Multimodal cortico-cortical associations induced by fear and sensory conditioning in the guinea pig.

Sensory cortices are defined by responses to physical stimulation in specific modalities. Recently, additional associatively induced responses have been reported for stimuli other than the main specific modality for each cortex in the human and mammalian brain. In this study, to investigate a type of consolidation, associative responses in the guinea pig cortices (auditory, visual, and somatosensory) were simultaneously measured using optical imaging after first- or second-order conditioning comprising foot shock as an aversive stimulus and tone and light as sensory stimuli. Our findings indicated that (1) after the first- and second-order conditioning, associative responses in each cortical area were additionally induced to stimulate the other specific modality; (2) an associative response to sensory conditioning with tone and light was also seen as a change in the response at the neuronal level without behavioral phenomena; and (3) when fear conditioning with light and foot shock was applied before sensory conditioning with tone and light, the associative response to foot shock in the primary visual cortex (V1) was decreased (extinction) compared with the response after the first-order fear conditioning, whereas the associative response was increased (facilitation) for fear conditioning after sensory conditioning. Our results suggest that various types of bottom-up information are consolidated as associative responses induced in the cortices, which are traced repetitively or alternatively by a change in plasticity involving facilitation and extinction in the cortical network. This information-combining process of cortical responses may play a crucial role in the dynamic linking of memory in the brain.

Physiological properties of Cantor coding-like iterated function system in the hippocampal CA1 network.

Cantor coding provides an information coding scheme for temporal sequences of events. In the hippocampal CA3-CA1 network, Cantor coding-like mechanism was observed in pyramidal neurons and the relationship between input pattern and recorded responses could be described as an iterated function system. However, detailed physiological properties of the system in CA1 remain unclear. Here, we performed a detailed analysis of the properties of the system related to the physiological basis of learning and memory. First, we investigated whether the system could be simply based on a series of on-off responses of excitatory postsynaptic potential (EPSP) amplitudes. We applied a series of three spatially distinct input patterns with similar EPSP peak amplitudes. The membrane responses showed significant differences in spatial clustering properties related to the iterated function system. These results suggest that existence of some factors, which do not simply depend on a series of on-off responses but on spatial patterns in the system. Second, to confirm whether the system is dependent on the interval of sequential input, we applied spatiotemporal sequential inputs at several intervals. The optimal interval was 30 ms, similar to the physiological input from CA3 to CA1. Third, we analyzed the inhibitory network dependency of the system. After GABAA receptor blocker (gabazine) application, quality of code discrimination in the system was lower under subthreshold conditions and higher under suprathreshold conditions. These results suggest that the inhibitory network increase the difference between the responses under sub- and suprathreshold conditions. In summary, Cantor coding-like iterated function system appears to be suitable for information expression in relation to learning and memory in CA1 network.

Comparison of Pattern Discrimination Mechanisms of Hebbian and Spatiotemporal Learning Rules in Self-Organization.

The spatiotemporal learning rule (STLR) proposed based on hippocampal neurophysiological experiments is essentially different from the Hebbian learning rule (HEBLR) in terms of the self-organization mechanism. The difference is the self-organization of information from the external world by firing (HEBLR) or not firing (STLR) output neurons. Here, we describe the differences of the self-organization mechanism between the two learning rules by simulating neural network models trained on relatively similar spatiotemporal context information. Comparing the weight distributions after training, the HEBLR shows a unimodal distribution near the training vector, whereas the STLR shows a multimodal distribution. We analyzed the shape of the weight distribution in response to temporal changes in contextual information and found that the HEBLR does not change the shape of the weight distribution for time-varying spatiotemporal contextual information, whereas the STLR is sensitive to slight differences in spatiotemporal contexts and produces a multimodal distribution. These results suggest a critical difference in the dynamic change of synaptic weight distributions between the HEBLR and STLR in contextual learning. They also capture the characteristics of the pattern completion in the HEBLR and the pattern discrimination in the STLR, which adequately explain the self-organization mechanism of contextual information learning.

Input integration around the dendritic branches in hippocampal dentate granule cells.

Recent studies have shown that the dendrites of several neurons are not simple translators but are crucial facilitators of excitatory postsynaptic potential (EPSP) propagation and summation of synaptic inputs to compensate for inherent voltage attenuation. Granule cells (GCs)are located at the gateway for valuable information arriving at the hippocampus from the entorhinal cortex. However, the underlying mechanisms of information integration along the dendrites of GCs in the hippocampus are still unclear. In this study, we investigated the input integration around dendritic branches of GCs in the rat hippocampus. We applied differential spatiotemporal stimulations to the dendrites using a high-speed glutamate-uncaging laser. Our results showed that when two sites close to and equidistant from a branching point were simultaneously stimulated, a nonlinear summation of EPSPs was observed at the soma. In addition, nonlinear summation (facilitation) depended on the stimulus location and was significantly blocked by the application of a voltage-dependent Ca(2+) channel antagonist. These findings suggest that the nonlinear summation of EPSPs around the dendritic branches of hippocampal GCs is a result of voltage-dependent Ca(2+) channel activation and may play a crucial role in the integration of input information.

Reward inference by primate prefrontal and striatal neurons.

The brain contains multiple yet distinct systems involved in reward prediction. To understand the nature of these processes, we recorded single-unit activity from the lateral prefrontal cortex (LPFC) and the striatum in monkeys performing a reward inference task using an asymmetric reward schedule. We found that neurons both in the LPFC and in the striatum predicted reward values for stimuli that had been previously well experienced with set reward quantities in the asymmetric reward task. Importantly, these LPFC neurons could predict the reward value of a stimulus using transitive inference even when the monkeys had not yet learned the stimulus-reward association directly; whereas these striatal neurons did not show such an ability. Nevertheless, because there were two set amounts of reward (large and small), the selected striatal neurons were able to exclusively infer the reward value (e.g., large) of one novel stimulus from a pair after directly experiencing the alternative stimulus with the other reward value (e.g., small). Our results suggest that although neurons that predict reward value for old stimuli in the LPFC could also do so for new stimuli via transitive inference, those in the striatum could only predict reward for new stimuli via exclusive inference. Moreover, the striatum showed more complex functions than was surmised previously for model-free learning.

Modulation of synaptic plasticity by the coactivation of spatially distinct synaptic inputs in rat hippocampal CA1 apical dendrites.

The phenomenon whereby the relative timing between presynaptic and postsynaptic spiking determines the direction and extent of synaptic changes in a critical temporal window is known as spike timing-dependent synaptic plasticity (STDP). We have previously reported that STDP profiles can be classified into two types depending on their layer-specific location along CA1 pyramidal neuron dendrites in the rat hippocampus, suggesting that there are differences in information processing between the proximal dendrite (PD) and distal dendrite (DD). However, how the different types of information processing interact at different dendritic locations remains unclear. To investigate how the temporal information of inputs to PD influences information processing at DD, PD stimulation was applied while the STDP protocol was simultaneously applied at DDs of CA1 pyramidal neurons. Synaptic plasticity induced by the STDP protocol at DDs was enhanced or depressed depending on the timing of the back-propagating action potentials (bAPs) and the excitatory and inhibitory postsynaptic potentials elicited by PD stimulation. These results suggested that bAPs function as carriers of temporal information of PD inputs to DD. Next, the influence of DD on PD was investigated using the same protocol. Synaptic plasticity at PD was modulated only if the pairing stimuli were applied to elicit coincidental timing of bAP and the excitatory postsynaptic potential. Such coding modulations could provide the basis for a novel learning rule and may be important factors in the integration of spatiotemporal input information in neural networks in the brain.

Fear conditioning induces guinea pig auditory cortex activation by foot shock alone.

The present study used an optical imaging paradigm to investigate plastic changes in the auditory cortex induced by fear conditioning, in which a sound (conditioned stimulus, CS) was paired with an electric foot-shock (unconditioned stimulus, US). We report that, after conditioning, auditory information could be retrieved on the basis of an electric foot-shock alone. Before conditioning, the auditory cortex showed no response to a foot-shock presented in the absence of sound. In contrast, after conditioning, the mere presentation of a foot-shock without any sound succeeded in eliciting activity in the auditory cortex. Additionally, the magnitude of the optical response in the auditory cortex correlated with variation in the electrocardiogram (correlation coefficient: -0.68). The area activated in the auditory cortex, in response to the electric foot-shock, statistically significantly had a larger cross-correlation value for tone response to the CS sound (12 kHz) compared to the non-CS sounds in normal conditioning group. These results suggest that integration of different sensory modalities in the auditory cortex was established by fear conditioning.

Context and the renewal of conditioned taste aversion: the role of rat dorsal hippocampus examined by electrolytic lesion.

An extinguished conditioned response can sometimes be restored. Previous research has shown that this renewal effect depends on the context in which conditioning versus extinction takes place. Here we provide evidence that the dorsal hippocampus is critically involved in the representation of context that underscores the renewal effect. We performed electrolytic lesions in dorsal hippocampus, before or after extinction, in a conditioned taste aversion paradigm with rats. Rats that underwent all conditioning, extinction and testing procedures in the same experimental context showed no renewal during testing in the original context. In contrast, rats that underwent extinction procedures in a different experimental context than the one in which they had acquired the conditioned response, showed a reliable renewal effect during testing in the original context. When electrolytic lesion was performed prior to extinction, the context-dependent renewal effect was disrupted. When electrolytic lesion was undertaken after extinction, we observed a complex pattern of data including the blockage of the conventional renewal effect, and the appearance of an unconventional renewal effect. The implications of these results are discussed with respect to current views on the role of the dorsal hippocampus in processing context information.

Optical imaging of plastic changes induced by fear conditioning in the auditory cortex.

The plastic changes in the auditory cortex induced by a fear conditioning, through pairing a sound (CS) with an electric foot-shock (US), were investigated using an optical recording method with voltage sensitive dye, RH795. In order to investigate the effects of association learning, optical signals in the auditory cortex in response to CS (12 kHz pure tone) and non-CS (4, 8, 16 kHz pure tone) were recorded before and after normal and sham conditioning. As a result, the response area to CS enlarged only in the conditioning group after the conditioning. Additionally, the rise time constant of the auditory response to CS significantly decreased and the relative peak value and the decay time constant of the auditory response to CS significantly increased after the conditioning. This study introduces an optical approach to the investigation of fear conditioning, representational plasticity, and the cholinergic system. The findings are synthesized in a model of the synaptic mechanisms that underlie cortical plasticity.

A mathematical model for Cantor coding in the hippocampus.

Recent studies suggest that the hippocampus is crucial for memory of sequentially organized information. Cantor coding in hippocampal CA1 is theoretically hypothesized to provide a scheme for encoding temporal sequences of events. Here, in order to investigate this Cantor coding in detail, we construct a CA1 network model consisting of conductance-based model neurons. It is assumed that CA3 outputs temporal sequences of spatial patterns to CA1. We examine the dependence of output patterns of CA1 neurons on input time series by taking each output and combining it with an input sequence. It is shown that the output patterns of CA1 were hierarchically clustered in a self-similar manner according to the similarity of input temporal sequences. The population dynamics of the network can be well approximated by a set of contractive affine transformations, which forms a Cantor set. Furthermore, it is shown that the performance of the encoding scheme sensitively depends on the interval of input sequences. The bursting neurons with NMDA synapses are effective for encoding sequential input with long (over 150 ms) intervals while the non-bursting neurons with AMPA synapses are effective for encoding input with short (less than 30 ms) intervals.

A context-sensitive mechanism in hippocampal CA1 networks.

This paper presents a possible context-sensitive mechanism in a neural network and at single neuron levels based on the experiments of hippocampal CA1 and their theoretical models. First, the spatiotemporal learning rule (STLR, non-Hebbian) and the Hebbian rule (HEBB) are experimentally shown to coexist in dendrite-soma interactions in single hippocampal pyramidal cells of CA1. Second, the functional differences between STLR and HEBB are theoretically shown in pattern separation and pattern completion. Third, the interaction between STLR and HEBB in neural levels is proposed to play an important role in forming a selective context determined by value information, which is related to expected reward and behavioral estimation.

Spatiotemporal characteristics of synaptic EPSP summation on the dendritic trees of hippocampal CA1 pyramidal neurons as revealed by laser uncaging stimulation.

Synaptic strength is modified by the temporal coincidence of synaptic inputs without back-propagating action potentials (BPAPs) in CA1 pyramidal neurons. In order to clarify the interactive mechanisms of associative long-term potentiation (LTP) without BPAPs, local paired stimuli were applied to the dendrites using high-speed laser uncaging stimulation equipment. When the spatial distance between the paired stimuli was <10 micrometer, nonlinear amplification in excitatory postsynaptic potential summation was observed. In the time window from -20 to 20 ms, supralinear amplification was observed. Supralinear amplification was modulated by antagonist of voltage-gated Na(+)/Ca(2+) channels and NMDA-type glutamate receptors. These results are closely related to the spatiotemporal-characteristics of associative LTP without BPAPs. This study proposes an essential aspect of dendritic information processing.

Prototypic seizure activity driven by mature hippocampal fast-spiking interneurons.

A variety of epileptic seizure models have shown that activation of glutamatergic pyramidal cells is usually required for rhythm generation and/or synchronization in hippocampal seizure-like oscillations in vitro. However, it still remains unclear whether GABAergic interneurons may be able to drive the seizure-like oscillations without glutamatergic transmission. Here, we found that electrical stimulation in rat hippocampal CA1 slices induced a putative prototype of seizure-like oscillations ("prototypic afterdischarge," 1.8-3.8 Hz) in mature pyramidal cells and interneurons in the presence of ionotropic glutamate receptor antagonists. The prototypic afterdischarge was abolished by GABA(A) receptor antagonists or gap junction blockers, but not by a metabotropic glutamate receptor antagonist or a GABA(B) receptor antagonist. Gramicidin-perforated patch-clamp and voltage-clamp recordings revealed that pyramidal cells were depolarized and frequently excited directly through excitatory GABAergic transmissions in each cycle of the prototypic afterdischarge. Interneurons that were actively spiking during the prototypic afterdischarge were mostly fast-spiking (FS) interneurons located in the strata oriens and pyramidale. Morphologically, these interneurons that might be "potential seizure drivers" included basket, chandelier, and bistratified cells. Furthermore, they received direct excitatory GABAergic input during the prototypic afterdischarge. The O-LM cells and most of the interneurons in the strata radiatum and lacunosum moleculare were not essential for the generation of prototypic afterdischarge. The GABA-mediated prototypic afterdischarge was observed later than the third postnatal week in the rat hippocampus. Our results suggest that an FS interneuron network alone can drive the prototypic form of electrically induced seizure-like oscillations through their excitatory GABAergic transmissions and presumably through gap junction-mediated communications.

Neural substrate of sound duration discrimination during an auditory sequence in the guinea pig primary auditory cortex.

Mismatch negativity (MMN) is a negative component of event-related brain potentials elicited by stimulus transitions. Stimulus duration transition also elicits MMN (duration MMN), with a magnitude that is related to the degree of duration change and the discrimination ability. The neural substrates of duration MMN have not yet been investigated. We therefore studied how duration transitions in an auditory stimulus train are represented in neurons in the primary auditory cortex of anesthetized guinea pigs. Two types of neuronal responses to the context of changes in stimulus duration were found. One was a reduced response as the duration of the preceding stimulus was increased. Second was an enhancement of the late components of the response including sustained and offset responses at the duration transition. The former may be explained by the previously proposed two-tone suppression, which is dependent on the preceding stimulus duration. The latter is likely to be caused by stimulus-specific adaptation that could be a possible neural generator of duration MMN.

Iterated function systems in the hippocampal CA1.

How does the information of spatiotemporal sequence stemming from the hippocampal CA3 area affect the postsynaptic membrane potentials of the hippocampal CA1 neurons? In a recent study, we observed hierarchical clusters of the distribution of membrane potentials of CA1 neurons, arranged according to the history of input sequences (Fukushima et al Cogn Neurodyn 1(4):305-316, 2007). In the present paper, we deal with the dynamical mechanism generating such a hierarchical distribution. The recording data were investigated using return map analysis. We also deal with a collective behavior at population level, using a reconstructed multi-cell recording data set. At both individual cell and population levels, a return map of the response sequence of CA1 pyramidal cells was well approximated by a set of contractive affine transformations, where the transformations represent self-organized rules by which the input pattern sequences are encoded. These findings provide direct evidence that the information of temporal sequences generated in CA3 can be self-similarly represented in the membrane potentials of CA1 pyramidal cells.

A code for spatial alternation during fixation in rat hippocampal CA1 neurons.

The classical notion of hippocampal CA1 "place cells," whose activity tracks physical locations, has undergone substantial revision in recent years. Here, we provide further evidence of an abstract spatial code in hippocampal CA1, which relies on memory and adds complexity to the basic "place cell." Using a nose-poking paradigm with four male Wistar rats, we specifically concentrated on activity during fixation, when the rat was immobile and waiting for the next task event in a memory-guided spatial alternation task. The rat had to alternate between choosing the right and left holes on a trial-by-trial basis, without any sensory cue, and relying on an internal representation of the sequence of trials. Twelve tetrodes were chronically implanted for single-unit recording in the right CA1 of each rat. We focus on 76 single neurons that showed significant activation during the fixation period compared with baseline activity between trials. Among these 76 fixation neurons, we observed 38 neurons that systematically changed their fixation activity as a function of the alternation sequence. That is, even though these rats were immobile during the fixation period, the neurons fired differently for trials in which the next spatial choice should be left (i.e., RIGHT-TO-LEFT trials) compared with trials in which the next spatial choice should be right (i.e., LEFT-TO-RIGHT trials), or vice versa. Our results imply that these neurons maintain a sequential code of the required spatial response during the alternation task and thus provide abstract information, derived from memory, that can be used for efficient navigation.

Behavioral state-dependent episodic representations in rat CA1 neuronal activity during spatial alternation.

Hippocampus is considered crucial for episodic memory, as confirmed by recent findings of "episode-dependent place cells" in rodent studies, and is known to show differential activity between active exploration and quiet immobility. Most place-cell studies have focused on active periods, so the hippocampal involvement in episodic representations is less well understood. Here, we draw a typology of episode-dependent hippocampal activity among three behavioral periods, presumably governed by different molecular mechanisms: Active exploration with type 1 theta, quiet alertness with type 2 theta, and consummation with large amplitude irregular activity. Five rats were trained to perform a delayed spatial alternation task with a nose-poke paradigm and 12 tetrodes were implanted for single-unit recordings. We obtained 135 CA1 pyramidal cells and found that 75 of these fired mainly during active exploration, whereas 42 fired mainly during quiet alertness and 18 during consummation. In each type of neuron, we found episode-dependent activity: 51/75, 22/42, and 15/18, respectively. These findings extend our knowledge on the hippocampal involvement in episodic memory: Episode dependency also exists during immobile periods, and functionally dissociated cell assemblies are engaged in the maintenance of episodic information throughout different events in a task sequence.

Dual synaptic plasticity in the hippocampus: Hebbian and spatiotemporal learning dynamics.

We assume that Hebbian learning dynamics (HLD) and spatiotemporal learning dynamics (SLD) are involved in the mechanism of synaptic plasticity in the hippocampal neurons. While HLD is driven by pre- and postsynaptic spike timings through the backpropagating action potential, SLD is evoked by presynaptic spike timings alone. Since the backpropagation attenuates as it nears the distal dendrites, we assume an extreme case as a neuron model where HLD exists only at proximal dendrites and SLD exists only at the distal dendrites. We examined how the synaptic weights change in response to three types of synaptic inputs in computer simulations. First, in response to a Poisson train having a constant mean frequency, the synaptic weights in HLD and SLD are qualitatively similar. Second, SLD responds more rapidly than HLD to synchronous input patterns, while each responds to them. Third, HLD responds more rapidly to more frequent inputs, while SLD shows fluctuating synaptic weights. These results suggest an encoding hypothesis in that a transient synchronous structure in spatiotemporal input patterns will be encoded into distal dendrites through SLD and that persistent synchrony or firing rate information will be encoded into proximal dendrites through HLD.

Reward prediction based on stimulus categorization in primate lateral prefrontal cortex.

To adapt to changeable or unfamiliar environments, it is important that animals develop strategies for goal-directed behaviors that meet the new challenges. We used a sequential paired-association task with asymmetric reward schedule to investigate how prefrontal neurons integrate multiple already-acquired associations to predict reward. Two types of reward-related neurons were observed in the lateral prefrontal cortex: one type predicted reward independent of physical properties of visual stimuli and the other encoded the reward value specific to a category of stimuli defined by the task requirements. Neurons of the latter type were able to predict reward on the basis of stimuli that had not yet been associated with reward, provided that another stimulus from the same category was paired with reward. The results suggest that prefrontal neurons can represent reward information on the basis of category and propagate this information to category members that have not been linked directly with any experience of reward.

Neural correlates of true memory, false memory, and deception.

We used functional magnetic resonance imaging (fMRI) to determine whether neural activity can differentiate between true memory, false memory, and deception. Subjects heard a series of semantically related words and were later asked to make a recognition judgment of old words, semantically related nonstudied words (lures for false recognition), and unrelated new words. They were also asked to make a deceptive response to half of the old and unrelated new words. There were 3 main findings. First, consistent with the notion that executive function supports deception, 2 types of deception (pretending to know and pretending not to know) recruited prefrontal activity. Second, consistent with the sensory reactivation hypothesis, the difference between true recognition and false recognition was found in the left temporoparietal regions probably engaged in the encoding of auditorily presented words. Third, the left prefrontal cortex was activated during pretending to know relative to correct rejection and false recognition, whereas the right anterior hippocampus was activated during false recognition relative to correct rejection and pretending to know. These findings indicate that fMRI can detect the difference in brain activity between deception and false memory despite the fact that subjects respond with "I know" to novel events in both processes.