Distinct patterns of striatal medium spiny neuron activity during the natural sleep-wake cycle.

Striatal medium-sized spiny neurons (MSNs) integrate and convey information from the cerebral cortex to the output nuclei of the basal ganglia. Intracellular recordings from anesthetized animals show that MSNs undergo spontaneous transitions between hyperpolarized and depolarized states. State transitions, regarded as necessary for eliciting action potential firing in MSNs, are thought to control basal ganglia function by shaping striatal output. Here, we use an anesthetic-free rat preparation to show that the intracellular activity of MSNs is not stereotyped and depends critically on vigilance state. During slow-wave sleep, much as during anesthesia, MSNs displayed rhythmic step-like membrane potential shifts, correlated with cortical field potentials. However, wakefulness was associated with a completely different pattern of temporally disorganized depolarizing synaptic events of variable amplitude. Transitions from slow-wave sleep to wakefulness converted striatal discharge from a cyclic brisk firing to an irregular pattern of action potentials. These findings illuminate different capabilities of information processing in basal ganglia networks, suggesting in particular that a novel style of striatal computation is associated with the waking state.

Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep.

Dopamine is involved in motivation, memory, and reward processing. However, it is not clear whether the activity of dopamine neurons is related or not to vigilance states. Using unit recordings in unanesthetized head restrained rats we measured the firing pattern of dopamine neurons of the ventral tegmental area across the sleep-wake cycle. We found these cells were activated during paradoxical sleep (PS) via a clear switch to a prominent bursting pattern, which is known to induce large synaptic dopamine release. This activation during PS was similar to the activity measured during the consumption of palatable food. Thus, as it does during waking in response to novelty and reward, dopamine could modulate brain plasticity and thus participate in memory consolidation during PS. By challenging the traditional view that dopamine is the only aminergic group not involved in sleep physiology, this study provides an alternative perspective that may be crucial for understanding the physiological function of PS and dream mentation.

The switch of subthalamic neurons from an irregular to a bursting pattern does not solely depend on their GABAergic inputs in the anesthetic-free rat.

The subthalamic nucleus (STN) powerfully controls basal ganglia outputs and has been implicated in movement disorders observed in Parkinson's disease because of its pathological mixed burst firing mode and hyperactivity. A recent study suggested that reciprocally connected glutamatergic STN and GABAergic globus pallidus (GP) neurons act in vitro as a generator of bursting activity in basal ganglia. In vivo, we reported that GP neurons increased their firing rate in wakefulness (W) compared with slow-wave sleep (SWS) without any change in their random pattern. In contrast, STN neurons exhibited similar firing rates in W and SWS, with an irregular pattern in W and a bursty one in SWS. Thus, the pallidal GABAergic tone might control the STN pattern. This hypothesis was tested by mimicking such variations with microiontophoresis of GABA receptor ligands. GABA agonists specifically decreased the STN firing rate but did not affect its firing pattern. GABA(A) (but not GABA(B)) antagonists strongly enhanced the STN mean discharge rate during all vigilance states up to three to five times its basal activity. However, such applications did not change the typical W random pattern. When applied during SWS, GABA(A) antagonists strongly reinforced the spontaneous bursty pattern into a particularly marked one with instantaneous frequencies reaching 500-600 Hz. SWS-W transitions occurring during ongoing antagonist iontophoresis invariably disrupted the bursty pattern into a random one. Thus GABA(A) receptors play a critical, but not exclusive, role in regulating the excitatory STN influence on basal ganglia outputs.

Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain.

The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT(1A) receptor antagonist WAY-100,635 (20-100 microg/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA(3) pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT(1A) receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED(50)=58 and 254 mug/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 microg/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 microg/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT(1A) autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.

Unsupervised online classifier in sleep scoring for sleep deprivation studies.

STUDY OBJECTIVE: This study was designed to evaluate an unsupervised adaptive algorithm for real-time detection of sleep and wake states in rodents. DESIGN: We designed a Bayesian classifier that automatically extracts electroencephalogram (EEG) and electromyogram (EMG) features and categorizes non-overlapping 5-s epochs into one of the three major sleep and wake states without any human supervision. This sleep-scoring algorithm is coupled online with a new device to perform selective paradoxical sleep deprivation (PSD). SETTINGS: Controlled laboratory settings for chronic polygraphic sleep recordings and selective PSD. PARTICIPANTS: Ten adult Sprague-Dawley rats instrumented for chronic polysomnographic recordings. MEASUREMENTS: The performance of the algorithm is evaluated by comparison with the score obtained by a human expert reader. Online detection of PS is then validated with a PSD protocol with duration of 72 hours. RESULTS: Our algorithm gave a high concordance with human scoring with an average κ coefficient > 70%. Notably, the specificity to detect PS reached 92%. Selective PSD using real-time detection of PS strongly reduced PS amounts, leaving only brief PS bouts necessary for the detection of PS in EEG and EMG signals (4.7 ± 0.7% over 72 h, versus 8.9 ± 0.5% in baseline), and was followed by a significant PS rebound (23.3 ± 3.3% over 150 minutes). CONCLUSIONS: Our fully unsupervised data-driven algorithm overcomes some limitations of the other automated methods such as the selection of representative descriptors or threshold settings. When used online and coupled with our sleep deprivation device, it represents a better option for selective PSD than other methods like the tedious gentle handling or the platform method.

In vivo comparison of two 5-HT1A receptors agonists alnespirone (S-20499) and buspirone on locus coeruleus neuronal activity.

The aim of the present study was to compare, in chloral-hydrate anaesthetized rats, the alpha(2)-adrenergic properties of the selective 5-HT(1A) receptor agonist, alnespirone (S-20499), with those of buspirone, a 5-HT(1A) receptor agonist exhibiting potent alpha(2)-adrenoceptor antagonist properties via its principal metabolite, 1-(2-pyrimidinyl)-piperazine. Both locus coeruleus spontaneous firing activity and noradrenaline release in the medial prefrontal cortex were potently inhibited by the alpha(2)-adrenoceptor agonist clonidine, at a dose of 40 microg/kg (i.p.). Such an inhibition was neither prevented nor reversed by alnespirone (10 mg/kg, i.p.), while buspirone, at the same dose, potently antagonized the locus coeruleus inhibitory effects of clonidine. These data demonstrate that, in contrast with some aryl-piperazine compounds (such as buspirone), alnespirone, either on its own or via a possible metabolite such as buspirone, is devoid in vivo of significant alpha(2)-adrenoceptor antagonist properties.

Glutamatergic-receptors blockade does not regularize the slow wave sleep bursty pattern of subthalamic neurons.

The subthalamic nucleus (STN) has been implicated in movement disorders observed in Parkinson's disease because of its pathological mixed burst firing mode and hyperactivity. In physiological conditions, STN bursty pattern has been shown to be dependent on slow wave cortical activity. Indeed, cortical ablation abolished STN bursting activity in urethane-anaesthetized intact or dopamine depleted rats. Thus, glutamate afferents might be involved in STN bursting activity during slow wave sleep (SWS) when thalamic and cortical cells oscillate in a low-frequency range. The present work was aimed to test, on non-anaesthetized rats, if it was possible to regularize the SWS STN bursty pattern by microiontophoresis of kynurenate, a broad-spectrum glutamate ionotropic receptors antagonist. As glutamatergic effects might be masked by GABAergic inputs arriving tonically and during the entire sleep-wake cycle on STN neurons, kynurenate was also co-iontophoresed with bicuculline, a GABA(A) receptors antagonist. Kynurenate iontophoretic applications had a weak inhibitory effect on the discharge rate of STN neurons whatever the vigilance state, and did not regularize the SWS STN bursty pattern. But, the robust bursty bicuculline-induced pattern was impaired by kynurenate, which elicited the emergence of single spikes between remaining bursts. These data indicate that the bursty pattern exhibited by STN neurons specifically in SWS, does not seem to exclusively depend on glutamatergic inputs to STN cells. Furthermore, GABA(A) receptors may play a critical role in regulating the influence of excitatory inputs on STN cells.

In-vivo modulation of central 5-hydroxytryptamine (5-HT1A) receptor-mediated responses by the cholinergic system.

The aim of the present study was to investigate a putative modulation of rat 5-HT system by the muscarinic receptor antagonist atropine using in-vivo electrophysiological and behavioural techniques. In the dorsal raphe nucleus, administration of atropine (1 mg/kg i.v.) prevented the suppressant effect of the selective serotonin reuptake inhibitor paroxetine (0.5 mg/kg i.v.) on the spontaneous firing activity of 5-HT neurons, suggesting that atropine could induce an attenuation of somatodendritic 5-HT1A autoreceptors responsiveness. The 5-HT1A receptor agonist 8-OH-DPAT decreased both immobility in the forced swim test and the body core temperature. Pre-treatment with atropine (5 and 10 mg/kg i.p.) enhanced antidepressant-like effect of 8-OH-DPAT (1 mg/kg s.c.) and reduced 8-OH-DPAT (0.1 mg/kg s.c.)-induced hypothermia. In conclusion, the present study reports a functional role of muscarinic receptors in the modulation of pre- and post-synaptic 5-HT1A receptors mediated responses.