The inhibitory gamma-aminobutyric acid-containing (GABAergic) neurons of the thalamic reticular and perigeniculate nuclei are involved in the generation of normal and abnormal synchronized activity in thalamocortical networks. An important factor controlling the generation of activity in this system is the amplitude and duration of inhibitory postsynaptic potentials (IPSPs) in thalamocortical cells, which depend on the pattern of activity generated in thalamic reticular and perigeniculate cells. Activation of single ferret perigeniculate neurons generated three distinct patterns of GABAergic IPSPs in thalamocortical neurons of the dorsal lateral geniculate nucleus: Low-frequency tonic discharge resulted in small-amplitude IPSPs mediated by GABAA receptors, burst firing resulted in large-amplitude GABAA IPSPs, and prolonged burst firing activated IPSPs mediated by GABAA and GABAB receptors. These functional properties of GABAergic inhibition can reconfigure the operations of thalamocortical networks into patterns of activity associated with waking, slow-wave sleep, and generalized seizures.

The habenular complex of the epithalamus in the mammalian brain receives input from the limbic forebrain and pallidum and, in turn, projects to numerous midbrain structures. Traditionally, the habenular complex is divided into the medial nucleus and two divisions of the lateral nucleus. Based on their distinct input and output pathways, the habenula is considered to constitute three, partially overlapping channels that regulate information flow from the limbic forebrain and pallidum to the midbrain. As a step to improve our understanding of how information delivered from the limbic forebrain and pallidum is processed in the habenula, we examined the electrical property and morphology of medial and lateral habenular cells. For this study, we generated live brain slices from rat habenula and performed whole cell recording. During recording, we filled habenular cells with biocytin. Medial habenular cells generate tonic trains of action potentials, whereas lateral habenular cells are capable of producing action potentials in burst mode. Lateral habenular cells produce dendrites that are much longer than those of medial habenular cells. Two distinct intrinsic circuits exist in the medial habenular nucleus, whereas in the lateral habenular nucleus, intrinsic axons travel largely from medial to lateral direction. The connection between the two habenular nuclei is asymmetrical in that only the medial habenula sends projection to the lateral habenula. The differences in the electrical and morphological properties of medial and lateral habenular cells indicate that the two nuclei process and integrate information in distinct fashions that is delivered from the limbic forebrain and pallidum.

The habenular complex of the epithalamus connects the limbic basal forebrain with numerous neuromodulatory centers in the midbrain. The habenula consists of the medial and lateral nuclei, each of which is speculated to contain multiple subdivisions. Such anatomical arrangements raise the possibility that the habenula accounts for multiple channels of information flow from the limbic forebrain to the midbrain. For understanding whether and, if so, how the multiple streams are organized via the habenula, knowledge of the precise input-output connectivity of each habenular subdivision is essential. In the present study, biotinylated dextran amine and cholera toxin subunit B were used to delineate the differential outputs of various subregions of the medial and lateral nuclei of the habenula in the rat. Both anterograde and retrograde tracing uncovered a heavy commissural connection between the two habenulae on the ipsilateral and contralateral sides. The commissural projection arises primarily in the lateral nucleus and exhibits a fine topography in that a local commissural efferent terminates primarily in the corresponding subregion on the contralateral side. The subregions of the medial and lateral nuclei also give rise to distinct projections to midbrain areas such as the interpeduncular nucleus, the median/paramedian nuclei, and the central gray. These projections produce terminal fields centered in different areas of the targets, supporting the topographically organized descending projections from the habenula. These data together support the organization of multiple channels in the habenula that convey parallel streams of information to the contralateral habenula, midbrain, and brainstem.

The precise mechanism whereby continuous high-frequency electrical stimulation of the subthalamic nucleus ameliorates motor symptoms of Parkinson's disease is unknown. We examined the effects of high-frequency stimulation of regions dorsal to and within the subthalamic nucleus on dopamine efflux in the striatum of urethane-anaesthetized rats using constant potential amperometry. Complementary extracellular electrophysiological studies determined the activity of subthalamic nucleus neurons in response to similar electrical stimulation of the subthalamic nucleus. High-frequency stimulation of the subthalamic nucleus increased action potential firing in the subthalamic nucleus only during the initial stimulation period and was followed by a cessation of firing over the remainder of stimulation. Electrical stimulation of the subthalamic nucleus with 15 pulses elicited stimulus-time-locked increases in striatal dopamine efflux with maximal peak effects occurring at 50 Hz frequency and 300 microA intensity. Extended subthalamic nucleus stimulation (1000 pulses at 50 Hz; 300 microA) elicited a similar peak increase in striatal dopamine efflux that was followed by a relatively lower steady-state elevation in extracellular dopamine over the course of stimulation. In contrast, extended stimulation immediately adjacent and dorsal to the subthalamic nucleus resulted in an 11-fold greater increase in dopamine efflux that remained elevated over the course of the stimulation. Immunohistochemical staining for tyrosine hydroxylase revealed catecholaminergic fibers running immediately dorsal to and through the subthalamic nucleus. Taken together, these results suggest that enhanced dopamine release within the basal ganglia may be an important mechanism whereby high-frequency stimulation of the subthalamic nucleus improves motor symptoms of Parkinson's disease.

Thalamocortical and perigeniculate (PGN) neurons can generate action potentials either as Ca2+ spike-mediated high-frequency bursts or as tonic trains. Using dual intracellular recordings in vitro in monosynaptically connected pairs of PGN and dorsal lateral geniculate nucleus (LGNd) neurons, we found that the functional effect of synaptic transmission between these cell types was strongly influenced by the membrane potential and hence the firing mode of both the pre- and postsynaptic neurons. Activation of single action potentials or low-frequency spike trains in PGN or thalamocortical neurons resulted in the generation of PSPs that were 0.5-2.0 mV in amplitude. In contrast, the generation of Ca2+ spike-mediated bursts of action potentials in the presynaptic cell increased these PSPs to an average of 4.4 mV for the IPSP and 3.0 mV for the EPSP barrage, because of temporal summation and/or facilitation. If the postsynaptic neuron was at a resting membrane potential (e.g., -65 mV), these PSP barrages could result in the activation of a low-threshold Ca2+ spike and burst of action potentials. These results demonstrate that the burst firing mode of action potential generation is a particularly effective means by which perigeniculate and thalamocortical neurons may influence one another. We propose that the activation of burst discharges in these cell types is essential for the generation of some forms of synchronized rhythmic oscillations of sleep and of epileptic seizures.

During HFS of STN neurons the mechanism of DBS may involve the release of neurotransmitters rather than the primary electrogenic inhibition of neurons.

The epithalamic lateral nucleus of the habenula (LHb) plays a key role in regulating firing of dopamine and serotonin neurons in the midbrain and is thereby involved in various cognitive and affective behaviors. It is not yet clear, however, from where the LHb receives cognitive and affective information relevant to its regulation of the midbrain monoaminergic systems. The prefrontal cortex would be among the ideal sources. Here, using anterograde and retrograde tracer injections in the rat brain, we characterized the topography of the corticohabenular projections. Following injections of cholera toxin subunit B into the LHb, retrogradely labeled neurons were produced in the anterior insular, cingulate, prelimbic and infralimbic cortices. Consistent with this retrograde tracing, injections of biotinylated dextran amine (BDA) into these cortical regions labeled robust terminals in the LHb. Our quantification of the BDA-impregnated varicosities revealed that projections from the anterior insula terminated mainly in the intersection regions of the lateral and ventral two-thirds of the LHb, while projections from the cingulate cortex terminated mainly in the lateral two-thirds of the LHb. By comparison, BDA-labeled terminals originating from the medial prefrontal regions were contained mainly in the medial plus ventral one-third of LHb. Based on these data, we hypothesize that LHb provides a link for conveying cognitive and affective information from prefrontal and insular regions to the midbrain monoaminergic centers.

In order to test the proposal that the zona incerta contributes to the generation of orienting movements, we examined the synaptic relationships between the incertotectal pathway and the cells of origin of the predorsal bundle. The predorsal bundle cells give rise to the major premotor pathway from the superior colliculus to the brainstem gaze centers. First, cytochrome oxidase histochemistry, gamma-aminobutyric acid (GABA), and glutamic acid decarboxylase (GAD) immunocytochemistry, and the axonal transport of markers were used to define the borders of a ventral subdivision of the zona incerta. This subdivision projects topographically to the same sublamina of the intermediate grey layer of the superior colliculus that contains the vast majority of the predorsal bundle cells. Experiments in which incertotectal cells were labeled by both retrograde transport and immunocytochemistry showed that this pathway is GABAergic. Retrograde and anterograde experiments also showed that this pathway is reciprocated by a pathway from the intermediate grey layer of the superior colliculus to the same ventral subdivision of the zona incerta. Finally, experiments combining axonal transport and electron microscopic methods showed that the incertotectal pathway is the source of a monosynaptic GABAergic input to the cells of origin of the predorsal bundle. The ventral subdivision of the zona incerta is contrasted with a second source of GABAergic input to the predorsal bundle cells, the substantia nigra pars reticulata.