Search tips
Search criteria

Results 1-9 (9)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
1.  A Distinct Class of Slow (∼0.2–2 Hz) Intrinsically Bursting Layer 5 Pyramidal Neurons Determines UP/DOWN State Dynamics in the Neocortex 
The Journal of Neuroscience  2015;35(14):5442-5458.
During sleep and anesthesia, neocortical neurons exhibit rhythmic UP/DOWN membrane potential states. Although UP states are maintained by synaptic activity, the mechanisms that underlie the initiation and robust rhythmicity of UP states are unknown. Using a physiologically validated model of UP/DOWN state generation in mouse neocortical slices whereby the cholinergic tone present in vivo is reinstated, we show that the regular initiation of UP states is driven by an electrophysiologically distinct subset of morphologically identified layer 5 neurons, which exhibit intrinsic rhythmic low-frequency burst firing at ∼0.2–2 Hz. This low-frequency bursting is resistant to block of glutamatergic and GABAergic transmission but is absent when slices are maintained in a low Ca2+ medium (an alternative, widely used model of cortical UP/DOWN states), thus explaining the lack of rhythmic UP states and abnormally prolonged DOWN states in this condition. We also characterized the activity of various other pyramidal and nonpyramidal neurons during UP/DOWN states and found that an electrophysiologically distinct subset of layer 5 regular spiking pyramidal neurons fires earlier during the onset of network oscillations compared with all other types of neurons recorded. This study, therefore, identifies an important role for cell-type-specific neuronal activity in driving neocortical UP states.
PMCID: PMC4388913  PMID: 25855163
acetylcholine; inhibition; muscarinic; rhythmic bursting; slow waves
3.  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.
PMCID: PMC3187667  PMID: 22007176
EEG; gap junctions; electrical synapse; alpha rhythms; acetylcholine; metabotropic glutamate receptor
4.  Infra-slow (<0.1 Hz) oscillations in thalamic relay nuclei: basic mechanisms and significance to health and disease states 
Progress in brain research  2011;193:145-162.
In the absence of external stimuli the mammalian brain continues to display a rich variety of spontaneous activity. Such activity is often highly stereotypical, invariably rhythmic and can occur with periodicities ranging from a few milliseconds to several minutes. Recently there has been a particular resurgence of interest in fluctuations in brain activity occurring at <0.1 Hz, commonly referred to as very slow or infra-slow oscillations (ISOs). Whilst this is primarily due to the emergence of functional magnetic resonance imaging (fMRI) as a technique which has revolutionised the study of human brain dynamics it is also a consequence of the application of full band electroencephalography (fbEEG). Despite these technical advances the precise mechanisms which lead to ISOs in the brain remain unclear. In a host of animal studies, one brain region that consistently shows oscillations at <0.1 Hz is the thalamus. Importantly, similar oscillations can also be observed in slices of isolated thalamic relay nuclei maintained in vitro. Here, we discuss the nature and mechanisms of these oscillations, paying particular attention to a potential role for astrocytes in their genesis. We also highlight the relationship between this activity and ongoing local network oscillations in the alpha (α) (~8-13 Hz) band, drawing clear parallels with observations made in vivo. Lastly, we consider the relevance of these thalamic ISOs to the pathological activity that occurs in certain types of epilepsy.
PMCID: PMC3173874  PMID: 21854961
acetylcholine; metabotropic glutamate receptor; EEG; gap junctions; alpha rhythm; epilepsy; adenosine; astrocytes; GIRK channels
5.  Activity of cortical and thalamic neurons during the slow (<1 Hz) rhythm in the mouse in vivo 
Pflugers Archiv  2011;463(1):73-88.
During NREM sleep and under certain types of anaesthesia, the mammalian brain exhibits a distinctive slow (<1 Hz) rhythm. At the cellular level, this rhythm correlates with so-called UP and DOWN membrane potential states. In the neocortex, these UP and DOWN states correspond to periods of intense network activity and widespread neuronal silence, respectively, whereas in thalamocortical (TC) neurons, UP/DOWN states take on a more stereotypical oscillatory form, with UP states commencing with a low-threshold Ca2+ potential (LTCP). Whilst these properties are now well recognised for neurons in cats and rats, whether or not they are also shared by neurons in the mouse is not fully known. To address this issue, we obtained intracellular recordings from neocortical and TC neurons during the slow (<1 Hz) rhythm in anaesthetised mice. We show that UP/DOWN states in this species are broadly similar to those observed in cats and rats, with UP states in neocortical neurons being characterised by a combination of action potential output and intense synaptic activity, whereas UP states in TC neurons always commence with an LTCP. In some neocortical and TC neurons, we observed ‘spikelets’ during UP states, supporting the possible presence of electrical coupling. Lastly, we show that, upon tonic depolarisation, UP/DOWN states in TC neurons are replaced by rhythmic high-threshold bursting at ~5 Hz, as predicted by in vitro studies. Thus, UP/DOWN state generation appears to be an elemental and conserved process in mammals that underlies the slow (<1 Hz) rhythm in several species, including humans.
PMCID: PMC3256325  PMID: 21892727
EEG; Oscillations; Sleep; Neocortex; Thalamocortical; Electroencephalogram; T-type calcium channel; Thalamus; Neocortical neurons
6.  Enhanced tonic GABAA inhibition in typical absence epilepsy 
Nature medicine  2009;15(12):1392-1398.
The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic 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 critical 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 behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.
PMCID: PMC2824149  PMID: 19966779
extrasynaptic; tonic current; GAT–1; thalamus; spike–and–wave discharge; GAERS; stargazer; lethargic; GHB; THIP
7.  Cellular dynamics of cholinergically-induced alpha (8-13 Hz) rhythms in sensory thalamic nuclei in vitro 
Although EEG alpha (α) (8-13 Hz) rhythms are traditionally thought to reflect an ‘idling’ brain state, they are also linked to several important aspects of cognition, perception and memory. Here we show that reactivating cholinergic input, a key component in normal cognition and memory operations, in slices of the cat primary visual and somatosensory thalamus, produces robust α rhythms. These rhythms rely on activation of muscarinic receptors and are primarily coordinated by activity in the recently discovered, gap junction (GJ)-coupled subnetwork of high-threshold (HT) bursting thalamocortical (TC) neurons. By performing extracellular field recordings in combination with intracellular recordings of these cells we show that, i) the coupling of HT bursting cells is sparse, with individual neurons typically receiving discernable network input from one or very few additional cells, ii) the phase of oscillatory activity at which these cells prefer to fire is readily modifiable and determined by a combination of network input, intrinsic properties and membrane polarization, and iii) single HT bursting neurons can potently influence the local network state. These results substantially extend the known effects of cholinergic activation on the thalamus and in combination with previous studies show that sensory thalamic nuclei possess powerful and dynamically reconfigurable mechanisms for generating synchronized α activity that can be engaged by both descending and ascending arousal systems.
PMCID: PMC2778076  PMID: 18199766
acetylcholine; lateral geniculate nucleus; electrical synapses; gap junctions; oscillations; EEG; cognition; memory
8.  Temporal Framing of Thalamic Relay-Mode Firing by Phasic Inhibition during the Alpha Rhythm 
Neuron  2009;63(5):683-696.
Several aspects of perception, particularly those pertaining to vision, are closely linked to the occipital alpha (α) rhythm. However, how the α rhythm relates to the activity of neurons that convey primary visual information is unknown. Here we show that in behaving cats, thalamocortical neurons in the lateral geniculate nucleus (LGN) that operate in a conventional relay-mode form two groups where the cumulative firing is subject to a cyclic suppression that is centered on the negative α rhythm peak in one group and on the positive peak in the other. This leads to an effective temporal framing of relay-mode output and results from phasic inhibition from LGN interneurons, which in turn are rhythmically excited by thalamocortical neurons that exhibit high-threshold bursts. These results provide a potential cellular substrate for linking the α rhythm to perception and further underscore the central role of inhibition in controlling spike timing during cognitively relevant brain oscillations.
PMCID: PMC2791173  PMID: 19755110
9.  ATP-Dependent Infra-Slow (<0.1 Hz) Oscillations in Thalamic Networks 
PLoS ONE  2009;4(2):e4447.
An increasing number of EEG and resting state fMRI studies in both humans and animals indicate that spontaneous low frequency fluctuations in cerebral activity at <0.1 Hz (infra-slow oscillations, ISOs) represent a fundamental component of brain functioning, being known to correlate with faster neuronal ensemble oscillations, regulate behavioural performance and influence seizure susceptibility. Although these oscillations have been commonly indicated to involve the thalamus their basic cellular mechanisms remain poorly understood. Here we show that various nuclei in the dorsal thalamus in vitro can express a robust ISO at ∼0.005–0.1 Hz that is greatly facilitated by activating metabotropic glutamate receptors (mGluRs) and/or Ach receptors (AchRs). This ISO is a neuronal population phenomenon which modulates faster gap junction (GJ)-dependent network oscillations, and can underlie epileptic activity when AchRs or mGluRs are stimulated excessively. In individual thalamocortical neurons the ISO is primarily shaped by rhythmic, long-lasting hyperpolarizing potentials which reflect the activation of A1 receptors, by ATP-derived adenosine, and subsequent opening of Ba2+-sensitive K+ channels. We argue that this ISO has a likely non-neuronal origin and may contribute to shaping ISOs in the intact brain.
PMCID: PMC2637539  PMID: 19212445

Results 1-9 (9)