Biomedical subjects

D J Surmeier

Publications and source records attributed to D J Surmeier.

At least 73 records · Page 4Linked to original sources

PubMed1991

High- and low-voltage activated calcium currents are expressed by neurons cultured from embryonic rat neostriatum.

Current-clamp studies have shown that voltage-dependent Ca currents are present in rat neostriatal neurons. Although these studies have provided evidence for the presence of high-voltage activated Ca channels, it has been unclear whether low-voltage activated channels are also present. Using the whole-cell variant of the patch-clamp technique, we have studied isolated Ca currents in an attempt to answer this question. We have found that both high- and low-voltage activated calcium currents are expressed by neostriatal neurons cultured from embryonic rat brain. These currents are similar in voltage-dependence and pharmacology to those found in other brain neurons.

Animals↗

PubMed1991

Developmental regulation of a slowly-inactivating potassium conductance in rat neostriatal neurons.

In late embryonic and early post-natal rat neostriatal neurons, the voltage-dependent potassium currents activated by depolarization are largely attributable to a rapidly inactivating A-current and a delayed rectifier current. Over the first 4 weeks of post-natal life, a third potassium current emerges in most cells. This slowly inactivating conductance is distinct from the A-current and delayed rectifier in voltage-dependence, kinetics and pharmacology. The properties of this conductance suggest that it may be of central importance to the integrative behavior of neostriatal neurons by controlling such features as first spike latency and interspike interval.

Animals↗

PubMed1990

Muscarinic regulation of cyclic AMP metabolism in rat neostriatal cultures.

Muscarinic receptor expression and function were investigated in cultured rat neostriatum. Muscarinic receptor levels were determined from saturation binding experiments performed on intact cultures using [3]N-methylscopolamine. In cultures maintained for 3, 7 and 12-14 days in vitro, the Bmax was 2.3, 5.4 and 10.9 fmol/culture. The average number of receptors per neuron increased during the 2nd week in vitro. Carbachol (100 microM) had no significant effect on basal cAMP levels but reduced cAMP levels elevated by forskolin. Carbachol significantly reduced cAMP levels stimulated with dopamine only in cultures untreated with a phosphodiesterase inhibitor. Comparing equimolar doses, the carbachol response was more sensitive to the M1 selective antagonist pirenzepine than the cardioselective M2 antagonist AF-DX 116. These results suggest that the muscarinic receptors regulate cAMP levels in neostriatal neurons and, in so doing, provide a post-synaptic substrate for the interaction of dopamine and acetylcholine.

1-Methyl-3-isobutylxanthine↗

PubMed1990

Serotonin enhances excitability in neostriatal neurons by reducing voltage-dependent potassium currents.

The physiological effects of serotonin (5-HT) on rat neostriatal neurons were investigated using current-clamp techniques in neostriatal slices and voltage-clamp techniques in acutely dissociated adult neostriatal neurons. In most neurons (35/51), bath-applied 5-HT (10-60 microM) decreased the first spike latency and increased the evoked firing frequency. Membrane input resistance was also increased in most neurons (33/35) but could not explain the enhanced responsiveness. Tetrodotoxin, at concentrations sufficient to block spike production, did not block the ability of 5-HT to enhance the slow ramp-like voltage trajectory produced by depolarizing current injection. The role of potassium currents in the 5-HT effect was examined using whole cell voltage-clamp; in 6 of 9 neurons, 5-HT reversibly decreased inactivating potassium currents activated by depolarization. These experiments suggest that 5-HT's effect on the ramp trajectory may be mediated by a reduction of potassium currents activated by sub-threshold depolarization.

Animals↗

PubMed1990

Quinolinate and kainate neurotoxicity in neostriatal cultures is potentiated by co-culturing with neocortical neurons.

It has been suggested that a disorder in the regulation of excitatory amino acids (EAA) may underlie the loss of neostriatal neurons seen in Huntington's disease. The role of neocortical afferent fibers in determining the EAA sensitivity of neostriatal neurons was assessed by comparing EAA toxicity in co-cultures of neocortex and neostriatum with that of neostriatum alone. In cultures of neostriatum alone, EAAs produced only modest neuronal losses. Kainate, which tended to be the most potent excitotoxin, produced a loss of approximately 30% of the neurons after a 5-min exposure at a 1-mM concentration. In co-cultures, the sensitivity of neostriatal neurons to EAA toxicity was dramatically enhanced; toxicity was increased about two-fold for kainate and quinolinate at millimolar concentrations and as much as 8-fold for quinolinate at micromolar concentrations. The effects of EAA co-incubation with the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonovaleric acid, suggested that the toxic actions of quinolinate, but not kainate, were mediated largely by NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1990

Muscarinic modulation of a transient K+ conductance in rat neostriatal neurons.

Neurons of the neostriatum are richly innervated by cholinergic neurons of intrinsic origin. Both pre- and post-synaptic muscarinic receptors mediate the effects of acetylcholine (ACh). Activation of these receptors is functionally significant, particularly in Parkinson's disease. Current-clamp studies indicate that muscarinic receptors serve to decrease the responsiveness of neostriatal neurons to excitatory inputs. Here we present evidence that this effect is caused, in part, by the muscarinic modulation of the A-current, a transient outward potassium current. The voltage dependence of this current suggests that normally it enhances spike repolarization and slows discharge rate, but does not affect 'synaptic integration'. We find that under the influence of muscarinic agonists, the voltage dependence of A-current activation and inactivation is shifted towards more negative membrane potentials and the peak conductance is increased. Therefore, at relatively hyperpolarized resting potentials, ACh transiently alters the functional role of the A-current, allowing it to suppress excitatory inputs and further slow the discharge rate. But at relatively depolarized resting potentials, ACh increases excitability by removing the A-current through inactivation.

Acetylcholine↗

PubMed1990

M1 muscarinic acetylcholine receptor in cultured rat neostriatum regulates phosphoinositide hydrolysis.

Muscarinic acetylcholine receptor expression and function in cultured rat neostriatal neurons were examined. All experiments were performed on intact neurons grown in vitro for 12-14 days. The muscarinic antagonist N-[3H]methylscopolamine [( 3H]NMS) binds to a single site in cultures with a KD of 89 pM and a Bmax of 187 fmol/mg of protein, or 32,000 sites/neuron. Competition studies using [3H]NMS were performed to determine what receptor subtypes were present. Nonlinear analysis of competition curves was best described with a single binding site for atropine, pirenzepine, and AF-DX 116 (11-[[2-[(diethylamino)-methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepine-6-one), with Ki values of 0.6, 62, and 758 nM, respectively. These results indicate that the muscarinic receptors present in neostriatal cultures are of the M1 subtype, having high affinity for pirenzepine and low affinity for AF-DX 116. In contrast with antagonists, carbachol displaced [3H]NMS from two sites with Ki values of 6.5 and 147 microM, with the higher-affinity form predominant (83% of sites). The M1 receptor subtype was linked to phosphoinositide turnover. Carbachol stimulated the formation of phosphoinositides with an EC50 of 37 microM and was antagonized by atropine. At equimolar doses, pirenzepine was more potent than AF-DX 116 at antagonizing the response.

Animals↗

PubMed1989

Two types of A-current differing in voltage-dependence are expressed by neurons of the rat neostriatum.

Transient potassium currents of the A type are thought to be important in a number of physiological processes of excitable cells, including spike repolarization and synaptic integration. This functional diversity may reflect the contribution of distinct subtypes of A channel to cellular behavior. Using the whole-cell variant of the patch clamp technique, we have found that two types of A-current are expressed in rat neostriatal neurons, one that is similar to previous descriptions in mammals and a second that is activated at considerably more depolarized potentials.

Animals↗

PubMed1989

Ultrastructural analysis of axosomatic contacts on functionally identified primate spinothalamic tract neurons.

The morphology and frequency of axosomatic contacts on three functionally identified primate spinothalamic tract (STT) cells were analyzed at the electron microscopic level. The STT cells analyzed were wide-dynamic-range neurons responsive to activation of low- and high-threshold cutaneous afferents innervating the foot. The somas were located in the lateral border of lamina V; the dendritic trees were oriented dorsally and were very extensive. Numerous spinelike appendages were observed emanating from two of the cell bodies. Terminal types contacting the cell bodies were categorized at several different layers through each neuron. Six morphologically different terminal types were established following analysis of serial sections. Profiles classified as round (R) terminals containing round clear vesicles and zero or one dense-core vesicle made up over 50% of the total population in contact with the STT somas. Profiles containing round clear vesicles and two to four small-diameter dense-core vesicles (D1 category) made up approximately 10% of the population in contact with each soma. Flat (F) terminals with oblong or flattened clear vesicles made up approximately 8% of the population. The remaining three categories (D2, L1, and L2) distinguished by the number and size of the dense-core vesicles made up a small percentage of the total population in contact with the cell bodies. The distribution of terminal types on the soma proper versus somatic spines was also determined for one cell. The proportions of the six terminal types contacting the soma of these cells were very similar, although the physiological characteristics of each cell were different. However, the relative proportions of terminal types on these three lamina V STT cell bodies were different from those previously reported contacting somata in lamina V, suggesting that there may be a unique innervation of STT cells that differentiates them from other cell types in lamina V.

Action Potentials↗

PubMed1989

Patterns of spontaneous discharge in primate spinothalamic neurons.

1. The spontaneous discharge of 30 spinothalamic tract (STT) neurons in the lumbosacral spinal cord of anesthetized monkeys was studied. Interval, correlation, and spectral analyses were performed. 2. Three patterns of discharge were found; these were referred to as the SP1, SP2, and SP3 patterns. 3. The SP1 group had moderately regular discharge trains that were devoid of short-interval spike bursts. 4. The SP2 group had spike trains dominated by short-interval bursts without evidence of low-frequency rhythmicity. 5. The SP3 group had spike trains with features of both the SP1 and SP2 groups. 6. Some correlations were found between the mean discharge rate and stimulus-response classes previously defined by our group (25). Correlations were deduced from a parent data set of 221 STT neurons. Type 1 neurons, which were driven primarily by tactile afferents, were found to have significantly lower mean rates than other "within-neuron" groups. On the other hand, type C neurons, which had strong input from afferents signalling pressure and noxious stimuli, were found to have significantly higher mean rates than all other "across-neuron" classes. 7. A weak relationship was found between the pattern of discharge and the within-neuron stimulus-response classification. Neurons with a largely tactile coding orientation (types 1 and 2) were most frequently of the SP1 and SP2 classes, whereas neurons with a more prominent nociceptive input (types 3 and 4) were most frequently of the SP2 and SP3 classes. No relationship was apparent between discharge pattern and the across-neuron classes.

Animals↗

PubMed1988

Voltage-clamp analysis of a transient potassium current in rat neostriatal neurons.

Whole cell voltage-clamp recordings were made from cultured rat neostriatal neurons. Depolarizing voltage commands evoked transient and sustained outward K-currents. The transient K-current was activated by depolarizing commands beyond -50 mV; peak current was dependent upon holding potential. Bath application of 4-aminopyridine, but not inorganic calcium channel blockers (Cd, Co, Mn), attenuated the transient current. Reversal was near the K-equilibrium potential. These properties suggest that this transient K-current is similar to the A-current described in a number of other neurons.

4-Aminopyridine↗

PubMed1988

The expression of gamma-aminobutyric acid and Leu-enkephalin immunoreactivity in primary monolayer cultures of rat striatum.

Primary monolayer cultures of rat striatum were examined for gamma-aminobutyric acid (GABA) and leucine-enkephalin (L-ENK) immunoreactivity. Cultures were established on polycation-treated glass coverslips from the striata of gestational day 17 rat embryos using a serum and insulin-supplemented medium. The proportion of GABA-immunoreactive (GABA-IR) neurons increased during the first week in vitro from approximately one third to nearly one half and remained relatively constant thereafter. On the other hand, the proportion of L-ENK-IR neurons increased gradually over the culturing period, increasing from about one-fifth of the neurons initially to one-half after 3-4 weeks in vitro. The changes in the proportions of GABA- and L-ENK-IR neurons appeared to be largely a consequence of the death of non-immunoreactive neurons, not delayed expression or induction of GABA or L-ENK traits. Light microscopic analysis of somatic-proximal neuritic morphology led to a partitioning of the neuronal population into 4 groups. GABA- and L-ENK-IR groups were heterogeneous in this regard and differed only modestly.

Animals↗

PubMed1988

Natural groupings of primate spinothalamic neurons based on cutaneous stimulation. Physiological and anatomical features.

1. Two hundred and twenty-one spinothalamic tract (STT) neurons in the lumbar spinal cord of anesthetized monkeys were studied. The majority of the recordings were in laminae IV-VI. Thirteen of these neurons were intracellularly injected with horseradish peroxidase and histologically reconstructed. 2. A standard series of four mechanical cutaneous stimuli, which ranged in intensity from innocuous brushing to tissue-damaging pinching, were used to test the mechanical responsiveness of STT neurons. The mean alterations in discharge rate produced by these test stimuli when delivered to a neuron's excitatory receptive field were used as response measures. 3. Univariate and bivariate analyses of these response measures failed to reveal natural groupings of STT neurons. To assess whether natural groupings dependent upon shared multivariate response patterns were present, a k-means cluster analysis of the responses was performed. 4. Because an assumption about the type of coding used by the STT system had to be made prior to clustering, two independent analyses were performed. One approach assumed a labeled line coding model; response magnitudes were determined within the context of the neuron under study (within-neuron analysis). The other approach assumed a population coding model; response magnitudes were determined within the context of the STT population (across-neuron analysis). 5. The within-neuron analysis suggested that the STT sample could be partitioned into four groups. The smallest group (n = 18, 8%) responded primarily to brushing but often had a convergent nociceptive input; this group was referred to as type I. A second group (n = 31, 14%) had strong responses to low-intensity stimuli, particularly pressure, and modestly larger responses to noxious stimuli; this group was referred to as type II. The clustering in these two groups was relatively weak, reflecting some heterogeneity in response pattern. 6. The largest within-neuron group (n = 108, 49%) was most responsive to noxious stimuli but had a saturating response function; because of their apparent role in coding intermediate intensity stimuli, this group was referred to as type III. The fourth group (n = 64, 29%) responded best to the most intense stimulus used; this group was referred to as type IV. 7. The across-neuron analysis also suggested that the STT sample could be partitioned into four groups. The largest group (n = 122, 55%) had relatively weak responses to all the cutaneous stimuli; this group was referred to as type A. 8. All of the remaining across-neuron groups had mean responses at or above the mean for all cutaneous stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1987

Properties of proprioceptive neurons in the cuneate nucleus of the cat.

Fifty-two slowly adapting proprioceptive neurons in the cuneate nucleus of chloralose-anesthetized cats were studied. Recordings were made from 3 mm rostral to the obex to 5 mm caudal. The highest densities of proprioceptive neurons were found above and more than 3 mm caudal to the obex. Analysis of the spike trains produced with the forelimb held fixed revealed three basic periodic patterns. Neurons exhibiting these patterns were partitioned into three groups, referred to as the A, B, and C classes. Class A neurons (42%; 22/52) produced regular spike trains that were qualitatively similar to muscle spindle fibers. Interval distributions for this class were typically unimodal and slightly positively skewed. Adjacent intervals were frequently positively correlated. Spectral analysis suggested that 91% of class A spike trains had one to two periodic components. Class B neurons (21%; 11/52) had additional spikes interposed in their periodic discharge; these "interrupting" spikes did not significantly alter the timing of the dominant periodic discharge. Interval distributions were typically bimodal and adjacent intervals were negatively correlated. Spectral analysis suggested that two or more periodic components were present in their spike trains. Class C neurons (36%; 26/52) had spike trains with a basic rhymicity, but when this specific discharge was interrupted, the subsequent interval was near modal length; thus, they were "reset." Interval distributions were usually multimodal and adjacent intervals were frequently negatively correlated. Spectral analysis suggested that C spike trains usually had four or more periodic components. Estimates of information-carrying capacity of each class using a mean rate code and those of primary muscle spindle fibers suggested that a sizable information loss may occur in synaptic transmission. This potential loss was smaller for A-neurons (40%) than for B- (69%) or C-neurons (64%). Electrical stimulation of cutaneous structures influenced 55% (22/52) of the sample. All were members of the B and C classes. Responses were typically biphasic. The cutaneous receptive fields nearly always included a portion of the forepaw. No relationship was found between movement sensitivity and receptive field topography. Contralateral input was found in half (10/20) the neurons tested.

Afferent Pathways↗

PubMed1987

Intrinsic features contributing to spike train patterning in proprioceptive cuneate neurons.

The intrinsic processes contributing to the three discharge patterns of proprioceptive cuneate neurons described by Surmeier and Towe were studied experimentally and with computer simulation. Examination of the alterations in excitability produced by antidromic activation suggested that a prolonged inhibition was a concomitant of discharge in proprioceptive cuneate neurons. Computer simulation was performed to test the possible roles of inhibitory hyperpolarizing processes in governing the observed discharge patterns. These simulations used two constant threshold models. The simplest model linearly integrated synaptic potentials until the spike threshold was reached. After the discharge, synaptic potentials that preceded the spike were ignored (i.e., the model was "reset"). The second model was similar to the first except that following a spike two hyperpolarizing processes were activated and preceding events continued to play a role in membrane potential. Simulation of class A spike trains that possessed positive correlations between nearby intervals was successful only with a resetting model. This suggested that class A neurons have fast, no-memory postspike conductance changes, which effectively shunt synaptic charge. Simulation of class B spike trains was possible with the nonresetting model. At least two periodic inputs, which evoked brief, relatively large EPSPs, were required. In addition, a prominent, fast, spike-dependent hyperpolarization and a small-amplitude, slow hyperpolarization were required. Simulation of class C spike trains was also possible with the nonresetting model. Several periodic inputs were required; one input had to evoke a slow suprathreshold EPSP. In contrast to class B simulations, class C spike train simulation required that a large-amplitude, slow hyperpolarization, as well as a brief hyperpolarization, following spike initiation. The results of class B and C simulations suggested that these two groups differed primarily in the amplitude of a slow, hyperpolarizing, postspike conductance. Some role may also be played by the time course of the driving EPSPs.

Animals↗

PubMed1986

Classification of primate spinothalamic and somatosensory thalamic neurons based on cluster analysis.

Data analyzed in this study were derived from the responses of 128 spinothalamic tract (STT) cells and 110 thalamic neurons recorded in 75 anesthetized monkeys. A k-means cluster analysis, a nonhierarchical clustering technique, was performed using the relative magnitudes of responses to a graded series of innocuous and noxious mechanical stimuli applied to the receptive field. For comparison, a parallel analysis was performed based on definitions of low-threshold (LT), wide dynamic range (WDR), and high-threshold (HT) cells used by our laboratory. For 128 STT cells, a classification scheme with three clusters was found statistically to be the best. This yielded groups of 22, 57, and 49 cells in clusters 1, 2, and 3, respectively. Cluster 1 cells were activated best by low-intensity mechanical stimuli, whereas cluster 3 cells were activated primarily by nociceptive stimuli. Cluster 2 cells had intermediate characteristics. When the classification scheme based on the cluster analysis was compared with the classification of the same neurons as LT, WDR, and HT cells, cluster 1 cells were divided into LT and WDR cells, whereas cluster 2 and 3 cells included WDR and HT cells. For 110 thalamic neurons, a classification scheme with five clusters was found statistically to be the best. Clusters 1-5 contained 25, 34, 17, 10, and 24 cells, respectively. Response characteristics of cells in each group indicated a gradual change in sensitivity to higher intensities of peripheral input from cluster 1 to 5. When this classification scheme was compared with the classification scheme previously used by our laboratory, cluster 1 cells belonged to the LT group, clusters 2 and 3 split into LT and WDR cells, and clusters 4 and 5 included WDR and HT cells. It is concluded that a classification scheme based on a cluster analysis of the responses of neurons to standardized stimuli may provide an objective and functionally meaningful way to categorize somatosensory neurons.

Animals↗

PubMed1986

Responses of primate spinothalamic neurons to noxious thermal stimulation of glabrous and hairy skin.

Extracellular recordings were made from 81 primate spinothalamic (STT) neurons in the L7-S1 segments of the spinal cord. The majority of the sample was recorded from within laminae IV-V. The responses of STT neurons to noxious thermal stimulation of glabrous and hairy skin were studied in an attempt to identify a neural substrate for the differences in thermal sensation evoked by noxious stimulation of these two types of skin. In addition, the responses to graded mechanical stimuli were examined for evidence of differential sensitivity. Thermal intensity-response functions were constructed from the alteration in the mean discharge rate produced by a 30-s thermal pulse of 43-55 degrees C. Generally, the functions derived from stimulation of both hairy and glabrous skin were either linear or positively accelerating. Deceleration in the response functions was occasionally observed above 53 degrees C. The population mean discharge rate derived from glabrous skin stimulation was significantly greater than that derived from hairy skin stimulation above 49 degrees C. Cluster analysis was used to assess whether the STT population could be partitioned into functionally relevant subgroups. No clustering was evident on the basis of the alteration in discharge rate during stimulation alone. Analysis of the alteration in mean discharge rate during and following thermal stimulation identified four groups; these were referred to as the Amnr, Bmnr, Cmnr, and Dmnr classes. The clustering was not dependent on differences in the responses evoked from hairy and glabrous skin. The mechanical and thermal sensitivities of each thermal class covaried. The capacity of the STT population to code the quality of noxious thermal stimuli, as judged by changes in the across-neuron discharge pattern, was assessed with a multidimensional scaling technique (MDS). The results suggest that the population discharge could be used to order stimuli correctly from 45 to 55 degrees C. Also, it was found that a substantial change in the population's discharge pattern occurred to stimuli between 47 and 49 degrees C when delivered to hairy skin. A similar alteration in the population's discharge pattern occurred to glabrous skin stimuli near 51 degrees C. These alterations in population behavior may underly the alterations in sensory quality in humans that occur in these temperature ranges when stimulating hairy and glabrous skin. The possible roles of the thermally and mechanically based classes in thermal intensity and quality coding were examined. Within the lower intensity ranges (less than 49-51 degrees C), the Cmnr and Dmnr classes appeared to be best suited to intensity coding.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Temporal features of the responses of primate spinothalamic neurons to noxious thermal stimulation of hairy and glabrous skin.

Extracellular recordings were made from 81 primate spinothalamic (STT) neurons in the L7-S1 segments of the spinal cord. The majority of the sample was recorded from within laminae IV-V. The temporal features of the responses to noxious thermal stimulation of glabrous and hairy skin were studied in an attempt to determine whether natural groupings of STT neurons could be identified on the basis of response time course alone and whether these groups were skin type dependent. The relationship between these groups and those based on static response features (37) was also explored in an attempt to define more fully their potential functional roles. In most STT neurons, the thermally evoked responses typically appeared to have two response components, particularly at stimulus temperatures above 49 degrees C. The first response phase typically peaked within 1-12 s of stimulus onset and then adapted. The second phase slowly rose to a maximum, typically 15-30 s following stimulus onset. The existence of natural groupings of STT neurons based upon the characteristics of these two response components was assessed with a k-means cluster analysis. On the basis of the onset and early peak latencies, two well-defined short and long latency neuronal clusters were found in the responses evoked from both glabrous and hairy skin; these were referred to as the SP1 and LP1 classes, respectively. The glabrous and hairy skin SP1 classes did not differ significantly in either onset or early peak latency for stimuli of 47-55 degrees C. However, the hairy skin LP1 class had significantly shorter onset latencies than the glabrous skin LP1 class for stimuli of 49-53 degrees C, as well as shorter peak latencies for stimuli of 49 and 51 degrees C. The SP1 class constituted 62% of the hairy skin subset, whereas the LP1 class constituted 57% of the glabrous skin subset. A cluster analysis of the late-peak latencies also revealed two subgroups. In the responses evoked from both glabrous and hairy skin, the longer latency classes (LP2) constituted more than 80% of the samples. With one exception, no dependence upon the type of skin that was stimulated was found in the latencies of either the LP2 class or the shorter latency SP2 class. Prior conditioning of the skin with a 30-s thermal pulse of 51-55 degrees C led to a suppression of the early response phase and an enhancement of the late phase in nearly all cases examined (n = 11). This pattern was independent of skin type.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗