Theta Peak Frequency Research Articles

Activation of 5-HT6 Receptors Modulates Sleep–Wake Activity and Hippocampal Theta Oscillation

The modulatory role of 5-HT neurons and a number of different 5-HT receptor subtypes has been well documented in the regulation of sleep-wake cycles and hippocampal activity. A high level of 5-HT(6) receptor expression is present in the rat hippocampus. Further, hippocampal function has been shown to be modulated by both 5-HT(6) agonists and antagonists. In the current study, the potential involvement of 5-HT(6) receptors in the control of hippocampal theta rhythms and sleep-wake cycles has been investigated. Hippocampal activity was recorded by intracranial hippocampal electrodes both in anesthetized (n = 22) and in freely moving rats (n = 9). Theta rhythm was monitored in different sleep-wake states in freely moving rats and was elicited by stimulation of the brainstem reticular formation under anesthesia. Changes in theta frequency and power were analyzed before and after injection of the 5-HT(6) antagonist (SAM-531) and the 5-HT(6) agonist (EMD386088). In freely moving rats, EMD386088 suppressed sleep for several hours and significantly decreased theta peak frequency, while, in anesthetized rats, EMD386088 had no effect on theta power but significantly decreased theta frequency, which could be blocked by coadministration of SAM-531. SAM-531 alone did not change sleep-wake patterns and had no effect on theta parameters in both unanesthetized and anesthetized rats. Decreases in theta frequency induced by the 5-HT(6) receptor agonist correspond to previously described electrophysiological patterns shared by all anxiolytic drugs, and it is in line with its behavioral anxiolytic profile. The 5-HT(6) antagonist, however, failed to potentiate theta power, which is characteristic of many pro-cognitive substances, indicating that 5-HT(6) receptors might not tonically modulate hippocampal oscillations and sleep-wake patterns.

Comparative analysis of the neurophysiological profile of group II metabotropic glutamate receptor activators and diazepam: Effects on hippocampal and cortical EEG patterns in rats

Selective activation of the Group II metabotropic glutamate receptors 2/3 (mGlu2/3) by either full agonists or positive allosteric modulators (PAMs) show anxiolytic activity. In the present study the anxiolytic profile of mGlu2/3 receptor agonists LY-354740 and LY-404039 and the mGlu2 receptor PAM 1-methyl-2-((cis-3-methyl-4-(4-trifluoromethyl-2-methoxy)-phenyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridine (MTFIP) were evaluated using neurophysiology-based assays. Activation of mGlu2/3 receptors by these compounds, as well as the positive control diazepam, significantly decreased the frequency of hippocampal theta oscillation elicited by stimulation of the brainstem nucleus pontis oralis (nPO), a characteristic action of anxiolytic compounds. Since the nPO is a critical region involved in regulation of rapid eye movement sleep, mGlu2/3 receptor activators were also tested on sleep parameters, as well as on cortical and hippocampal encephalography (EEG) activity. Both mGlu2/3 agonists and the mGlu2 PAM significantly prolonged REM sleep latency and reduced total REM sleep duration while during the active awake state all compounds lowered hippocampal peak theta frequency. However, diazepam and mGlu2/3 agonists/PAM elicited opposite changes in cortical EEG delta and beta bands. Delta power significantly increased after any of the mGlu2/3 compounds but decreased after diazepam. In the beta band, mGlu2/3 receptor agonists dose-dependently decreased beta power in contrast to the well-known beta activation by diazepam. These effects lasted 3–4h and could not be explained by modest, transient changes (<1h) in waking and slow wave sleep. The current observations support the role of mGlu2/3 receptor activators as potential anxiolytic compounds, but indicate a distinct action on cortical EEG activity which is different from the effects of GABAA PAMs.This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Activation of immobility‐related hippocampal theta by cholinergic septohippocampal neurons during vestibular stimulation

The vestibular system has been suggested to participate in spatial navigation, a function ascribed to the hippocampus. Vestibular stimulation during spatial navigation activates a hippocampal theta rhythm (4-10 Hz), which may enhance spatial processing and motor response. We hypothesize that a cholinergic, atropine-sensitive theta is generated during passive whole-body rotation in freely behaving rats. Hippocampal EEGs were recorded by implanted electrodes in CA1 while rats were rotated on a vertical axis, for a minute or longer, at different angular velocities. Rotation induced a continuous hippocampal theta rhythm while the rat was immobile, in both light and dark conditions. Theta peak frequency showed a significant increase during high (50-70 rpm) as compared with a lower (20-49 rpm) rotational velocity. Rotation-induced theta was abolished by muscarinic receptor antagonist atropine sulfate (50 mg/kg i.p.) but not by atropine methyl nitrate (50 mg/kg i.p.), which did not pass the blood-brain barrier. Theta was attenuated in rats in which cholinergic neurons in the medial septum (MS) were lesioned with 192 IgG-saporin (0.14 μg in 0.4 μl), as confirmed by depletion of MS cells immunoreactive to choline acetyltransferase and an absence of acetylcholinesterase staining in the hippocampus. Bilateral lesion of the vestibular receptors by sodium arsanilate (30 mg in 0.1 ml, intratympanically) also attenuated the rotation-induced theta rhythm. In intact rats, field excitatory postsynaptic potentials (fEPSPs) in CA1 evoked by commissural stimulation were smaller during walking or rotation as compared with during immobility. Modulation of fEPSP was absent following atropine sulfate in intact rats and in 192 IgG-saporin lesion rats. In summary, this is the first report of a continuous atropine-sensitive hippocampal theta in the rat induced by vestibular stimulation during rotation, and accompanied by cholinergic modulation of hippocampal synaptic transmission. Vestibular-activated septohippocampal cholinergic activity could be an important component in sensorimotor processing and spatial memory.

Hippocampal Theta Dysfunction after Lateral Fluid Percussion Injury

Chronic memory deficits are a major cause of morbidity following traumatic brain injury (TBI). In the rat, the hippocampal theta rhythm is a well-studied correlate of memory function. This study sought to investigate disturbances in hippocampal theta rhythm following lateral fluid percussion injury in the rat. A total of 13 control rats and 12 TBI rats were used. Electrodes were implanted in bilateral hippocampi and an electroencephalogram (EEG) was recorded while the rats explored a new environment, and also while navigating a modified version of the Barnes maze. Theta power and peak theta frequency were significantly attenuated in the injured animals. Further, injured rats were less likely to develop a spatial strategy for Barnes maze navigation compared to control rats. In conclusion, rats sustaining lateral fluid percussion injury demonstrated deficits in hippocampal theta activity. These deficits may contribute to the underlying memory problems seen in chronic TBI.

Activity Patterns in the Prefrontal Cortex and Hippocampus during and after Awakening from Etomidate Anesthesia

The anesthetic properties of etomidate are largely mediated by gamma-aminobutyric acid type A receptors. There is evidence for the existence of gamma-aminobutyric acid type A receptor subtypes in the brain, which respond to small concentrations of etomidate. After awakening from anesthesia, these subtypes are expected to cause cognitive dysfunction for a yet unknown period of time. The corresponding patterns of brain electrical activity and the molecular identity of gamma-aminobutyric acid type A receptors contributing to these actions remain to be elucidated. Anesthesia was induced in wild-type and beta3(N265M) knock-in mice by intravenous injection of 10 mg/kg etomidate. Local field potentials were recorded simultaneously in the prefrontal cortex and hippocampus using chronically implanted electrode arrays. Local field potentials were sampled before, during, and after anesthesia. In the prefrontal cortex and hippocampus of wild-type mice, intravenous bolus injection of etomidate evoked isoelectric baselines and subsequent burst suppression. These effects were largely attenuated by the beta3(N265M) mutation. During emergence from anesthesia, power density in the theta band (5-15 Hz) transiently increased in the hippocampus of wild types, but not in the mutants, indicating that this action was caused by the receptors harboring beta3 subunits. In both genotypes, etomidate produced a long-lasting (> 1 h after recovery of righting reflexes) decrease in theta-peak frequency. Significant slowing of theta activity was apparent in the hippocampus and prefrontal cortex. Etomidate-induced patterns of brain activity during deep anesthesia mostly involve actions at beta3 containing gamma-aminobutyric acid type A receptors. During the postanesthesia period, altered theta-band activity indicates ongoing anesthetic action.

Electrical hippocampal activity during danger and safety signals in classical conditioning in the rat.

The effect of stimuli predicting danger (DS) and safety (SS) in Pavlovian aversive conditioning on hippocampal local field potentials (LFP) was studied in 25 partially restrained adult male rats (Long-Evans). DS lasting 5 s preceded tail-shock, while SS overlapping DS during DS last 3 s predicted omission of shock. The power spectra of LFPs during trials were analyzed in theta and delta frequency bands. In DS, theta frequency during the last 3 s was lower that in first 2 s. In danger and safety situation theta peak frequency was different for dorsal CA1 activity (5.99 Hz vs. 6.86 Hz, respectively) while delta peak frequency was different for ventral CA1 (1.56 Hz vs. 1.07 Hz) for the last 3 s of trial. Differences in theta frequency in danger and safety situation may reflect differences in sensory processing during induced emotional states and/or related differences in motor behavior.

The effect of atropine administered in the medial septum or hippocampus on high‐ and low‐frequency theta rhythms in the hippocampus of urethane anesthetized rats

Cholinergic mechanisms are critical for the generation of hippocampal theta rhythm. Cholinergic innervation of the hippocampus originates from the medial septum (MS) and cholinergic receptors are expressed in both the MS and hippocampus. In this study, we compared the effects of the muscarinic receptor antagonist atropine in the MS and the hippocampus on theta generation. Hippocampal theta rhythm was elicited by electrical stimulation of the pontine reticular formation using series of stimuli with varying intensities. Atropine was administered either systemically (50 mg/kg i.p.) or locally in the MS (microdialysis; 25 and 75 mM for 30 or 90 min) or in the hippocampus on one side (microinjection; 20 or 40 ug). The relative power at the peak theta frequency was calculated and averaged over episodes of low-intensity and high-intensity stimulations. We found that atropine drastically reduced theta rhythmic synchronization when injected in either location. After MS administration of atropine, however, high-frequency theta elicited by high-intensity stimuli was more resistant (58% and 67% decrease after 25 mM and 75 mM atropine, respectively) than slow theta elicited by low-intensity stimuli (86% and 91% decrease). There was no significant difference between the powers of the two oscillations after hippocampal injections (70-75% decrease). We conclude that the theta suppressing effect of atropine involves both hippocampal and septal mechanisms and that low-frequency theta as compared with fast theta rhythm is more sensitive to muscarinic acetylcholine receptor antagonism in the MS but not in the hippocampus.

Atropine acts in both medial septum and hippocampus to suppress theta rhythm in urethane anesthetized rats

Cholinergic mechanisms are critical for the generation of hippocampal theta rhythm. Cholinergic innervation of the hippocampus originates from the medial septum (MS) and cholinergic receptors (AChR) are expressed in both the MS and hippocampus. In this study, we compared the effects of the M1 AChR antagonist atropine in the MS and the hippocampus on theta generation. Hippocampal field potentials were recorded in the CA1 region and at the hippocampal fissure. Theta rhythm was elicited by electrical stimulation (0.2 ms square waves; 100 Hz, 8–10 s) of the pontine reticular formation. The stimulus intensity varied between 0.3 (threshold) and 2.0 mA (maximum effect). Atropine was administered in the MS (microdialysis; 25 and 75 mM for 30 min) or in the hippocampus on one side (microinjection; 20 ug). The relative power at the peak theta frequency was calculated using FFT and averaged over episodes of low-intensity (0.3–0.7 mA) and high-intensity stimulations (0.8–2.0 mA). We found that atropine drastically reduced theta rhythmic synchronization when injected in either location. After MS administration of atropine, high frequency theta elicited by high intensity stimuli was more resistant (58% and 67% decrease after 25mM and 75mM atropine, respectively) than slow theta elicited by low intensity stimuli (86% and 91%). There was no significant difference between the power of the two oscillations after hippocampal injections. We conclude that the theta suppressing effect of atropine involves both hippocampal and septal mechanisms and that low-frequency theta as compared with fast theta rhythm is more sensitive to M1 AChR antagonism.

Hippocampal theta state in relation to formalin nociception

In the present study using extracellular electrophysiological recording techniques, we explored the temporal characteristics of hippocampal theta activation in relation to formalin nociception. Results indicate that, compared to hind paw injection of saline, formalin injection in behaving rat evoked biphasic increase in duration of dorsal CA1 theta. Such an increase broadly paralleled animal biphasic behavioral activation, especially lick and moment-to-moment agitated behaviors. Correspondingly, theta-modulated cell firing was observed following formalin injection in anesthetized rat. The formalin-induced theta activation in behaving rat was most marked during peak of theta activation in the 2nd theta state (11–40 min post-injection) comprising 73% of the time in the 5 min block. An increase in theta peak frequency was also observed with respect to pre-injection control. However, the peak of theta in the 2nd theta state mostly preceded the peak of lick and flinch of the affected paw. In the 41–60 min, following formalin injection while the animals displayed robust nociceptive flinching and lifting, the theta activity approached control levels. Furthermore, the theta peak frequency at peak of theta was higher than the corresponding values of sustained theta observed in correlation with the nociceptive behaviors; in contrast, high frequency theta rhythm was observed during formalin-induced other moment-to-moment agitated behaviors. These findings favor the notion that in the formalin model the theta state of the hippocampus reflects a neural drive that is dissociated from the duration of nociceptive experience and is not selective to the typical nociceptive indices of lick, flinch, and lift of the injured paw.

Paradoxical Sleep in Mice Lacking M3 and M2/M4 Muscarinic Receptors

Acetylcholine is crucial for the regulation of paradoxical sleep (PS) and EEG theta activity. To determine the contribution of individual muscarinic receptors to these events, we analyzed the sleep-waking cycle and EEG activities of mice lacking functional M₃ or M₂/M₄receptors. Daily PS amounts were significantly decreased in M3–/– (–22%) but not in M2/M4–/– mice. Further, the theta peak frequency for PS was significantly increased in both M2/M4–/– and M3–/– mice. This study supports the potential role of M₃ rather than M₂ and M₄ muscarinic receptors in the modulation of PS in mice and strengthens the idea that multiple muscarinic receptors contribute to the regulation of the EEG theta activity during PS.

Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome

Angelman syndrome (AS) is a severe neurodevelopmental disorder with electroencephalographic (EEG) abnormalities and sleep disturbances. It results from lack of the functional maternal allele of UBE3A, which encodes a ubiquitin-protein ligase. Different mechanisms of UBE3A inactivation correlate with clinical phenotypes of varying severity; the majority of cases of AS are due to a de novo maternal deletion of the 15q11-q13 region. Ube3a maternal-deficient mice (Ube3a m-/p+) were generated in a C57Bl/6J background. This study compares cortical EEG and architecture of the sleep-waking cycle in adult Ube3a m-/p+ mice compared with those of age-matched WT (m+/p+) mice, under baseline conditions or after 4-h sleep deprivation (SD). Ube3a m-/p+ mice exhibited: reduced slow-wave sleep (SWS) amount with increase waking (W) at the dark/light transitions; increased SWS and W episode numbers; and deterioration of paradoxical sleep (PS) over 24 h [amount: -44%; episode duration: -46%; episode number: -40%; theta peak frequency (TPF) acceleration: 7.6 Hz vs. 7.0 Hz in WT mice]. Characteristic paroxysmal EEG discharges are observed during W and SWS associated with synchronous muscle bursting activity during hypoactive W. During the recovery period following SD, Ube3a m-/p+ mice exhibited no rebound either in slow-wave activity (+89% in WT) or in delta-power spectra but a slight rebound in PS amount (+20%). These data validate the mouse model produced by null mutation of the maternal Ube3a gene and provide useful results to investigate and better understand the molecular basis of sleep disturbances in AS patients.

Hippocampal theta activity and behavioral sequences in a reward‐directed approach locomotor task

Hippocampal rhythmic slow wave activity (theta) has been implicated in the processing of stimuli associated with movement. This study determined whether the theta rhythm showed phase relationships or changes in amplitude and frequency with the onset of stimuli and behavioral sequences in a skilled locomotor approach task. Rats with bipolar electrodes spanning CA1 approached a stall, turned to enter it, approached and depressed a treadle, waited 1.35 s, and approached a milk reward located forward either to the right or to the left. Auditory cues indicated the location of the reward during the waiting period and at the reward onset. A video capture system (20-ms sampling) was synchronized to the hippocampal recording system (10-ms sampling). Behavioral events identified by motion analysis were used to generate averages of hippocampal slow wave activity, theta peak amplitudes, and intervals between peaks. Theta activity at 8-10 Hz was almost continuous during the behavioral sequences. Phase relations with stimuli or movement onsets occurred infrequently and were not consistent across the four subjects. Theta peak amplitude and frequency decreased as the rat slowed locomotion in the stall and reached the treadle. Onset of locomotion directed to a reward location occurred on a positive peak of averaged theta activity. When locomotion had short latencies, increases in theta frequency appeared after the onset but, when it had longer latencies, frequency increases appeared 200 ms before onset. The results indicate that the execution of instrumental movement modulates both theta amplitude and frequency, and that the preparation for locomotion modulates theta frequency.

The relationship between hippocampal EEG theta activity and locomotor behaviour in freely moving rats: effects of vigabatrin

The relationship between hippocampal electroencephalogram (EEG) theta activity and locomotor speed in both spontaneous and forced walking conditions was studied in rats after vigabatrin injection (500 mg/kg i.p.). Vigabatrin increased the percentage of time that rats spent being immobile. During spontaneous walking in the open field, the speed of locomotion was increased by vigabatrin, while theta peak frequency was decreased. Vigabatrin also reduced the theta peak frequency during forced (speed controlled) walking. There was only a weak positive correlation ( r = 0.22) between theta peak frequency and locomotor speed for the saline condition. Furthermore, vigabatrin abolishes the weak relationship between speed of locomotion and theta peak frequency. Vigabatrin and saline did not differ in the slope of the regression line, but showed different offset points at the theta peak frequency axis. Thus, other factors than speed of locomotion seem to be involved in determination of the theta peak frequency.

The interaction between vigabatrin and diazepam on the electroencephalogram during active behaviour in rats: an isobolic analysis

To test whether polytherapy with two gamma-aminobutyric acid (GABA) -ergic drugs might be clinically relevant for epilepsy treatment, effects on spike and wave discharges, the fraction of time spent being behaviourally active, and the background electroencephalogram (EEG) during behavioural activity of vigabatrin (15–500 mg/kg i.p.) and diazepam (1.25–10 mg/kg i.p.) were compared with their combination (dose ratio 1:25) in rats. Isobolic analyses were performed to describe the interactions. Unfortunately, no conclusions can be drawn concerning the interaction of both drugs on the spike and wave discharge activity because the effect of diazepam was shown to be dominant. Only vigabatrin decreased the behavioural activity, whereas there was a trend towards a decrease after diazepam. All treatments dose dependently increased the power in the beta frequency band. Unfortunately, the dose ratio was not optimal to describe the interaction. The theta peak frequency was dose dependently decreased after all treatments. There was a synergistic interaction between the two drugs on this variable. These data support both the idea that an increase in power in the beta frequency band can serve as a biomarker for GABAergic inhibition and the suggestion that clinically effective anxiolytics decrease the theta peak frequency. Furthermore, we show that on different variables, there might be different optimal dosage combinations, which might complicate the clinical application of polytherapy.

Sleep wake profile and EEG spectral power in young or old senescence accelerated mice

Changes occurring with age in cortical EEG and sleep-wake states architecture were examined in senescence accelerated prone (SAMP8) or senescence resistant (SAMR1) mice (age: 2 and 12 months) under baseline conditions or after a 4 h sleep deprivation (SD). In baseline conditions, an increase in slow wave sleep (SWS) amount (21–24%) occurs at the expense of the wakefulness (W) in old SAMP8 and SAMR1 mice versus young animals. In these conditions, SWS latency is reduced (67–72%). Moreover, in SAMP8 and SAMR1 mice, aging deteriorates paradoxical sleep (PS) architecture with more pronounced changes in SAMP8 (amount: −63%; episode duration: −44%; latency: +286%; circadian component loss; and EEG theta ( θ) peak frequency (TPF): −1 Hz). During the 4 h recovery subsequent to a 4 h sleep deprivation, old SAMP8 mice exhibit an enhanced sensitivity resulting in SWS (+62%) and PS (+120%) rebounds, a characteristic of this inbred strain. Results obtained are discussed in line with the age-related learning and memory impairments existing in SAMP8 animals. In particular, the reduced cognitive performances described in old SAMP8 might be linked to the TPF deterioration during PS.

Enhanced cortical and hippocampal neuronal excitability in mice deficient in the extracellular matrix glycoprotein tenascin-R

Mice deficient in the extracellular matrix protein tenascin-R (TN-R−/− mice) show several indices of impaired perisomatic inhibition in hippocampal slices. The present study examined electroencephalograms (EEGs) and auditory-evoked potentials (AEPs) in freely moving TN-R−/− and wild-type control mice, focusing on the hippocampal CA1 field and cerebral cortex. TN-R−/− mice expressed normal high-frequency oscillations (ripples) in CA1 and only a slight reduction of peak theta frequency. In contrast, their hippocampal gamma oscillations were significantly enhanced in amplitude. Also, the amplitude of the cortical EEG of TN-R−/− mice was increased over a wide frequency range. The amplitude of cortical and, to a lesser degree hippocampal, AEPs was clearly enhanced in TN-R−/− mice. In addition, response habituation to repeated sound stimuli was significantly attenuated in TN-R−/− mice. These findings indicate that tenascin-R is involved in the regulation of certain inhibitory mechanisms in the intact brain.

Electroencephalogram theta frequency changes in parallel with euthermic brain temperature

To test whether moderate changes in brain temperature can influence electroencephalogram (EEG) frequencies in a significant way the behaviour of peak theta frequency (∼6 Hz) in the rapid-eye movement (REM) sleep EEG was investigated in the Djungarian hamster under influence of the spontaneous euthermic changes in brain temperature. In contrast to in vitro data, collected from hippocampal tissue, theta peak frequency shifted significantly when temperature changed between 33 and 37 °C. The results support the hypothesis that moderate changes in brain temperature can influence EEG power density spectra.

Magnesium involvement in sleep: genetic and nutritional models.

Alterations of peripheral magnesium (Mg) concentration have been reported in association with several behavioral disorders and sleep organization. Blood Mg regulation is under a strong genetic control, whereas brain Mg regulation does not seem to be affected. We have studied peripheral and central levels of Mg and analyzed sleep in two lines of mice selected for low (MGL) and high (MGH) red blood cell (RBC) Mg levels. The same variables were also studied in C57BL/6J mice before and after 3 weeks of Mg deficiency. Whereas blood Mg was highly affected by the selection, brain Mg exhibited only small differences between the two lines. In contrast, Mg deficiency strongly decreased both central and peripheral Mg levels. Sleep analysis indicated that in both models the amount of paradoxical sleep was lower in mice with higher Mg levels. The amplitude of daily variation in sleep and slow-wave sleep delta power was markedly decreased in MGH line. Quantitative electroencephalogram (EEG) analysis also revealed a faster theta peak frequency in MGH mice, irrespective of behavioral states. Central Mg showed significant correlations with the amount of paradoxical sleep and sleep consolidation. However, because the direction of these correlations was not consistent, it is concluded that optimal, (physiological) rather than high or low, Mg levels are needed for normal sleep regulation.

Acetylcholine release in the hippocampus of the urethane anaesthetised rat positively correlates with both peak theta frequency and relative power in the theta band

The need to achieve a clearer understanding of relations between hippocampal theta characteristics and cholinergic septohippocampal neuron activity, prompted us to re-examine, in the urethane-anaesthetised rat, the statistical relationships between the electrophysiological and neurochemical variables using a procedure which is believed to enhance significantly the degree of confidence with which parameters of theta recorded with classic macroelectrodes can be related to concomitant acetylcholine output measured by high-performance liquid chromatography with electrochemical detection. Firstly, the theta rhythm and the acetylcholine content were derived from the same hippocampus. Secondly, the hippocampal electroencephalogram was quantified using spectral analysis which permits the more objective quantitative evaluation of selected electroencephalogram samples. Thirdly, a larger number of rats than in our previous study was used here, thus enhancing the validity of statistical results. This procedure yielded, in our time-course determination, two main findings. The first finding is that acetylcholine release was positively correlated with frequency at the peak power of the theta band which reflects the frequency of the theta signal. This finding had not been reported yet. The second finding is that hippocampal acetylcholine outflow also covaried with relative power of the theta band which reflects the amplitude of the theta signal. This finding is consistent with our previous study in which EEG was quantified by means of a traditional method. These findings suggest that the cholinergic component of the septohippocampal system, which is the main source of hippocampal acetylcholine, and neurophysiological mechanisms involved in the modulation of both the amplitude and the frequency of theta are functionally related. The possibility that, at least in the urethane-anaesthetised rat, hippocampal acetylcholine is involved in these modulator mechanisms is discussed.

The Transcription Factor DBP Affects Circadian Sleep Consolidation and Rhythmic EEG Activity

Albumin D-binding protein (DBP) is a PAR leucine zipper transcription factor that is expressed according to a robust circadian rhythm in the suprachiasmatic nuclei, harboring the circadian master clock, and in most peripheral tissues. Mice lacking DBP display a shorter circadian period in locomotor activity and are less active. Thus, although DBP is not essential for circadian rhythm generation, it does modulate important clock outputs. We studied the role of DBP in the circadian and homeostatic aspects of sleep regulation by comparing DBP deficient mice (dbp-/-) with their isogenic controls (dbp+/+) under light-dark (LD) and constant-dark (DD) baseline conditions, as well as after sleep loss. Whereas total sleep duration was similar in both genotypes, the amplitude of the circadian modulation of sleep time, as well as the consolidation of sleep episodes, was reduced in dbp-/- under both LD and DD conditions. Quantitative EEG analysis demonstrated a marked reduction in the amplitude of the sleep-wake-dependent changes in slow-wave sleep delta power and an increase in hippocampal theta peak frequency in dbp-/- mice. The sleep deprivation-induced compensatory rebound of EEG delta power was similar in both genotypes. In contrast, the rebound in paradoxical sleep was significant in dbp+/+ mice only. It is concluded that the transcriptional regulatory protein DBP modulates circadian and homeostatic aspects of sleep regulation.