Specialization in pyramidal cell structure in the cingulate cortex of the Chacma baboon (Papio ursinus): An intracellular injection study of the posterior and anterior cingulate gyrus with comparative notes on the macaque and vervet monkeys

This study forms part of an ongoing investigation of pyramidal cell structure in the cingulate cortex of primates. Recently we have demonstrated that layer III pyramidal cells in the anterior cingulate gyrus are considerably larger, more branched and more spinous than those in the posterior cingulate gyrus (areas 24 and 23, respectively) in the macaque and vervet monkeys. Moreover, the extent of the interareal difference in specialization in pyramidal cell structure differed between the two species. These data suggest that pyramidal cell circuitry may have evolved differently in these closely related species. Presently there are too few data to speculate on what is selecting for this specialization in structure. Here we extend the basis for comparison by studying pyramidal cell structure in cingulate gyrus of the Chacma baboon (Papio ursinus). Methodology used here is the same as that for our previous studies: intracellular injection of Lucifer Yellow in flat-mounted cortical slices. We found that pyramidal cells in anterior cingulate gyrus (area 24) were more branched and more spinous than those in posterior cingulate gyrus (area 23). Moreover, the complexity in pyramidal cell structure in both the anterior and posterior cingulate gyrus of the baboon differed to that in the corresponding regions in either the macaque or vervet monkeys. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

Specialization in pyramidal cell structure in the sensory-motor cortex of the chacma baboon (Papio ursinus) with comparative notes on macaque and vervet monkeys

The systematic study of pyramidal cell structure has revealed new insights into specialization of the phenotype in the primate cerebral cortex. Regional specialization in the neuronal phenotype may influence patterns of connectivity and the computational abilities of the circuits they compose. The comparative study of pyramidal cells in homologous cortical areas is beginning to yield data on the evolution and development of such specialized circuitry in the primate cerebral cortex. Recently, we have focused our efforts on sensory-motor cortex. Based on our intracellular injection methodology, we have demonstrated a progressive increase in the size of, the branching structure in, and the spine density of the basal dendritic trees of pyramidal cells through somatosensory areas 3b, 1, 2, 5, and 7 in the macaque and vervet monkeys. In addition, we have shown that pyramidal cells in premotor area 6 are larger, more branched, and more spinous than those in the primary motor cortex (MI or area 4) in the macaque monkey, vervet monkey, and baboon. Here we expand the basis for comparison by studying the basal dendritic trees of layer III pyramidal cells in these same sensory-motor areas in the chacma baboon. The baboon was selected because it has a larger cerebral cortex than either the macaque or vervet monkeys; motor cortex has expanded disproportionately in these three species; and motor cortex in the baboon reportedly has differentiated to include a new cortical area not present in either the macaque or vervet monkeys. We found, as in monkeys, a progressive increase in the morphological complexity of pyramidal cells through areas 3b, 5, and 7, as well as from area 4 to area 6, suggesting that areal specialization in microcircuitry was likely to be present in a common ancestor of primates. In addition, we found subtle differences in the extent of the interareal differences in pyramidal cell structure between homologous cortical areas in the three species. (c) 2005 Wiley-Liss, Inc.

Pyramidal cell specialization in the occipitotemporal cortex of the vervet monkey

Pyramidal cells were injected intracellularly in fixed, flat-mounted cortical slices taken from the first and fourth visual areas (VI and V4, respectively) and cytoarchitectonic areas TEO and TE of two age and gender-matched vervet monkeys and the size, branching complexity and spine density of their basal dendritic trees determined. In both animals, we found marked differences in the pyramidal cell phenotype between cortical areas. More specifically, a consistent trend for larger, more branched and more spinous pyramidal cells with progression through VI, V4, TEO and TE was observed. These findings support earlier reports of interareal specialization in pyramidal cell structure in occipitotemporal visual areas in the macaque monkey. (c) 2005 Lippincott Williams & Wilkins.

Pyramidal neurons of granular prefrontal cortex of the galago: Complexity in evolution of the psychic cell in primates

Typically, cognitive abilities of humans have been attributed to their greatly expanded cortical mantle, granular prefrontal cortex (gPFC) in particular. Recently we have demonstrated systematic differences in microstructure of gPFC in different species. Specifically, pyramidal cells in adult human gPFC are considerably more spinous than those in the gPFC of the macaque monkey, which are more spinous than those in the gPFC of marmoset and owl monkeys. As most cortical dendritic spines receive at least one excitatory input, pyramidal cells in these different species putatively receive different numbers of inputs. These differences in the gPFC pyramidal cell phenotype may be of fundamental importance in determining the functional characteristics of prefrontal circuitry and hence the cognitive styles of the different species. However, it remains unknown as to why the gPFC pyramidal cell phenotype differs between species. Differences could be attributed to, among other things, brain size, relative size of gPFC, or the lineage to which the species belong. Here we investigated pyramidal cells in the dorsolateral gPFC of the prosimian galago to extend the basis for comparison. We found these cells to be less spinous than those in human, macaque, and marmoset. (c) 2005 Wiley-Liss, Inc.

Areal specialization of pyramidal cell structure in the visual cortex of the tree shrew: a new twist revealed in the evolution of cortical circuitry

Cortical pyramidal cells, while having a characteristic morphology, show marked phenotypic variation in primates. Differences have been reported in their size, branching structure and spine density between cortical areas. In particular, there is a systematic increase in the complexity of the structure of pyramidal cells with anterior progression through occipito-temporal cortical visual areas. These differences reflect area-specific specializations in cortical circuitry, which are believed to be important for visual processing. However, it remains unknown as to whether these regional specializations in pyramidal cell structure are restricted to primates. Here we investigated pyramidal cell structure in the visual cortex of the tree shrew, including the primary (V1), second (V2) and temporal dorsal (TD) areas. As in primates, there was a trend for more complex branching structure with anterior progression through visual areas in the tree shrew. However, contrary to the trend reported in primates, cells in the tree shrew tended to become smaller with anterior progression through V1, V2 and TD. In addition, pyramidal cells in V1 of the tree shrew are more than twice as spinous as those in primates. These data suggest that variables that shape the structure of adult cortical pyramidal cells differ among species.

Regional specialization in pyramidal cell structure in the visual cortex of the galago: An intracellular injection study of striate and extrastriate areas with comparative notes on New World and Old World monkeys

Recent studies have revealed marked differences in the basal dendritic structure of layer III pyramidal cells in the cerebral cortex of adult simian primates. In particular, there is a consistent trend for pyramidal cells of increasing complexity with anterior progression through occipitotemporal cortical visual areas. These differences in pyramidal cell structure, and their systematic nature, are believed to be important for specialized aspects of visual processing within, and between, cortical areas. However, it remains unknown whether this regional specialization in the pyramidal cell phenotype is unique to simians, is unique to primates in general or is widespread amongst mammalian species. In the present study we investigated pyramidal cell structure in the prosimian galago (Otolemur garnetti). We found, as in simians, that the basal dendritic arbors of pyramidal cells differed between cortical areas. More specifically, pyramidal cells became progressively more spinous through the primary (V1), second (V2), dorsolateral (DL) and inferotemporal ( IT) visual areas. Moreover, pyramidal neurons in V1 of the galago are remarkably similar to those in other primate species, in spite of large differences in the sizes of this area. In contrast, pyramidal cells in inferotemporal cortex are quite variable among primate species. These data suggest that regional specialization in pyramidal cell phenotype was a likely feature of cortex in a common ancestor of simian and prosimian primates, but the degree of specialization varies between species. Copyright (C) 2005 S. Karger AG, Basel.

Pyramidal cell specialization in the occipitotemporal cortex of the Chacma baboon (Papio ursinus)

Pyramidal cell structure varies systematically in occipitotemporal visual areas in monkeys. The dendritic trees of pyramidal cells, on average, become larger, more branched and more spinous with progression from the primary visual area (V1) to the second visual area (V2), the fourth (V4, or dorsolateral DL visual area) and inferotemporal (IT) cortex. Presently available data reveal that the extent of this increase in complexity parallels the expansion of occipitotemporal cortex. Here we extend the basis for comparison by studying pyramidal cell structure in occipitotemporal cortical areas in the chacma baboon. We found a systematic increase in the size of and branching complexity in the basal dendritic trees, as well as a progressive increase in the spine density along the basal dendrites of layer III pyramidal cells through V1, V2 and V4. These data suggest that the trend for more complex pyramidal cells with anterior progression through occipitotemporal visual areas is not a feature restricted to monkeys and prosimians, but is a widespread feature of occipitotemporal cortex in primates.

Regional specialization in pyramidal cell structure in the limbic cortex of the vervet monkey (Cercopithecus pygerythrus): an intracellular injection study of the anterior and posterior cingulate gyrus

The pyramidal cell phenotype varies quite dramatically in structure among different cortical areas in the primate brain. Comparative studies in visual cortex, in particular, but also in sensorimotor and prefrontal cortex, reveal systematic trends for pyramidal cell specialization in functionally related cortical areas. Moreover, there are systematic differences in the extent of these trends between different primate species. Recently we demonstrated differences in pyramidal cell structure in the cingulate cortex of the macaque monkey; however, in the absence of other comparative data it remains unknown as to whether the neuronal phenotype differs in cingulate cortex between species. Here we extend the basis for comparison by studying the structure of the basal dendritic trees of layer III pyramidal cells in the posterior and anterior cingulate gyrus of the vervet monkey (Brodmann's areas 23 and 24, respectively). Cells were injected with Lucifer Yellow in flat-mounted cortical slices, and processed for a light-stable DAB reaction product. Size, branching pattern, and spine density of basal dendritic arbors were determined, and somal areas measured. As in the macaque monkey, we found that pyramidal cells in anterior cingulate gyrus (area 24) were more branched and more spinous than those in posterior cingulate gyrus (area 23). In addition, the extent of the difference in pyramidal cell structure between these two cortical regions was less in the vervet monkey than in the macaque monkey.

Specialization of pyramidal cell structure in the visual areas V1, V2 and V3 of the South American rodent, Dasyprocta primnolopha

Marked phenotypic variation has been reported in pyramidal cells in the primate cerebral cortex. These extent and systematic nature of these specializations suggest that they are important for specialized aspects of cortical processing. However, it remains unknown as to whether regional variations in the pyramidal cell phenotype are unique to primates or if they are widespread amongst mammalian species. In the present study we determined the receptive fields of neurons in striate and extrastriate visual cortex, and quantified pyramidal cell structure in these cortical regions, in the diurnal, large-brained, South American rodent Dasyprocta primnolopha. We found evidence for a first, second and third visual area (V1, V2 and V3, respectively) forming a lateral progression from the occipital pole to the temporal pole. Pyramidal cell structure became increasingly more complex through these areas, suggesting that regional specialization in pyramidal cell phenotype is not restricted to primates. However, cells in V1, V2 and V3 of the agouti were considerably more spinous than their counterparts in primates, suggesting different evolutionary and developmental influences may act on cortical microcircuitry in rodents and primates. (c) 2006 Elsevier B.V. All rights reserved.

Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro

Beta frequency oscillations (10-35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27-30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at -80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation.

Tonically Active Kainate Receptors (tKARs) : A Novel Mechanism Regulating Neuronal Function in the Brain

Fast excitatory transmission between neurons in the central nervous system is mainly mediated by L-glutamate acting on ligand gated (ionotropic) receptors. These are further categorized according to their pharmacological properties to AMPA (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid), NMDA (N-Methyl-D-aspartic acid) and kainate (KAR) subclasses. In the rat and the mouse hippocampus, development of glutamatergic transmission is most dynamic during the first postnatal weeks. This coincides with the declining developmental expression of the GluK1 subunit-containing KARs. However, the function of KARs during early development of the brain is poorly understood. The present study reveals novel types of tonically active KARs (hereafter referred to as tKARs) which play a central role in functional development of the hippocampal CA3-CA1 network. The study shows for the first time how concomitant pre- and postsynaptic KAR function contributes to development of CA3-CA1 circuitry by regulating transmitter release and interneuron excitability. Moreover, the tKAR-dependent regulation of transmitter release provides a novel mechanism for silencing and unsilencing early synapses and thus shaping the early synaptic connectivity. The role of GluK1-containing KARs was studied in area CA3 of the neonatal hippocampus. The data demonstrate that presynaptic KARs in excitatory synapses to both pyramidal cells and interneurons are tonically activated by ambient glutamate and that they regulate glutamate release differentially, depending on target cell type. At synapses to pyramidal cells these tKARs inhibit glutamate release in a G-protein dependent manner but in contrast, at synapses to interneurons, tKARs facilitate glutamate release. On the network level these mechanisms act together upregulating activity of GABAergic microcircuits and promoting endogenous hippocampal network oscillations. By virtue of this, tKARs are likely to have an instrumental role in the functional development of the hippocampal circuitry. The next step was to investigate the role of GluK1 -containing receptors in the regulation of interneuron excitability. The spontaneous firing of interneurons in the CA3 stratum lucidum is markedly decreased during development. The shift involves tKARs that inhibit medium-duration afterhyperpolarization (mAHP) in these neurons during the first postnatal week. This promotes burst spiking of interneurons and thereby increases GABAergic activity in the network synergistically with the tKAR-mediated facilitation of their excitatory drive. During development the amplitude of evoked medium afterhyperpolarizing current (ImAHP) is dramatically increased due to decoupling tKAR activation and ImAHP modulation. These changes take place at the same time when the endogeneous network oscillations disappear. These tKAR-driven mechanisms in the CA3 area regulate both GABAergic and glutamatergic transmission and thus gate the feedforward excitatory drive to the area CA1. Here presynaptic tKARs to CA1 pyramidal cells suppress glutamate release and enable strong facilitation in response to high-frequency input. Therefore, CA1 synapses are finely tuned to high-frequency transmission; an activity pattern that is common in neonatal CA3-CA1 circuitry both in vivo and in vitro. The tKAR-regulated release probability acts as a novel presynaptic silencing mechanism that can be unsilenced in response to Hebbian activity. The present results shed new light on the mechanisms modulating the early network activity that paves the way for oscillations lying behind cognitive tasks such as learning and memory. Kainate receptor antagonists are already being developed for therapeutic use for instance against pain and migraine. Because of these modulatory actions, tKARs also represent an attractive candidate for therapeutic treatment of developmentally related complications such as learning disabilities.

GABA release by hippocampal astrocytes

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Biophysical and network mechanisms of high frequency extracellular potentials in the rat hippocampus

A fundamental question in neuroscience is how distributed networks of neurons communicate and coordinate dynamically and specifically. Several models propose that oscillating local networks can transiently couple to each other through phase-locked firing. Coherent local field potentials (LFP) between synaptically connected regions is often presented as evidence for such coupling. The physiological correlates of LFP signals depend on many anatomical and physiological factors, however, and how the underlying neural processes collectively generate features of different spatiotemporal scales is poorly understood. High frequency oscillations in the hippocampus, including gamma rhythms (30-100 Hz) that are organized by the theta oscillations (5-10 Hz) during active exploration and REM sleep, as well as sharp wave-ripples (SWRs, 140-200 Hz) during immobility or slow wave sleep, have each been associated with various aspects of learning and memory. Deciphering their physiology and functional consequences is crucial to understanding the operation of the hippocampal network.

We investigated the origins and coordination of high frequency LFPs in the hippocampo-entorhinal network using both biophysical models and analyses of large-scale recordings in behaving and sleeping rats. We found that the synchronization of pyramidal cell spikes substantially shapes, or even dominates, the electrical signature of SWRs in area CA1 of the hippocampus. The precise mechanisms coordinating this synchrony are still unresolved, but they appear to also affect CA1 activity during theta oscillations. The input to CA1, which often arrives in the form of gamma-frequency waves of activity from area CA3 and layer 3 of entorhinal cortex (EC3), did not strongly influence the timing of CA1 pyramidal cells. Rather, our data are more consistent with local network interactions governing pyramidal cells' spike timing during the integration of their inputs. Furthermore, the relative timing of input from EC3 and CA3 during the theta cycle matched that found in previous work to engage mechanisms for synapse modification and active dendritic processes. Our work demonstrates how local networks interact with upstream inputs to generate a coordinated hippocampal output during behavior and sleep, in the form of theta-gamma coupling and SWRs.

Contribution of the temporoammonic pathway to hippocampal processing

The temporoammonic (TA) pathway is the direct, monosynaptic projection from layer III of entorhinal cortex to the distal dendritic region of area CA1 of the hippo­ campus. Although this pathway has been implicated in various functions, such as memory encoding and retrieval, spatial navigation, generation of oscillatory activity, and control of hippocampal excitability, the details of its physiology are not well understood. In this thesis, I examine the contribution of the TA pathway to hippocampal processing. I find that, as has been previously reported, the TA pathway includes both excitatory, glutamatergic components and inhibitory, GABAergic components. Several new discoveries are reported in this thesis. I show that the TA pathway is subject to forms of short-term activity-dependent regulation, including paired-pulse and frequency­ dependent plasticity, similar to other hippocampal pathways such as the Schaffer collateral (SC) input from CA3 to CA1. The TA pathway provides a strongly excitatory input to stratum radiatum giant cells of CA1. The excitatory component of the TA pathway undergoes a long-lasting decrease in synaptic strength following low-frequency stimulation in a manner partially dependent on the activation of NMDA receptors. High­ frequency activation of the TA pathway recruits a feedforward inhibition that can prevent CA1 pyramidal cells from spiking in response to SC input; this spike-blocking effect shows that the TA pathway can act to regulate information flow through the hippocampal trisynaptic pathway.

A Neural Network of Adaptively Timed Reinforcement Learning and Hippocampal Dynamics

A neural model is described of how adaptively timed reinforcement learning occurs. The adaptive timing circuit is suggested to exist in the hippocampus, and to involve convergence of dentate granule cells on CA3 pyramidal cells, and NMDA receptors. This circuit forms part of a model neural system for the coordinated control of recognition learning, reinforcement learning, and motor learning, whose properties clarify how an animal can learn to acquire a delayed reward. Behavioral and neural data are summarized in support of each processing stage of the system. The relevant anatomical sites are in thalamus, neocortex, hippocampus, hypothalamus, amygdala, and cerebellum. Cerebellar influences on motor learning are distinguished from hippocampal influences on adaptive timing of reinforcement learning. The model simulates how damage to the hippocampal formation disrupts adaptive timing, eliminates attentional blocking, and causes symptoms of medial temporal amnesia. It suggests how normal acquisition of subcortical emotional conditioning can occur after cortical ablation, even though extinction of emotional conditioning is retarded by cortical ablation. The model simulates how increasing the duration of an unconditioned stimulus increases the amplitude of emotional conditioning, but does not change adaptive timing; and how an increase in the intensity of a conditioned stimulus "speeds up the clock", but an increase in the intensity of an unconditioned stimulus does not. Computer simulations of the model fit parametric conditioning data, including a Weber law property and an inverted U property. Both primary and secondary adaptively timed conditioning are simulated, as are data concerning conditioning using multiple interstimulus intervals (ISIs), gradually or abruptly changing ISis, partial reinforcement, and multiple stimuli that lead to time-averaging of responses. Neurobiologically testable predictions are made to facilitate further tests of the model.