Thalamocortical Neurons Research Articles

Phase advancement and nucleus-specific timing of thalamocortical activity during slow cortical oscillation.

The exact timing of cortical afferent activity is instrumental for the correct coding and retrieval of internal and external stimuli. Thalamocortical inputs represent the most significant subcortical pathway to the cortex, but the precise timing and temporal variability of thalamocortical activity is not known. To examine this question, we studied the phase of thalamic action potentials relative to cortical oscillations and established correlations among phase, the nuclear location of the thalamocortical neurons, and the frequency of cortical activity. The phase of thalamic action potentials depended on the exact frequency of the slow cortical oscillation both on long (minutes) and short (single wave) time scales. Faster waves were accompanied by phase advancement in both cases. Thalamocortical neurons located in different nuclei fired at significantly different phases of the slow waves but were active at a similar phase of spindle oscillations. Different thalamic nuclei displayed distinct burst patterns. Bursts with a higher number of action potentials displayed progressive phase advancement in a nucleus-specific manner. Thalamic neurons located along nuclear borders were characterized by mixed burst and phase properties. Our data demonstrate that the temporal relationship between cortical and thalamic activity is not fixed but displays dynamic changes during oscillatory activity. The timing depends on the precise location and exact activity of thalamocortical cells and the ongoing cortical network pattern. This variability of thalamic output and its coupling to cortical activity can enable thalamocortical neurons to actively participate in the coding and retrieval of cortical signals.

The Mitochondrial Permeability Transition Pore Regulates Nitric Oxide-Mediated Apoptosis of Neurons Induced by Target Deprivation

Ablation of mouse occipital cortex induces precisely timed and uniform p53-modulated and Bax-dependent apoptosis of thalamocortical projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 d after lesion. We tested the hypothesis that this neuronal apoptosis is initiated by oxidative stress and the mitochondrial permeability transition pore (mPTP). Preapoptotic LGN neurons accumulate mitochondria, Zn(2+) and Ca(2+), and generate higher levels of reactive oxygen species (ROS), including superoxide, nitric oxide (NO), and peroxynitrite, than LGN neurons with an intact cortical target. Preapoptosis of LGN neurons is associated with increased formation of protein carbonyls, protein nitration, and protein S-nitrosylation. Genetic deletion of nitric oxide synthase 1 (nos1) and inhibition of NOS1 with nitroindazole protected LGN neurons from apoptosis, revealing NO as a mediator. Putative components of the mPTP are expressed in mouse LGN, including the voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT), and cyclophilin D (CyPD). Nitration of CyPD and ANT in LGN mitochondria occurs by 2 d after cortical injury. Chemical cross-linking showed that LGN neuron preapoptosis is associated with formation of CyPD and VDAC oligomers, consistent with mPTP formation. Mice without CyPD are rescued from neuron apoptosis as are mice treated with the mPTP inhibitors TRO-19622 (cholest-4-en-3-one oxime) and TAT-Bcl-X(L)-BH4. Manipulation of the mPTP markedly attenuated the early preapoptotic production of reactive oxygen/nitrogen species in target-deprived neurons. Our results demonstrate in adult mouse brain neurons that the mPTP functions to enhance ROS production and the mPTP and NO trigger apoptosis; thus, the mPTP is a target for neuroprotection in vivo.

Correlation transfer from basal ganglia to thalamus in Parkinson's disease

Spike trains from neurons in the basal ganglia of parkinsonian primates show increased pairwise correlations, oscillatory activity, and burst rate compared to those from neurons recorded during normal brain activity. However, it is not known how these changes affect the behavior of downstream thalamic neurons. To understand how patterns of basal ganglia population activity may affect thalamic spike statistics, we study pairs of model thalamocortical (TC) relay neurons receiving correlated inhibitory input from the internal segment of the globus pallidus (GPi), a primary output nucleus of the basal ganglia. We observe that the strength of correlations of TC neuron spike trains increases with the GPi correlation level, and bursty firing patterns such as those seen in the parkinsonian GPi allow for stronger transfer of correlations than do firing patterns found under normal conditions. We also show that the T-current in the TC neurons does not significantly affect correlation transfer, despite its pronounced effects on spiking. Oscillatory firing patterns in GPi are shown to affect the timescale at which correlations are best transferred through the system. To explain this last result, we analytically compute the spike count correlation coefficient for oscillatory cases in a reduced point process model. Our analysis indicates that the dependence of the timescale of correlation transfer is robust to different levels of input spike and rate correlations and arises due to differences in instantaneous spike correlations, even when the long timescale rhythmic modulations of neurons are identical. Overall, these results show that parkinsonian firing patterns in GPi do affect the transfer of correlations to the thalamus.

Thalamic Gap Junctions Control Local Neuronal Synchrony and Influence Macroscopic Oscillation Amplitude during EEG Alpha Rhythms.

Although EEG alpha (α; 8–13 Hz) rhythms are often considered to reflect an “idling” brain state, numerous studies indicate that they are also related to many aspects of perception. Recently, we outlined a potential cellular substrate by which such aspects of perception might be linked to basic α rhythm mechanisms. This scheme relies on a specialized subset of rhythmically bursting thalamocortical (TC) neurons (high-threshold bursting cells) in the lateral geniculate nucleus (LGN) which are interconnected by gap junctions (GJs). By engaging GABAergic interneurons, that in turn inhibit conventional relay-mode TC neurons, these cells can lead to an effective temporal framing of thalamic relay-mode output. Although the role of GJs is pivotal in this scheme, evidence for their involvement in thalamic α rhythms has thus far mainly derived from experiments in in vitro slice preparations. In addition, direct anatomical evidence of neuronal GJs in the LGN is currently lacking. To address the first of these issues we tested the effects of the GJ inhibitors, carbenoxolone (CBX), and 18β-glycyrrhetinic acid (18β-GA), given directly to the LGN via reverse microdialysis, on spontaneous LGN and EEG α rhythms in behaving cats. We also examined the effect of CBX on α rhythm-related LGN unit activity. Indicative of a role for thalamic GJs in these activities, 18β-GA and CBX reversibly suppressed both LGN and EEG α rhythms, with CBX also decreasing neuronal synchrony. To address the second point, we used electron microscopy to obtain definitive ultrastructural evidence for the presence of GJs between neurons in the cat LGN. As interneurons show no phenotypic evidence of GJ coupling (i.e., dye-coupling and spikelets) we conclude that these GJs must belong to TC neurons. The potential significance of these findings for relating macroscopic changes in α rhythms to basic cellular processes is discussed.

Augmentation of Tonic GABAAInhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAAReceptors

It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABAA receptors (eGABAAR) and augmented “tonic” GABAA inhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABAAR gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABAARs in absence epilepsy.

Functional Anatomy of Non-REM Sleep.

The state of non-REM sleep (NREM), or slow wave sleep, is associated with a synchronized EEG pattern in which sleep spindles and/or K complexes and high-voltage slow wave activity (SWA) can be recorded over the entire cortical surface. In humans, NREM is subdivided into stages 2 and 3–4 (presently named N3) depending on the proportions of each of these polygraphic events. NREM is necessary for normal physical and intellectual performance and behavior. An overview of the brain structures involved in NREM generation shows that the thalamus and the cerebral cortex are absolutely necessary for the most significant bioelectric and behavioral events of NREM to be expressed; other structures like the basal forebrain, anterior hypothalamus, cerebellum, caudal brain stem, spinal cord and peripheral nerves contribute to NREM regulation and modulation. In NREM stage 2, sustained hyperpolarized membrane potential levels resulting from interaction between thalamic reticular and projection neurons gives rise to spindle oscillations in the membrane potential; the initiation and termination of individual spindle sequences depends on corticothalamic activities. Cortical and thalamic mechanisms are also involved in the generation of EEG delta SWA that appears in deep stage 3–4 (N3) NREM; the cortex has classically been considered to be the structure that generates this activity, but delta oscillations can also be generated in thalamocortical neurons. NREM is probably necessary to normalize synapses to a sustainable basal condition that can ensure cellular homeostasis. Sleep homeostasis depends not only on the duration of prior wakefulness but also on its intensity, and sleep need increases when wakefulness is associated with learning. NREM seems to ensure cell homeostasis by reducing the number of synaptic connections to a basic level; based on simple energy demands, cerebral energy economizing during NREM sleep is one of the prevalent hypotheses to explain NREM homeostasis.

Melanopsin Contributions to Irradiance Coding in the Thalamo-Cortical Visual System

Author SummaryThe ability to convert light into electrical signals in the mammalian retina has traditionally been thought to occur through only two types of photoreceptors, the rods and cones. However, this ability also extends to a small number of neurons expressing the protein melanopsin. To date these melanopsin retinal ganglion cells (mRGCs) have been thought to act as photoreceptors primarily for those brain regions regulating subconscious responses to ambient light, such as pupil size. In this study, we provide evidence that mRGCs also contribute extensively to conventional visual pathways. We use a newly developed strategy to characterize the brain regions to which these cells project and then directly monitor visually evoked neural activity in these target regions. We find that mRGCs allow the mouse visual system to faithfully encode ambient illumination over at least a million-fold range and to continue to show light responses even in the absence of all rods and cones. These data reveal a new role for mRGCs during normal vision and suggest that mRGCs could make a significant contribution to assessing brightness and supporting vision even in people with advanced retinal degeneration.

Bifurcations of lurching waves in a thalamic neuronal network

We consider a two-layer, one-dimensional lattice of neurons; one layer consists of excitatory thalamocortical neurons, while the other is comprised of inhibitory reticular thalamic neurons. Such networks are known to support "lurching" waves, for which propagation does not appear smooth, but rather progresses in a saltatory fashion; these waves can be characterized by different spatial widths (different numbers of neurons active at the same time). We show that these lurching waves are fixed points of appropriately defined Poincaré maps, and follow these fixed points as parameters are varied. In this way, we are able to explain observed transitions in behavior, and, in particular, to show how branches with different spatial widths are linked with each other. Our computer-assisted analysis is quite general and could be applied to other spatially extended systems which exhibit this non-trivial form of wave propagation.

GABAergic gain‐of‐function in absence seizures

SummaryNew evidence indicates that increased, rather than decreased, γ‐aminobutyric acid (GABA)ergic inhibition characterizes typical absence seizures. In particular, enhanced tonic GABAA inhibition, resulting from a malfunction of the astrocytic GABA transporter GAT‐1, occurs in thalamocortical neurons of all well‐established pharmacologic and genetic models. Interestingly, GABAB receptors positively modulate this tonic current. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado‐Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).

Abnormalities in GABAergic synaptic transmission of intralaminar thalamic neurons in a genetic rat model of absence epilepsy

Synaptic activity mediated via GABA receptors in thalamic circuits is critically involved in the generation of hypersynchrony associated with absence epilepsy. Neurons of “unspecific” intralaminar thalamic nuclei display characteristic burst patterns during seizure activity, although their synaptic properties remain largely unknown. Here, we used in vitro patch-clamp techniques in neurons of the paracentral (PC) thalamic nucleus, derived from a genetic model of absence epilepsy (WAG-Rij) and a non-epileptic control strain (ACI) to elucidate intrinsic and synaptic properties. PC neurons displayed voltage-dependent low threshold spike bursts or tonic spike firing, typical of thalamic neurons. These parameters, and electrotonic properties, were similar in PC neurons of the two strains. Analyses of miniature inhibitory post synaptic currents (mIPSCs) mediated via GABAA receptors revealed no difference in decay time constant and inter-event interval between strains, but a significantly larger amplitude and higher single channel conductance (as assessed by non-stationary variance analysis) in WAG-Rij compared to ACI. By comparison, thalamocortical neurons from the ventrobasal complex of the thalamus showed no difference in mIPSC kinetics and unitary conductance between the two rat strains. In view of the critical role of GABAergic inhibition for synchronous activity in thalamocortical circuits, it is concluded that the increase in unitary conductance of IPSCs in PC neurons contributes to hypersynchrony characterizing seizure activity.

Low-Threshold Ca2+Current Amplifies Distal Dendritic Signaling in Thalamic Reticular Neurons

The low-threshold transient calcium current (I(T)) plays a critical role in modulating the firing behavior of thalamic neurons; however, the role of I(T) in the integration of afferent information within the thalamus is virtually unknown. We have used two-photon laser scanning microscopy coupled with whole-cell recordings to examine calcium dynamics in the neurons of the strategically located thalamic reticular nucleus (TRN). We now report that a single somatic burst discharge evokes large-magnitude calcium responses, via I(T), in distal TRN dendrites. The magnitude of the burst-evoked calcium response was larger than those observed in thalamocortical projection neurons under the same conditions. We also demonstrate that direct stimulation of distal TRN dendrites, via focal glutamate application and synaptic activation, can locally activate distal I(T), producing a large distal calcium response independent of the soma/proximal dendrites. These findings strongly suggest that distally located I(T) may function to amplify afferent inputs. Boosting the magnitude ensures integration at the somatic level by compensating for attenuation that would normally occur attributable to passive cable properties. Considering the functional architecture of the TRN, elongated nature of their dendrites, and robust dendritic signaling, these distal dendrites could serve as sites of intense intra-modal/cross-modal integration and/or top-down modulation, leading to focused thalamocortical communication.

State-Dependent Firing Determines Intrinsic Dendritic Ca2+Signaling in Thalamocortical Neurons

Activity-dependent dendritic Ca(2+) signals play a critical role in multiple forms of nonlinear cellular output and plasticity. In thalamocortical neurons, despite the well established spatial separation of sensory and cortical inputs onto proximal and distal dendrites, respectively, little is known about the spatiotemporal dynamics of intrinsic dendritic Ca(2+) signaling during the different state-dependent firing patterns that are characteristic of these neurons. Here we demonstrate that T-type Ca(2+) channels are expressed throughout the entire dendritic tree of rat thalamocortical neurons and that they mediate regenerative propagation of low threshold spikes, typical of, but not exclusive to, sleep states, resulting in global dendritic Ca(2+) influx. In contrast, actively backpropagating action potentials, typical of wakefulness, result in smaller Ca(2+) influxes that can temporally summate to produce dendritic Ca(2+) accumulations that are linearly related to firing frequency but spatially confined to proximal dendritic regions. Furthermore, dendritic Ca(2+) transients evoked by both action potentials and low-threshold spikes are shaped by Ca(2+) uptake by sarcoplasmic/endoplasmic reticulum Ca(2+) ATPases but do not rely on Ca(2+)-induced Ca(2+) release. Our data demonstrate that thalamocortical neurons are endowed with intrinsic dendritic Ca(2+) signaling properties that are spatially and temporally modified in a behavioral state-dependent manner and suggest that backpropagating action potentials faithfully inform proximal sensory but not distal corticothalamic synapses of neuronal output, whereas corticothalamic synapses only "detect" Ca(2+) signals associated with low-threshold spikes.

Too Much Inhibition Leads to Excitation in Absence Epilepsy

Enhanced Tonic GABAA Inhibition in Typical Absence Epilepsy. Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V. Nat Med 2009;(12):1392–1398. The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired γ-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT-1 in the genetic models tested, and GAT-1 is crucial in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioral correlates of seizures in normal rats. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy.

Dopamine enhances the excitability of somatosensory thalamocortical neurons

The thalamus conveys sensory information from peripheral and subcortical regions to the neocortex in a dynamic manner that can be influenced by several neuromodulators. Alterations in dopamine (DA) receptor function in thalami of Schizophrenic patients have recently been reported. In addition, schizophrenia is associated with sensory gating abnormalities and sleep-wake disturbances, thus we examined the role of DA on neuronal excitability in somatosensory thalamus. The ventrobasal (VB) thalamus receives dopaminergic innervation and expresses DA receptors; however, the action of DA on VB neurons is unknown. In the present study, we performed whole cell current- and voltage-clamp recordings in rat brain slices to investigate the role of DA on excitability of VB neurons. We found that DA increased action potential discharge and elicited membrane depolarization via activation of different receptor subtypes. Activation of D2-like receptors (D 2R) leads to enhanced action potential discharge, whereas the membrane depolarization was mediated by D1-like receptors (D 1R). The D 2R-mediated increase in spike discharge was mimicked and occluded by α-dendrotoxin (α-DTX), indicating the involvement of a slowly inactivating K + channels. The D1R-mediated membrane depolarization was occluded by barium, suggesting the involvement of a G protein–coupled K + channel or an inwardly rectifying K + channel. Our results indicate that DA produces dual modulatory effects acting on subtypes of DA receptors in thalamocortical relay neurons, and likely plays a significant role in the modulation of sensory information.

Calcium window currents, periodic forcing, and chaos: Understanding single neuron response with a discontinuous one-dimensional map

Thalamocortical (TC) neurones are known to express the low-voltage activated, inactivating Ca2+ current I(T). The triggering of this current underlies the generation of low threshold Ca2+ potentials that may evoke single or bursts of action potentials. Moreover, this current can contribute to an intrinsic slow (<1 Hz) oscillation whose rhythm is partly determined by the steady state component of I(T) and its interaction with a leak current. This steady state, or window current as it is so often called, has received relatively little theoretical attention despite its importance in determining the electroresponsiveness and input-output relationship of TC neurones. In this paper, we introduce an integrate-and-fire spiking neuron model that includes a biophysically realistic model of I(T). We briefly review the subthreshold bifurcation diagram of this model with constant current injection before moving on to consider its response to periodic forcing. Direct numerical simulations show that as well as the expected mode-locked responses there are regions of parameter space that support chaotic behavior. To reveal the mechanism by which the window current generates a chaotic response to periodic forcing we consider a piecewise linear caricature of the dynamics for the gating variables in the model of I(T). This model can be analyzed in closed form and is shown to support an unstable set of periodic orbits. Trajectories are repelled from these organizing centers until they reach the threshold for firing. By determining the condition for a grazing bifurcation (at the border between a spiking and nonspiking event) we show how knowledge of the unstable periodic orbits (existence and stability) can be combined with the grazing condition to determine an effective one-dimensional map that captures the essentials of the chaotic behavior. This map is discontinuous and has strong similarities with the universal limit mapping in grazing bifurcations derived in the context of impacting mechanical systems [A. B. Nordmark, Phys. Rev. E 55, 266 (1997)].

Correlation transfer from basal ganglia to thalamus in Parkinson’s disease

There is much experimental evidence that neurons located in the basal ganglia of parkinsonian primates show increased pairwise correlations, oscillatory activity, and burst rate compared to normal brain activity. Past computational work has suggested that such changes in the firing pattern of neurons in the globus pallidus internus (GPi), the main output nucleus of the basal ganglia, may compromise thalamocortical relay capabilities. To understand how changes in the patterns of basal ganglia activity affect correlation transfer, we study pairs of realistic models of thalamocortical (TC) relay neurons receiving correlated inhibitory input from the GPi, as well as uncorrelated excitatory signals from cortex. We observe that bursty firing patterns such as those seen in the parkinsonian GPi allow for stronger transfer of correlations and higher correlation susceptibility than do firing patterns found under normal conditions. We also show that removing the T-current in the TC neurons does not significantly affect the correlation transfer, despite its pronounced effects on the spiking of the neurons. Oscillatory firing patterns in GPi are shown to affect the time scale at which correlations are best transferred through the system. We obtain the same results using an integrate-and-fire-or-burst (IFB) model of TC neurons as we do with a more realistic conductance-based model of the TC neurons, suggesting that the IFB model is a good reduced model for studying correlation transfer. In a reduced point process model, we derive analytic calculations of the spike count correlation coefficient for the time-inhomogeneous case. The analysis indicates that the rhythms seen in the transfer of correlations at varying time scales are very robust to different levels of spike correlations and rate correlations between the neurons. It also points to the fact that these rhythms can be seen because of differences in instantaneous spike correlations, even when the long time scale rhythmic modulation of the neurons in identical. Overall, these results show that parkinsonian firing patterns in GPi do indeed affect the way that correlations are transferred to the thalamus.

Sensory and cortical activation of distinct glial cell subtypes in the somatosensory thalamus of young rats

The rodent ventrobasal (VB) thalamus receives sensory inputs from the whiskers and projects to the cortex, from which it receives reciprocal excitatory afferents. Much is known about the properties and functional roles of these glutamatergic inputs to thalamocortical neurons in the VB, but no data are available on how these afferents can affect thalamic glial cells. In this study, we used combined electrophysiological recordings and intracellular calcium ([Ca2+]i) imaging to investigate glial cell responses to synaptic afferent stimulation. VB thalamus glial cells can be divided into two groups based on their [Ca2+]i and electrophysiological responses to sensory and corticothalamic stimulation. One group consists of astrocytes, which stain positively for S100B and preferentially load with SR101, have linear current–voltage relations and low input resistance, show no voltage-dependent [Ca2+]i responses, but express mGluR5-dependent [Ca2+]i transients following stimulation of the sensory and/or corticothalamic excitatory afferent pathways. Cells of the other glial group, by contrast, stain positively for NG2, and are characterized by high input resistance, the presence of voltage-dependent [Ca2+]i elevations and voltage-gated inward currents. There were no synaptically induced [Ca2+]i elevations in these cells under control conditions. These results show that thalamic glial cell responses to synaptic input exhibit different properties to those of thalamocortical neurons. As VB astrocytes can respond to synaptic stimulation and signal to neighbouring neurons, this glial cell organization may have functional implications for the processing of somatosensory information and modulation of behavioural state-dependent thalamocortical network activities.

Analysis of morphological features of thalamocortical neurons from the ventroposterolateral nucleus of the cat

Morphological features of the dendritic arborization can affect neuronal responses and thus the input-output function of a particular neuron. In this study, morphological data of eight fully reconstructed thalamocortical (TC) neurons from the ventroposterolateral (VPL) nucleus of adult cats have been analyzed. We examined several geometrical and topological parameters, which have been previously shown to have a high impact on the neuron firing pattern and propagation of signals in the dendritic tree. In addition to well-known morphological parameters such as number of dendritic trees (8.3 +/- 1.5) and number of branching points (80-120), we investigated the distribution of dendritic membrane area, branching points, geometrical ratio, asymmetry index, and mean path length for all subtrees of the TC neurons. We demonstrate that due to extensive branching in proximal and middle dendritic sections, the maximum value of the dendritic area distribution is reached at 120-160 mum from the soma. Our analysis reveals that TC neurons are highly branched cells and their dendritic branching pattern does not follow Rall's 3/2 power rule; average values at proximal vs. distal dendritic sections were different. We also found that the dendritic branching pattern of each subtree of the cell had a wide range in symmetry index, whereas the mean path length did not show a large variation through the dendritic arborizations.

Cholinergic Activation of M2 Receptors Leads to Context-Dependent Modulation of Feedforward Inhibition in the Visual Thalamus

Author SummaryWithin the visual thalamus, a single type of inhibitory interneuron regulates activity evoked by retinal ganglion cells and controls the visual signals that reach the cortex. Here, we find that neuromodulation, of the sort thought to occur when an animal is attending to a task, regulates the firing mode of these interneurons and controls the resulting inhibition in an input-dependent manner. When few ganglion cells are activated, neuromodulation greatly decreases the number of spikes in interneurons, and as a result, strongly reduces the inhibition of relay neurons. This favors the lossless transmission of weak visual signals to the cortex by virtually eliminating inhibition within the thalamus. In contrast, when many ganglion cells are activated, the same neuromodulator leads to strong and prolonged inhibition. This is accomplished by promoting the generation of calcium spikes and prolonged depolarizations in interneurons. In this way, a modulator can regulate the flow of visual information in a context-dependent manner.

Mechanisms of inhibition of CaV3.1 T-type calcium current by aliphatic alcohols

Many aliphatic alcohols modulate activity of various ion channels involved in sensory processing and also exhibit anesthetic capacity in vivo. Although the interaction of one such compound, 1-octanol (octanol) with different T-type calcium channels (T-channels) has been described, the mechanisms of current modulation and its functional significance are not well studied. Using patch-clamp technique, we investigated the mechanisms of inhibition of T-currents by a series of aliphatic alcohols in recombinant human Ca(V)3.1 (alpha1G) T-channel isoform expressed in human embryonic kidney (HEK) 293 cells and thalamocortical (TC) relay neurons in brain slices of young rats. Octanol, 1-heptanol (heptanol) and 1-hexanol (hexanol) inhibited the recombinant Ca(V)3.1 currents in concentration-dependent manner yielding IC(50) values of 362 microM, 1063 microM and 3167 microM, respectively. Octanol similarly inhibited native thalamic Ca(V)3.1 T-currents with an IC(50) of 287 microM and diminished burst firing without significant effect on passive membrane properties of these neurons. Inhibitory effect of octanol on T-currents in both native and recombinant cells was accompanied with accelerated macroscopic inactivation kinetics and hyperpolarizing shift in the steady-state inactivation curve. Additionally, octanol induced a depolarizing shift in steady-state activation curves of T-current in TC neurons. Surprisingly, the recovery from fast inactivation at hyperpolarized membrane potentials was accelerated by octanol up 3-fold in native but not recombinant channels. Given the importance of thalamocortical pathways in providing sleep, arousal, and anesthetic states, modulation of thalamic T-currents may at least contribute to the pharmacological effects of aliphatic alcohols.