Acetylcholine and associative memory in the piriform cortex

The significance of cholinergic modulation for associative memory performance in the piriform cortex was examined in a study combining cellular neurophysiology in brain slices with realistic biophysical network simulations. Three different physiological effects of acetylcholine were identified at the single-cell level: suppression of neuronal adaptation, suppression of synaptic transmission in the intrinsic fibers layer, and activity-dependent increase in synaptic strength. Biophysical simulations show how these three effects are joined together to enhance learning and recall performance of the cortical network. Furthermore, our data suggest that activity-dependent synaptic decay during learning is a crucial factor in determining learning capability of the cortical network. Accordingly, it is predicted that acetylcholine should also enhance long-term depression in the piriform cortex.     

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.     

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.     

Long-term potentiation of excitatory inputs to brain reward areas by nicotine

Nicotine reinforces smoking behavior by activating nicotinic acetylcholine receptors (nAChRs) in the midbrain dopaminergic (DA) reward centers, including the ventral tegmental area (VTA). Although nicotine induces prolonged excitation of the VTA in vivo, the nAChRs on the DA neurons desensitize in seconds. Here, we show that activation of nAChRs on presynaptic terminals in the VTA enhances glutamatergic inputs to DA neurons. Under conditions where the released glutamate can activate NMDA receptors, long-term potentiation (LTP) of the excitatory inputs is induced. Both the short- and the long-term effects of nicotine required activation of presynaptic alpha7 subunit-containing nAChRs. These results can explain the long-term excitation of brain reward areas induced by a brief nicotine exposure. They also show that nicotine alters synaptic function through mechanisms that are linked to learning and memory.     

The functional upregulation of piriform cortex is associated with cross-modal plasticity in loss of whisker tactile inputs

Background

Cross-modal plasticity is characterized as the hypersensitivity of remaining modalities after a sensory function is lost in rodents, which ensures their awareness to environmental changes. Cellular and molecular mechanisms underlying cross-modal sensory plasticity remain unclear. We aim to study the role of different types of neurons in cross-modal plasticity.

Methodology/Principal Findings

In addition to behavioral tasks in mice, whole-cell recordings at the excitatory and inhibitory neurons, and their two-photon imaging, were conducted in piriform cortex. We produced a mouse model of cross-modal sensory plasticity that olfactory function was upregulated by trimming whiskers to deprive their sensory inputs. In the meantime of olfactory hypersensitivity, pyramidal neurons and excitatory synapses were functionally upregulated, as well as GABAergic cells and inhibitory synapses were downregulated in piriform cortex from the mice of cross-modal sensory plasticity, compared with controls. A crosswire connection between barrel cortex and piriform cortex was established in cross-modal plasticity.

Conclusion/Significance

An upregulation of pyramidal neurons and a downregulation of GABAergic neurons strengthen the activities of neuronal networks in piriform cortex, which may be responsible for olfactory hypersensitivity after a loss of whisker tactile input. This finding provides the clues for developing therapeutic strategies to promote sensory recovery and substitution.     

Receptive fields in the rat piriform cortex.

Current models of odor discrimination in mammals involve molecular feature detection by a large family of diverse olfactory receptors, refinement of molecular feature extraction through precise projections of olfactory receptor neurons to the olfactory bulb to form an odor-specific spatial map of molecular features across glomerular layer, and synthesis of these features into odor objects within the piriform cortex. This review describes our recent work on odor and spatial receptive fields within the anterior piriform cortex and compares these fields with receptive fields of their primary afferent, olfactory bulb mitral/tufted cells. The results suggest that receptive fields in the piriform cortex are ensemble in nature, highly dynamic, and may contribute to odor discrimination and odor memory.     

N-methyl-d-aspartate andl-aspartate activate distinct receptors in piriform cortex

The effects of ionophoretically applied N-methyl-DL-aspartate (NMDA) and aspartate on identified pyramidal neurons in rat piriform cortex were examined in isolated, submerged, and perfused brain slices. NMDA was more potent than aspartate in eliciting neuronal discharge. Perfusion of the acidic amino acid antagonists, DL-2-amino-5-phosphonovalerate (APV), 10(-6) or 10(-5) M, DL-2-amino-7-phosphonoheptanoate (APH), 10(-5) M, and gamma-D-glutamylglycine (gamma DGG), 10(-5) M, selectively blocked the response to NMDA without effect on the response to aspartate. At higher concentrations which blocked responses to both NMDA and aspartate, gamma DGG blocked kainate responses and depressed glutamate and quisqualate responses. These results suggest that in piriform neurons NMDA and aspartate act at distinct receptor sites, not a common receptor site, and that both of these sites are distinct from those that mediate responses to glutamate, quisqualate, and kainate.     

Recurrent circuitry dynamically shapes the activation of piriform cortex

In the piriform cortex, individual odorants activate a unique ensemble of neurons that are distributed without discernable spatial order. Piriform neurons receive convergent excitatory inputs from random collections of olfactory bulb glomeruli. Pyramidal cells also make extensive recurrent connections with other excitatory and inhibitory neurons. We introduced channelrhodopsin into the piriform cortex to characterize these intrinsic circuits and to examine their contribution to activity driven by afferent bulbar inputs. We demonstrated that individual pyramidal cells are sparsely interconnected by thousands of excitatory synaptic connections that extend, largely undiminished, across the piriform cortex, forming a large excitatory network that can dominate the bulbar input. Pyramidal cells also activate inhibitory interneurons that mediate strong, local feedback inhibition that scales with excitation. This recurrent network can enhance or suppress bulbar input, depending on whether the input arrives before or after the cortex is activated. This circuitry may shape the ensembles of piriform cells that encode odorant identity.     

Neuromodulation and the functional dynamics of piriform cortex.

Acetylcholine and norepinephrine have a number of effects at the cellular level in the piriform cortex. Acetylcholine causes a depolarization of the membrane potential of pyramidal cells and interneurons, and suppresses the action potential frequency accommodation of pyramidal cells. Acetylcholine also has strong effects on synaptic transmission, suppressing both excitatory and inhibitory synaptic transmission. At the same time as it suppresses synaptic transmission, acetylcholine enhances synaptic modification, as demonstrated by experiments showing enhancement of long-term potentiation. Norepinephrine has similar effects. In this review, we discuss some of these different cellular effects and provide functional proposals for these individual effects in the context of the putative associative memory function of this structure.     

Olfactory predictive codes and stimulus templates in piriform cortex

Neuroscientific models of sensory perception suggest that the brain utilizes predictive codes in advance of a stimulus encounter, enabling organisms to infer forthcoming sensory events. However, it is poorly understood how such mechanisms are implemented in the olfactory system. Combining high-resolution functional magnetic resonance imaging with multivariate (pattern-based) analyses, we examined the spatiotemporal evolution of odor perception in the human brain during an olfactory search task. Ensemble activity patterns in anterior piriform cortex (APC) and orbitofrontal cortex (OFC) reflected the attended odor target both before and after stimulus onset. In contrast, prestimulus ensemble representations of the odor target in posterior piriform cortex (PPC) gave way to poststimulus representations of the odor itself. Critically, the robustness of target-related patterns in PPC predicted subsequent behavioral performance. Our findings directly show that the brain generates predictive templates or "search images" in PPC, with physical correspondence to odor-specific pattern representations, to augment olfactory perception.     

Dynamics of learning-induced cellular modifications in the cortex

This aim of this review is to describe the dynamics of learning-induced cellular modifications in the rat piriform (olfactory) cortex after olfactory discrimination learning and to describe their functional significance to long-term memory consolidation. The first change to occur is in the intrinsic properties of the neurons. One day after learning, pyramidal neurons show enhanced neuronal excitability. This enhancement results from reduction in calcium-dependent conductance that mediates the post burst after-hyperpolarization. Such enhanced excitability lasts for 3 days and is followed by a series of synaptic modifications. Several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons in the piriform cortex accompany olfactory learning. Enhanced synaptic release is indicated by reduced paired-pulse facilitation. Post-synaptic enhancement of synaptic transmission is indicated by reduced rise time of post-synaptic potentials and formation of new synaptic connections is indicated by increased spine density along dendrites of these neurons. Such modifications last for up to 5 days. Thus, olfactory discrimination rule learning is accompanied by a series of cellular modifications which occur and then disappear at different times. These modifications overlap partially, allowing the maintenance of the cortical system in a ‘learning mode’ in which memories for specific odors can be acquired rapidly and efficiently.     

Linear summation of excitatory inputs by CA1 pyramidal neurons

A fundamental problem in neurobiology is understanding the arithmetic that dendrites use to integrate inputs. The impact of dendritic morphology and active conductances on input summation is still unknown. To study this, we use glutamate iontophoresis and synaptic stimulation to position pairs of excitatory inputs throughout the apical, oblique, and basal dendrites of CA1 pyramidal neurons in rat hippocampal slices. Under a variety of stimulation regimes, we find a linear summation of most input combinations that is implemented by a surprising balance of boosting and shunting mechanisms. Active conductances in dendrites paradoxically serve to make summation linear. This "active linearity" can reconcile predictions from cable theory with the observed linear summation in vivo and suggests that a simple arithmetic is used by apparently complex dendritic trees.     

Origin of associative evoked potential of the orbital cortex

In acute experiments on cats evoked potentials (EP) of the orbital cortex were recorded and the electrogenesis and functional purpose of individual components of associative responses (AR) were investigated. It was concluded that the initial negative fluctuation of the AR arises as a consequence of the physical propagation of potentials from the projection somatosensory cortex and the second, positive, component and the following negative component are the result of arrival of an afferent volley into the orbital cortex via specific thalamic nuclei. These two components are due to activation of neurons of the orbital cortex. The afterdischarge, which appears sometimes, develops under the effect of impulses arriving from nonspecific thalamic nuclei. It is shown that during the second, positive, phase of the AR, primarily afferent neurons are activated, and during the negative phase, efferent neurons of the orbital cortex. The afterdischarge, which complicates the negative phase of the AR, is due to inhibition of afferent neurons.N. I. Pirogov Medical Institute, Vinnitsa. Translated from Neirofiziologiya, Vol. 2, No. 4, pp. 384–390, July–August, 1970.     

Analysis of the organization of afferent inputs in the projection cortex

Fast fluctuations in the evoked potentials (EP) at a local point of the projection cortex following stimulation of different pathways may reflect the activity of pyramidal neurons of different cortical layers. Analysis shows that the afferent and interarea projections to the somatic sensory cortex terminate on different neurons which can be regarded as relay neurons for a given pathway. Each group of neurons has its own system of inhibition for selective control of impulses coming along this pathway at the cortical level.Institute of Normal and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 2, No. 4, pp. 368–372, July–August, 1970.     

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.     

Evidence for synchronised responses in the piriform cortex by using Gibbs potential analysis

 The piriform cortex is a large paleocortical area which receives direct projections from the olfactory bulb. In order to study the spatiotemporal distribution of the piriform cortex activity, we chose optical recording of the responses evoked by olfactory bulb electrical stimulation. Such a stimulation elicited a large signal corresponding to cortical reactivation (disynaptic activity) via intrinsic association fibres. As the disynaptic activity was observed over the entire piriform area, we wondered whether or not this redistribution contributes to a synchronisation of the activity in the piriform cortex. In order to answer this question, we developed a statistical approach which allows us to take the temporal dimension into account. The analysis was performed by using the Gibbs potential analysis. The neural response of the diode is represented by a stochastic point process (occurrence of latency peak), and the response of the diode array is given as successive realisations of a binary random field defined on a finite set. The Gibbs measure associated with this field is then estimated through the interaction potentials of the field’s configurations, which provide a quantitative evaluation of the interaction and the synchronisation between the neural sites. The analysis was performed on the latency of the peak of disynaptic activity, which was determined from signals from 60 different acquisitions realised with the same stimulus parameters. From these 60 files of latency values, we estimated the Gibbs interaction potential of singletons and pairs. The former gave an image of the spatiotemporal distribution of the disynaptic activity, which appears to propagate from the anterior to the posterior part of the area recorded. The estimation of the interaction potential of pairs allows us to characterise the degree of synchronisation between two neighbouring recording sites. It appeared that, in the anterior half of the area recorded, the disynaptic activity was statistically desynchronised whereas, in the posterior part the disynaptic activity appeared strongly synchronised. The functional implications of such a spatiotemporal distribution of the activity are discussed. Received : 10 January 1996 / Accepted in revised form: 25 October 1996     

Dissociable codes of odor quality and odorant structure in human piriform cortex

The relationship between odorant structure and odor quality has been a focus of olfactory research for 100 years, although no systematic correlations are yet apparent. Animal studies suggest that topographical representations of odorant structure in olfactory bulb form the perceptual basis of odor quality. Whether central olfactory regions are similarly organized is unclear. Using an olfactory version of fMRI cross-adaptation, we measured neural responses in primary olfactory (piriform) cortex as subjects smelled pairs of odorants systematically differing in quality and molecular functional group (as one critical attribute of odorant structure). Our results indicate a double dissociation in piriform cortex, whereby posterior regions encode quality (but not structure) and anterior regions encode structure (but not quality). The presence of structure-based codes suggests fidelity of sensory information arising from olfactory bulb. In turn, quality-based codes are independent of any simple structural configuration, implying that synthetic mechanisms may underlie our experience of smell.     

Development of dendritic spines in the piriform neurons of the cerebellar cortex in human prenatal ontogeny

The submicroscopic investigation on developmental peculiarities of the dendritic spines in the piriform neurons of the cerebellar cortex has been performed during the human prenatal ontogenesis. The process of morphogenesis of the spines of the tertiary dendrites in the piriform neurons is demonstrated to start rather early--on the 24th week of embryogenesis and goes through three successive stages: 1) formation of a long cytoplasmic processes deprived of any membranous specialization; 2) formation of the terminal spinal head, making synapses with parallel fibers of the cerebellar cortex; 3) definitive stage. A suggestion is made that differentiation processes of the spines depend on inductive influence of the parallel fibers of the cerebellar cortex.