Inward rectifier potassium current IKir promotes intrinsic pacemaker activity of thalamocortical neurons.

Slow repetitive burst firing by hyperpolarized thalamocortical (TC) neurons correlates with global slow rhythms (<4 Hz), which are the physiological oscillations during non-rapid eye movement sleep or pathological oscillations during idiopathic epilepsy. The pacemaker activity of TC neurons depends on the expression of several subthreshold conductances, which are modulated in a behaviorally dependent manner. Here we show that upregulation of the small and neglected inward rectifier potassium current IKir induces repetitive burst firing at slow and delta frequency bands. We demonstrate this in mouse TC neurons in brain slices by manipulating the Kir maximum conductance with dynamic clamp. We also performed a thorough theoretical analysis that explains how the unique properties of IKir enable this current to induce slow periodic bursting in TC neurons. We describe a new ionic mechanism based on the voltage- and time-dependent interaction of IKir and hyperpolarization-activated cationic current Ih that endows TC neurons with the ability to oscillate spontaneously at very low frequencies, even below 0.5 Hz. Bifurcation analysis of conductance-based models of increasing complexity demonstrates that IKir induces bistability of the membrane potential at the same time that it induces sustained oscillations in combination with Ih and increases the robustness of low threshold-activated calcium current IT-mediated oscillations. NEW & NOTEWORTHY The strong inwardly rectifying potassium current IKir of thalamocortical neurons displays a region of negative slope conductance in the current-voltage relationship that generates potassium currents activated by hyperpolarization. Bifurcation analysis shows that IKir induces bistability of the membrane potential; generates sustained subthreshold oscillations by interacting with the hyperpolarization-activated cationic current Ih; and increases the robustness of oscillations mediated by the low threshold-activated calcium current IT. Upregulation of IKir in thalamocortical neurons induces repetitive burst firing at slow and delta frequency bands (<4 Hz).

Leptin alters somatosensory thalamic networks by decreasing gaba release from reticular thalamic nucleus and action potential frequency at ventrobasal neurons.

Leptin is an adipose-derived hormone that controls appetite and energy expenditure. Leptin receptors are expressed on extra-hypothalamic ventrobasal (VB) and reticular thalamic (RTN) nuclei from embryonic stages. Here, we studied the effects of pressure-puff, local application of leptin on both synaptic transmission and action potential properties of thalamic neurons in thalamocortical slices. We used whole-cell patch-clamp recordings of thalamocortical VB neurons from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We observed differences in VB neurons action potentials and synaptic currents kinetics when comparing WT vs. ob/ob. Leptin reduced GABA release onto VB neurons throughout the activation of a JAK2-dependent pathway, without affecting excitatory glutamate transmission. We observed a rapid and reversible reduction by leptin of the number of action potentials of VB neurons via the activation of large conductance Ca2+-dependent potassium channels. These leptin effects were observed in thalamocortical slices from up to 5-week-old WT but not in leptin-deficient obese mice. Results described here suggest the existence of a leptin-mediated trophic modulation of thalamocortical excitability during postnatal development. These findings could contribute to a better understanding of leptin within the thalamocortical system and sleep deficits in obesity.

Retinal projections and neurochemical characterization of the pregeniculate nucleus of the common marmoset (Callithrix jacchus).

In mammals, the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) are the main components of the circadian timing system. The SCN is the site of the endogenous biological clock that generates rhythms and synchronizes them to environmental cues. The IGL is a key structure that modulates SCN activity and is responsible for the transmission of non-photic information to the SCN, thus participating in the integration between photic and non-photic stimuli. Both the SCN and IGL receive projections of retinal ganglion cells and the IGL is connected to the SCN through the geniculohypothalamic tract. Little is known about these structures in the primate brain and the pregeniculate nucleus (PGN) has been suggested to be the primate equivalent of the rodent IGL. The aim of this study was to characterize the PGN of a primate, the common marmoset (Callithrix jacchus), and to analyze its retinal afferents. Here, the marmoset PGN was found to be organized into three subsectors based on neuronal size, pattern of retinal projections, and the distribution of neuropeptide Y-, GAD-, serotonin-, enkephalin- and substance P-labeled terminals. This pattern indicates that the marmoset PGN is equivalent to the IGL. This detailed description contributes to the understanding of the circadian timing system in this primate species considering the importance of the IGL within the context of circadian regulation.

Dynamics of action potential initiation in the GABAergic thalamic reticular nucleus in vivo.

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold.

Spatial organization of the pigeon tectorotundal pathway: an interdigitating topographic arrangement.

The retinotectofugal system is the main visual pathway projecting upon the telencephalon in birds and many other nonmammalian vertebrates. The ascending tectal projection arises exclusively from cells located in layer 13 of the optic tectum and is directed bilaterally toward the thalamic nucleus rotundus. Although previous studies provided evidence that different types of tectal layer 13 cells project to different subdivisions in Rt, apparently without maintaining a retinotopic organization, the detailed spatial organization of this projection remains obscure. We reexamined the pigeon tectorotundal projection using conventional tracing techniques plus a new method devised to perform small deep-brain microinjections of crystalline tracers. We found that discrete injections involving restricted zones within one subdivision retrogradely label a small fraction of layer 13 cells that are distributed throughout the layer, covering most of the tectal representation of the contralateral visual field. Double-tracer injections in one subdivision label distinct but intermingled sets of layer 13 neurons. These results, together with the tracing of tectal axonal terminal fields in the rotundus, lead us to propose a novel "interdigitating" topographic arrangement for the tectorotundal projection, in which intermingled sets of layer 13 cells, presumably of the same particular class and distributed in an organized fashion throughout the surface of the tectum, terminate in separate regions within one subdivision. This spatial organization has significant consequences for the understanding of the physiological and functional properties of the tectofugal pathway in birds.

Neuronal connections of the paratrigeminal nucleus: a topographic analysis of neurons projecting to bulbar, pontine and thalamic nuclei related to cardiovascular, respiratory and sensory functions.

The paratrigeminal nucleus, which receives sensory input from trigeminal, glossopharyngeal and vagus nerves, has efferent projections to bulbar, pontine and possibly to thalamic structures associated with nociception, thermoregulation and cardiovascular control. Anterograde neuronal tracers were used to study paratrigeminal efferent connections. Labeled terminal fibers, evidencing bilateral efferent paratrigeminal projections were observed in the medial and caudal solitary tract (sol), lateral reticular nucleus (LRt), ambiguus nucleus (Amb), rostroventrolateral reticular nucleus (RVL), while ipsilateral projections were found in the parabrachial (PB) nuclei and ventral portion of the ventral posteromedial thalamic nucleus (VPM). This extends other findings that describe paratrigeminal projections. Retrograde neuronal transport tracers, microinjected in the defined projection areas were used to map distribution of the paratrigeminal neurons originating different efferent connections. Microinjection of latex microspheres containing fluorescein or rhodamine and Fluoro-gold in the ventral VPM, PB, RVL, Amb, LRt and NTS revealed sets of labeled paratrigeminal nucleus neurons respectively organised in a rostral-caudal sequence. The largest extent of the paratrigeminal nucleus (medial portion) contained neurons projecting to the RVL/Amb, structures associated with cardiovascular regulation. The data show a segmented topographical organization of the nucleus, with different sets of neurons within delimited segments, projecting to neuronal structures associated with different functions. This points to a complex and extensive role for the paratrigeminal nucleus in the integration of somatosensory reflexes related to cardiovascular, respiratory and pain mechanisms. The nucleus may act as a medullary relay interposed between sensory afferents and different structures related to homoeostatic functions.

Efferent connections of the caudal part of the globus pallidus in the rat.

The efferent connections of the caudal pole of the globus pallidus (GP) were examined in the rat by employing the anterograde axonal transport of Phaseolus vulgaris leucoagglutinin (PHA-L), and the retrograde transport of fluorescent tracers combined with choline acetyltransferase (ChAT) or parvalbumin (PV) immunofluorescence histochemistry. Labeled fibers from the caudal GP distribute to the caudate-putamen, nucleus of the ansa lenticularis, reuniens, reticular thalamic nucleus (mainly its posterior extent), and along a thin strip of the zona incerta adjacent to the cerebral peduncle. The entopeduncular and subthalamic nuclei do not appear to receive input from the caudal GP. Descending fibers from the caudal GP course in the cerebral peduncle and project to posterior thalamic nuclei (the subparafascicular and suprageniculate nuclei, medial division of the medial geniculate nucleus, and posterior intralaminar nucleus/peripeduncular area) and to extensive brainstem territories, including the pars lateralis of the substantia nigra, lateral terminal nucleus of the accessory optic system, nucleus of the brachium of the inferior colliculus, nucleus sagulum, external cortical nucleus of the inferior colliculus, cuneiform nucleus, and periaqueductal gray. In cases with deposits of PHA-L in the ventral part of the caudal GP, labeled fibers in addition distribute to the lateral amygdaloid nucleus, amygdalostriatal transition area, cerebral cortex (mainly perirhinal, temporal, and somatosensory areas) and rostroventral part of the lateral hypothalamus. Following injections of fluorescent tracer centered in the lateral hypothalamus, posterior intralaminar nucleus, substantia nigra, pars lateralis, or lateral terminal nucleus, a substantial number of retrogradely labeled cells is observed in the caudal GP. None of these cells express ChAT immunoreactivity, but, except for the ones projecting to the lateral hypothalamus, a significant proportion is immunoreactive to PV. Our results indicate that caudal GP efferents differ from those of the rostral GP in that they project to extensive brainstem territories and appear to be less intimately related to intrinsic basal ganglia circuits. Moreover, our data suggest a possible participation of the caudal GP in feedback loops involving posterior cortical areas, posterior striatopallidal districts, and posterior thalamic nuclei. Taken as a whole, the projections of the caudal GP suggest a potential role of this pallidal district in visuomotor and auditory processes.

Activation of subthalamic neurons produces NMDA receptor-mediated dendritic dopamine release in substantia nigra pars reticulata: a microdialysis study in the rat.

Here we have studied whether the activation of the subthalamic neurons induces the release of dopamine (DA) from dopaminergic dendrites in the pars reticulata of the substantia nigra. Subthalamic neurons were activated by carbachol microinjected into the subthalamic nucleus. A microdialysis probe was implanted in the medial aspect of the pars reticulata to collect samples of the perfusate. Carbachol (1 microgram/0.25 microliter saline) enhanced (58 +/- 8% over basal values) nigral DA release. The enhancement was fully blocked by the NMDA antagonist AP5 added to the microdialysis medium perfusing the pars reticulata. Perfusion of the pars reticulata with NMDA also increased (125 +/- 25% over basal) nigral DA release. Again, AP5 reversed the effect. These results suggest that activation of the glutamatergic subthalamonigral pathway enhances dendritic DA release by activating NMDA receptors present on dopaminergic dendrites.

Fetal brain grafts induce recovery of learning deficits and connectivity in rats with gustatory neocortex lesion.

Three groups of rats showing disrupted taste aversion due to gustatory neocortex lesions, were studied. One group received a transplant of homotopic cortical tissue, another of heterotopic tectal tissue, obtained from 17-day-old fetuses. The third group remained without transplant as a lesioned control group. Comparisons of the taste aversion scores before and after graft, revealed that cortical grafted animals significantly improved the taste aversion, whereas those which received tectal grafts, and the cortical-lesioned controls did not. Moreover, results with horseradish peroxidase (HRP) histochemistry revealed that the homotopic, but not the heterotopic, brain transplants were able to re-establish connections with amygdala and with the ventromedial nucleus of the thalamus areas who normally kept connectivity with the gustatory neocortex. These results support the hypothesis that fetal brain transplants can reestablish cognitive functions, as well as connectivity with its host tissue.

Double cortical control acting upon activities of intralaminar thalamic cells.

We report the effects exerted by the cortex upon the intralaminar thalamic nucleic, as revealed by reversible blockade of the cortex with spreading depression in awake rats. Extracellular recordings of spontaneous activity were made simultaneously at thalamic and cortical sites. The effect of peripheral receptive field stimulation was to decrease activity of intralaminar thalamic cells. Cortical recordings revealed the cortical regions affected by spreading depression. Two type of cells were identified depending on the changes in their sensorial responses during the cortical spreading depression propagation. The first exhibited a tonic facilitating cortical control when the cortical spreading depression was located at A 8.0 to A 10.0. The second type exhibited a disappearance of the sensorial responses when cortical spreading depression was located at A 4.0 to A 8.0 and also displayed the tonic facilitating control. This indicates that two different identified cortical regions influenced the thalamic activity.