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Single PGN neurons can activate GABA A and GABA B receptors in LGNd thalamocortical cells. (A) Activation of a burst of action potentials in the presynaptic PGN neuron results in a large IPSP and small rebound Ca 2 spike in the thalamocortical cell. The burst of action potentials in the PGN cell is followed by "return EPSPs," which are generated by the rebound burst firing of inhibited thalamocortical neurons (14). (B) Spontaneous generation of a spindle wave is associated with repetitive burst firing in the PGN neuron and the occurrence of repetitive IPSPs in the LGNd cell. The IPSPs are generated by the activity of this PGN cell as well as others. Note the duration of the bursts of action potentials in the PGN cell. (C) Bath application of bicuculline (100 M) results in the abolition of the response to a burst of five action potentials. (D) Induction of a burst of 11 action potentials results in a small (1 mV ) slow IPSP in the thalamocortical cell (arrow). (E) Increasing the discharge of the PGN neuron to 40 action potentials results in a 3-mV-amplitude slow IPSP in the thalamocortical cell. (F) After bath application of bicuculline, the geniculate slice spontaneously generates abnormal oscillations during which the PGN neuron generates prolonged high-frequency (30 to 50 action potentials at 600 to 700 Hz) burst discharges, and the thalamocortical cell is hyperpolarized through the occurrence of large GABA B-receptor-mediated IPSPs. (G) Bath application of the GABA B receptor antagonist CGP 35348 (0.8 mM) abolishes the slow IPSP occurring in response to the activation of the PGN neuron, as well as the paroxysmal network oscillations. (H) This effect of CGP 35348 is reversible. Scales for recordings in (C), (D), (E), (G), and (H) are the same as that in (A).
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The inhibitory γ-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 postsynap...
Contexts in source publication
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... normal bathing medium, the interac- tion of PGN and thalamocortical neurons resulted in the generation of spindle waves (Fig. 2B) (6,15). Burst firing in PGN neu- rons resulted in the generation of rebound low-threshold Ca 2 spikes and bursts of Na -dependent action potentials in thal- amocortical neurons, which in turn re-ex- cited the PGN neurons through the gener- ation of excitatory postsynaptic potentials (EPSPs) in these cells. Bath (20 to 100 M; n 6) or local (1 mM in micropipette; n 2) application of the GABA A receptor an- tagonist bicuculline methiodide resulted in ...
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... SCIENCE VOL. 278 3 OCTOBER 1997 a transformation of these normal spindle waves into abnormal, "paroxysmal" events ( Fig. 2F) that resembled the activity in some animal models of generalized absence seizures (16). These abnormal network os- cillations are generated through the activa- tion of large, slow GABA B -receptor-medi- ated IPSPs in thalamocortical cells by PGN neurons (Fig. 2F) ...
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... SCIENCE VOL. 278 3 OCTOBER 1997 a transformation of these normal spindle waves into abnormal, "paroxysmal" events ( Fig. 2F) that resembled the activity in some animal models of generalized absence seizures (16). These abnormal network os- cillations are generated through the activa- tion of large, slow GABA B -receptor-medi- ated IPSPs in thalamocortical cells by PGN neurons (Fig. 2F) ...
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... examination of the IPSPs gener- ated in thalamocortical cells by a single PGN neuron revealed that the application of bicuculline methiodide (n 8) resulted in a complete block of IPSPs generated by low-frequency (100 Hz) tonic trains of action potentials in the presynaptic neuron and a complete, or near complete, abolition of IPSPs generated by normal burst firing in PGN cells at normal discharge frequencies (250 to 350 Hz) (Fig. 2C), indicating that these events are mediated largely, if not exclusively, by the activation of GABA A receptors. However, in the presence of GABA A receptor antagonists, PGN neu- rons also generated prolonged high-fre- quency burst discharges, particularly during the generation of "paroxysmal" activity ( Fig. 2F), owing to disinhibition from other PGN cells (6,17). In six out of eight cells, the activation of prolonged discharges in single PGN neurons resulted in the activa- tion of slow bicuculline-resistant IPSPs in thalamocortical cells (Fig. 2E), whereas in the other two pairs, there was no detectable postsynaptic response. Bath application of the GABA B receptor antagonist CGP 35348 (0.8 mM) or local application of CGP 54626A (200 M in micropipette) resulted in an abolition of this slow IPSP (n 2), confirming that it is mediated by GABA B receptors, an effect that is revers- ible (Fig. 2, G and H). The activation of the PGN with local application of glutamate (0.5 mM in micropipette) in the presence of bicuculline also resulted in the generation of slow IPSPs (Fig. 3B), and these were completely blocked by local application of CGP 35348 (2 mM in micropipette; n 12) or CGP 54626A (1 mM in micropi- pette; n 4), confirming their mediation by GABA B receptors ...
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... examination of the IPSPs gener- ated in thalamocortical cells by a single PGN neuron revealed that the application of bicuculline methiodide (n 8) resulted in a complete block of IPSPs generated by low-frequency (100 Hz) tonic trains of action potentials in the presynaptic neuron and a complete, or near complete, abolition of IPSPs generated by normal burst firing in PGN cells at normal discharge frequencies (250 to 350 Hz) (Fig. 2C), indicating that these events are mediated largely, if not exclusively, by the activation of GABA A receptors. However, in the presence of GABA A receptor antagonists, PGN neu- rons also generated prolonged high-fre- quency burst discharges, particularly during the generation of "paroxysmal" activity ( Fig. 2F), owing to disinhibition from other PGN cells (6,17). In six out of eight cells, the activation of prolonged discharges in single PGN neurons resulted in the activa- tion of slow bicuculline-resistant IPSPs in thalamocortical cells (Fig. 2E), whereas in the other two pairs, there was no detectable postsynaptic response. Bath application of the GABA B receptor antagonist CGP 35348 (0.8 mM) or local application of CGP 54626A (200 M in micropipette) resulted in an abolition of this slow IPSP (n 2), confirming that it is mediated by GABA B receptors, an effect that is revers- ible (Fig. 2, G and H). The activation of the PGN with local application of glutamate (0.5 mM in micropipette) in the presence of bicuculline also resulted in the generation of slow IPSPs (Fig. 3B), and these were completely blocked by local application of CGP 35348 (2 mM in micropipette; n 12) or CGP 54626A (1 mM in micropi- pette; n 4), confirming their mediation by GABA B receptors ...
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... examination of the IPSPs gener- ated in thalamocortical cells by a single PGN neuron revealed that the application of bicuculline methiodide (n 8) resulted in a complete block of IPSPs generated by low-frequency (100 Hz) tonic trains of action potentials in the presynaptic neuron and a complete, or near complete, abolition of IPSPs generated by normal burst firing in PGN cells at normal discharge frequencies (250 to 350 Hz) (Fig. 2C), indicating that these events are mediated largely, if not exclusively, by the activation of GABA A receptors. However, in the presence of GABA A receptor antagonists, PGN neu- rons also generated prolonged high-fre- quency burst discharges, particularly during the generation of "paroxysmal" activity ( Fig. 2F), owing to disinhibition from other PGN cells (6,17). In six out of eight cells, the activation of prolonged discharges in single PGN neurons resulted in the activa- tion of slow bicuculline-resistant IPSPs in thalamocortical cells (Fig. 2E), whereas in the other two pairs, there was no detectable postsynaptic response. Bath application of the GABA B receptor antagonist CGP 35348 (0.8 mM) or local application of CGP 54626A (200 M in micropipette) resulted in an abolition of this slow IPSP (n 2), confirming that it is mediated by GABA B receptors, an effect that is revers- ible (Fig. 2, G and H). The activation of the PGN with local application of glutamate (0.5 mM in micropipette) in the presence of bicuculline also resulted in the generation of slow IPSPs (Fig. 3B), and these were completely blocked by local application of CGP 35348 (2 mM in micropipette; n 12) or CGP 54626A (1 mM in micropi- pette; n 4), confirming their mediation by GABA B receptors ...
Context 7
... examination of the IPSPs gener- ated in thalamocortical cells by a single PGN neuron revealed that the application of bicuculline methiodide (n 8) resulted in a complete block of IPSPs generated by low-frequency (100 Hz) tonic trains of action potentials in the presynaptic neuron and a complete, or near complete, abolition of IPSPs generated by normal burst firing in PGN cells at normal discharge frequencies (250 to 350 Hz) (Fig. 2C), indicating that these events are mediated largely, if not exclusively, by the activation of GABA A receptors. However, in the presence of GABA A receptor antagonists, PGN neu- rons also generated prolonged high-fre- quency burst discharges, particularly during the generation of "paroxysmal" activity ( Fig. 2F), owing to disinhibition from other PGN cells (6,17). In six out of eight cells, the activation of prolonged discharges in single PGN neurons resulted in the activa- tion of slow bicuculline-resistant IPSPs in thalamocortical cells (Fig. 2E), whereas in the other two pairs, there was no detectable postsynaptic response. Bath application of the GABA B receptor antagonist CGP 35348 (0.8 mM) or local application of CGP 54626A (200 M in micropipette) resulted in an abolition of this slow IPSP (n 2), confirming that it is mediated by GABA B receptors, an effect that is revers- ible (Fig. 2, G and H). The activation of the PGN with local application of glutamate (0.5 mM in micropipette) in the presence of bicuculline also resulted in the generation of slow IPSPs (Fig. 3B), and these were completely blocked by local application of CGP 35348 (2 mM in micropipette; n 12) or CGP 54626A (1 mM in micropi- pette; n 4), confirming their mediation by GABA B receptors ...
Context 8
... we demonstrate that single GABAergic PGN neurons are responsible for the activation of IPSPs mediated by both GABA A and GABA B receptors and that the pattern of presynaptic discharge is critical in determining which of these two types of IPSP are activated. With single action potentials, we could not detect GABA B -receptor-mediated IPSPs; the ac- tivation of these IPSPs required the gener- ation of prolonged bursts of action poten- tials (Fig. 2). The delay to onset of these IPSPs may have multiple origins, including the properties of G-protein-mediated events that are the intermediaries between receptor binding and K channel opening (23) or the location of receptors in relation to the synaptic terminals ...
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Introduction
Epileptiform activity is the most striking result of hyperexcitation of a group of neurons that can occur in different brain regions and then spread to other sites. Later it was shown that these rhythms have a cellular correlate in vitro called paroxysmal depolarization shift (PDS). In 13–15 DIV neuron-glial cell culture, inhibition of...
Citations
... This lack of understanding is likely due to complex CT circuit interactions, the nature of which is only beginning to emerge. For instance, L6 CT cells monosynaptically excite thalamic relay cells in both core sensory and higher-order nuclei, such as the VPm and POm (Scharfman et al., 1990;Golshani et al., 2001;Landisman and Connors, 2007;Lam and Sherman, 2010;Hoerder-Suabedissen et al., 2018), but CT cells also indirectly inhibit them by exciting GABAergic neurons in the thalamic reticular nucleus (TRN) (Cox et al., 1997;Kim et al., 1997;Golshani et al., 2001;Crandall et al., 2015). Evidence also suggests that the magnitude and sign of influence (enhancement or suppression) likely reflect complex interactions involving the spatial specificity and temporal properties of feedback (von Krosigk et al., 1999;Temereanca and Simons, 2004;Li and Ebner, 2007;Crandall et al., 2015;Guo et al., 2017;Hasse and Briggs, 2017a;Kirchgessner et al., 2020;Born et al., 2021;Dimwamwa et al., 2024). ...
Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by modulating thalamic excitability. However, the functional role(s) feedback serves during sensory processing is unclear. One hypothesis is that CT feedback is under the control of extra-sensory signals originating from higher-order cortical areas, yet we know nothing about the mechanisms of such control. It is also unclear whether such regulation is specific to CT neurons with distinct thalamic connectivity. Using mice (either sex) combined with in vitro electrophysiology techniques, optogenetics, and retrograde labeling, we describe studies of vibrissal primary motor cortex (vM1) influences on different CT neurons in the vibrissal primary somatosensory cortex (vS1) with distinct intrathalamic axonal projections. We found that vM1 inputs are highly selective, evoking stronger postsynaptic responses in Dual ventral posterior medial nucleus (VPm) and posterior medial nucleus (POm) projecting CT neurons located in lower L6a than VPm-only projecting CT cells in upper L6a. A targeted analysis of the specific cells and synapses involved revealed that the greater responsiveness of Dual CT neurons was due to their distinctive intrinsic membrane properties and synaptic mechanisms. These data demonstrate that vS1 has at least two discrete L6 CT subcircuits distinguished by their thalamic projection patterns, intrinsic physiology, and functional connectivity with vM1. Our results also provide insights into how a distinct CT subcircuit may serve specialized roles specific to contextual modulation of tactile-related sensory signals in the somatosensory thalamus during active vibrissa movements.
... The method can be adapted to study other genetic and toxin-induced forms of abnormal thalamocortical oscillations. Specifically, the barrel somatosensory cortex, which was included in our slice preparation, and the interconnected thalamic circuitry are of interest in disorders other than G1D because they can become hypersynchronized, causing absence seizures in numerous epilepsy models (Kim et al., 1997;Huntsman et al., 1999;Macdonald et al., 2010). ...
Glucose represents the principal brain energy source. Thus, not unexpectedly, genetic glucose transporter 1 (Glut1) deficiency (G1D) manifests with encephalopathy. G1D seizures, which constitute a prominent disease manifestation, often prove refractory to medications but may respond to therapeutic diets. These seizures are associated with aberrant thalamocortical oscillations as inferred from human electroencephalography and functional imaging. Mouse electrophysiological recordings indicate that inhibitory neuron failure in thalamus and cortex underlies these abnormalities. This provides the motivation to develop a neural circuit testbed to characterize the mechanisms of thalamocortical synchronization and the effects of known or novel interventions. To this end, we used mouse thalamocortical slices on multielectrode arrays and characterized spontaneous low frequency oscillations and less frequent 30–50 Hz or gamma oscillations under near-physiological bath glucose concentration. Using the cortical recordings from layer IV among other regions recorded, we quantified oscillation epochs via an automated wavelet-based algorithm. This method proved analytically superior to power spectral density, short-time Fourier transform or amplitude-threshold detection. As expected from human observations, increased bath glucose reduced the lower frequency oscillations while augmenting the gamma oscillations, likely reflecting strengthened inhibitory neuron activity, and thus decreasing the low:high frequency ratio (LHR). This approach provides an ex vivo method for the evaluation of mechanisms, fuels, and pharmacological agents in a crucial G1D epileptogenic circuit.
... The activity of TC neurons is influenced by GABAergic inputs from nRT neurons, and GABA A and GABA B receptor activation in the thalamocortical circuit has long been implicated in the generation of SWDs (Coulter et al., 1990b;Hosford et al., 1997;Kim et al., 1997). ...
... Activation of GABA receptors in TC neurons can be pro-epileptic, because GABA A and GABA B receptors hyperpolarize TC neurons with differing time courses and promote posthyperpolarization rebound firing (Kim et al., 1997). Consistent with this idea, enhancing the bioavailability of endogenous GABA with reuptake inhibitors (D'Amore et al., 2015), loss-of-function mutations in Slc6a1 (a mutation encoding GABA transporter GAT-1 and implicated in a generalized DEE, epilepsy with myoclonic-atonic seizures) (Pirttimaki et al., 2013), or administering GABA pro-drug GHB (Godschalk et al., 1977;Liu et al., 1991), can all provoke SWDs. ...
Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.
... Despite the promising results, the mechanism of action of DBS is not thoroughly clear. From the cellular perspective, DBS can regulate the activity of GABAergic neurons located in the reticular thalamic nucleus to produce inhibitory postsynaptic potentials and induce synaptic inhibition of excitatory corticothalamic relay neurons 38 . It has been demonstrated that the strength and duration of absence epilepsy are weakened by amplifying the GABAergic inhibitory power 39 . ...
Deep brain stimulation (DBS) is a promising technique to relieve the symptoms in patients with intractable seizures. Although the DBS therapy for seizure suppression dates back more than 40 years, determining stimulation parameters is a significant challenge to the success of this technique. One solution to this challenge with application in a real DBS system is to design a closed-loop control system to regulate the stimulation intensity using computational models of epilepsy automatically. The main goal of the current study is to develop a robust control technique based on adaptive fuzzy terminal sliding mode control (AFTSMC) for eliminating the oscillatory spiking behavior in childhood absence epilepsy (CAE) dynamical model consisting of cortical, thalamic relay, and reticular nuclei neurons. To this end, the membrane voltage dynamics of the three coupled neurons are considered as a three-input three-output nonlinear state delay system. A fuzzy logic system is developed to estimate the unknown nonlinear dynamics of the current and delayed states of the model embedded in the control input. Chattering-free control input (continuous DBS pulses) without any singularity problem is the superiority of the proposed control method. To guarantee the bounded stability of the closed-loop system in a finite time, the upper bounds of the external disturbance and minimum estimation errors are updated online with adaptive laws without any offline tuning phase. Simulation results are provided to show the robustness of AFTSMC in the presence of uncertainty and external disturbances.
... Burst discharge of TRN neurons produces long-lasting inhibitory responses dependent on the activation of both GABAA and GABAB receptors. In contrast, tonic discharge predominantly produces short duration inhibition dependent on GABAA receptor activation 3,20,21 . ...
The thalamic reticular nucleus (TRN) sits at the interface of the thalamus and neocortex and provides the majority of inhibition to thalamic relay nuclei. Functionally, the activity of TRN neurons can impact sensory processing and may influence arousal states. TRN neurons discharge action potentials in two distinct output modes: tonic or burst firing. Burst output, a transient high frequency discharge of action potentials, is dependent on the activation of transient low-threshold voltage-dependent T-type calcium current (IT). In our current study, we identify a broad range of burst firing frequencies in TRN neurons, which depend on the activation of IT. The amplitude of the low-threshold calcium spike (LTS) underlying the burst positively correlated with burst frequency and number of action potentials per burst. Activation of small conductance calcium-activated potassium (SK) channels on TRN neurons can impact burst discharge. Attenuation of SK channels increased TRN neuron burst frequency through an increase in LTS duration, but not magnitude. The broad range of burst firing frequencies could provide distinct downstream inhibition within thalamic nuclei.
... One function of these CT cells may be to selectively enhance or suppress afferent sensory signals in a context-dependent manner. CT fibers from L6 are glutamatergic and thus a direct source of monosynaptic excitatory input to thalamic relay cells (Scharfman et al., 1990;Bourassa et al., 1995;Golshani et al., 2001), but they also indirectly inhibit them by recruiting GABAergic neurons in the thalamic reticular nucleus (TRN; Cox et al., 1997;Kim et al., 1997;Golshani et al., 2001;Crandall et al., 2015). Previous work has shown that the sign of CT influence on thalamic relay cells is highly dynamic, with the excitatory-inhibitory balance shifting in an activity-dependent manner (von Krosigk et al., 1999;Crandall et al., 2015). ...
Layer 6 corticothalamic (L6 CT) neurons are in a strategic position to control sensory input to the neocortex, yet we understand very little about their functions. Apart from studying their anatomical, physiological and synaptic properties, most recent efforts have focused on the activity-dependent influences CT cells can exert on thalamic and cortical neurons through causal optogenetic manipulations. However, few studies have attempted to study them during behavior. To address this gap, we performed juxtacellular recordings from optogenetically identified CT neurons in whisker-related primary somatosensory cortex (wS1) of awake, head-fixed mice (either sex) free to rest quietly or self-initiate bouts of whisking and locomotion. We found a rich diversity of response profiles exhibited by CT cells. Their spiking patterns were either modulated by whisking-related behavior (∼28%) or not (∼72%). Whisking-responsive neurons exhibited either increases, activated-type, or decreases in firing rates, suppressed-type, that aligned with whisking onset better than locomotion. We also encountered responsive neurons with preceding modulations in firing rate before whisking onset. Overall, whisking better explained these changes in rates than overall changes in arousal. Whisking-unresponsive CT cells were generally quiet, with many having low spontaneous firing rates, sparse-type, and others being completely silent. Remarkably, the sparse firing CT population preferentially spiked at the state transition point when pupil diameter constricted and the mouse entered quiet wakefulness. Thus, our results demonstrate that L6 CT cells in wS1 show diverse spiking patterns, perhaps subserving distinct functional roles related to precisely timed responses during complex behaviors and transitions between discrete waking states.SIGNIFICANCE STATEMENTLayer 6 corticothalamic neurons provide a massive input to the sensory thalamus and local connectivity within cortex, but their role in thalamocortical processing remains unclear due to difficulty accessing and isolating their activity. Although several recent optogenetic studies reveal that the net influence of corticothalamic actions, suppression versus enhancement, depends critically on the rate these neurons fire, the factors that influence their spiking are poorly understood, particularly during wakefulness. Using the well-established Ntsr1-Cre line to target this elusive population in the whisker somatosensory cortex of awake mice, we found that corticothalamic neurons show diverse state-related responses and modulations in firing rate. These results suggest separate corticothalamic populations can differentially influence thalamocortical excitability during rapid state transitions in awake, behaving animals.
... To model synapse kinetics, we used existing models of synaptic currents and included literature findings on decay time constants, reversal potentials and the relative contribution of AMPA, NMDA, GABA A and GABA B currents, summarized in Table 1 (Arsenault and Zhang, 2006;Deleuze and Huguenard, 2016;Miyata and Imoto, 2006;Warren et al., 1994;Zhu et al., 1999). In the case of inhibitory synapses, we included only GABA A currents in this first draft, since our existing GABA model does not take into account the non-linear dependence of GABA B activation on presynaptic activity (Destexhe and Sejnowski, 1995;Kim et al., 1997;Wang et al., 1995). ...
Thalamoreticular circuitry is central to sensory processing, attention, and sleep, and is implicated in numerous brain disorders, but the cellular and synaptic mechanisms remain intractable. Therefore, we developed the first detailed microcircuit model of mouse thalamus and thalamic reticular nucleus that captures morphological and biophysical properties of ∼14,000 neurons connected via ∼6M synapses, and recreates biological synaptic and gap junction connectivity. Realistic spontaneous and evoked activity during wakefulness and sleep emerge allowing dissection of cellular and synaptic contributions. Computer simulations suggest that reticular inhibition shapes thalamic responses and cortex can drive frequency-selective thalamic enhancement during wakefulness, whereas in sleep, reticular inhibition and cortical UP-states can trigger thalamic bursts and spindles. Gap junctions and short-term synaptic plasticity underlie spindle properties such as waxing and waning, and neuromodulation influences the occurrence of spindles. The model is openly available to support testing hypotheses of thalamoreticular circuitry in normal brain function and in disease.
... 28 Thus, the receptors are largely inactive during basal conditions or during moderate synaptic activity. [108][109][110] However, if GABAergic inputs are sufficiently active, then released GABA can spillover to extrasynaptic regions to activate GABA B receptors. 75 We propose that AMPK-mediated potentiation of thalamic GABA B -receptor activity during hypoglycaemia reduces the threshold for such receptor activation. ...
Metabolism regulates neuronal activity and modulates the occurrence of epileptic seizures. Here, using two rodent models of absence epilepsy, we show that hypoglycemia increases the occurrence of spike-wave seizures. We then show that selectively disrupting glycolysis in the thalamus, a structure implicated in absence epilepsy, is sufficient to increase spike-wave seizures. We propose that activation of thalamic AMP-activated protein kinase (AMPK), a sensor of cellular energetic stress and potentiator of metabotropic GABAB receptor function, is a significant driver of hypoglycemia-induced spike-wave seizures. We show that AMPK augments postsynaptic GABAB receptor-mediated currents in thalamocortical neurons and strengthens epileptiform network activity evoked in thalamic brain slices. Selective thalamic AMPK activation also increases spike-wave seizures. Finally, systemic administration of metformin, an AMPK agonist and common diabetes treatment, profoundly increased spike-wave seizures. These results advance the decades-old observation that glucose metabolism regulates thalamocortical circuit excitability by demonstrating that AMPK and GABAB receptor cooperativity is sufficient to provoke spike-wave seizures.
... The GABAergic system in the thalamus is comprised by local interneurons and neurons of the thalamic reticular nucleus (TRN) [48]. These neurons participate in the production of spontaneous and evoked (i.e., in response to stimulation) synchronous activity associated with movement, sleep and seizures [49]. ...
Human and animal studies have elucidated the apparent neurodevelopmental effects resulting from neonatal anesthesia. Observations of learning and behavioral deficits in children, who were exposed to anesthesia early in development, have instigated a flurry of studies that have predominantly utilized animal models to further interrogate the mechanisms of neonatal anesthesia-induced neurotoxicity. Specifically, while neonatal anesthesia has demonstrated its propensity to affect multiple cell types in the brain, it has shown to have a particularly detrimental effect on the gamma aminobutyric acid (GABA)ergic system, which contributes to the observed learning and behavioral deficits. The damage to GABAergic neurons, resulting from neonatal anesthesia, seems to involve structure-specific changes in excitatory-inhibitory balance and neurovascular coupling, which manifest following a significant interval after neonatal anesthesia exposure. Thus, to better understand how neonatal anesthesia affects the GABAergic system, we first review the early development of the GABAergic system in various structures that have been the focus of neonatal anesthesia research. This is followed by an explanation that, due to the prolonged developmental curve of the GABAergic system, the entirety of the negative effects of neonatal anesthesia on learning and behavior in children are not immediately evident, but instead take a substantial amount of time (years) to fully develop. In order to address these concerns going forward, we subsequently offer a variety of in vivo methods which can be used to record these delayed effects.
... /2021https://doi.org/10. .11.08.467762 doi: bioRxiv preprint 1997Kim et al., 1997;Golshani et al., 2001;Crandall et al., 2015). Previous work has shown that the sign of CT influence on thalamic relay cells is highly dynamic, with the excitatory-inhibitory balance shifting in an activity-dependent manner (von Krosigk et al., 1999;Crandall et al., 2015). ...
Layer 6 corticothalamic (L6 CT) neurons are in a strategic position to control sensory input to the neocortex, yet we understand very little about their functions. Apart from studying their anatomical, physiological and synaptic properties, most recent efforts have focused on the activity-dependent influences CT cells can exert on thalamic and cortical neurons through causal optogenetic manipulations. However, few studies have attempted to study them during behavior. To address this gap, we performed juxtacellular recordings from optogenetically identified CT neurons in whisker-related primary somatosensory cortex (wS1) of awake, head-fixed mice (either sex) free to rest quietly or self-initiate bouts of whisking and locomotion. We found a rich diversity of response profiles exhibited by CT cells. Their spiking patterns were either modulated by whisking-related behavior (∼28%) or not (∼72%). Whisking-responsive neurons exhibited either increases, activated-type, or decreases in firing rates, suppressed-type, that aligned with whisking onset better than locomotion. We also encountered responsive neurons with preceding modulations in firing rate before whisking onset. Overall, whisking better explained these changes in rates than overall changes in arousal. Whisking-unresponsive CT cells were generally quiet, with many having low spontaneous firing rates, sparse-type, and others being completely silent. Remarkably, the sparse firing CT population preferentially spiked at the state transition point when pupil diameter constricted and the mouse entered quiet wakefulness. Thus, our results demonstrate that L6 CT cells in wS1 show diverse spiking patterns, perhaps subserving distinct functional roles related to precisely timed responses during complex behaviors and transitions between discrete waking states.
SIGNIFICANCE STATEMENT
Layer 6 corticothalamic neurons provide a massive input to the sensory thalamus and local connectivity within cortex, but their role in thalamocortical processing remains unclear due to difficulty accessing and isolating their activity. Although several recent optogenetic studies reveal that the net influence of corticothalamic actions, suppression versus enhancement, depends critically on the rate these neurons fire, the factors that influence their spiking are poorly understood, particularly during wakefulness. Using the well-established Ntsr1-Cre line to target this elusive population in the whisker somatosensory cortex of awake mice, we found that corticothalamic neurons show diverse state-related responses and modulations in firing rate. These results suggest separate corticothalamic populations can differentially influence thalamocortical excitability during rapid state transitions in awake, behaving animals.
