HCN channels and absence seizures.

Hyperpolarization-activation cyclic nucleotide-gated (HCN) channels were for the first time implicated in absence seizures (ASs) when an abnormal Ih (the current generated by these channels) was reported in neocortical layer 5 neurons of a mouse model. Genetic studies of large cohorts of children with Childhood Absence Epilepsy (where ASs are the only clinical symptom) have identified only 3 variants in HCN1 (one of the genes that code for the 4 HCN channel isoforms, HCN1-4), with one (R590Q) mutation leading to loss-of-function. Due to the multi-faceted effects that HCN channels exert on cellular excitability and neuronal network dynamics as well as their modulation by environmental factors, it has been difficult to identify the detailed mechanism by which different HCN isoforms modulate ASs. In this review, we systematically and critically analyze evidence from established AS models and normal non-epileptic animals with area- and time-selective ablation of HCN1, HCN2 and HCN4. Notably, whereas knockout of rat HCN1 and mouse HCN2 leads to the expression of ASs, the pharmacological block of all HCN channel isoforms abolishes genetically determined ASs. These seemingly contradictory results could be reconciled by taking into account the well-known opposite effects of Ih on cellular excitability and network function. Whereas existing evidence from mouse and rat AS models indicates that pan-HCN blockers may provide a novel approach for the treatment of human ASs, the development of HCN isoform-selective drugs would greatly contribute to current research on the role for these channels in ASs generation and maintenance as well as offer new potential clinical applications.

Higher-order thalamic nuclei facilitate the generalization and maintenance of spike-and-wave discharges of absence seizures.

Spike-and-wave discharges (SWDs), generated by the cortico-thalamo-cortical (CTC) network, are pathological, large amplitude oscillations and the hallmark of absence seizures (ASs). SWDs begin in a cortical initiation network in both humans and animal models, including the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), where it is located in the primary somatosensory cortex (S1). The behavioral manifestation of an AS occurs when SWDs spread from the cortical initiation site to the whole brain, however, the mechanisms behind this rapid propagation remain unclear. Here we investigated these processes beyond the principal CTC network, in higher-order (HO) thalamic nuclei (lateral posterior (LP) and posterior (PO) nuclei) since their diffuse connectivity and known facilitation of intracortical communications make these nuclei key candidates to support SWD generation and maintenance. In freely moving GAERS, multi-site LFP in LP, PO and multiple cortical regions revealed a novel feature of SWDs: during SWDs there are short periods (named SWD-breaks) when cortical regions far from S1, such the primary visual cortex (V1), become transiently unsynchronized from the ongoing EEG rhythm. Inactivation of HO nuclei with local muscimol injections or optogenetic perturbation of HO nuclei activity increased the occurrence of SWD-breaks and the former intervention also increased the SWD propagation-time from S1. The neural underpinnings of these findings were explored further by silicon probe recordings from single units of PO which uncovered two previously unknown groups of excitatory neurons based on their burst firing dynamics at SWD onset. Moreover, a switch from tonic to burst firing at SWD onset was shown to be an important feature since it was much less prominent for non-generalized events, i.e. SWDs that remained local to S1. Additionally, one group of neurons showed a reverse of this switch during SWD-breaks, demonstrating the importance of this firing pattern throughout the SWD. In summary, these results support the view that multiple HO thalamic nuclei are utilized at SWD onset and contribute to cortical synchrony throughout the paroxysmal discharge.

Dual function of thalamic low-vigilance state oscillations: rhythm-regulation and plasticity.

During inattentive wakefulness and non-rapid eye movement (NREM) sleep, the neocortex and thalamus cooperatively engage in rhythmic activities that are exquisitely reflected in the electroencephalogram as distinctive rhythms spanning a range of frequencies from <1 Hz slow waves to 13 Hz alpha waves. In the thalamus, these diverse activities emerge through the interaction of cell-intrinsic mechanisms and local and long-range synaptic inputs. One crucial feature, however, unifies thalamic oscillations of different frequencies: repetitive burst firing driven by voltage-dependent Ca2+ spikes. Recent evidence reveals that thalamic Ca2+ spikes are inextricably linked to global somatodendritic Ca2+ transients and are essential for several forms of thalamic plasticity. Thus, we propose herein that alongside their rhythm-regulation function, thalamic oscillations of low-vigilance states have a plasticity function that, through modifications of synaptic strength and cellular excitability in local neuronal assemblies, can shape ongoing oscillations during inattention and NREM sleep and may potentially reconfigure thalamic networks for faithful information processing during attentive wakefulness.

Differential Serotonergic Modulation of Synaptic Inputs to the Olfactory Cortex.

Serotonin (5-hydroxytriptamine, 5-HT) is an important monoaminergic neuromodulator involved in a variety of physiological and pathological functions. It has been implicated in the regulation of sensory functions at various stages of multiple modalities, but its mechanisms and functions in the olfactory system have remained elusive. Combining electrophysiology, optogenetics and pharmacology, here we show that afferent (feed-forward) pathway-evoked synaptic responses are boosted, whereas feedback responses are suppressed by presynaptic 5-HT1B receptors in the anterior piriform cortex (aPC) in vitro. Blocking 5-HT1B receptors also reduces the suppressive effects of serotonergic photostimulation of baseline firing in vivo. We suggest that by regulating the relative weights of synaptic inputs to aPC, 5-HT finely tunes sensory inputs in the olfactory cortex.

Reciprocal Lateral Hypothalamic and Raphe GABAergic Projections Promote Wakefulness.

The lateral hypothalamus (LH), together with multiple neuromodulatory systems of the brain, such as the dorsal raphe nucleus (DR), is implicated in arousal, yet interactions between these systems are just beginning to be explored. Using a combination of viral tracing, circuit mapping, electrophysiological recordings from identified neurons, and combinatorial optogenetics in mice, we show that GABAergic neurons in the LH selectively inhibit GABAergic neurons in the DR, resulting in increased firing of a substantial fraction of its neurons that ultimately promotes arousal. These DRGABA neurons are wake active and project to multiple brain areas involved in the control of arousal, including the LH, where their specific activation potently influences local network activity leading to arousal from sleep. Our results show how mutual inhibitory projections between the LH and the DR promote wakefulness and suggest a complex arousal control by intimate interactions between long-range connections and local circuit dynamics.SIGNIFICANCE STATEMENT: Multiple brain systems including the lateral hypothalamus and raphe serotonergic system are involved in the regulation of the sleep/wake cycle, yet the interaction between these systems have remained elusive. Here we show that mutual disinhibition mediated by long range inhibitory projections between these brain areas can promote wakefulness. The main importance of this work relies in revealing the interaction between a brain area involved in autonomic regulation and another in controlling higher brain functions including reward, patience, mood and sensory coding.

Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures.

OBJECTIVE: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a proabsence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, which is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection into the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. METHODS: We used electroencephalographic recordings in freely moving Genetic Absence Epilepsy Rats From Strasbourg (GAERSs) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected into the CIN and VB of GAERSs in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical Layer 5/6 and thalamocortical neurons, respectively. RESULTS: Oral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection into CIN abolished ASs and elicited small-amplitude 4-7-Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN channel-dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively. SIGNIFICANCE: These results provide the first demonstration of the antiabsence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures.

Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures.

(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5-4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have been involved in their modulation and associated comorbidities including the serotonergic system. Neuronal activity in one of the major synaptic input structures to the brainstem dorsal raphé nucleus (DRN), the lateral hypothalamus (LH), has not been characterized. (2) Methods: We used viral tract tracing and optogenetics combined with in vitro and in vivo electrophysiology to assess the involvement of the LH in absence epilepsy in a genetic rodent model. (3) Results: We found that a substantial fraction of LH neurons project to the DRN of which a minority is GABAergic. The LH to DRN projection can lead to monosynaptic iGluR mediated excitation in DRN 5-HT neurons. Neuronal activity in the LH is coupled to SWDs. (4) Conclusions: Our results indicate that a brain area involved in the regulation of autonomic functions and heavily innervating the RN is involved in ASs. The decreased activity of LH neurons during SWDs could lead to both a decreased excitation and disinhibition in the DRN. These results support a long-range subcortical regulation of serotonergic neuromodulation during ASs and further our understanding of the state-dependence of these seizures and some of their associated comorbidities.

Suppression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function in Thalamocortical Neurons Prevents Genetically Determined and Pharmacologically Induced Absence Seizures.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the Ih current they generate contribute to the pathophysiological mechanisms of absence seizures (ASs), but their precise role in neocortical and thalamic neuronal populations, the main components of the network underlying AS generation, remains controversial. In diverse genetic AS models, Ih amplitude is smaller in neocortical neurons and either larger or unchanged in thalamocortical (TC) neurons compared with nonepileptic strains. A lower expression of neocortical HCN subtype 1 channels is present in genetic AS-prone rats, and HCN subtype 2 knock-out mice exhibit ASs. Furthermore, whereas many studies have characterized Ih contribution to "absence-like" paroxysmal activity in vitro, no data are available on the specific role of cortical and thalamic HCN channels in behavioral seizures. Here, we show that the pharmacological block of HCN channels with the antagonist ZD7288 applied via reverse microdialysis in the ventrobasal thalamus (VB) of freely moving male Genetic Absence Epilepsy Rats from Strasbourg decreases TC neuron firing and abolishes spontaneous ASs. A similar effect is observed on γ-hydroxybutyric acid-elicited ASs in normal male Wistar rats. Moreover, thalamic knockdown of HCN channels via virally delivered shRNA into the VB of male Stargazer mice, another genetic AS model, decreases spontaneous ASs and Ih-dependent electrophysiological properties of VB TC neurons. These findings provide the first evidence that block of TC neuron HCN channels prevents ASs and suggest that any potential anti-absence therapy that targets HCN channels should carefully consider the opposite role for cortical and thalamic Ih in the modulation of absence seizures.SIGNIFICANCE STATEMENT Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in the fine-tuning of cellular and network excitability and have been suggested to be a key element of the pathophysiological mechanism underlying absence seizures. However, the precise contribution of HCN channels in neocortical and thalamic neuronal populations to these nonconvulsive seizures is still controversial. In the present study, pharmacological block and genetic suppression of HCN channels in thalamocortical neurons in the ventrobasal thalamic nucleus leads to a marked reduction in absence seizures in one pharmacological and two genetic rodent models of absence seizures. These results provide the first evidence that block of TC neuron HCN channels prevents absence seizures.

Optogenetic Activation of Dorsal Raphe Serotonin Neurons Rapidly Inhibits Spontaneous But Not Odor-Evoked Activity in Olfactory Cortex.

Serotonin (5-hydroxytriptamine; 5-HT) is implicated in a variety of brain functions including not only the regulation of mood and control of behavior but also the modulation of perception. 5-HT neurons in the dorsal raphe nucleus (DRN) often fire locked to sensory stimuli, but little is known about how 5-HT affects sensory processing, especially on this timescale. Here, we used an optogenetic approach to study the effect of 5-HT on single-unit activity in the mouse primary olfactory (anterior piriform) cortex. We show that activation of DRN 5-HT neurons rapidly inhibits the spontaneous firing of olfactory cortical neurons, acting in a divisive manner, but entirely spares sensory-driven firing. These results identify a new role for serotonergic modulation in dynamically regulating the balance between different sources of neural activity in sensory systems, suggesting a possible role for 5-HT in perceptual inference. SIGNIFICANCE STATEMENT: Serotonin is implicated in a wide variety of (pato)physiological functions including perception, but its precise role has remained elusive. Here, using optogenetic tools in vivo, we show that serotonergic neuromodulation prominently inhibits the spontaneous electrical activity of neurons in the primary olfactory cortex on a rapid (<1 s) timescale but leaves sensory responses unaffected. These results identify a new role for serotonergic modulation in rapidly changing the balance between different sources of neural activity in sensory systems.

A distinct class of slow (~0.2-2 Hz) intrinsically bursting layer 5 pyramidal neurons determines UP/DOWN state dynamics in the neocortex.

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 Ca(2+) 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.

Closed-loop brain stimulation augments fear extinction in male rats.

Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., 'renewal' and 'reinstatement') and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.

Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents.

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

Activity of cortical and thalamic neurons during the slow (<1 Hz) rhythm in the mouse in vivo.

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 Ca(2+) 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.

Differential Serotonergic Modulation of Principal Neurons and Interneurons in the Anterior Piriform Cortex.

Originating from the brainstem raphe nuclei, serotonin is an important neuromodulator involved in a variety of physiological and pathological functions. Specific optogenetic stimulation of serotonergic neurons results in the divisive suppression of spontaneous, but not sensory evoked activity in the majority of neurons in the primary olfactory cortex and an increase in firing in a minority of neurons. To reveal the mechanisms involved in this dual serotonergic control of cortical activity we used a combination of in vitro electrophysiological recordings from identified neurons in the primary olfactory cortex, optogenetics and pharmacology and found that serotonin suppressed the activity of principal neurons, but excited local interneurons. The results have important implications in sensory information processing and other functions of the olfactory cortex and related brain areas.

Temporally Targeted Interactions With Pathologic Oscillations as Therapeutical Targets in Epilepsy and Beyond.

Self-organized neuronal oscillations rely on precisely orchestrated ensemble activity in reverberating neuronal networks. Chronic, non-malignant disorders of the brain are often coupled to pathological neuronal activity patterns. In addition to the characteristic behavioral symptoms, these disturbances are giving rise to both transient and persistent changes of various brain rhythms. Increasing evidence support the causal role of these "oscillopathies" in the phenotypic emergence of the disease symptoms, identifying neuronal network oscillations as potential therapeutic targets. While the kinetics of pharmacological therapy is not suitable to compensate the disease related fine-scale disturbances of network oscillations, external biophysical modalities (e.g., electrical stimulation) can alter spike timing in a temporally precise manner. These perturbations can warp rhythmic oscillatory patterns via resonance or entrainment. Properly timed phasic stimuli can even switch between the stable states of networks acting as multistable oscillators, substantially changing the emergent oscillatory patterns. Novel transcranial electric stimulation (TES) approaches offer more reliable neuronal control by allowing higher intensities with tolerable side-effect profiles. This precise temporal steerability combined with the non- or minimally invasive nature of these novel TES interventions make them promising therapeutic candidates for functional disorders of the brain. Here we review the key experimental findings and theoretical background concerning various pathological aspects of neuronal network activity leading to the generation of epileptic seizures. The conceptual and practical state of the art of temporally targeted brain stimulation is discussed focusing on the prevention and early termination of epileptic seizures.

Cell Type-Specific Arousal-Dependent Modulation of Thalamic Activity in the Lateral Geniculate Nucleus.

State-dependent thalamocortical activity is important for sensory coding, oscillations, and cognition. The lateral geniculate nucleus (LGN) relays visual information to the cortex, but the state-dependent spontaneous activity of LGN neurons in awake behaving animals remains controversial. Using a combination of pupillometry, extracellular, and intracellular recordings from identified LGN neurons in behaving mice, we show that thalamocortical (TC) neurons and interneurons are distinctly correlated to arousal forming two complementary coalitions. Intracellular recordings indicated that the membrane potential of LGN TC neurons was tightly correlated to fluctuations in pupil size. Inactivating the corticothalamic feedback to the LGN suppressed the arousal dependency of LGN neurons. Taken together, our results show that LGN neuronal membrane potential and action potential output are dynamically linked to arousal-dependent brain states in awake mice, and this might have important functional implications.

Cellular dynamics of cholinergically induced alpha (8-13 Hz) rhythms in sensory thalamic nuclei in vitro.

Although EEG alpha (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 alpha rhythms. These rhythms rely on activation of muscarinic receptors and are primarily coordinated by activity in the recently discovered, gap junction-coupled subnetwork of high-threshold (HT) bursting thalamocortical neurons. By performing extracellular field recordings in combination with intracellular recordings of these cells, we show that (1) the coupling of HT bursting cells is sparse, with individual neurons typically receiving discernable network input from one or very few additional cells, (2) 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 (3) 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 alpha activity that can be engaged by both descending and ascending arousal systems.

Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons.

It is now widely accepted that certain types of cognitive functions are intimately related to synchronized neuronal oscillations at both low (alpha/theta) (4-7/8-13 Hz) and high (beta/gamma) (18-35/30-70 Hz) frequencies. The thalamus is a key participant in many of these oscillations, yet the cellular mechanisms by which this participation occurs are poorly understood. Here we describe how, under appropriate conditions, thalamocortical (TC) neurons from different nuclei can exhibit a wide array of largely unrecognised intrinsic oscillatory activities at a range of cognitively-relevant frequencies. For example, both metabotropic glutamate receptor (mGluR) and muscarinic Ach receptor (mAchR) activation can cause rhythmic bursting at alpha/theta frequencies. Interestingly, key differences exist between mGluR- and mAchR-induced bursting, with the former involving extensive dendritic Ca2+ electrogenesis and being mimicked by a non-specific block of K+ channels with Ba2+, whereas the latter appears to be more reliant on proximal Na+ channels and a prominent spike afterdepolarization (ADP). This likely relates to the differential somatodendritic distribution of mGluRs and mAChRs and may have important functional consequences. We also show here that in similarity to some neocortical neurons, inhibiting large-conductance Ca2+-activated K+ channels in TC neurons can lead to fast rhythmic bursting (FRB) at approximately 40 Hz. This activity also appears to rely on a Na+ channel-dependent spike ADP and may occur in vivo during natural wakefulness. Taken together, these results show that TC neurons are considerably more flexible than generally thought and strongly endorse a role for the thalamus in promoting a range of cognitively-relevant brain rhythms.

Functional consequences of retinopetal fibers originating in the dorsal raphe nucleus.

The existence of centrifugal fibers projecting into the mammalian retina is well known. However, their precise physiological role is poorly understood. Here we report that stimulation of the dorsal raphe nucleus (DRN) in freely moving rats produces profound effects on the electroretinogram (ERG). Most notably, activation of the dorsal raphe-retinal pathway causes a significant decrease in the latency of the b-wave and accompanying oscillatory potentials. In addition, dorsal raphe stimulation leads to a significant increase in the amplitude of oscillatory potentials. These results, therefore, provide the first demonstration of a functional role for the retinopetal fiber system originating in the and suggest that this structure can exert a powerful influence over the temporal sharpness and efficacy of retinal responsiveness.