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J R Wickens

Publications and source records attributed to J R Wickens.

At least 19 recordsLinked to original sources
PubMed2004

Dissociation of hypertension and fixed interval responding in two separate strains of genetically hypertensive rat.

The behaviour of spontaneously hypertensive rats (SHR) may model attention-deficit hyperactivity disorder. For example, SHR are hyperactive in an open field and show high terminal rates of responding on certain fixed-interval schedules. Open field behaviour has been dissociated from the accompanying spontaneous hypertension but fixed interval responding has not. We compared the fixed interval responding of two unrelated strains of genetically hypertensive rat, the SHR (n = 6) and the New Zealand genetically hypertensive rat (GH, n = 5), with their normotensive control strains, the Wistar Kyoto (WKY, n = 6) and Wistar (n = 5), respectively. Both hypertensive rat strains showed increased terminal lever-pressing rates on a multiple fixed-interval schedule (FI-EXT) compared to controls. In order to investigate the association of hypertension and the behavioural characteristics in question, an F-2 hybrid strain was obtained by cross-breeding GH and Wistar rats. When these F-2 hybrids (n = 33) were tested on the FI-EXT schedule, terminal lever-pressing rate was not correlated with blood pressure. The independent segregation of these phenotypical characteristics in the hybrids suggests independent genetic control. By contrast, other behavioural characteristics, including high lever-pressing rates during the extinction component and a tendency to emit responses in bursts, did cosegregate with terminal lever-pressing rates. Taken together, these findings suggest that the genetic loci for high blood pressure and responding on the FI-EXT schedule in these two unrelated rat strains are close but distinct.

Animals↗
PubMed2001

A cellular mechanism of reward-related learning.

Positive reinforcement helps to control the acquisition of learned behaviours. Here we report a cellular mechanism in the brain that may underlie the behavioural effects of positive reinforcement. We used intracranial self-stimulation (ICSS) as a model of reinforcement learning, in which each rat learns to press a lever that applies reinforcing electrical stimulation to its own substantia nigra. The outputs from neurons of the substantia nigra terminate on neurons in the striatum in close proximity to inputs from the cerebral cortex on the same striatal neurons. We measured the effect of substantia nigra stimulation on these inputs from the cortex to striatal neurons and also on how quickly the rats learned to press the lever. We found that stimulation of the substantia nigra (with the optimal parameters for lever-pressing behaviour) induced potentiation of synapses between the cortex and the striatum, which required activation of dopamine receptors. The degree of potentiation within ten minutes of the ICSS trains was correlated with the time taken by the rats to learn ICSS behaviour. We propose that stimulation of the substantia nigra when the lever is pressed induces a similar potentiation of cortical inputs to the striatum, positively reinforcing the learning of the behaviour by the rats.

Animals↗
PubMed2001

Dopamine D-1/D-5 receptor activation is required for long-term potentiation in the rat neostriatum in vitro.

Dopamine and glutamate are key neurotransmitters involved in learning and memory mechanisms of the brain. These two neurotransmitter systems converge on nerve cells in the neostriatum. Dopamine modulation of activity-dependent plasticity at glutamatergic corticostriatal synapses has been proposed as a cellular mechanism for learning in the neostriatum. The present research investigated the role of specific subtypes of dopamine receptors in long-term potentiation (LTP) in the corticostriatal pathway, using intracellular recording from striatal neurons in a corticostriatal slice preparation. In agreement with previous reports, LTP could be induced reliably under Mg(2+)-free conditions. This Mg(2+)-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABA(A) antagonist picrotoxin. In dopamine-depleted slices, the ability to induce LTP could be restored by bath application of the dopamine D-1/D-5 receptor agonist, SKF 38393. These results show that activation of dopamine D-1/D-5 receptors by either endogenous dopamine or exogenous dopamine agonists is a requirement for the induction of LTP in the corticostriatal pathway. These findings have significance for current understanding of learning and memory mechanisms of the neostriatum and for theoretical understanding of the mechanism of action of drugs used in the treatment of psychotic illnesses and Parkinson's disease.

Action Potentials↗
PubMed2000

Substantia nigra dopamine regulates synaptic plasticity and membrane potential fluctuations in the rat neostriatum, in vivo.

The spiny projection neurons of the neostriatum are a site at which dopamine inputs from the substantia nigra converge with excitatory inputs from the cerebral cortex. These two systems interact in certain learning and motor control mechanisms of the brain. We investigated these interactions using intracellular recording from spiny striatal neurons in urethane-anaesthetized rats. We found that acute dopamine depletion was associated with long-term depression of corticostriatal synaptic input. Electrical stimulation of the cortex which mimicked synchronous cortical input to striatal neurons also induced long-term depression of corticostriatal inputs. In intact control animals, but not in dopamine-depleted animals, this depression was prevented or reversed by concomitant stimulation of the substantia nigra. In agreement with previous in vitro studies, our in vivo findings show that long-term depression occurs in the corticostriatal pathway, and in addition show that it is regulated by dopaminergic inputs from the substantia nigra. This form of synaptic plasticity may therefore be important for understanding disturbances of the motor system seen in humans with Parkinson's disease.

Animals↗
PubMed2000

Dopamine and synaptic plasticity in the neostriatum.

After the unilateral destruction of the dopamine input to the neostriatum there are enduring changes in rat behaviour. These have been ascribed to the loss of dopamine and the animals are often referred to as 'hemiparkinsonian'. In the denervated neostriatum, we have shown that not only are the tyrosine hydroxylase positive boutons missing, but also the medium sized densely spiny output cells have fewer spines. Spines usually have asymmetric synapses on their heads. In a recent stereological study we were able to show that there is a loss of approximately 20% of asymmetric synapses in the lesioned neostriatum by 1 mo after the lesion. Current experiments are trying to establish the specificity of this loss. So far we have evidence suggesting that there is no obvious preferential loss of synapses from either D1 or D2 receptor immunostained dendrites in the neostriatum with damaged dopamine innervation. These experiments suggest that dopamine is somehow necessary for the maintenance of corticostriatal synapses in the neostriatum. In a different series of experiments slices of cortex and neostriatum were maintained in vitro in such a way as to preserve at least some of the corticostriatal connections. In this preparation we have been able to show that cortical stimulation results in robust excitatory postsynaptic potentials (EPSPs) recorded from inside striatal neurons. Using stimulation protocols derived from the experiments on hippocampal synaptic plasticity we have shown that the usual consequence of trains of high frequency stimulation of the cortex is the depression of the size of EPSPs in the striatal cell. In agreement with similar experiments by others, the effect seems to be influenced by NMDA receptors since the unblocking of these receptors with low Mg++ concentrations in the perfusate uncovers a potentiation of the EPSPs after trains of stimulation. Dopamine applied in the perfusion fluid round the slices has no effect but pulsatile application of dopamine, close to the striatal cell being recorded from, and in temporal association with the cortical trains, leads to a similar LTP like effect. The reduction of K+ channel conductance in the bath with TEA also has the effect of making cortical trains induce potentiation of corticostriatal transmission. TEA applied only to the cell being recorded from has no similar effect; the cortical stimulation again depresses the EPSP amplitude, so the site of action of TEA may well be presynaptic to the striatal cell. The morphological and physiological experiments may not necessarily be related but it is tempting to suggest that dopamine protects some corticostriatal synapses by potentiating them but that in the absence of dopamine others simply disconnect and are no longer detectable on electron microscopy.

Animals↗
PubMed2000

Parameter precuing and motor preparation.

A movement task was used to investigate the effects of precued variables on reaction time. The task involved rapid rotation of a hand-held manipulandum to target locations and required either pronation or supination of the forearm through short or long extent. The effects on reaction time of precues signalling target direction, extent, or a combination of direction and extent, were measured. The longest reaction times occurred when no information about direction or extent was provided in the precue (all parameters uncertain). Complete prior specification of target position produced the shortest reaction times. Specification of direction when extent was uncertain produced a significantly larger reduction in reaction time than specification of extent when direction was uncertain. Prior specification of extent also produced a small but significant reduction in reaction time relative to the condition in which direction and extent were specified in a mutually conditional manner. The results are discussed in relation to parameter precuing and motor programming, in which the direction is programmed by the pre-selection of neurons representing the muscles to be used in the task while programming of extent is represented by their level of activity during task performance.

Acoustic Stimulation↗
PubMed1998

Foreperiod length, but not memory, affects human reaction time in a precued, delayed response.

The effect of foreperiod length on reaction time in memorized (MM) and nonmemorized (NM), precued, delayed responses was investigated. Six subjects participated in one long and one short foreperiod schedule testing session. An aiming task, using elbow supination/pronation, in response to a visual stimulus was employed. In the MM condition, target spatial information was available for a fraction of the foreperiod duration. In the NM condition, target information was available continuously until the subject attained the target position. Subjects responded with a significantly longer latency in the long foreperiod schedule. Within each foreperiod schedule, the shortest foreperiod resulted in significantly longer reaction time. However, the absolute value of foreperiod did not have a major effect on reaction time latency. Memorization and nonmemorization conditions did not affect reaction time.

Adult↗
PubMed1998

Regulation of action-potential firing in spiny neurons of the rat neostriatum in vivo.

Both silent and spontaneously firing spiny projection neurons have been described in the neostriatum, but the reason for their differences in firing activity are unknown. We compared properties of spontaneously firing and silent spiny neurons in urethan-anesthetized rats. Neurons were identified as spiny projection neurons after labeling by intracellular injection of biocytin. The threshold for action-potential firing was measured under three different conditions: 1) electrical stimulation of the contralateral cerebral cortex, 2) brief directly applied current pulses, and 3) spontaneous action-potentials occurring during spontaneous episodes of depolarization ( state). The average membrane potential and the amplitude of noiselike fluctuations of membrane potential in the state were determined by fitting a Gaussian curve to the membrane-potential distribution. All neurons in the sample exhibited spontaneous membrane potential shifts between a hyperpolarized state and a depolarized state, but not all fired action potentials while in the state. The difference between the spontaneously firing and the silent spiny neurons was in the average membrane potential in the state, which was significantly more depolarized in the spontaneously firing than in the silent spiny neurons. There were no significant differences in the threshold, the amplitude of the noiselike fluctuations of membrane potential in the state, or in the proportion of time that the membrane potential was in the state. In both spontaneously firing and silent neurons, the threshold for action potentials evoked by current pulses was significantly higher than for those evoked by cortical stimulation. Application of more intense current pulses that reproduced the excitatory postsynaptic potential rate of rise produced firing at correspondingly lower thresholds. Because the membrane potential in the state is mainly determined by the balance between the synaptic drive and the outward potassium conductances activated in the subthreshold range of membrane potentials, either or both of these factors may determine whether firing occurs in response to spontaneous afferent activity.

Action Potentials↗
PubMed1996

Dopamine reverses the depression of rat corticostriatal synapses which normally follows high-frequency stimulation of cortex in vitro.

Learning deficits resulting from dopamine depletion suggest that striatal dopamine release is crucial for reinforcement. Recently described firing patterns of dopamine neurons in behaving monkeys show that transient increases in dopamine release are brought about by reinforcement. We describe an enduring change in the strength of synaptic transmission following pulsatile application of dopamine intended to mimic the transient increases associated with reinforcement. Intracellular records were made from neurons in slices of the rat corticostriatal system. Neurons having the properties of the medium-sized spiny neurons responded to cortical stimulation with depolarizing potentials (peak amplitude 12.0 +/- 1.3 mV; latency 9.2 +/- 0.1 ms; mean +/- S.D., n = 19), which had the properties of monosynaptic excitatory postsynaptic potentials. After trains of stimuli to the cortex had been applied in conjunction with intracellular depolarizing current, the size of these excitatory postsynaptic potentials was reduced (-27% at 20 min). Application of dopamine (approximately 30 microM) in a solution containing KCl concomitant with depolarization and presynaptic activation increased the subsequent excitatory postsynaptic potentials (+21% at 20 min) without significant lasting change in the membrane properties of the postsynaptic cell. This suggests that dopamine has an enduring, activity-dependent action on the efficacy of corticostriatal transmission, which may be a cellular basis for the learning-related effects of the nigrostriatal system.

Animals↗
PubMed1995

Effects of local connectivity on striatal function: stimulation and analysis of a model.

Neuronal population activity was investigated by computer simulation of a network model based on the neostriatum. Three network topologies were studied, based on different assumptions about the synaptic connectivity among medium spiny neurons. In all networks neurons were interconnected by inhibitory synapses. The connectivity was either symmetric, in which case all connections between cells were reciprocal and equal in strength; or asymmetric. Simulations showed that networks with symmetric connectivity receiving randomly distributed afferent excitation produced stationary spatial activity patterns. In contrast, asymmetric connectivity in homogeneous networks produced slow travelling-wave activity across the network. We suggest that the shape of the medium spiny neurons is an important determinant of synaptic connectivity and that changes in the shape of these neurons caused by Huntington's disease would result in asymmetric connectivity. Slow travelling-wave activity produced by asymmetric connectivity in the neostriatum could explain some aspects of the choreic movement and some electromyographic features seen in Huntington's patients.

Computer Simulation↗
PubMed1993

Analysis of striatal dynamics: the existence of two modes of behaviour.

The qualitative dynamical behaviour of a neural model based on the mammalian neostriatum was analyzed. The neostriatum was modelled as a mutually inhibitory network of physiological neurones, which was driven by excitatory afferents from the cerebral cortex. The analysis defined the conditions under which the system would enter into one of two dynamic modes, competition or co-activation, in terms of the parameters defining receptor-operated and voltage-sensitive channels in the neuronal membrane. We have previously argued that the mode of co-activation in the neostriatum may correspond to the state of muscular rigidity which occurs as a symptom of Parkinson's disease. The present work extends a preliminary analysis of a two-neurone system to a system of arbitrary size. An explicit prediction is made of the conditions under which a transition from co-activation to competition will occur, which is testable experimentally. The wavelength of a non-uniform activity pattern produced by small departures from uniform afferent drive is determined for one- and two-dimensional arrays of neurones. Two mild assumptions about the connectivity of the network were used to simplify the analysis, namely that the network was symmetric and homogeneous. The implications of departures from these assumptions for understanding the disordered movement seen in Huntington's disease are also considered.

Animals↗
PubMed1991

The involvement of L-type calcium channels in heterosynaptic long-term depression in the hippocampus.

The involvement of L-type calcium channels in heterosynaptic long-term depression (LTD) of the stratum radiatum input to area CA1 was studied in rat hippocampal slices. LTD of the radiatum field excitatory postsynaptic potential (EPSP) and population spike, produced by tetanization of the alveus in the presence of picrotoxin, was blocked by the calcium antagonist nimodipine and by a monoclonal antibody to the L-type calcium channel. LTD was produced in the absence of picrotoxin when the L-type calcium channel agonist, BAY-K8644, was applied. This effect was also blocked by nimodipine. These results indicate that L-type calcium channels are involved in heterosynaptic long-term depression.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus.

Non-associative long-term depression (LTD) of the stratum radiatum input to area CA1 was studied in rat hippocampal slices. Tetanization of either the alveus or stratum oriens produced greater than 30 min depression of the radiatum field EPSP and population spike, but generally only in the presence of picrotoxin. The spike depression was accounted for by the EPSP depression, and could be blocked by prior administration of an N-methyl-D-aspartate receptor antagonist. These data suggest that the induction of non-associative LTD is depolarization-dependent and involves the N-methyl-D-aspartate receptor/channel complex.

Animals↗
PubMed1991

Two dynamic modes of striatal function under dopaminergic-cholinergic control: simulation and analysis of a model.

A neural network model based on the anatomy and physiology of the matrix compartment of the striatum is described. The model consists of a network of neurons which are mutually inhibitory within a defined domain. A membrane potassium conductance (GK) under dopaminergic-cholinergic control is included in the model. Computer simulation results show that changes in GmaxK can modulate the behaviour of the network to produce either competition or coactivation among striatal output neurons. An analysis of a two-neuron system based on the model shows that the maximum steepness of the threshold function plays a decisive role in the dynamics, in particular with regard to the competition that exists between the neurons. Competitive interactions predominate at low GmaxK, while coactivation predominates at high GmaxK. We suggest that the former dynamic governs reciprocal inhibition of antagonistic muscles, while the latter governs cocontraction and rigidity. The model offers insights into the control of striatal neurodynamics by GmaxK which establish closer links between dopaminergic actions in the striatum and the mechanism of Parkinsonian rigidity. A prediction of the model is that acetylcholine should increase GKmax in striatal output neurons.

Acetylcholine↗