Basal ganglia macrocircuits.

This is the introductory chapter to an edited volume comprising 18 chapters written by 38 specially selected authors covering the anatomy, physiology, biochemistry/pharmacology and behavioral aspects of GABA in the basal ganglia. In this chapter the various nuclei of the basal ganglia are defined and their cellular structure, connections and function reviewed in brief in order to provide an orientation for the subsequent 17 chapters.

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels.

The firing patterns of dopaminergic neurons in vivo are strongly modulated by afferent input. The principal GABAergic inputs to the dopaminergic neurons of the substantia nigra originate from neurons of the neostriatum, globus pallidus and substantia nigra pars reticulata. It has previously been shown that the firing pattern of nigral dopaminergic neurons can be manipulated by pharmacologically induced excitation or inhibition of the globus pallidus with relatively little effect on firing rate. We used this technique to explore the relation between the firing pattern of dopaminergic neurons and extracellular dopamine levels in the neostriatum in vivo. Specifically, we tested whether an increase in burst firing in dopaminergic neurons produced by increased pallidal activity led to increased extracellular dopamine levels in the neostriatum. Single unit extracellular recording combined with simultaneous microdialysis was used to measure the firing rates and patterns of dopaminergic neurons and extracellular striatal dopamine levels, respectively, during bicuculline-induced excitation of the globus pallidus. Pallidal excitation resulted in a marked increase in burst firing in dopaminergic neurons along with only a slight increase in firing rate, but produced a significant elevation (approximately 45%) in neostriatal dopamine levels. These data suggest that afferent-induced burst firing in dopaminergic neurons leads to an increase in extracellular dopamine levels in the neostriatum when compared with less bursty patterns with similar overall firing rates.

Reducing gene expression in the brain via antisense methods.

This unit presents protocols that employ antisense oligodeoxynucleotides to reduce expression of target proteins in the brain. These oligonucleotides are generally designed to inhibit synthesis of a specific protein by hybridization to its mRNA. Because oligonucleotides show very poor penetration into the central nervous system (CNS) after systemic administration, they are either injected into the cerebrospinal fluid (CSF) or infused directly into the brain parenchyma. In this unit, the procedure most commonly used for delivering oligonucleotides continuously into CSF is outlined. In addition, a procedure is described for continuous infusion of oligonucleotides into a specific brain region, using the substantia nigra as an example.

Subthalamic stimulation-induced synaptic responses in substantia nigra pars compacta dopaminergic neurons in vitro.

The subthalamic nucleus (STN) is one of the principal sources of excitatory glutamatergic input to dopaminergic neurons of the substantia nigra, yet stimulation of the STN produces both excitatory and inhibitory effects on nigral dopaminergic neurons recorded extracellularly in vivo. The present experiments were designed to determine the sources of the excitatory and inhibitory effects. Synaptic potentials were recorded intracellularly from substantia nigra pars compacta dopaminergic neurons in parasagittal slices in response to stimulation of the STN. Synaptic potentials were analyzed for onset latency, amplitude, duration, and reversal potential in the presence and absence of GABA and glutamate receptor antagonists. STN-evoked depolarizing synaptic responses in dopaminergic neurons reversed at approximately -31 mV, intermediate between the expected reversal potential for an excitatory and an inhibitory postsynaptic potential (EPSP and IPSP). Blockade of GABA(A) receptors with bicuculline caused a positive shift in the reversal potential to near 0 mV, suggesting that STN stimulation evoked a near simultaneous EPSP and IPSP. Both synaptic responses were blocked by application of the glutamate receptor antagonist, 6-cyano-7-nitroquinoxalene-2,3-dione. The confounding influence of inhibitory fibers of passage from globus pallidus and/or striatum by STN stimulation was eliminated by unilaterally transecting striatonigral and pallidonigral fibers 3 days before recording. The reversal potential of STN-evoked synaptic responses in dopaminergic neurons in slices from transected animals was approximately -30 mV. Bath application of bicuculline shifted the reversal potential to approximately 5 mV as it did in intact animals, suggesting that the source of the IPSP was within substantia nigra. These data indicate that electrical stimulation of the STN elicits a mixed EPSP-IPSP in nigral dopaminergic neurons due to the coactivation of an excitatory monosynaptic and an inhibitory polysynaptic connection between the STN and the dopaminergic neurons of substantia nigra pars compacta. The EPSP arises from a direct monosynaptic excitatory glutamatergic input from the STN. The IPSP arises polysynaptically, most likely through STN-evoked excitation of GABAergic neurons in substantia nigra pars reticulata, which produces feed-forward GABA(A)-mediated inhibition of dopaminergic neurons through inhibitory intranigral axon collaterals.

GABAA receptor stimulation blocks NMDA-induced bursting of dopaminergic neurons in vitro by decreasing input resistance.

The effects of the GABAA agonist, isoguvacine, on NMDA-induced burst firing of substantia nigra dopaminergic neurons were studied with intracellular and whole cell recordings in vitro. NMDA application caused the neurons to fire in rhythmic bursts. Although the NMDA-induced bursty firing pattern was insensitive to hyperpolarization by current injection, it was reversibly abolished by the selective GABAA agonist, isoguvacine. The block of the rhythmic burst pattern by isoguvacine application occurred regardless of whether the chloride reversal potential was hyperpolarizing (ECl-=-70 mV) or depolarizing (ECl-=-40 mV). In either case, the input resistance of the dopaminergic neurons was dramatically decreased by application of isoguvacine. It is concluded that GABAA receptor activation by isoguvacine disrupts NMDA receptor-mediated burst firing by increasing the input conductance and thereby shunting the effects of NMDA acting at a distally located generator of rhythmic burst firing.

GABA(A) and GABA(B) antagonists differentially affect the firing pattern of substantia nigra dopaminergic neurons in vivo.

The effects of local pressure application of the selective GABA(A) antagonists, bicuculline, gabazine, and picrotoxin, and the selective GABA(B) antagonists, 2-OH-saclofen and CGP-55845A, on the spontaneous activity of electrophysiologically identified substantia nigra dopaminergic neurons were recorded in vivo in urethane anesthetized rats. Blockade of GABA(A) inputs by bicuculline powerfully and reversibly induced burst firing in dopaminergic neurons along with a modest (25%) increase in firing rate, but the increase in burst firing was not correlated with the increase in firing rate. Picrotoxin and gabazine also produced an increase in burst firing without an increase in firing rate. In contrast, local application of GABA(B) antagonists did not produce bursting but rather caused a modest shift to a more regular firing pattern in 50% of the cases. These data demonstrate that dopaminergic neurons in vivo are under tonic GABAergic inhibition mediated by GABA(A) receptors and suggest that GABAergic afferents to substantia nigra comprise a major pathway by which the firing pattern of dopaminergic neurons is controlled in vivo.

Inhibitory control of neostriatal projection neurons by GABAergic interneurons.

The basal ganglia are a highly interconnected network of nuclei essential for the modulation and execution of voluntary behavior. The neostriatum is the principal input and one of the principal controllers of the output of the basal ganglia. Neostriatal projection neurons seem to be dynamically and powerfully controlled by GABAergic inputs, but the source(s) and physiological properties of these inputs remain unclear. Here we use paired whole-cell recordings to show that this inhibition derives from small populations of GABAergic interneurons that are themselves interconnected through functional electrotonic synapses. Inhibitory synaptic potentials generated from single interneurons are sufficiently powerful to delay or entirely block the generation of action potentials in a large number of projection neurons simultaneously.

Striatal, pallidal, and pars reticulata evoked inhibition of nigrostriatal dopaminergic neurons is mediated by GABA(A) receptors in vivo.

Dopaminergic neurons express both GABA(A) and GABA(B) receptors and GABAergic inputs play a significant role in the afferent modulation of these neurons. Electrical stimulation of GABAergic pathways originating in neostriatum, globus pallidus or substantia nigra pars reticulata produces inhibition of dopaminergic neurons in vivo. Despite a number of prior studies, the identity of the GABAergic receptor subtype(s) mediating the inhibition evoked by electrical stimulation of neostriatum, globus pallidus, or the axon collaterals of the projection neurons from substantia nigra pars reticulata in vivo remain uncertain. Single-unit extracellular recordings were obtained from substantia nigra dopaminergic neurons in urethane anesthetized rats. The effects of local pressure application of the selective GABA(A) antagonists, bicuculline and picrotoxin, and the GABA(B) antagonists, saclofen and CGP-55845A, on the inhibition of dopaminergic neurons elicited by single-pulse electrical stimulation of striatum, globus pallidus, and the thalamic axon terminals of the substantia nigra pars reticulata projection neurons were recorded in vivo. Striatal, pallidal, and thalamic induced inhibition of dopaminergic neurons was always attenuated or completely abolished by local application of the GABA(A) antagonists. In contrast, the GABA(B) antagonists, saclofen or CGP-55845A, did not block or attenuate the stimulus-induced inhibition and at times even increased the magnitude and/or duration of the evoked inhibition. Train stimulation of globus pallidus and striatum also produced an inhibition of firing in dopaminergic neurons of longer duration. However this inhibition was largely insensitive to either GABA(A) or GABA(B) antagonists although the GABA(A) antagonists consistently blocked the early portion of the inhibitory period indicating the presence of a GABA(A) component. These data demonstrate that dopaminergic neurons of the substantia nigra pars compacta are inhibited by electrical stimulation of striatum, globus pallidus, and the projection neurons of substantia nigra pars reticulata in vivo. This inhibition appears to be mediated via the GABA(A) receptor subtype, and all three GABAergic afferents studied appear to possess inhibitory presynaptic GABA(B) autoreceptors that are active under physiological conditions in vivo.

GABAergic control of rat substantia nigra dopaminergic neurons: role of globus pallidus and substantia nigra pars reticulata.

Dopaminergic neurons in vivo fire spontaneously in three distinct patterns or modes. It has previously been shown that the firing pattern of substantia nigra dopaminergic neurons can be differentially modulated by local application of GABA(A) and GABA(B) receptor antagonists. The GABA(A) antagonists, bicuculline or picrotoxin, greatly increase burst firing in dopaminergic neurons whereas GABA(B) antagonists cause a modest shift away from burst firing towards pacemaker-like firing. The three principal GABAergic inputs to nigral dopaminergic neurons arise from striatum, globus pallidus and from the axon collaterals of nigral pars reticulata projection neurons, each of which appear to act in vivo primarily on GABA(A) receptors (see preceding paper). In this study we attempted to determine on which afferent pathway(s) GABA(A) antagonists were acting to cause burst firing. Substantia nigra dopaminergic neurons were studied by single unit extracellular recordings in urethane anesthetized rats during pharmacologically induced inhibition and excitation of globus pallidus. Muscimol-induced inhibition of pallidal neurons produced an increase in the regularity of firing of nigral dopaminergic neurons together with a slight decrease in firing rate. Bicuculline-induced excitation of globus pallidus neurons produced a marked increase in burst firing together with a modest increase in firing rate. These changes in firing rate were in the opposite direction to what would be expected for a monosynaptic GABAergic pallidonigral input. Examination of the response of pars reticulata GABAergic neurons to similar manipulations of globus pallidus revealed that the firing rates of these neurons were much more sensitive to changes in globus pallidus neuron firing rate than dopaminergic neurons and that they responded in the opposite direction. Pallidal inhibition produced a dramatic increase in the firing rate of pars reticulata GABAergic neurons while pallidal excitation suppressed the spontaneous activity of pars reticulata GABAergic neurons. These data suggest that globus pallidus exerts significant control over the firing rate and pattern of substantia nigra dopaminergic neurons through a disynaptic pathway involving nigral pars reticulata GABAergic neurons and that at least one important way in which local application of bicuculline induces burst firing of dopaminergic neurons is by disinhibition of this tonic inhibitory input.

Postnatal development of the rat neostriatum: electrophysiological, light- and electron-microscopic studies.

The postnatal development of the electrophysiological properties and morphology of rat neostriatum was studied using in vivo and in vitro intracellular recording and biocytin staining and light and electron microscopy. The principal neurons, the medium spiny neurons, were found to undergo a protracted postnatal development of their electrophysiological and morphological characteristics. Most of the intrinsic membrane properties of medium spiny neurons came to resemble those in the adult by the end of the 3rd postnatal week. Synaptic responses and spontaneous activity patterns in medium spiny neurons were dependent on the arrival and functional maturation of excitatory afferents from cortex and thalamus and did not become adult-like until the end of the 1st postnatal month.

Do silent dopaminergic neurons exist in rat substantia nigra in vivo?

A subpopulation of inactive or "silent" dopaminergic neurons has been reported to exist in vivo in rat substantia nigra, comprising up to 50% of nigral dopaminergic neurons. The existence of this large proportion of silent neurons has been inferred from various experimental manipulations, but never demonstrated directly. In the present study, striatal or medial forebrain bundle stimulation was used to activate antidromically substantia nigra dopaminergic neurons in vivo. Antidromic spikes of dopaminergic neurons observed by extracellular single-unit recordings in the absence of spontaneous activity were employed as indicators of the presence of a silent cell. A total of 312 dopamine neurons were recorded, including 190 neurons that could be antidromically activated from the striatum and/or the medial forebrain bundle. All neurons exhibited spontaneous activity. The firing rates were unimodally distributed about the mean of 4 spikes/s, and very few cells were observed to fire at less than 0.5 spikes/s. The numbers of spontaneously active and antidromically activated dopaminergic neurons per track were recorded and compared with the number of antidromically responding silent dopaminergic neurons per track after systemic apomorphine administration. Under control conditions, 0.80 +/- 0.10 or 1.36 +/- 0.13 spontaneously active neurons per track could be antidromically activated at 1.0 mA by striatal or medial forebrain bundle stimulation, respectively. After apomorphine completely suppressed spontaneous activity, 0.69 +/- 0.08 and 1.39 +/- 0.14 antidromic neurons per track were detected by stimulating the striatum or medial forebrain bundle respectively at 1.0 mA, demonstrating that silent dopaminergic neurons can be reliably identified through antidromic activation. In sharp contrast to previous reports, these data suggest that silent neurons do not comprise a substantial proportion of the total number of dopaminergic neurons in the substantia nigra. Reverse chi2 analysis revealed that, if they exist at all, silent dopaminergic neurons make up less than 2% of the dopaminergic cells in the substantia nigra. These findings are related to current theories of the mechanisms of action of antipsychotic drugs and the maintenance of near-normal levels of dopamine in the striatum following large-scale loss of nigral dopaminergic neurons.

Postnatal development of excitatory synaptic input to the rat neostriatum: an electron microscopic study.

The distribution and density of asymmetric synapses including biocytin-labelled corticostriatal synapses of the rat neostriatum were examined at postnatal day 10 (P10), P15, P21 and in adults. The density of asymmetric synapses in the adult neostriatum (28.0 synapses/100 microm2) was significantly greater than that in neonates at P15 (14.4 synapses/100 microm2) and P10 (11.5 synapses/100 microm2), but not at P21 (24.2+/-1.5 synapses/100 microm2). The increased density of asymmetric synapses in the adult neostriatum was due primarily to an increase in the number of axospinous synapses. The density of axospinous synapses was greatest in adults (22.3 synapses/100 microm2) and significantly less at P21 (15.3 synapses/100 microm2), P15 (5.9 synapses/100 microm2), and P10 (2.0 synapses/100 microm2). The density of axodendritic synapses, however, remained similar at all ages (adult, 3.9+/-1.1 synapses/100 microm2; P21, 6.0+/-1.2 synapses/100 microm2; P15, 5.7+/-0.8 synapses/100 microm2 or P10, 7.2+/-1.3 synapses/100 microm2). Iontophoretic injection of biocytin into the lateral frontal agranular cortex produced labelling of corticostriatal afferents which formed asymmetric synapses in the neostriatum. The distribution of termination sites of biocytin-labelled corticostriatal boutons showed a pattern of development similar to the unlabelled asymmetric synapses. The present study shows that the increase in the overall number of asymmetric synapses over the first three postnatal weeks can be attributed to an increase in the density of asymmetric axospinous synapses. During the same period little change is noted in the number or density of asymmetric axodendritic synapses. These changes in excitatory synaptic input to medium spiny neurons may explain some of the previously described electrophysiological differences noted between the neonatal and adult neostriatum.

Morphological and electrophysiological characteristics of noncholinergic basal forebrain neurons.

Cholinergic neurons in the basal forebrain are the focus of considerable interest because they are severely affected in Alzheimer's disease. However, both cholinergic and noncholinergic neurons are intermingled in this region. The goal of the present study was to characterize the morphology and in vivo electrophysiology of noncholinergic basal forebrain neurons. Neurons in the ventral pallidum and substantia innominata were recorded extracellularly, labeled juxtacellularly with biocytin and characterized for the presence of choline acetyltransferase immunoreactivity. Two types of ventral pallidal cells were observed. Type I ventral pallidal neurons had axons that rarely branched near the cell body and tended to have smaller somata and lower spontaneous firing rates than did type II ventral pallidal neurons, which displayed extensive local axonal arborizations. Subtypes of substantia innominata neurons could not be distinguished based on axonal morphology. These noncholineregic neurons exhibited local axon arborizations along a continuum that varied from no local collaterals to quite extensive arbors. Substantia innominata neurons had lower spontaneous firing rates, more variable interspike intervals, and different spontaneous firing patterns than did type II ventral pallidal neurons and could be antidromically activated from cortex or substantia nigra, indicating that they were projection neurons. Ventral pallidal neurons resemble, both morphologically and electrophysiologically, previously described neurons in the globus pallidus, whereas the substantia innominata neurons bore similarities to isodendritic neurons of the reticular formation. These results demonstrate the heterogeneous nature of noncholinergic neurons in the basal forebrain.

Functional roles of dopamine D2 and D3 autoreceptors on nigrostriatal neurons analyzed by antisense knockdown in vivo.

Two different 19-mer antisense oligodeoxynucleotides complementary to the initial coding regions of dopamine D2 or D3 receptor mRNA were infused unilaterally into the substantia nigra of rats for 3-6 d to suppress synthesis of D2 and/or D3 receptors on substantia nigra dopaminergic neurons, thereby producing specific reductions of D2 and/or D3 receptors. Autoradiographic receptor binding revealed that D2 and D3 antisense oligodeoxynucleotides specifically and significantly reduced D2 or D3 binding in the ipsilateral substantia nigra, respectively, without affecting dopamine receptor binding in the neostriatum. Either D2 or D3 antisense oligodeoxynucleotides greatly attenuated the ability of apomorphine to inhibit dopaminergic neurons in vivo, an effect that was potentiated by simultaneous administration of D2 and D3 antisenses. Despite these effects, neither the rate nor the pattern of spontaneous activity of antisense-treated nigrostriatal neurons differed from those in the control groups. The proportion of antidromic responses consisting of full spikes from antisense-treated rats was significantly greater, and the mean antidromic threshold was significantly lower than in controls, indicating that autoreceptor knockdown increased both somatodendritic and terminal excitability. These data demonstrate that selective reduction of specific dopamine receptor subtypes by antisense infusion can be effected in vivo, and that nigrostriatal neurons express both D2 and D3 autoreceptors at their somatodendritic and axon terminal regions. Although the somatodendritic and terminal autoreceptors modulate dendritic and terminal excitability, respectively, the interaction of endogenously released dopamine with somatodendritic autoreceptors does not appear to exert a significant effect on spontaneous activity in anesthetized rats.

Local infusion of brain-derived neurotrophic factor modifies the firing pattern of dorsal raphé serotonergic neurons.

Previous studies have reported a neuromodulatory effect of brain-derived neurotrophic factor (BDNF) on serotonin neurons in the central nervous system. In the present study, we examined the effects of local infusion of BDNF on the electrophysiological activity of serotonergic neurons in the rat dorsal raphé nucleus with extracellular single unit recording in vivo. Compared with vehicle-infused rats, chronic administration of BDNF (10-14 days) caused serotonergic neurons to fire in a significantly less regular pattern, without altering the mean firing rate or other measures of electrical activity. These results suggest that the ability of similar infusions of BDNF to produce behavioral effects (i.e. analgesia and an antidepressant-like effect) associated with elevated serotonin turnover may be in part the result of more irregular firing patterns of dorsal raphé neurons.

GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons.

Evidence from electrophysiological studies has suggested an inhibitory interaction between GABAergic neurons in substantia nigra pars reticulata and dopaminergic neurons in pars compacta. However, that this inhibitory interaction is due to a projection from pars reticulata to pars compacta has never been demonstrated directly, nor has the GABAergic neuron that mediates the interaction been identified either electrophysiologically or anatomically. To more closely examine interactions between substantia nigra pars reticulata GABA neurons and dopaminergic neurons, single unit extracellular recordings were obtained from antidromically identified nigrostriatal neurons and their response to antidromic activation of nigral GABAergic projection neurons observed. Stimulation of superior colliculus or thalamus produced a short latency inhibition of dopaminergic neurons. This inhibition was blocked by local application of bicuculline but not 2-hydroxysaclofen. Bicuculline caused most dopaminergic neurons to fire in a bursty mode, whereas saclofen caused most dopaminergic neurons to fire in a pacemaker-like mode. The thalamic-evoked inhibition was not affected by kainate lesions of the globus pallidus, but these lesions produced effects on firing pattern identical to those produced by saclofen. These data demonstrate a short latency inhibition of nigral dopaminergic neurons mediated by GABAA receptors that arises from the axon collaterals of pars reticulata projection neurons. We propose a model in which the firing pattern of nigral dopaminergic neurons in vivo is modulated differentially by disinhibition of GABAA inputs arising from pars reticulata projection neuron axon collaterals and disinhibition of pallidonigral GABAergic inputs mediated by GABAB receptors.

Cerebellar-responsive neurons in the thalamic ventroanterior-ventrolateral complex of rats: in vivo electrophysiology.

In vivo intracellular recordings were obtained from identified thalamocortical neurons in the ventroanterior-ventrolateral complex in urethane-anesthetized rats. This thalamic nucleus has few interneurons. Neurons that responded to cerebellar stimulation were injected intracellularly with horseradish peroxidase or biocytin and examined with light and electron microscopy (see companion paper). Intrinsic membrane properties and voltage-dependent rhythmic activity of cerebellar-responsive ventroanterior-ventrolateral neurons were similar to those described previously for thalamic neurons. Thus, in addition to conventional "fast" Na(+)-dependent spikes, rat ventroanterior-ventrolateral neurons had "slow" Ca(2+)-mediated low-threshold spikes and membrane conductances that supported rhythmic oscillations. Two modes of spontaneous activity were observed: (i) a tonic firing pattern that consisted of irregularly occurring fast spikes that predominated when the membrane potential was more positive than about -60 mV, and (ii) a rhythmic firing pattern, observed when the membrane potential was more negative than about -65 mV, composed of periodic (4-8 Hz) membrane hyperpolarizations and ramp depolarizations that often produced a low-threshold spike and a burst of fast spikes. In some neurons, spontaneous fast prepotentials were also observed, often with a relatively constant rate (up to 70 Hz). Cerebellar stimulation elicited excitatory postsynaptic potentials that in some cases appeared to be all-or-none and were similar in form to fast prepotentials. Stimulation of ipsilateral motor cortex elicited a short-latency antidromic response followed by a monosynaptic excitatory postsynaptic potential, which had a slower rise time than excitatory postsynaptic potentials evoked from cerebellum, suggesting that cortical inputs were electrotonically distal to cerebellar inputs. In the presence of moderate membrane hyperpolarization, the cortically evoked excitatory postsynaptic potential was followed by a long-lasting hyperpolarization (100-400 ms duration), a rebound depolarization and one or two cycles resembling spontaneous rhythmic activity. Membrane conductance was increased during the initial component of the long hyperpolarization, much of which was probably due to an inhibitory postsynaptic potential. In contrast, membrane conductance was unchanged or slightly decreased during the latter three-quarters of the long hyperpolarization. The amplitude of this component of the long hyperpolarization usually decreased when the membrane was hyperpolarized with intracellular current injection. Thus, both disfacilitation and an inhibitory postsynaptic potential may have contributed to the latter portion of the cortically-evoked long hyperpolarization. The cortically-evoked inhibitory postsynaptic potentials likely originated predominantly from feedforward activation of GABAergic neurons in the thalamic reticular nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebellar-responsive neurons in the thalamic ventroanterior-ventrolateral complex of rats: light and electron microscopy.

The morphology and synaptic organization of neurons in the ventroanterior-ventrolateral nucleus of rats was examined using in vivo intracellular staining techniques. Neurons were characterized electrophysiologically based on intrinsic membrane properties and synaptic responses to stimulation of motor cortex and cerebellar nuclei, as described in the companion paper. Cerebellar-responsive neurons were stained intracellularly with either horseradish peroxidase or biocytin. All stained ventroanterior-ventrolateral nucleus neurons were identified as thalamocortical neurons on anatomical (and often electrophysiological) grounds, consistent with previous findings that rat ventroanterior-ventrolateral nucleus is interneuron-sparse. Ventroanterior-ventrolateral nucleus neurons had three to eight thick primary dendrites. Proximal dendrites often exhibited a tufted branching pattern, from which many thinner, higher order dendrites arose. Dendrites branched to form a funnel-like infiltration of the neuropil that resulted in a spherical, roughly homogeneous dendritic field. The axon originated from the cell body or a proximal dendrite and coursed laterally and dorsally to innervate motor cortex. One to five axon collaterals were emitted in the rostral dorsolateral sector of the thalamic reticular nucleus; collaterals were not observed in the ventroanterior-ventrolateral nucleus or other nuclei in dorsal thalamus. The synaptic organization of the ventroanterior-ventrolateral nucleus was examined with electron microscopy, including two intracellularly labeled ventroanterior-ventrolateral nucleus neurons that were shown electrophysiologically to receive monosynaptic inputs from the cerebellum. The neuropil of rat ventroanterior-ventrolateral nucleus lacked the complexity and diversity found in corresponding thalamic nuclei of felines and primates, due to the paucity of interneurons. Vesicle-containing dendrites, dendrodendritic synapses and glomeruli were not observed. Three broad classes of presynaptic terminals were identified. (1) Small round boutons: small boutons containing densely-packed, small round vesicles that formed asymmetric synapses predominantly with the distal dendrites of thalamocortical neurons. These were the most prevalent type of bouton in the ventroanterior-ventrolateral nucleus (78% of presynaptic elements) and likely arose from the cerebral cortex. (2) Large round boutons: large terminals with loosely packed small round vesicles that made multiple asymmetric synapses with proximal and intermediate dendrites. Large round boutons comprised 8% of the neuropil, and likely arose from the cerebellar nuclei. (3) Medium size boutons with pleomorphic vesicles: medium-sized profiles containing pleomorphic vesicles that formed symmetric synapses with proximal, intermediate and distal dendrites and, less frequently, with cell bodies.(ABSTRACT TRUNCATED AT 400 WORDS)