Article

Neuronal Activity of Histaminergic Tuberomammillary Neurons During Wake-Sleep States in the Mouse

Institut National de la Santé et de la Recherche Médicale U628, Université Claude-Bernard-Lyon I, 69373 Lyon Cedex 08, France.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2006; 26(40):10292-8. DOI: 10.1523/JNEUROSCI.2341-06.2006
Source: PubMed

ABSTRACT

Using extracellular single-unit recordings alone and in combination with neurobiotin juxtacellular labeling and histamine immunohistochemistry, we have identified, for the first time in nonanesthetized, head-restrained mice, histamine neurons in the tuberomammillary nuclei of the posterior hypothalamus. They are all characterized by triphasic broad action potentials. They are active only during wakefulness, and their activity is related to a high level of vigilance. During waking states, they display a slow (<10 Hz) tonic, repetitive, irregular firing pattern. Their activity varies in the different waking states, being lowest during quiet waking, moderate during active waking, and highest during attentive waking. They cease firing during quiet waking before the onset of EEG synchronization, the EEG sign of sleep (drowsy state), and remain silent during slow-wave sleep and paradoxical (or rapid eye movement) sleep. They exhibit a pronounced delay in firing during transitions from sleep to wakefulness or remain quiescent during the same transitions if the animals are not fully alert. They either respond with a long delay, or do not respond, to an arousing stimulus if the stimulus does not elicit an overt alert state. These data support the view that the activity of histaminergic tuberomammillary neurons plays an important role, not in the induction of wakefulness per se, but in the maintenance of the high level of vigilance necessary for cognitive processes. Conversely, cessation of their activity may play an important role in both the initiation and maintenance of sleep.

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    • "Therefore other receptors must be involved. Since the number of HA neurons appear greater in 129Sv (Parmentier et al., 2002) than that in C57BL/6J (Takahashi et al., 2006) mice, it remains to be determined whether such an anatomic variation reflects a difference in terms of functional outputs and whether in the 129Sv mouse strain the HA neurons constitute a more powerful permissive system to PS. "
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    ABSTRACT: Using knockout (KO) mice lacking the histamine (HA)-synthetizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1-/-) mice. We found that H1-/-mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1-/-mice. Finally, H1-/-mice showed markedly greater changes in EEG power (notably in the 0.8-5Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1 receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system.
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    • "Earlier studies found also lower (than wake) LC firing in SWS in rats (Aston-Jones and Bloom, 1981) but lack of NA in SWS fits its alarm/alert inducing function. Histamine neurons of TMN in posterior hypothalamus (PH) are active only in wakefulness, highest at high vigillance, low at quiet waking and silent during SWS and REM (Takahashi et al., 2006). "

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    • "Earlier studies found also lower (than wake) LC firing in SWS in rats (Aston-Jones and Bloom, 1981) but lack of NA in SWS fits its alarm/alert inducing function. Histamine neurons of TMN in posterior hypothalamus (PH) are active only in wakefulness, highest at high vigillance, low at quiet waking and silent during SWS and REM (Takahashi et al., 2006). "
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    ABSTRACT: The multisynaptic axonal tracts between hippocampus and medial habenula (MHb) observed in my DTI study using probabilistic tractography made me explore their connectivity. Found tract linked hippocampus to septum, and amygdala to bed nucleus of stria terminalis (BNST). Axons from septum and BNST passed by anteromedial thalamic nucleus (AM) to MHb, and from MHb to pineal gland, linked to control of circadian cycles and sleep. Combination of known findings about septum and MHb connectivity and function led to idea that posterior septum activates MHb, leading to activation of IPN, MRN and serotonin release. This MHb-IPN-MRN circuit promotes slow wave sleep (SWS), high serotonin and low acetylcholine state. This SWS promoting circuit reciprocally suppresses the theta oscillations promoting circuit, linked to high acetylcholine in brain, and formed by supramamillary area (SUM) projections to the medial septum (MS) that activates hippocampus or other theta-coupled regions. The MHb pathway inhibits, possibly reciprocally also some stimulating input to theta-generating SUM and MS, from wake-on nucleus incertus (NI), posterior hypothalamus (PH) and laterodorsal tegmentum (LDT) neurons, and REM-on reticular nucleus pontis oralis (PnO). So the SWS-promoting circuit attenuates theta and both active wake state and REM sleep promoting regions. As the theta in wake state is linked to recording and binding information with their spatio-temporal and relational context by hippocampus, while the SWS supports replay of hippocampally stored information/memory trace and its cortical reactivation, e. g. in retrosplenial cortex linked to autobiographic memory or in prefrontal cortex that can combine any information.
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