Department of Neurobiology; Brudnick Neuropsychiatric Research Institute; NeuroNexus Institute; Anaclet Lab
Neuroscience and Neurobiology
The histaminergic neurons of the tuberomammillary nucleus (TMN(HDC)) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMN(HDC) neurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMN(HDC) neurons on sleep-wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMN(HDC) neurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep-wake quantities, perhaps because very few TMN(HDC) neurons coexpressed VGAT. Acute chemogenetic activation of TMN(HDC) neurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMN(HDC) neurons in arousal control. Further, if TMN(HDC) neurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMN(HDC) neurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions.SIGNIFICANCE STATEMENT The histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMN(HDC)) have long been thought to promote arousal. Additionally, TMN(HDC) neurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMN(HDC) neurons does not impact sleep-wake amounts and that few TMN(HDC) neurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMN(HDC) neurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMN(HDC) neurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.
EEG/EMG, chemogenetics, histidine decarboxylase, optogenetics, sleep, wake
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DOI of Published Version
J Neurosci. 2019 Nov 6;39(45):8929-8939. doi: 10.1523/JNEUROSCI.1032-19.2019. Epub 2019 Sep 23. Link to article on publisher's site
The Journal of neuroscience : the official journal of the Society for Neuroscience
Venner A, Mochizuki T, De Luca R, Anaclet C, Scammell TE, Saper CB, Arrigoni E, Fuller PM. (2019). Reassessing the Role of Histaminergic Tuberomammillary Neurons in Arousal Control. Neurobiology Publications. https://doi.org/10.1523/JNEUROSCI.1032-19.2019. Retrieved from https://escholarship.umassmed.edu/neurobiology_pp/251
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