Oscillatory state transition as a function of ACh/NE modulation and afferent input.

<p>(A)Oscillation frequency heat map as a function of ACh/NE modulation and afferent input. (B) Oscillation power (spectral peak) heat map as a function of ACh/NE modulation and afferent input. (C) Distribution of different oscillatory states as a function of ACh/NE modulation and afferent input. (D) Voltage traces of two representative HTC, IN, RTC and RE neurons each under low ACh/NE modulation (0%) at four different levels of afferent input (<b>D1:</b> 2 nS; <b>D2:</b> 5 nS; <b>D3:</b> 10 nS; <b>D4:</b> 15 nS). (E) Voltage traces of two representative HTC, IN, RTC and RE neurons each under medium ACh/NE modulation (50%) at four different levels of afferent input (<b>E1:</b> 2.5 nS; <b>E2:</b> 3.5 nS; <b>E3:</b> 5 nS; <b>E4:</b> 15 nS). The horizontal bar in (<b>E1</b>) indicates the injection of a transient current input (100 ms × 100 pA) into RE neurons to trigger spindle oscillations. (F)Voltage traces of two representative HTC, IN, RTC and RE neurons each under high ACh/NE modulation (100%) at four different levels of afferent input (<b>F1:</b> 0 nS; <b>F2:</b> 1.5 nS; <b>F3:</b> 10 nS; <b>F4:</b> 15 nS). Note the scale difference in x axis between (<b>E</b>) and (<b>D</b>, <b>F</b>).</p

Generation of multiple distinct oscillations in the thalamic network model under three different levels of ACh/NE modulation and four different levels of afferent excitation.

<p><b>The parameters used in different oscillatory states are shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005797#pcbi.1005797.t001" target="_blank">Table 1</a>. (A)</b> Generation of δ oscillations in the low ACh/NE modulatory state and with minimal afferent excitation. <b>(A1)</b> Voltage traces of two representative HTC, IN, RTC and RE cells each. <b>(A2)</b> Spike rastergrams of HTC, IN, RTC and RE cells. <b>(A3)</b> Simulated LFP (<i>top</i>) with associated frequency power spectrum (<i>bottom</i>). <b>(B)</b> Generation of spindle oscillations in the medium ACh/NE modulatory state and with slight afferent excitation. The black horizontal bars in (<b>B1-B2</b>) indicate the injection of a transient current input (100 ms × 100 pA) into RE neurons to trigger spindle oscillations. <b>(C)</b> Generation of α oscillations in the high ACh/NE modulatory state and with weak afferent excitation. <b>(D)</b> Generation of γ oscillations in the high ACh/NE modulatory state and with strong afferent excitation.</p

Thalamic α oscillations are sculpted by the high-threshold bursting dynamics of HTC cells.

<p><b>(A</b>) Effect of varying the maximal conductance density of the high-threshold T-type Ca²⁺ current (g_Ca/HT) in HTC cells. <b>(A1)</b> Spike rastergrams of HTC, IN, RTC and RE cells when g_Ca/HT is reduced to 1 mS/cm². <b>(A2)</b> g_Ca/HT is increased to 5 mS/cm². The default value is 3 mS/cm². <b>(A3)</b> Dominant network oscillation frequency (blue) and spectral peak power (red) when g_Ca/HT varies from 1 mS/cm² to 5 mS/cm². <b>(B)</b> Effect of varying the maximal input conductance to all thalamic cells. <b>(B1)</b> Spike rastergrams of HTC, IN, RTC and RE cells when the maximal input conductance is reduced to 0 nS. <b>(B2)</b> Maximal input conductance increases to 4 nS. The default value is 1.5 nS. <b>(B3)</b> Dominant network oscillation frequency (blue) and spectral peak power (red) when the maximal input conductance varies from 0 nS to 4 nS.</p

Thalamic δ oscillations are synchronized by both gap junctions and synaptic inhibition from IN and RE neurons.

<p><b>(A)</b> Rastergrams of HTC, IN, RTC and RE cells when the gap junctions among HTC cells are removed. <b>(B)</b> Gap junctions among HTC cells and between HTC and RTC cells are removed. <b>(C)</b> Projection from HTC cells to IN neurons is removed. <b>(D)</b> Projection from TC cells to RE neurons is removed. <b>(E)</b> Projection from TC cells to both IN and RE neurons is removed. <b>(F)</b> Projection from TC cells to both IN and RE neurons is removed and the gap junctions between HTC and RTC cells are blocked.</p

Model parameters for different oscillatory states.

<p>Model parameters for different oscillatory states.</p

Model parameters for different oscillatory states.

<p>Model parameters for different oscillatory states.</p

HTC gap junctions are required for thalamic γ oscillations in the absence of extra-strong feedback RE inhibition.

<p><b>(A)</b> Thalamic γ oscillations are eliminated when the gap junctions among HTC cells are removed. <b>(A1)</b> Spike rastergrams of HTC, IN, RTC and RE cells. <b>(A2)</b> Frequency power spectrum of sLFP from HTC cells (<i>top</i>), RTC cells (<i>middle</i>) and combined HTC and RTC cells (<i>bottom</i>) in the control (blue) and HTC uncoupled (red) conditions, respectively. <b>(B)</b> The RE→TC synaptic weight needs to increase four-fold to generate similar γ oscillations in the absence of gap junctions among HTC cells. <b>(B1-B2)</b> As <b>(A1-A2),</b> but with fourfold increase of the RE→TC synaptic weight.</p

A unified hypothesis for thalamic oscillatory state generation and transition.

<p>During deep sleep, both the ACh/NE modulation and afferent excitation are very low. TC cells generate intrinsic slow low-threshold bursts (LTBs) that underlie δ oscillations. During light sleep with increased ACh/NE modulation and afferent excitation, TC cells are not spontaneously bursting but can produce rebound LTBs that mediate spindle oscillations. During relaxed wakefulness or drowsiness, the ACh/NE modulation is significantly increased and HTC cells fire spontaneous high-threshold bursts (HTBs) which underlie both α and θ oscillations depending on afferent excitation. During attention or cognitive processing, TC cells are further depolarized to fire high-frequency tonic spiking that is synchronized by gap junctions and feedback inhibition to generate fast β or γ oscillations.</p

Unified thalamic model generates multiple distinct oscillations with state-dependent entrainment by stimulation

<div><p>The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh) and norepinephrine (NE) and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations) that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed.</p></div

Spindle oscillations are mainly generated through the TC-RE interaction and the spindle duration is tightly regulated by RE inhibition.

<p><b>(A)</b> Voltage traces of two representative HTC, IN, RTC and RE cells each when the excitatory inputs from HTC cells to IN neurons are blocked. Black horizontal bar indicates the presence of transient current injection (100 ms) into RE neurons to trigger spindles (same for below). <b>(B)</b> Excitatory inputs from HTC cells to IN neurons are blocked and the maximal synaptic conductance of the inhibitory RE→TC synapses increased 33% (from 3 nS to 4 nS). <b>(C)</b> Excitatory inputs from TC cells to RE neurons are blocked. <b>(D)</b> Excitatory inputs from TC cells to RE neurons are blocked and the maximal synaptic conductance of the inhibitory IN→RTC synapses increases fourfold (from 3 nS to 12 nS). <b>(E)</b> STD at the TC→RE synapses is blocked. <b>(F)</b> STD at the RE→TC synapses is blocked.</p