Differing properties of putative fast-spiking interneurons in the striatum of two rat strains.

Local circuits within the striatum of the basal ganglia include a small number of γ-aminobutyric acid (GABA)-ergic fast-spiking interneurons (FSI). The number of these cells is reduced in disorders of behavioral control, but it is unknown whether this is accompanied by altered electrophysiological properties. The genetically hypertensive (GH) rat strain exhibits impulsiveness and hyperactivity. We investigated if resting-state FSI activity is affected in this strain using extracellular recordings. We also examined the effect of systemic amphetamine (AMPH), a stimulant drug used in the treatment of these particular behavioral deficits. Putative FSI (pFSI) were encountered less often in GH rats compared to the Wistar control strain. pFSI in GH rats also exhibited a higher mean firing rate, higher intraburst firing rate, lower interburst interval, and shorter bursts compared to controls. AMPH increased the mean overall firing rate of Wistar rat pFSI but did not significantly alter the firing properties of this subtype in GH rats. These differences in the resting-state electrophysiological activity of pFSI in GH rats point to them as a cell type of particular interest in understanding striatal functioning across different strains.

Enhanced c-Fos expression in superior colliculus, paraventricular thalamus and septum during learning of cue-reward association.

Reward-mediated associative learning is important for recognizing the significance of environmental cues. Such learning involves convergence of multimodal sensory inputs with circuits involved in affective and memory processes. Dopamine-dependent plasticity in the striatum plays a pivotal role, but the wider circuits engaged in cue-reward association are poorly understood. To identify candidate structures that may be of particular interest for further detailed electrophysiological and functional analysis, we quantified c-Fos expression in a selection of brain structures. c-Fos is a well-known marker of cell activation with additional potential importance for synaptic plasticity. We compared c-Fos expression between animals exposed to 100 pairings of a novel conditioned stimulus with a subsequent reward, and control animals exposed to the same number of cues and rewards, but where the cues and rewards occurred at random with respect to each other. We found significant increases in c-Fos expression in the superior colliculus in the group exposed to cue-reward pairing. This is consistent with previous recordings in conscious animals, showing modulation of phasic visual responses of single collicular neurons depending on their association with reward. Further, the data also suggest the possibility that the thalamic paraventricular nucleus and septal nuclei may be selectively activated during cue-reward association learning. Little is known of the neurophysiological responses in these structures during such tasks, so the present results suggest they would be targets of interest for future single-neuron recording experiments, designed to confirm whether the neurons show learning-specific modulation.

Regulation of hind-limb tone by adenosine A2A receptor in rats.

Adenosine A2A receptor agonists produce a hypokinetic state (catalepsy) that is believed to reflect antagonistic interaction of A2A and dopamine D2 receptors in the basal ganglia. In addition to catalepsy, pharmacological blockade of D2 receptors produces rigidity. However there are conflicting data about the effect of A2A agonists on muscle tone, with some reports indicating an increase, while other data suggest that A2A catalepsy is dominated by muscle hypotonia. We investigated the effect on resistance to imposed movements of systemic cataleptic doses of the selective A2A agonist CGS21680 (5 mg/kg), and compared it with the effect of the D2 antagonist raclopride (5 mg/kg), in rats. Total resistance is made up of elastic and viscous components. The elastic component is velocity independent, and is referred to as "stiffness," whereas viscosity, which dampens responses to imposed movements, is velocity dependent. Using a method for quantifying total joint resistance that enabled separate identification of stiffness and viscosity, we found that during catalepsy evoked by either drug there was a clear increase in joint rigidity. Both CGS21680 and raclopride significantly increased joint stiffness, the velocity independent component of rigidity that is most affected in Parkinsonism. In contrast, the effect of CGS21680 on the velocity-dependent viscosity component was less robust than for raclopride, and did not reach significance, possibly reflecting an interaction with sedative effects via extrastriatal receptors. The effect of CGS21680 and raclopride on joint stiffness is thus consistent with previous findings suggesting functional antagonism of A2A and D2 receptors in the basal ganglia.

Biomechanical and electromyogram characterization of neuroleptic-induced rigidity in the rat.

Rodent models of Parkinson's disease (PD) are usually assessed using measures of akinesia, but other important parkinsonian symptoms such as rigidity are only rarely quantified. This is in part due to technical difficulties in obtaining such measures in small animals. In the present study we developed quantitative methods to provide time-course assessment of the alternations of muscle tone of parkinsonian rats. A portable and miniature biomechanical stretching device was established to manually stretch the hindlimb of awake rats with muscle rigidity induced by dopamine D2-receptor antagonist raclopride (5 mg/kg, i.p.). From the measured angular displacement angle and reactive torque of sinusoidal stretches at five varied frequencies, viscoelastic components of the muscle tone can be derived. In addition, non-invasive multielectrode was applied to record the tonic and phasic components of the gastrocnemius muscle electromyogram (EMG). Our biomechanical measurements showed not only increase in stiffness (P<0.05) but also increase in viscous components (P<0.05) that matched the time course of increased amplitude of EMG activity (P<0.05). There was a significant positive correlation between all of these measures and akinesia, as measured by the conventional bar-test for catalepsy (with a correlation coefficient of 0.87 at stiffness, 0.92 at viscosity and 0.96 at amplitude of EMG). Phasic contraction counts (PCC) of voluntary EMG exhibited a significantly negative correlation with the bar test scores (correlation coefficient=-0.78). These results confirm that akinesia induced by D2-receptor blockade also induces a rigidity that shares many features with human PD. These novel techniques for quantifying biomechanical and electromyographic parameters provide objective assessment methods for investigating the time-course changes of abnormal muscle tone in rat models of PD that will be useful for evaluating novel treatments.

Precision branching ratio measurement for the superallowed beta+ emitter 62Ga and isospin-symmetry-breaking corrections in A>or=62 nuclei.

A high-precision branching ratio measurement for the superallowed beta+ decay of 62Ga was performed at the Isotope Separator and Accelerator radioactive ion beam facility. Nineteen gamma rays emitted following beta+ decay of 62Ga were identified, establishing the dominant superallowed branching ratio to be (99.861+/-0.011)%. Combined with recent half-life and Q-value measurements, this branching ratio yields a superallowed ft value of 3075.6+/-1.4 s for 62Ga decay. These results demonstrate the feasibility of high-precision superallowed branching ratio measurements in the A>or=62 mass region and provide the first stringent tests of the large isospin-symmetry-breaking effects predicted for these decays.

Evidence for nontermination of rotational bands in 74Kr.

Three rotational bands in 74Kr were studied up to (in one case one transition short of) the maximum spin I(max) of their respective single-particle configurations. Their lifetimes have been determined using the Doppler-shift attenuation method. The deduced transition quadrupole moments reveal a modest decrease, but far from a complete loss of collectivity at the maximum spin I(max). This feature, together with the results of mean field calculations, indicates that the observed bands do not terminate at I = I(max).

Firing modes of midbrain dopamine cells in the freely moving rat.

There is a large body of data on the firing properties of dopamine cells in anaesthetised rats or rat brain slices. However, the extent to which these data relate to more natural conditions is uncertain, as there is little quantitative information available on the firing properties of these cells in freely moving rats. We examined this by recording from the midbrain dopamine cell fields using chronically implanted microwire electrodes. (1) In most cases, slowly firing cells with broad action potentials were profoundly inhibited by the dopamine agonist apomorphine, consistent with previously accepted criteria. However, a small group of cells was found that were difficult to classify because of ambiguous combinations of properties. (2) Presumed dopamine cells could be divided into low and high bursting (>40% of their spikes in bursts) groups, with the majority having low bursting rates. The distribution of burst incidence was similar to that previously reported with chloral hydrate anaesthesia, but the average intraburst frequency was higher in the conscious animal at rest and was higher again in bursts triggered by salient stimuli. (3) There was no evidence for spike frequency adaptation within bursts on average, consistent with the hypothesis that afterhyperpolarisation currents may be disabled during behaviourally induced bursting. (4) Presumed dopamine cells responded to reward-related stimuli with increased bursting rates and significantly higher intraburst frequencies compared to bursts emitted outside task context, indicating that modulation of afferent activity might not only trigger bursting, but may also regulate burst intensity. (5) In addition to the irregular single spike and bursting modes we found that extremely regular (clock-like) firing, previously only described for dopamine cells in reduced preparations, can also be expressed in the freely moving animal. (6) Cross-correlation analysis of activity recorded from simultaneously recorded neurones revealed coordinated activity in a quarter of dopamine cell pairs consistent with at least "functional" connectivity. On the other hand, most dopamine cell pairs showed no correlation, leaving open the possibility of functional sub-groupings within the dopamine cell fields. Taken together, the data suggest that the basic firing modes described for dopamine cells in reduced or anaesthetised preparations do reflect natural patterns of activity for these neurones, but also that the details of this activity are dependent upon modulation of afferent inputs by behavioural stimuli.

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.

Different tonic regulation of neuronal activity in the rat dorsal raphe and medial prefrontal cortex via 5-HT(1A) receptors.

It has been established that 5-HT(1A) receptors are expressed both presynaptically as autoreceptors by 5-HT containing neurones, and postsynaptically by a variety of other neurones. Activation of either somatodendritic 5-HT(1A) autoreceptors or postsynaptic 5-HT(1A) receptors induces hyperpolarisation and inhibition of action potential discharge of the neurones, but it is unclear whether 5-HT(1A) receptors are under a general tonic influence by 5-HT. In the present study, using single unit recordings from both anesthetized and non-anesthetized rats, we show that the activity of neurones in the medial prefrontal cortex is not altered by systemic administration of the selective 5-HT(1A) receptor antagonist, WAY 100635. In contrast, WAY 100635 increased the firing rate of 5-HT neurones in the dorsal raphe nucleus. Our findings indicate a tonic activation of presynaptic somatodendritic but not postsynaptic cortical 5-HT(1A) receptors.

Cardiovascular risk factors for people with mental illness.

OBJECTIVE: The objective of this study was to document the prevalence of risk factors for cardiovascular disease among people with chronic mental illness. METHOD: A cross-sectional survey was conducted of 234 outpatients attending a community mental health clinic in the North-western Health Care Network in Melbourne, Australia. Prevalence of smoking, alcohol consumption, body mass index, hypertension, salt intake, exercise and history of hypercholesterolemia was assessed. RESULTS: Compared with a community sample, the mentally ill had a higher prevalence of smoking, overweight and obesity, lack of moderate exercise, harmful levels of alcohol consumption and salt intake. No differences were found on hypertension. Men, but not women, with mental illness were less likely to undertake cholesterol screening. CONCLUSIONS: Psychiatric outpatients have a high prevalence of cardiovascular risk factors which may account for the higher rate of cardiovascular mortality among the mentally ill. Further research is needed to trial and evaluate interventions to effectively modify risk factors in this vulnerable population.

Risk factors for HIV/AIDS and hepatitis C among the chronic mentally ill.

OBJECTIVE: The objective of this study was to document the prevalence of risk factors for HIV/AIDS and hepatitis C among people with chronic mental illness treated in a community setting. METHOD: 234 patients attending four community mental health clinics in the North-western Health Care Network in Melbourne, Australia, completed an interviewer-administered questionnaire which covered demographics, risk behaviour and psychiatric diagnosis. RESULTS: The sample was 58% male, and 79% of the sample had a primary diagnosis of schizophrenia. Forty-three per cent of mentally ill men and 51% of mentally ill women in the survey had been sexually active in the 12 months preceding the survey. One-fifth of mentally ill men and 57% of mentally ill women who had sex with casual partners never used condoms. People with mental illness were eight times more likely than the general population to have ever injected illicit drugs and the mentally ill had a lifetime prevalence of sharing needles of 7.4%. CONCLUSIONS: The prevalence of risk behaviours among the study group indicate that people with chronic mental illness should be regarded as a high-risk group for HIV/AIDS and hepatitis C. It is essential that adequate resources and strategies are targeted to the mentally ill as they are for other high-risk groups.

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.

Neural activity of supplementary and primary motor areas in monkeys and its relation to bimanual and unimanual movement sequences.

A chronic single-unit study of motor cortical activity was undertaken in two monkeys trained to perform a bimanually coordinated task. The hypothesis was tested that the supplementary motor area plays a specific role in coordinating the two hands for common goal-oriented actions. With this objective, a special search was made for neurons that might exhibit properties exclusively related to bimanual task performance. Monkeys learned to reach for and to pull open a spring-loaded drawer with one hand, while the other hand reached out to grasp food from the drawer recess. The two hands were precisely coordinated for achievement of this goal. Monkeys also performed, in separate blocks of trials, only the pulling or grasping movements, using the same hands as in the bimanual task. Task-related activity of 348 neurons from the supplementary motor area and 341 neurons from the primary motor area, each examined in the bimanual and in both unimanual tasks, was recorded in the two hemispheres. Most neurons from the supplementary motor area were recorded within its caudal microexcitable portion. Contrary to expectation, the proportion of neurons with activity patterns related exclusively to the bimanual task was small, but somewhat higher in the supplementary motor area (5%) than in the primary motor cortex (2%). Another group of neurons that were equally modulated during the bimanual as well as to both unimanual task components might also contribute in controlling bimanual actions. Such "task-dependent" rather than "effector-dependent" activity patterns were more common in neurons of the supplementary motor area (19%) than of the primary motor cortex (5%). Bilateral receptive fields were also more numerous among the supplementary motor area neurons. However, a large majority of neurons from primary and supplementary motor areas had activity profiles clearly related only to contralateral hand movements (65% in the primary motor and 51% in the supplementary motor area). A similar group of neurons showed an additional slight modulation with ipsilateral movements; they were equally common in the two areas (14% and 16%, respectively) and their significance for bimanual coordination is questionable. Summed activity profiles of all neurons recorded in the primary and supplementary motor areas of the same hemisphere were compared. The modulations of the three histograms, corresponding to the two unimanual and the bimanual tasks, were similar for the two motor areas, i.e. prominent with bimanual and contralateral movements and weak with ipsilateral movements. It is concluded that the supplementary motor area is likely to contribute to bimanual coordination, perhaps more than the primary motor cortex, but that it is not a defining function for the former cortical area. Instead, it is suggested that the supplementary motor area is part of a callosally interconnected and distributed network of frontal and parietal cortical areas that together orchestrate bimanual coordination.

Neuronal activity in rat red nucleus during forelimb reach-to-grasp movements.

The activity of 259 task-related red nucleus neurons was recorded using chronic electrophysiological methods in free moving rats. Modulations in activity were analysed in relation to onset (first detected wrist movement) and end (arrival of the paw over the food) of a reach-to-grasp movement. Excitatory peaks were found to begin before, during and after the reach, but there were clear peaks in the distribution of onset times after reach-onset and before reach-end, reflecting the fact that one third of all peaks began specifically during the reach, although this occupied only a small fraction of the analysis time. Both excitations and inhibitions showed a strong tendency to end in close temporal association with reach-end. Analysis of excitatory modulation amplitudes showed that the largest peaks were formed when data was aligned to reach-end, and that these largest peaks nearly all began during the reach and ended precisely at the time the paw would have been about to grasp the food. The spread of neural activation onset times throughout the course of the complex reach-to-grasp movement is consistent with a relationship of individual neurons in the rat red nucleus with movements of all parts of the forelimb, as would be expected if all limb muscle groups are represented in the nucleus. On the other hand the disproportionate number of modulations that occur during the reach and their strong alignment with time of reach-end suggests there is a bias in red nucleus function towards the control of distal motions associated with accurate grasp, consistent with the result of recent lesion studies. This provides indirect evidence that functionally the rat red nucleus may be organized in a similar way to that of monkeys, in which an important role in control of accurate distal movements is well established. The possibility is discussed that red nucleus offers a timing signal for co-ordination of movements across joints, in particular the precise distal-proximal binding normally seen in accurate reach-to-grasp movements.

Spatiotemporal activity patterns of rat cortical neurons predict responses in a conditioned task.

Precise and repeated spike-train timings within and across neurons define spatiotemporal patterns of activity. Although the existence of these patterns in the brain is well established in several species, there has been no direct evidence of their influence on behavioral output. To address this question, up to 15 neurons were recorded simultaneously in the auditory cortex of freely moving rats while animals waited for acoustic cues in a Go/NoGo task. A total of 235 significant patterns were detected during this interval from an analysis of 13 hr of recording involving over 1 million spikes. Of particular interest were 129 (55%) patterns that were significantly associated with the type of response the animal made later, independent of whether the response was that prompted by the cue because the response occurred later and the cue was chosen randomly. Of these behavior-predicting patterns, half (59/129) were associated with an enhanced tendency to go in response to the stimulus, and for 11 patterns of this subset, trials including the pattern were followed by significantly faster reaction time than those lacking the pattern. The remaining behavior-predicting patterns were associated with an enhanced NoGo tendency. Overall mean discharge rates did not vary across trials. Hence, these data demonstrate that particular spatiotemporal patterns predict future behavioral responses. Such presignal activity could form templates for extracting specific sensory information, motor programs prespecifying preference for a particular act, and/or some intermediate, associative brain process.

Stimulus congruence affects perceptual processes in a novel Go/Nogo conflict paradigm in rats.

The performance of freely moving rats (n=18) in a decision-making reaction time task was analyzed to provide data that can be compared with noise-compatibility paradigms previously obtained in humans. Rats were first trained in an auditory pitch discrimination task involving a Go/Nogo response choice. In a subsequent phase, the two tones used in the previous phase were simultaneously presented in different combinations from two locations. Only the presence of the correct tone from the correct location was predictive of the reward. The observed behavioral strategies suggest a competition between two processes: one involving stimulus evaluation, response preparation and execution, the other involving recognition of the stimulus features associated with inhibition of the Go-response. The reaction times in the most adopted strategies towards the end of the experiment suggest an effect of stimulus congruence. Perceptual processes are affected by the congruence of 'pitch' and 'location' stimulus dimensions and the duration of the response may, but need not, be affected by overlapping dimensions. The analysis of error and aborted trials also suggest that subject's reaction and subsequent motor action may depend on whether stimulus identification processes can pass information to the response activation system prior to completion of sensory processing. The data are discussed in the framework of processing stages theory and dimensional overlap model.

Neural activity related to reaching and grasping in rostral and caudal regions of rat motor cortex.

The objective of this study was to assess the relation of motor cortical neural activity in the rat to self-paced reach-to-grasp movements. Overall, around 40% of excitatory and 60% of inhibitory modulations in neuronal activity began prior to reach onset. These data are consistent with a role for rat motor cortex in the initiation and control of the reaching movement. In addition, although the reach only lasted a short time, 30% of excitations and inhibitions began while it was in progress. The existence of such modulations occurring during the reach is consistent with previous data showing activity of cortical neurons late in the reach, and suggests a heavy involvement of cortical neurons in controlling the recently described, complex movements associated with grasping that are seen in the rat. These features were broadly similar in neurones from both the caudal and rostral subdivisions of rat motor cortex.

Effects of lesions in the mesial frontal cortex on bimanual co-ordination in monkeys.

The hypothesis was tested that the mesial frontal cortex, including the supplementary motor area, is engaged in bimanual co-ordination. Three monkeys, trained in a well-co-ordinated bimanual pull-and-grasp task, were subjected to unilateral or bilateral lesions of the mesial frontal cortex. With unilateral lesions, the deficit consisted in a delay in movement initiation of the contralateral arm. With a bilateral lesion, the deficit was more pronounced with marked bilateral delays in movement onset and slowing in reaching. However, in the three monkeys bimanual co-ordination at the moment of goal achievement remained intact with an excellent temporal co-variation of the two limbs. In the two unilateral cases, an adaptive strategy developed after a few sessions, either by catching up during reaching with the limb contralateral to the lesion (monkey M1) or by delaying movement initiation of the limb ipsilateral to the lesion (monkey M2). This outcome is discussed in terms of Lashley's principle of motor equivalence, i.e. invariant goal achievement with variable means. Bilateral lesions led to a transient and near-total impairment in movement self-initiation when all external cues were absent. It is concluded that in monkeys the mesial frontal cortex does not play a crucial role in bimanual co-ordination but rather in movement initiation, especially when sensory cues are absent.

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.

Does having to remember the position of a target improve reaction time?

In the monkey, reaction time in a precued delayed response task was found to be faster when the animals had to remember the precue than when it was continually available (Smyrnis, Taira, Ashe, & Georgopoulos, 1992). We investigated whether this reflects a general principle that applies to all types of precued tasks. However, we found the opposite result in a simpler task in humans. Our findings suggest that the beneficial effect of a memory requirement on reaction time in the monkey may reflect an effect of task difficulty, rather than a fundamental process involved in all precued movement tasks.