Hypothalamic tuberomammillary nucleus histaminergic neurons are electrophysiologically diverse and necessary for the stability of behavioral arousal
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1
Universite Libre de Bruxelles ULB-UNI, Lab of Neurophysiology, Belgium
Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over multiple physiological systems. Several lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Importantly, new drugs targeting histamine H3-receptor (inverse agonists) are gaining entrance in sleep medicine as a therapeutic approach for sleep disorders such as narcolepsy, but also in the treatment of neuropsychiatric and neurodegenerative diseases for its pro-cognitive effects, emphasizing the importance to unravel the roles of the brain HA system.
Recently, the use of transgenesis combined with chemo- (DREADD) and opto-genetics developed to specifically control HA neuronal activity and neurotransmission, have allowed to directly interrogate the causal role between HA neuron activation and wakefulness, and the dissection of the synaptic mechanisms associated with it.
Given the strong correlation between the excitability of HA neurons and behavioral arousal, we investigated both the electrophysiological phenotype of identified HA neurons in brain slices and the effect of their acute silencing in vivo in mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase (HDC)-expressing neurons (Hdc-Cre). We then carried out a systematic analysis of the membrane properties of both TMN HA and nearby non-HA neurons. Through hierarchical clustering analysis, we found a new dichotomy in the distinctive electrophysiological signatures of HA neurons. Finally, to directly interrogate the role of HA neurons activity during waking states, we tested the impact of acute cessation of HA neuron activity in vivo. To do so, we examined the effects of optogenetic silencing of HA neurons in behaving mice. We found that acute silencing of HA neurons during wakefulness at a period of low sleep pressure specifically promotes slow-wave sleep within seconds.
Taken together, these data provide the first proof-of-concept that slow, tonic firing of HA neurons during wake states is necessary for the maintenance of arousal and their acute silencing not only impairs arousal but is sufficient to rapidly induce slow-wave sleep. In addition, our data raise certain heterogeneity within HA neurons, whose physiological significance requires further investigations.
Keywords:
tuberomammillary nucleus,
histaminergic neurons,
Transgenic mouse,
Membrane properties,
optogenetics,
slow-wave sleep,
Sleep behavior
Conference:
12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017.
Presentation Type:
Oral Presentation
Topic:
Cognition and Behavior
Citation:
Bonnavion
P
(2019). Hypothalamic tuberomammillary nucleus histaminergic neurons are electrophysiologically diverse and necessary for the stability of behavioral arousal.
Front. Neurosci.
Conference Abstract:
12th National Congress of the Belgian Society for Neuroscience.
doi: 10.3389/conf.fnins.2017.94.00072
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Received:
24 Apr 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Dr. Patricia Bonnavion, Universite Libre de Bruxelles ULB-UNI, Lab of Neurophysiology, Brussels, Belgium, pbonnavi@ulb.ac.be