyric acid (L-AP4) were shown to be qualitatively different to those of 1S,3R-ACPD, in particular suggesting that the presynaptic depression produced by 1S,3R-ACPD is not mediated by L-AP4-type receptors. The functional implications of different mGluR actions in the primary somatosensory cortex are discussed.

The effects of the metabotropic glutamate receptor agonist 1S,3R-ACPD on neurones in the rat primary somatosensory cortex in vivo.

The selective glutamate metabotropic receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) was applied iontophoretically to cells in the rat primary somatosensory cortex (SI) in vivo. In contrast to other in vivo studies, distinct excitatory and depressant effects were observed. The excitatory responses could not be blocked by ionotropic antagonists, as evidence that they were mediated by a metabotropic receptor. The depressant effects were most pronounced on natural synaptic transmission, suggesting that a presynaptic receptor may be involved, although responses to iontophoretically applied agonists were also affected. Comparison with the presumed presynaptic glutamate receptor agonist L-2-amino-4-phosphonobutyrate (L-AP4) suggest that the depressant effects of 1S,3R-ACPD could be partially mediated by a presynaptic autoreceptor.

Responses of single neurons in the hippocampus of the macaque related to recognition memory.

In order to analyse how hippocampal activity is related to memory, the activity of single hippocampal neurons was recorded while macaques performed a recognition memory task. In the task, the first time a stimulus was shown, no reward could be obtained, and the second time a visual stimulus was shown, the monkeys could lick to obtain fruit juice. Many other stimuli could intervene between the novel and familiar presentations of each stimulus. Of 660 neurons analysed, 15 (2.3%) responded differently to novel and to familiar stimuli, with the majority of these responding more to novel than to familiar stimuli. The latencies of the differential responses of the neurons were typically in the range 140-260 ms. The responses of these neurons reflected whether a visual stimulus had been seen recently, in that the neurons responded differently to novel and familiar presentations of a stimulus when a median of 21 other stimuli intervened between the novel and familiar presentations. The responses of these neurons were shown to be related to whether the stimuli had been seen before, not to the reinforcement or the lick responses made, in that the neurons did not have comparable responses in a visual discrimination task in which licks were made to a rewarding stimulus but not to another stimulus. It is concluded that the activity of a small but significant proportion of hippocampal neurons is related to whether a stimulus has been seen before recently, and that this processing is likely to be involved in memory.

Modification of the responses of hippocampal neurons in the monkey during the learning of a conditional spatial response task.

In order to analyze the function of the hippocampus in learning, the activity of single neurons was recorded while monkeys learned a task of the type known to be impaired by damage to the hippocampus. In the conditional response task, the monkey had to learn to make one response when one stimulus was shown, and a different response when a different stimulus was shown. It had previously been shown that there are neurons in the hippocampal formation that respond in this task, to, for example, a combination of a particular visual stimulus that had been associated in previous learning with a particular behavioral response. In the present study, it was found that during such conditional response learning, the activity of 22% of the neurons in the hippocampus and parahippocampal gyrus with activity specifically related to the task altered their responses so that their activity, which was initially equal to the two new stimuli, became progressively differential to the two stimuli when the monkey learned to make different responses to the two stimuli. These changes occurred for different neurons just before, at, or just after the time when the monkey learned the correct response to make to the stimuli. In addition to these neurons, which had differential responses that were sustained for as long as the recordings continued, another population of neurons (45% of those with activity specifically related to the task) developed differential activity to the two new stimuli, yet showed such differential responses transiently for only a small number of trials at about the time when the monkey learned. These findings are consistent with the hypothesis that some synapses on hippocampal neurons modify during this type of learning so that some neurons come to respond to particular stimulus-response associations that are being learned. Further, the finding that many hippocampal neurons started to reflect the new learning, but then stopped responding differentially (the transient neurons), is consistent with the hypothesis that the hippocampal neurons with large sustained changes in their activity inhibited the transient neurons, which then underwent reverse learning, thus providing a competitive mechanism by which not all neurons are allocated to any one learned association or event.

Potentiation of neuronal responses to natural visual input paired with postsynaptic activation in the hippocampus of the awake monkey.

Extracellular recordings were made in the hippocampal formation while the monkey performed a simple visual discrimination task in which the stimuli consisted of coloured patterns presented serially. By using this natural visual input to single hippocampal neurones, and experimentally pairing one of the stimuli with postsynaptic excitation induced by iontophoretically applied L-glutamate, we demonstrate that selective synaptic potentiation can result. Seven of 29 neurones tested showed potentiation. The potentiation was selective in that enhanced responses only occurred to the previously paired stimulus, and not to other visual stimuli. The potentiation was observed in CA3 neurones and lasted approximately 15 min. In each case the latency of the potentiated response occurred at 160 ms following the onset time of the stimulus.

Sensory responses of caudal trigeminal neurons to thermal and mechanical stimuli and their behavioural correlates in the rat.

Behavioural experiments in the freely moving rat were carried out to determine thermal and mechanical nociceptive thresholds to ramp stimuli applied to the face. The mean thermal escape threshold was 43.5 degrees C, and the mean mechanical escape threshold was 179.2 g/mm2. In a parallel set of experiments recordings were made from single neurons in the caudal trigeminal nucleus of the anaesthetized rat. Neurons were classified according to their responses to a range of thermal and mechanical stimuli applied to the face. Three classes of neuron responded exclusively to mechanical stimuli and four classes responded to thermal stimuli (usually in addition to responding to mechanical stimuli). The mean thermal threshold of neurons responsive to warming stimulation was 44.4 degrees C. Neurons responsive to innocuous warming were located in deeper laminae. Many of the neurons responsive to noxious heat appeared to show an exponential relation between temperature and firing rate. An argument is made for a direct role of exponentially responding neurons in thermal nociception. The distribution of all neuronal response thresholds was left-skewed compared with a normal distribution, whereas the behavioural escape thresholds approximated a normal distribution.

Responses of hippocampal formation neurons in the monkey related to delayed spatial response and object-place memory tasks.

The memory for where in the environment a particular visual stimulus has been seen is one of the types of memory relatively specifically impaired by hippocampal damage in primates including man. In order to investigate what processing might be performed by the hippocampus related to this type of memory, the activity of hippocampal neurons was recorded while monkeys performed an object-place memory task. In this task, the monkey was shown a sample stimulus in one position on a video screen, there was a delay of 2 s, and then the same or a different stimulus was shown in the same or in a different position. The monkey remembered the sample and its position, and if both matched the delayed stimulus, he licked to obtain fruit juice. Of the 600 neurons analysed in this task, 3.8% responded differently for the different spatial positions, with some of these responding differentially during the sample presentation, some in the delay period, and some in the match period. Thus some hippocampal neurons respond differently for stimuli shown in different positions in space, and some respond differently when the monkey is remembering different positions in space. In addition some of the neurons responded to a combination of object and place information, in that they responded only to a novel object in a particular place. These neuronal responses were not due to any response being made or prepared by the monkey, for information about which behavioral response was required was not available until the match stimulus was shown. This is the first demonstration that some hippocampal neurons in the primate have activity related to the spatial position of stimuli. The activity of these neurons was also measured in a delayed spatial response task, in which the monkey was shown a stimulus in one position, and, after a 2 s delay when two identical stimuli were shown, had to reach to touch the stimulus which was in the position in which it had previously been seen. It was found that the majority of the neurons which responded in the object-place memory task did not respond in the delayed response task. Instead, a different population of neurons (5.7% of the total) responded in the delayed spatial response task, with differential left-right responses in the sample, delay, or match periods.(ABSTRACT TRUNCATED AT 400 WORDS)

Hippocampal neurons in the monkey with activity related to the place in which a stimulus is shown.

In order to analyze the functions of the hippocampus in the primate, and to advance the understanding of amnesia, the activity of 994 single hippocampal neurons in the monkey was analyzed during the performance of a task known to be affected by hippocampal damage in which both an object, and its position in space, must be remembered. The serial multiple object-place memory task required a memory for the position on a video monitor in which a given object had appeared previously. It was found that 9.3% of neurons recorded in the hippocampus and hippocampal gyrus had spatial fields in this and related tasks, in that they responded whenever there was a stimulus in some but not in other positions on the screen. We found that 2.4% of the neurons responded to a combination of spatial information and information about the object seen, in that they responded more the first time a particular object was seen in any position. Six of these neurons were found that showed this combination even more clearly, in that, for example, they responded only to some positions and only if it was the first time that a particular stimulus had appeared there. It is concluded that there are neurons in the primate hippocampus which (1) respond to position in space and (2) in some cases combine information about stimuli and their position in space, responding to a stimulus only the first time it is seen in a position in space, for example. Thus, not only is spatial information processed by the primate hippocampus, but it can be combined with information about which stimuli have been seen before. The ability of the hippocampus to form such conjunctions may be an important property for its role in memory.

Activity of hippocampal formation neurons in the monkey related to a conditional spatial response task.

To analyze neurophysiologically the functions of the primate hippocampus, the activity of 905 single hippocampal formation neurons was analyzed in two rhesus monkeys performing a conditional spatial response task known to be impaired in monkeys and in man by damage to the hippocampus or fornix. In the task, the monkey learned to make one spatial response, touching a screen three times when he saw one visual stimulus on the video monitor, and a different spatial response, of withdrawing his hand from the screen, when a different visual stimulus was shown. Fourteen percent of the neurons fired differentially to one or the other of the stimulus-spatial response associations. The mean latency of these differential responses was 154 +/- 44 (SD) ms. The firing of these neurons was shown to reflect a combination of the particular stimulus and the particular response associated by learning in the stimulus-response association task and could not be accounted for by the motor requirements of the task, nor wholly the stimulus aspects of the task, as demonstrated by testing their firing in related visual discrimination tasks. Responsive neurons were found throughout the hippocampal formation, but were particularly concentrated in the subicular complex and the CA3 subfield. These results show that single hippocampal neurons respond to combinations of the visual stimuli and the spatial responses with which they must become associated in conditional spatial response tasks and are consistent with the suggestion that part of the mechanism of this learning involves associations between visual stimuli and spatial responses learned by single hippocampal neurons.