NMDA receptor-dependent long-term potentiation is dependent on low-voltage-activated calcium currents in the sensorimotor cortex of cats

The role of low-voltage-activated (LVA) calcium channels in the expression of long-term potentiation (LTP) was examined by intracellular recording in slices from cat agranular cortex. In the normal solution, LTP was induced, and the potentiation of low-threshold rebound potential was evoked by negative current injection. In the cells, in which resting membrane potential was depolarized, the incidence of LTP was very low. LTP was blocked completely in the presence of NMDA receptor antagonist or 50-100 microM nickel. It was suggested that LVA calcium channels function downstream of NMDA receptor-dependent signaling.     

Calcium-induced long-term potentiation in horizontal connections of rat motor cortex

A transient (10 min) exposure of brain slices of young adult rats to elevated extracellular calcium (5 mM) resulted in a long-lasting potentiation of field potentials evoked in layer II/III and layer V horizontal connections of the primary motor cortex. This form of synaptic plasticity was blocked by D,L-2-amino-5-phosphonovalerate (APV, 100 micro M), an antagonist of NMDA receptors.     

Synaptic relationships involving local axon collaterals of pyramidal neurons in the cat motor cortex

The intracortical synaptic relationships of pyramidal neurons in the cat motor cortex were studied by intracellular recording and labeling techniques. Neurons that responded with monosynaptic excitatory postsynaptic potentials (EPSPs) to microstimulation in the somatosensory cortex were identified by intracellular recordings. Long-term potentiation (LTP) was evoked in all of these neurons (n = 15), following tetanic stimulation (50 Hz, 5 s) of their afferents from the somatosensory cortex. Three of these cells (cells A-C) were identified as pyramidal neurons, following intracellular injections of Neurobiotin. The intracortical axon collaterals of these labeled cells arborized extensively, forming terminal clusters both in clse proximity to the parent soma and along their long, horizontal branches. Terminal clusters in both the proximal and in the distal termination zones of each of the cells were studied by electron microscopy. In their proximal arborization zones, the axon collaterals of the labeled pyramidal neurons synapsed preferentially with dendritic spines belonging to other pyramidal cells. In contrast, in their distal terminal clusters, the axon collateals of each of the cells formed synapses in different proportions with different postsynaptic targets. The distal axon collaterals of cell A formed 86% of their synapses with pyramidal neurons; those of cell B formed 64% of their synapses with pyramidal cells, the remaining synapses with the dendritic shafts and somata of nonpyramidal neurons, and those of cell C provided most of their output (68%) to nonpyramidal, presumably inhibitory neurons. These findings suggest a high selectivity of intrinsic axon collaterals to form specific patterns of synapses. The patterns of synaptic interactions formed by these intrinsic axon collaterals may be a substrate for shaping and modulating representation maps in the motor cortex. © 1993 Wiley-Liss, Inc.     

Afferent-induced facilitation of primary motor cortex excitability in the region controlling hand muscles in humans

Sensory inputs from cutaneous and limb receptors are known to influence motor cortex network excitability. Although most recent studies have focused on the inhibitory influences of afferent inputs on arm motor responses evoked by transcranial magnetic stimulation (TMS), facilitatory effects are rarely considered. In the present work, we sought to establish how proprioceptive sensory inputs modulate the excitability of the primary motor cortex region controlling certain hand and wrist muscles. Suprathreshold TMS pulses were preceded either by median nerve stimulation (MNS) or index finger stimulation with interstimulus intervals (ISIs) ranging from 20 to 200 ms (with particular focus on 40–80 ms). Motor-evoked potentials recorded in the abductor pollicis brevis (APB), first dorsalis interosseus and extensor carpi radialis muscles were strongly facilitated (by up to 150%) by MNS with ISIs of around 60 ms, whereas digit stimulation had only a weak effect. When MNS was delivered at the interval that evoked the optimal facilitatory effect, the H-reflex amplitude remained unchanged and APB motor responses evoked with transcranial electric stimulation were not increased as compared with TMS. Afferent-induced facilitation and short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) mechanisms are likely to interact in cortical circuits, as suggested by the strong facilitation observed when MNS was delivered concurrently with ICF and the reduction of SICI following MNS. We conclude that afferent-induced facilitation is a mechanism which probably involves muscle spindle afferents and should be considered when studying sensorimotor integration mechanisms in healthy and disease situations.     

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) induced by high‐ (HFS) and low‐frequency stimulations (LFS), respectively. Using a pairing protocol under whole‐cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age‐matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V_ms) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD–LTP crossover point of the voltage–response curve for synaptic plasticity. Prior repeated short‐term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes‐ and activity‐dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in V_ms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.     

Absence of localized grey matter volume changes in the motor cortex following spinal cord injury

The consequences of spinal cord injury (SCI) have considerable effects on motor function, typically resulting in functional impairment. Pathological changes have been studied at the site of trauma, rostrocaudally within the cord, and in the periphery. Few studies, however, have investigated the consequences of SCI at the cortical level. Magnetic resonance imaging (MRI) was used to explore the morphological changes in the grey and white matter within the primary motor (M1) cortex of individuals with cervical SCI. The "precentral knob," a landmark of M1 cortex dedicated to hand function, was selected for regionally specific measurements of change. Thirty-one hemispheres of SCI subjects and 28 hemispheres of control subjects were compared using a manual measurement after the images were segmented into grey matter, white matter, and cerebral spinal fluid (CSF). No significant differences in grey matter area measured at the precentral knob were found with the manual approach. An automated voxel-based morphometric analysis was also performed and demonstrated no significant differences in grey or white matter volume within an M1 region of interest. These data suggest that there is no gross anatomical change within M1 following cervical SCI. Our previously reported findings of reorganization of cortical motor output maps following SCI therefore likely result from changes in functional organization rather than anatomical changes.     

Short-term and long-term plasticity interaction in human primary motor cortex

Repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) elicits changes in motor evoked potential (MEP) size thought to reflect short‐ and long‐term forms of synaptic plasticity, resembling short‐term potentiation (STP) and long‐term potentiation/depression (LTP/LTD) observed in animal experiments. We designed this study in healthy humans to investigate whether STP as elicited by 5‐Hz rTMS interferes with LTP/LTD‐like plasticity induced by intermittent and continuous theta‐burst stimulation (iTBS and cTBS). The effects induced by 5‐Hz rTMS and iTBS/cTBS were indexed as changes in MEP size. We separately evaluated changes induced by 5‐Hz rTMS, iTBS and cTBS applied alone and those induced by iTBS and cTBS delivered after priming 5‐Hz rTMS. Interactions between 5‐Hz rTMS and iTBS/cTBS were investigated under several experimental conditions by delivering 5‐Hz rTMS at suprathreshold and subthreshold intensity, allowing 1 and 5 min intervals to elapse between 5‐Hz rTMS and TBS, and delivering one and ten 5‐Hz rTMS trains. We also investigated whether 5‐Hz rTMS induces changes in intracortical excitability tested with paired‐pulse transcranial magnetic stimulation. When given alone, 5‐Hz rTMS induced short‐lasting and iTBS/cTBS induced long‐lasting changes in MEP amplitudes. When M1 was primed with 10 suprathreshold 5‐Hz rTMS trains at 1 min before iTBS or cTBS, the iTBS/cTBS‐induced after‐effects disappeared. The 5‐Hz rTMS left intracortical excitability unchanged. We suggest that STP elicited by suprathreshold 5‐Hz rTMS abolishes iTBS/cTBS‐induced LTP/LTD‐like plasticity through non‐homeostatic metaplasticity mechanisms. Our study provides new information on interactions between short‐term and long‐term rTMS‐induced plasticity in human M1.     

Response properties and morphological identification of neurons in the cat motor cortex

Intracellular recordings and morphological identification of neurons using intracellular HRP staining were performed in the cat motor cortex. By thalamic ventrolateral (VL) or cerebellar nucleus stimulation, pyramidal cells in layer III, fast pyramidal tract neurons (PTNs) and stellate cells in layers II and III were activated with short latency and fast rising EPSPs, while pyramidal cells in layer II and slow PTNs showed longer latency and slow rising EPSPs. This difference may be related to activation through the deep and superficial thalamocortical projections. Although pyramidal cells in layer VI did not respond orthodromically to VL or cerebellar stimulation, some of them proved to receive the recurrent action of PTNs because of the response to stimulation of the cerebral peduncle (CP). One aspinous stellate cell in layer III was activated by CP as well as VL stimulation. This cell was supposed to be an inhibitory interneuron responsible for both recurrent and VL-evoked inhibition.     

Plasticity of the motor cortex in Parkinson's disease patients on and off therapy.

We used the paired associative stimulation (PAS) technique to investigate associative plasticity of the sensorimotor cortex in 16 Parkinson's disease (PD) patients off and on therapy and in 10 age-matched controls. After PAS, motor evoked potential (MEP) amplitudes increased more and the cortical silent period showed a reduced prolongation in patients off therapy than in controls. These changes lasted for at least 30 minutes. In addition, MEP amplitudes increased in a less focal manner in patients off therapy than in controls. After patients received dopaminergic therapy, these abnormalities normalized. The abnormal responsiveness of sensorimotor cortex neurons to PAS in PD patients off therapy probably reflects disordered plasticity within the motor cortex.     

Long-lasting potentiation of synaptic potentials in the motor cortex produced by stimulation of the sensory cortex in the cat: a basis of motor learning

A long-lasting increase in the efficiency of synaptic transmission in the central nervous system has been thought to be one of the bases of learning and memory. To explore the possibility that the motor cortex (area 4γ) itself is involved in motor learning, the existence of long-term potentiation (LTP) was examined by recording excitatory postsynaptic potentials (EPSPs) from motor cortical neurons. Short tetanic intracortical microstimulation (ICMS) of the somatic sensory cortex produced a marked potentiation of the EPSPs in a small group of motor cortical neurons. The results raised the possibility that the input from the sensory cortex participates in motor learning and retention of the learned motor skills.     

Long-term potentiation and depression in layer III and V pyramidal neurons of the cat sensorimotor cortex in vitro

Synaptic plasticity of the cat sensorimotor cortex was examined intracellularly in vitro. After tetanic stimulation of the white matter, layer III and V pyramidal neurons showed long-term potentiation (LTP) of EPSPs in high incidence without GABA_A antagonist. The incidence and magnitude of LTP were very conspicuous in layer V cells. After an NMDA receptor antagonist application, the synaptic potentiation was blocked completely in layer III but not in layer V cells. Long-term depression (LTD) of the evoked EPSPs was also induced by the same stimulation in some layer III cells, where a transient hyperpolarization of the membrane potential was observed during tetanus.© 1997 Elsevier Science B.V. All rights reserved.     

A quantitative study of the distribution of neurons projecting to the precentral motor cortex in the monkey (M. fascicularis)

The relative numbers and locations of neurons projecting to the "forelimb" region of the precentral motor cortex were studied in three monkeys by using the retrograde transport of horseradish peroxidase. Within the forelimb area of the motor cortex itself, there are extensive and profuse interconnections. However, regions within this area receive afferents from very few neurons in other parts of the motor cortex representing hindlimb or head movements. Most of the motor cortical representation of the forelimb in the anterior bank of the central sulcus is devoid of callosal connections. In both the ipsilateral and contralateral hemispheres, the premotor (lateral area 6) and supplementary motor (medial area 6) areas dominate quantitatively the inputs to the motor cortical representation of the forelimb. The afferents from the premotor area are restricted and come from a region immediately behind the arcuate spur and adjacent parts of the superior and inferior limbs of the arcuate sulcus in the floor, caudal bank, and caudal lip of that sulcus. From the supplementary motor area (SMA), afferents originate from its whole rostrocaudal extent. Thalamic nuclear regions projecting to a restricted zone in the anterior bank of the central sulcus are recipients of cerebellar and somatosensory outputs. Involvement of more anterior parts of the motor cortex by the tracer labels thalamocortical cells, which are targets of pallidal output also. Within the first somatosensory cortex, cytoarchitectonic areas 1, 2, and 3a project to area 4. The projection from area 3a may provide one pathway by which short-latency peripheral inputs, especially from muscles, reach the motor cortex.     

Dystonia: A disorder of motor programming or motor execution?

For some time, dystonia has been seen as purely a motor disorder. Relatively novel concepts published approximately 10 years ago also presumed that in the development of dystonic dyskinesias, only motor behaviour was abnormal. Neurophysiological observations of various types of dystonic disorders, which were performed using sophisticated electromyography, polymyography, H-reflex examination, long-latency reflex, etc., as well as new insights into the behaviour of dystonia, have urged the inclusion of sensory (particularly somatosensory) mechanisms into the pathophysiological background of dystonia. The major role has been considered to be played by abnormal proprioceptive input by means of the Ia proprioceptive afferents, with the source of this abnormality found in the abnormal processing of muscle spindle afferent information. However, neurophysiological investigations have also provided evidence that the abnormality in the central nervous system is located not only at the spinal and subcortical level, but also at the cortical level; specifically, the cortical excitability and intracortical inhibition have been revealed as abnormal. This evidence was revealed by SEP recordings, paired transcranial magnetic stimulation recordings, and BP and CNV recordings. The current concept of dystonic movement connects the abnormal function of somatosensory pathways and somatosensory analysers with the dystonic performance of motor action, which is based on the abnormality of sensorimotor integration.     

Neurophysiologic correlates of fMRI in human motor cortex

The neurophysiological underpinnings of functional magnetic resonance imaging (fMRI) are not well understood. To understand the relationship between the fMRI blood oxygen level dependent (BOLD) signal and neurophysiology across large areas of cortex, we compared task related BOLD change during simple finger movement to brain surface electric potentials measured on a similar spatial scale using electrocorticography (ECoG). We found that spectral power increases in high frequencies (65-95 Hz), which have been related to local neuronal activity, colocalized with spatially focal BOLD peaks on primary sensorimotor areas. Independent of high frequencies, decreases in low frequency rhythms (<30 Hz), thought to reflect an aspect of cortical-subcortical interaction, colocalized with weaker BOLD signal increase. A spatial regression analysis showed that there was a direct correlation between the amplitude of the task induced BOLD change on different areas of primary sensorimotor cortex and the amplitude of the high frequency change. Low frequency change explained an additional, different part of the spatial BOLD variance. Together, these spectral power changes explained a significant 36% of the spatial variance in the BOLD signal change (R(2) = 0.36). These results suggest that BOLD signal change is largely induced by two separate neurophysiological mechanisms, one being spatially focal neuronal processing and the other spatially distributed low frequency rhythms.     

Layer V in cat primary auditory cortex (AI): cellular architecture and identification of projection neurons

The cytoarchitectonic organization and the structure of layer V neuronal populations in cat primary auditory cortex (AI) were analyzed in Golgi, Nissl, immunocytochemical, and plastic-embedded preparations from mature specimens. The major cell types were characterized as a prelude to identifying their connections with the thalamus, midbrain, and cerebral cortex using axoplasmic transport methods. The goal was to describe the structure and connections of layer V neurons more fully. Layer V has three sublayers based on the types of neuron and their sublaminar projections. Four types of pyramidal and three kinds of nonpyramidal cells were present. Classic pyramidal cells had a long apical dendrite, robust basal arbors, and an axon with both local and corticofugal projections. Only the largest pyramidal cell apical dendrites reached the supragranular layers, and their somata were found mainly in layer Vb. Three types departed from the classic pattern; these were the star, fusiform, and inverted pyramidal neurons. Nonpyramidal cells ranged from large multipolar neurons with radiating dendrites, to Martinotti cells, with smooth dendrites and a primary trunk oriented toward the white matter. Many nonpyramidal cells were multipolar, of which three subtypes (large, medium, and small) were identified; bipolar and other types also were seen. Their axons formed local projections within layer V, often near pyramidal neurons. Several features distinguish layer V from other layers in AI. The largest pyramidal neurons were in layer V. Layer V neuronal diversity aligns it with layer VI (Prieto and Winer [1999] J. Comp. Neurol. 404:332--358), and it is consistent with the many connectional systems in layer V, each of which has specific sublaminar and neuronal origins. The infragranular layers are the source for several parallel descending systems. There were significant differences in somatic size among these projection neurons. This finding implies that diverse corticofugal roles in sensorimotor processing may require a correspondingly wide range of neuronal architecture.     

Linear relationship between the maintenance of hippocampal long-term potentiation and retention of an associative memory.

The hypothesis that the maintenance or decay of an associative memory trace after an extended retention interval is a function of the residual strength of the synapses originally strengthened during learning was examined in a classical conditioning paradigm in which high-frequency stimulation of a hippocampal input--the medial perforant path--served as a conditioned stimulus. Rats received perforant path stimulus-foot shock pairings while engaged in a previously acquired food-motivated lever-pressing task. Conditioned suppression of lever pressing was the behavioral measure of learning and retention of the association. Stimulus trains to the perforant path at an intensity above the threshold for eliciting a population spike induced long-term potentiation of synaptic transmission in the dentate gyrus. Synaptic potentials recorded extracellularly in the dentate gyrus were subsequently monitored for 31 days to examine quantitatively the decay of synaptic potentiation, a period after which retention of the learned association was assessed. All rats learned the association to a similar extent and displayed equivalent amounts of long-term potentiation by the end of conditioning. A slowly decaying function of synaptic potentiation was observed in remembering rats, i.e., rats with high retention performance after the 31-day learning-to-retention interval, while forgetting was associated with a rapid decay of long-term potentiation. Behavioral performance at the long-term memory test was linearly correlated with the amplitude of long-term potentiation maintained just prior to the retention test. The results favor the hypothesis that long-term associative memory depends, at least in part, on the maintenance of elevated synaptic strengths in the pathway activated during learning and suggest a role for the lasting component of long-term potentiation in the maintenance of memory.