Towards understanding of the cortical network underlying associative memory

Declarative knowledge and experiences are represented in the association cortex and are recalled by reactivation of the neural representation. Electrophysiological experiments have revealed that associations between semantically linked visual objects are formed in neural representations in the temporal and limbic cortices. Memory traces are created by the reorganization of neural circuits. These regions are reactivated during retrieval and contribute to the contents of a memory. Two different types of retrieval signals are suggested as follows: automatic and active. One flows backward from the medial temporal lobe during the automatic retrieval process, whereas the other is conveyed as a top-down signal from the prefrontal cortex to the temporal cortex during the active retrieval process. By sending the top-down signal, the prefrontal cortex manipulates and organizes to-be-remembered information, devises strategies for retrieval and monitors the outcome. To further understand the neural mechanism of memory, the following two complementary views are needed: how the multiple cortical areas in the brain-wide network interact to orchestrate cognitive functions and how the properties of single neurons and their synaptic connections with neighbouring neurons combine to form local circuits and to exhibit the function of each cortical area. We will discuss some new methodological innovations that tackle these challenges.     

Nicotinic Acetylcholine Receptors Control Encoding and Retrieval of Associative Recognition Memory through Plasticity in the Medial Prefrontal Cortex

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A neuronal basis of iconic memory in macaque primary visual cortex

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Long-term modifications in the strength of excitatory associative inputs in the piriform cortex

Afferent olfactory information, in vivo and in vitro, can be rapidly adapted to through a metabotropic glutamate receptor (mGluR)-mediated attenuation of synaptic strength. Specific cellular and synaptic mechanisms underlying olfactory learning and habituation at the cortical level remain unclear. Through whole-cell recording, excitatory postsynaptic currents (EPSCs) were obtained from piriform cortex (PC) principal cells. Using a coincidental, pre- and postsynaptic stimulation protocol, long-term depression (LTD) in synaptic strength was induced at associative, excitatory synapses onto layer II pyramidal neurons of the mouse (P15-27) PC. LTD was mimicked and occluded by mGluR agonists and blocked by nonselective mGluR antagonist (RS)-alpha-methyl-4-sulfonophenylglycine (MSPG) but not by N-methyl-D-aspartic acid (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV). Analysis of the paired-pulse ratio, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/NMDA current ratio, and spontaneous EPSCs indicate that electrically induced LTD was mediated predominantly by postsynaptic mechanisms. Additionally, presynaptic mGluRs were involved in agonist-mediated synaptic depression. Immunohistochemical analysis supports the presence of multiple subclasses of mGluRs throughout the PC, with large concentrations of several receptors present in layer II. These observations provide further evidence of activity-dependent, long-term modification of associative inputs and its underlying mechanisms. Cortical adaptation at associative synapses provides an additional link between cortical olfactory processing and subcortical centers that influence behavior.     

Mechanism Underlying the Effect of Mecamylamine on Nicotinic Acetylcholine Receptors of Rat Sympathetic Ganglion Neurons

On neurons of the superior cervical ganglion of 3-week-old rats, we studied the mechanism underlying the blocking effect of mecamylamine on transmembrane currents evoked by iontophoretic application of acetylcholine (ACh currents); these currents were recorded with the use of a patch-clamp technique in the whole-cell configuration. The IC₅₀ of the above agent equaled (2.7 ± 0.3) · 10^-10 M. The blocking effect of mecamylamine on ACh current did not depend on the membrane potential and decreased with rise in the concentration of the drug. Thus, a competitive blocking mechanism mostly underlies the above phenomenon.     

Ensembles code for associative learning in the primate lateral prefrontal cortex

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Long-term potentiation in the piriform cortex is blocked by lead

Summary 1. Long-term potentiation (LTP) is a prolonged increase in synaptic efficacy that is triggered by a brief tetanic stimulation at certain central synapses. LTP is one of the best available model systems available to the neurophysiologist of neuronal plasticity such as that underlying learning and memory.2. We have studied the susceptibility of LTP to blockade by lead as a test of the hypothesis that the negative effect of lead on intelligence in children may result from interference with this process. LTP was studied in slices of rat piriform cortex. At this site, as in many other central synapses, LTP requires activation of postsynapticN-methyl-d-aspartate (NMDA) receptors, and we investigated whether lead actions, if any, were mediated via effects on NMDA-activation ion channels or, alternatively, at voltage-activated calcium channels.3. We find that lead blocks LTP at low micromolar concentrations. However, concentrations of lead that totally block LTP had no apparent effect on either NMDA-activated responses or presynaptic calcium channels, as monitored by transmitter release from presynaptic terminals.4. While the mechanism of lead blockade of LTP remains to be determined, these observations are consistent with the hypothesis that the cognitive effects of lead neurotoxicity may result from effects on LTP.     

Characterization and isolation of immature neurons of the adult mouse piriform cortex

Physiological studies indicate that the piriform or primary olfactory cortex of adult mammals exhibits a high degree of synaptic plasticity. Interestingly, a subpopulation of cells in the layer II of the adult piriform cortex expresses neurodevelopmental markers, such as the polysialylated form of neural cell adhesion molecule (PSA‐NCAM) or doublecortin (DCX). This study analyzes the nature, origin, and potential function of these poorly understood cells in mice. As previously described in rats, most of the PSA‐NCAM expressing cells in layer II could be morphologically classified as tangled cells and only a small proportion of larger cells could be considered semilunar‐pyramidal transitional neurons. Most were also immunoreactive for DCX, confirming their immature nature. In agreement with this, detection of PSA‐NCAM combined with that of different cell lineage‐specific antigens revealed that most PSA‐NCAM positive cells did not co‐express markers of glial cells or mature neurons. Their time of origin was evaluated by birthdating experiments with halogenated nucleosides performed at different developmental stages and in adulthood. We found that virtually all cells in this paleocortical region, including PSA‐NCAM‐positive cells, are born during fetal development. In addition, proliferation analyses in adult mice revealed that very few cells were cycling in layer II of the piriform cortex and that none of them was PSA‐NCAM‐positive. Moreover, we have established conditions to isolate and culture these immature neurons in the adult piriform cortex layer II. We find that although they can survive under certain conditions, they do not proliferate in vitro either. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 748–763, 2016     

Crossmodal associative memory representations in rodent orbitofrontal cortex

Firing patterns of neurons in the orbitofrontal cortex (OF) were analyzed in rats trained to perform a task that encouraged incidental associations between distinct odors and the places where their occurrence was detected. Many of the neurons fired differentially when the animals were at a particular location or sampled particular odors. Furthermore, a substantial fraction of the cells exhibited odor-specific firing patterns prior to odor presentation, when the animal arrived at a location associated with that odor. These findings suggest that neurons in the OF encode cross-modal associations between odors and locations within long-term memory.     

The Neuronal Nicotinic Acetylcholine Receptor in Some Hereditary Epilepsies

Recent advances in human genetics and in the neurobiology of neurotransmitter receptors and channels have led to the discovery of specific genes associated with hereditary epileptic phenotypes. All the genes identified to date code for ligand- and voltage-gated ion channels. Some clinically rare idiopathic epilepsies are associated with mutations in genes coding for different neuronal nicotinic acetylcholine receptor (AChR) subunits. Distinct subunits are found in the brain and in the peripheral nervous system, and structural, non- subunits like 2 and 4 confer different properties to neuronal receptors. Thus, the final properties of the oligomeric AChR depend on the different combinations of and subunits. Most mutations found so far occur in the 4 chain, the most abundant subunit in the central nervous system. Specifically, the identification of mutations in the 4 subunit of neuronal AChR in human benign familial neonatal convulsions (BFNC) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) raise the possibility that the observed gene defects are linked (causatively) with these two diseases or, alternatively, that AChR 4 mutants increase the probability of epileptic discharges. We discuss testable hypotheses for unraveling the pathophysiology of these two disorders associated with AChR mutations.     

Convergence in the piriform cortex

How are the responses to distinct chemical features integrated to form an olfactory perceptual object? In this issue of Neuron, Davison and Ehlers show that individual piriform cortex neurons receive convergent input from up to 10% of main olfactory bulb glomeruli and are activated by specific spatial patterns of coactive glomeruli.     

Selective blockade of dopamine D(3) versus D(2) receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis

Though dopaminergic mechanisms modulate cholinergic transmission and cognitive function, the significance of specific receptor subtypes remains uncertain. Here, we examined the roles of dopamine D(3) versus D(2) receptors. By analogy with tacrine (0.16-2.5 mg/kg, s.c.), the selective D(3) receptor antagonists, S33084 (0.01-0.63) and SB277,011 (0.63-40.0), elicited dose-dependent, pronounced and sustained elevations in dialysis levels of acetylcholine (ACh) in the frontal cortex, but not the hippocampus, of freely-moving rats. The actions of these antagonists were stereospecifically mimicked by (+)S14297 (1.25), whereas its inactive distomer, (-)S17777, was ineffective. The preferential D(2) receptor antagonist, L741,626 (10.0), failed to modify levels of ACh. S33084 (0.01-0.63) and SB277,011 (0.16-2.5) also mimicked tacrine (0.04-0.63) by dose-dependently attenuating the deleterious influence of scopolamine (1.25) upon social memory (recognition by an adult rat of a juvenile conspecific). Further, (+)S14297 (1.25) versus (-)S17777 stereospecifically blocked the action of scopolamine. Using an intersession interval of 120 min (spontaneous loss of recognition), S33084 (0.04-0.63), SB277,011 (0.16-10.0) and (+)S14297 (0.63-10.0) likewise mimicked tacrine (0.16-2.5) in enhancing social memory. In contrast, L741,626 (0.16-10.0) displayed amnesic properties. In conclusion, selective blockade of D(3) receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D(3) receptors as a target for treatment of disorders in which cognitive function is compromised.     

Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex

Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCK_B antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCK_B antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.     

Some characteristics of spatial associative memory in the pigeon, Columba livia

Willson and Wilkie (1993) developed a novel procedure to assess pigeons' memory for the spatial location of food. Only one of four locations provided food each daily session. Each location consisted of an illuminated pecking key and grain feeder. Over different days different locations, randomly selected, provided food during a 16-min session. The pigeons tended to revisit the location at which food was found on the previous day thereby demonstrating memory for food-spatial location associations over 24 h. Three experiments were conducted to further investigate this phenomenon. In Experiment 1 the session duration was varied between 4 and 32 min. Longer sessions had no detectable effect on their ability to remember the rewarded location 24 h later, a result that suggests that only brief encounters with food at a particular location are necessary for recall. In Experiment 2 the necessity of an active search for the day's rewarded location was removed; a 5-min period in which only the rewarded key was lit preceded the regular 16-min session. Pecks to the lit key in this 5-min period produced grain on the standard schedule. This manipulation facilitated the pigeons' discovery of food but did not affect their ability to remember the rewarded location, suggesting that the process of search and discovery is not essential to the associative memory process. In Experiment 3, food was available during the complete session (non-depleting condition) or was available only during the first half of the session (depleting condition). No detectable differences in the birds' memory of yesterday's profitable location were found. This suggests that non-depletion of food is not a necessary condition for day-to-day recall of food location. Taken together these findings enlarge our understanding of the spatial associative memory process.     

Models of distributed associative memory networks in the brain

Summary Although experimental evidence for distributed cell assemblies is growing, theories of cell assemblies are still marginalized in theoretical neuroscience. We argue that this has to do with shortcomings of the currently best understood assembly theories, the ones based on formal associative memory models. These only insufficiently reflect anatomical and physiological properties of nervous tissue, and their functionality is too restricted to provide a framework for cognitive modeling. We describe cell assembly models that integrate more neurobiological constraints and review results from simulations of a simple nonlocal associative network formed by a reciprocal topographic projection. Impacts of nonlocal associative projections in the brain are discussed with respect to the functionality they can explain.     

Specificity of the Rat Vesicular Acetylcholine Transporter

The protein kinase A–deficient PC12 cell line PC12^A123.7 lacks both choline acetyltransferase and the vesicular acetylcholine transporter. This cell line has been used to establish a stably transfected cell line expressing recombinant rat vesicular acetylcholine transporter that is appropriately trafficked to small synaptic vesicles. Acetylcholine is transported by the rat vesicular acetylcholine transporter at a maximal rate of 1.45 nmol acetylcholine/min/mg protein and exhibits a Km for transport of 2.5 mM. The transporter binds vesamicol with a Kd of 7.5 nM. The ability of structural analogs of acetylcholine to inhibit both acetylcholine uptake and vesamicol binding was measured. The results demonstrate that like Torpedo vesicular acetylcholine transporter, the mammalian transporter can bind a diverse group of acetylcholine analogs.