Terminals In Thalamic Reticular Nucleus Research Articles

Synaptic properties of the feedback connections from the thalamic reticular nucleus to the dorsal lateral geniculate nucleus.

The thalamic reticular nucleus (TRN) is a shell-like structure comprised of GABAergic neurons that surrounds the dorsal thalamus. While playing a key role in modulating thalamocortical interactions, TRN inhibition of thalamic activity is often thought of as having an all-or-none impact. Although TRN neurons have a dynamic firing range, it remains unclear how variable rates of TRN activity gate thalamocortical transmission. To address this, we examined the ultrastructural features and functional synaptic properties of the feedback connections in the mouse thalamus between TRN and the dorsal lateral geniculate nucleus (dLGN), the principal relay of retinal signals to visual cortex. Using electron microscopy to identify TRN input to dLGN, we found that TRN terminals formed synapses with non-GABAergic postsynaptic profiles. Compared with other nonretinal terminals in dLGN, those from TRN were relatively large and tended to contact proximal regions of relay cell dendrites. To evoke TRN activity in dLGN, we adopted an optogenetic approach by expressing ChR2, or a variant (ChIEF) in TRN terminals. Both in vitro and in vivo recordings revealed that repetitive stimulation of TRN terminals led to a frequency-dependent inhibition of dLGN activity, with higher rates of stimulation resulting in increasing levels of membrane hyperpolarization and corresponding decreases in spike firing. This relationship suggests that alterations in TRN activity lead to graded changes in relay cell spike firing.NEW & NOTEWORTHY The thalamic reticular nucleus (TRN) modulates thalamocortical transmission through inhibition. In mouse, TRN terminals in the dorsal lateral geniculate nucleus (dLGN) form synapses with relay neurons but not interneurons. Stimulation of TRN terminals in dLGN leads to a frequency-dependent form of inhibition, with higher rates of stimulation leading to a greater suppression of spike firing. Thus, TRN inhibition appears more dynamic than previously recognized, having a graded rather than an all-or-none impact on thalamocortical transmission.

0098 BASAL FOREBRAIN PARVALBUMIN NEURONS CONTROL THALAMIC RETICULAR NEURONS: AN OPTOGENETIC STUDY INVESTIGATING SPINDLES AND NREM SLEEP REGULATION

Spindles are EEG oscillations (12-15Hz humans, 8-15Hz rodents) that occur during non-REM (NREM) sleep. Recent studies in schizophrenia (Sz) patients showed consistent evidence for sleep spindles abnormalities (number/intrinsic frequency) and an association with cognitive deficits. Spindles originate in the thalamic reticular nucleus (TRN). A major, likely inhibitory input comes from wake-promoting basal forebrain (BF) PV neurons, as these neurons project extensively into TRN. Thus, here we used optogenetic techniques to investigate whether BF PV neurons control TRN neurons and in doing so modulate spindles and/or NREM sleep. AAV-ChR2-EYFP (excitation) were bilaterally injected into BF of PV-Cre mice. Optical stimulation of BF PV fibers in TRN was performed to study the effects on spindles and NREM sleep. Sleep-wake activity (EEG/EMG electrodes) and TRN single-units (microwire assembly) were recorded in freely moving mice. Excitation was induced by 473nM bilateral laser illumination and was compared with no illumination in the same animal. A custom-designed script (Spike2/Matlab) was used to detect/verify individual spindles (10-15Hz), allowing analysis of spindle density (spindles/min) during NREM. Single-unit recordings showed TRN neuron discharge during spindle was inhibited by optogenetic activation BF PV cells. Bilateral ChR2 excitation (5s/min 40Hz; 6hrs) of BF PV neuron terminals in TRN (N=11) produced increased wakefulness (+16%; p<0.05), decreased NREM (-7%; p<0.05) and REM sleep (-11%; p<0.05). Excitation of BF PV fibers also produced an immediate cessation of spindles followed by a strong rebound resulting in an overall increase (+6%; <0.05, vs. sham stimulation) in the spindle density. This effect was similar to direct ArchT inhibition of TRN PV neurons (N=7). These data suggest BF PV neurons promote wakefulness and suppress spindles through projections to TRN neurons. Hence, BF PV neurons may provide a potential target for pharmacologic manipulation to increase spindles in disorders such as Sz. Dept. of Veterans Affairs [(VA merit Awards, I01 BX001356 (RWM), IK2BX002130 (JMM), I01BX002774 (RES)], NIMH RO1 MH039683 (RWM), NHLBI HL095491 (RWM). JTM received partial salary compensation and funding from Merck MISP, but has no conflict of interest with this work.

GABAA , NMDA and mGlu2 receptors tonically regulate inhibition and excitation in the thalamic reticular nucleus.

Traditionally, neurotransmitters are associated with a fast, or phasic, type of action on neurons in the central nervous system (CNS). However, accumulating evidence indicates that γ-aminobutyric acid (GABA) and glutamate can also have a continual, or tonic, influence on these cells. Here, in voltage- and current-clamp recordings in rat brain slices, we identify three types of tonically active receptors in a single CNS structure, the thalamic reticular nucleus (TRN). Thus, TRN contains constitutively active GABAA receptors (GABAA Rs), which are located on TRN neurons and generate a persistent outward Cl(-) current. When TRN neurons are depolarized, blockade of this current increases their action potential output in response to current injection. Furthermore, TRN contains tonically active GluN2B-containing N-methyl-D-aspartate receptors (NMDARs). These are located on reticuloreticular GABAergic terminals in TRN and generate a persistent facilitation of vesicular GABA release from these terminals. In addition, TRN contains tonically active metabotropic glutamate type 2 receptors (mGlu2Rs). These are located on glutamatergic cortical terminals in TRN and generate a persistent reduction of vesicular glutamate release from these terminals. Although tonically active GABAA Rs, NMDARs and mGlu2Rs operate through different mechanisms, we propose that the continual and combined activity of these three receptor types ultimately serves to hyperpolarize TRN neurons, which will differentially affect the output of these cells depending upon the current state of their membrane potential. Thus, when TRN cells are relatively depolarized, their firing in single-spike tonic mode will be reduced, whereas when these cells are relatively hyperpolarized, their ability to fire in multispike burst mode will be facilitated.

Synaptic targets of thalamic reticular nucleus terminals in the visual thalamus of the cat.

A major inhibitory input to the dorsal thalamus arises from neurons in the thalamic reticular nucleus (TRN), which use gamma-aminobutyric acid (GABA) as a neurotransmitter. We examined the synaptic targets of TRN terminals in the visual thalamus, including the A lamina of the dorsal lateral geniculate nucleus (LGN), the medial interlaminar nucleus (MIN), the lateral posterior nucleus (LP), and the pulvinar nucleus (PUL). To identify TRN terminals, we injected biocytin into the visual sector of the TRN to label terminals by anterograde transport. We then used postembedding immunocytochemical staining for GABA to distinguish TRN terminals as biocytin-labeled GABA-positive terminals and to distinguish the postsynaptic targets of TRN terminals as GABA-negative thalamocortical cells or GABA-positive interneurons. We found that, in all nuclei, the TRN provides GABAergic input primarily to thalamocortical relay cells (93-100%). Most of this input seems targeted to peripheral dendrites outside of glomeruli. The TRN does not appear to be a significant source of GABAergic input to interneurons in the visual thalamus. We also examined the synaptic targets of the overall population of GABAergic axon terminals (F1 profiles) within these same regions of the visual thalamus and found that the TRN contacts cannot account for all F1 profiles. In addition to F1 contacts on the dendrites of thalamocortical cells, which presumably include TRN terminals, another population of F1 profiles, most likely interneuron axons, provides input to GABAergic interneuron dendrites. Our results suggest that the TRN terminals are ideally situated to modulate thalamocortical transmission by controlling the response mode of thalamocortical cells.

Connectional studies of the primate lateral geniculate nucleus: Distribution of axons arising from the thalamic reticular nucleus of Galago crassicaudatus

Anterograde and retrograde transport methods have been used to explore the interconnections between the thalamic reticular nucleus (TRN) and the dorsal lateral geniculate nucleus of Galago crassicaudatus. We first defined the region of the TRN, which is connected to the lateral geniculate nucleus, by examining the distribution of geniculo-TRN axons, cortico-TRN axons arising from area 17, and the location of TRN-geniculate neurons. Following an intraocular injection of 3H-proline/3 H-leucine, trans-synaptically transported protein is present bilaterally within the lateral portion of the caudal TRN. This same caudal and lateral region is also targeted by cortico-TRN axons and contains neurons which project upon the lateral geniculate nucleus. Light microscopic anterograde transport methods were used to analyze the distribution of TRN-geniculate axons. Our data reveal that all layers and interlaminar zones of the dorsal lateral geniculate nucleus contain TRN axons. Electron microscopic-autoradiographic data support and extend our light microscopic findings by revealing labeled TRN terminals within all geniculate layers. These TRN profiles are the same size throughout the geniculate and exhibit morphological characteristics similar to F1 terminals described by others. That is, they possess predominantly pleomorphic vesicles, a dark cytoplasmic matrix, dark mitochondria, and symmetrical synaptic contacts. Two additional features of TRN terminals have been observed in some profiles. These include dense-core vesicles and a dense, punctate cytoplasmic matrix, which is sometimes associated with the postsynaptic specialization. In addition to their morphology and size, the postsynaptic targets of TRN terminals are similar within the three sets (parvi-, magno-, and koniocellular) of geniculate layers. TRN profiles terminate upon dendrites of all sizes and somata. These findings suggest that the TRN modulates the retino-geniculocortical pathway and that this modulation is occurring in all three streams.

Synaptic terminals in the dorsal lateral geniculate nucleus from neurons of the thalamic reticular nucleus: A light and electron microscope autoradiographic study

( 3H)-proline was injected in the caudodorsal part (visual segment) of the thalamic reticular nucleus to study its projection to the dorsal lateral geniculate nucleus. This was done by autoradiographic tracing of anterograde axonal transport of tritium at the light- and electron microscopic level. The results of the light-microscope autoradiography show that connections of the thalamic reticular nucleus are distributed along lines of projections in the dorsal lateral geniculate nucleus, indicating a retinotopic arrangement of this projection. The results of the electron microscope autoradiography provide direct evidence that axons of cells in the thalamic reticular nucleus terminate in the dorsal lateral geniculate nucleus as synaptic boutons that contain flattened synaptic vesicles, dark mitochondria and establish symmetrical synapses with perikarya and with proximal, intermediate and distal dendrites. They do not take part in intraglomerular synapses (as boutons with pleomorphic synaptic vesicles do) and are not postsynaptic to other vesicle-containing boutons in the dorsal lateral geniculate nucleus. The present results, taken in conjunction with physiological studies that have shown postsynaptic inhibitory effects of the thalamic reticular nucleus on dorsal lateral geniculate nucleus relay cells in the rat, establish a correlation of an inhibitory synapse with the presence of flattened synaptic vesicles in the corresponding synaptic boutons. Also, the observation that thalamic reticular nucleus terminals in the dorsal lateral geniculate nucleus avoid forming synapses with boutons containing pleomorphic vesicles, believed to be synaptic processes of interneurons, is indicative that the inhibitory effects are exerted monosynaptically on geniculate relay cells.