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Galanin Neurons in the Ventrolateral Preoptic Area Promote Sleep and Heat Loss in Mice

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Galanin Neurons in the Ventrolateral Preoptic Area Promote Sleep and Heat Loss in Mice ARTICLE DOI: 10.1038/s41467-018-06590-7 OPEN Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice Daniel Kroeger1, Gianna Absi1, Celia Gagliardi1, Sathyajit S. Bandaru1, Joseph C. Madara2, Loris L. Ferrari1, Elda Arrigoni1, Heike Münzberg3, Thomas E. Scammell1, Clifford B. Saper 1 & Ramalingam Vetrivelan1 The preoptic area (POA) is necessary for sleep, but the fundamental POA circuits have remained elusive. Previous studies showed that galanin (GAL)- and GABA-producing neu- 1234567890():,; rons in the ventrolateral preoptic nucleus (VLPO) express cFos after periods of increased sleep and innervate key wake-promoting regions. Although lesions in this region can produce insomnia, high frequency photostimulation of the POAGAL neurons was shown to para- doxically cause waking, not sleep. Here we report that photostimulation of VLPOGAL neurons in mice promotes sleep with low frequency stimulation (1–4 Hz), but causes conduction block and waking at frequencies above 8 Hz. Further, optogenetic inhibition reduces sleep. Che- mogenetic activation of VLPOGAL neurons confirms the increase in sleep, and also reduces body temperature. In addition, chemogenetic activation of VLPOGAL neurons induces short- latency sleep in an animal model of insomnia. Collectively, these findings establish a causal role of VLPOGAL neurons in both sleep induction and heat loss. 1 Department of Neurology, Program in Neuroscience and Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. 2 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 3 Neurobiology of Nutrition and Metabolism, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. Correspondence and requests for materials should be addressed to C.B.S. (email: [email protected]) or to R.V. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:4129 | DOI: 10.1038/s41467-018-06590-7 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06590-7 lmost a century ago, von Economo discovered that VLPOGAL neurons innervate wake and thermoregulatory cen- patients with injury to the rostral hypothalamus often had ters. To determine whether VLPOGAL neurons influence brain A 1 unrelenting insomnia . Subsequent animal research regions that regulate sleep-wake behavior and Tb, we unilaterally showed that lesions of the preoptic area (POA) reduced sleep2–4 microinjected the VLPO of GAL-IRES-cre mice (n = 8) with a whereas stimulation increased sleep5–8. However, the specific Cre-dependent adeno-associated viral vector (AAV) coding for circuits constituting this preoptic sleep-inducing area remained channelrhodospsin-2 (ChR2) and mCherry (AAV8-EF1α-DIO- unknown. Sherin et al. identified a cluster of neurons in the ChR2-mCherry, hereafter ‘AAV-ChR2’)26–28. Six weeks later, we ventrolateral preoptic nucleus (VLPO) and scattered neurons in immunolabeled the brain sections for mCherry. We analyzed the the adjacent ventromedial and dorsolateral preoptic area (the projections of 3 cases in which the bulk of the injection involved extended VLPO) of rats that express cFos during sleep and the three VLPOGAL populations, with little or no involvement of project to the wake-promoting tuberomammillary nucleus the periventricular, median, or medial preoptic nuclei. Similar to (TMN)9,10. About 85% of these neurons contain the inhibitory the pattern in rats10, we found a high density of mCherry-labeled neurotransmitters galanin (GAL) and GABA9,10; similar obser- terminals in wake-promoting regions, including the lateral vations in other species confirmed that most sleep-active neurons hypothalamic area (LH), TMN, pedunculopontine tegmental in the VLPO and extended VLPO are galaninergic and form a nucleus (PPT), lateral and medial parabrachial nucleus (PB) and single population, referred to here as the VLPOGAL neurons11. locus coeruleus (LC). We also observed intense mCherry-labeled Lesions in this region in rodents reduce sleep by 40–50%12–14.In terminal fields in the ventrolateral and lateral periaqueductal gray humans, loss-of-VLPOGAL neurons is associated with sleep matter (lPAG) and the adjacent lateral pontine tegmentum, a key fragmentation and fewer bouts of consolidated sleep15. region for REM sleep regulation29. In addition, labeled axons Although GAL is a specific marker for sleep-active neurons in were dense in the dorsal hypothalamic area (DHA) and dor- the VLPO and extended VLPO in rats, in mice about 20% of all somedial hypothalamic nucleus (DMH), the raphe pallidus (RPa), VLPOGAL cells are active during wake11. In addition, a recent and parapyramidal region (PPR) in the rostral medulla, regions optogenetic study found that photostimulation of POAGAL neu- essential for thermoregulation17,18. These results indicate that rons at 10 Hz failed to increase sleep and surprisingly increased VLPOGAL neurons have projections that may allow them to wake16. These results call into question whether POAGAL neurons influence many brain regions that regulate both sleep-wake promote sleep. behavior and Tb. In addition to sleep regulation, the POA is also a key site for thermoregulation17–19. Large preoptic lesions cause hyperthermia3,20, whereas photoactivation of specific POA neu- Photoactivation of VLPOGAL neurons increases NREM sleep. rons causes profound hypothermia (4–6 °C)21–23. Interestingly, To determine whether VLPOGAL neurons can promote sleep, we many sleep-active VLPO neurons are also activated by increased injected AAV-ChR2 bilaterally into the VLPO of GAL-IRES-Cre GAL skin or body temperature (Tb), and may drive reductions in Tb, mice (‘VLPO -ChR2 mice’) and implanted bilateral optical demonstrating the tight coupling of sleep and heat loss fibers in the POA27 (Fig. 1a). We also placed electrodes for pathways24,25. However, it is unknown whether VLPOGAL neu- recording the electroencephalogram (EEG) and electromyogram rons contribute to thermoregulation. (EMG), and intraperitoneally implanted a telemetry transmitter fi GAL 30,31 To determine the speci c role of VLPO neurons in sleep for recording Tb . As negative controls, we injected GAL- and thermoregulation, we selectively activated and inhibited IRES-cre mice with an AAV without ChR2 (AAV-EF1α-DIO- VLPOGAL neurons in mice. We find that activation of VLPOGAL mCherry, ‘AAV-mCherry’). As expected, preoptic injections of neurons promotes sleep even in an animal model of insomnia. either AAV resulted in robust and specific expression of ChR2- Conversely, inhibition of VLPOGAL neurons reduces NREM sleep mCherry in VLPOGAL neurons, consistent with the distribution and increases wake. Interestingly, chemoactivation of VLPOGAL of GAL neurons in GAL-IRES-cre::L10-GFP reporter mice neurons also causes profound hypothermia, indicating that (Fig. 1b, c Supplementary Fig. 1). AAV-ChR2 injections in wild- VLPOGAL neurons can also promote heat loss. type (WT) littermates did not result in any expression of mCherry. In vitro, whole cell, current clamp recordings from ChR2- Results expressing GAL neurons in POA slices indicated that 10 ms blue Distribution of GAL neurons in the POA.Wefirst investigated light pulses at stimulation frequencies ≤2 Hz evoked single action the distribution of GAL neurons in the POA of GAL-IRES-Cre:: potentials and entrained VLPO neurons in a temporally precise L10-GFP mice (Methods). In rats and humans, POAGAL neu- manner with each light pulse evoking a full action potential rons are predominantly found in three major clusters, including (crossing 0 mV level) for the entire duration of a 60 s stimulation the VLPO and extended VLPO; the medial preoptic nucleus; train (Fig. 2a, b). Similarly, in vivo, low frequency photostimula- and the supraoptic nucleus11. We found that in mice, a larger tion (1 Hz, 10 ms duration) for 2 h increased cFos expression in proportion of the VLPOGAL neurons is located in the dorsal VLPO and extended VLPO ChR2-expressing neurons. Identical extended VLPO. The cluster of GAL neurons in the medial stimulation in VLPOGAL-mCherry mice did not increase cFos preoptic nucleus is less dense than in rats, but there are many expression (Fig. 1c). more small (15–20 µm) GAL-expressing neurons that extend During spontaneous sleep, VLPO neurons typically fire at only along the wall of the third ventricle and into the median pre- 2–5Hz25,32, and we found that VLPOGAL neurons cannot entrain optic nucleus (Supplementary Fig. 1). There are very few GAL- to higher frequency photostimulation in vitro. At stimulation expressing magnocellular supraoptic neurons at the levels of the frequencies >2 Hz, the peak of the photo-evoked excitatory POA studied here. Further, the entire POA in a mouse is so response, fell below 0 mV, at which point it likely failed to elicit small that these cell groups, which are quite distinct in larger action potentials. While 75% of 4 Hz stimulations triggered action species, appear to be crowded together, with a tendency to potentials, at 8 and 16 Hz, only the first light pulses evoked an overlap at the edges. Thus, identifying GAL-expressing cell action potential while the following light flashes evoked only groups involved in a specific function requires careful histolo- excitatory potentials, indicating depolarization block (Fig. 2a, b). gical examination. To determine whether photoactivation affects sleep-wake GAL behavior and Tb, we photostimulated VLPO neurons 2 NATURE COMMUNICATIONS | (2018) 9:4129 | DOI: 10.1038/s41467-018-06590-7 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06590-7 ARTICLE a AAV8-EF1α-DIO- b ChR2(h134r)-mCherry or Least MPO, PVPO MnPO AAV8-EF1α-DIO- AC AC mCherry Animal ID - % Sleep MnPO 832–82% PvPO PvPO 886–48% VLPOed 888–97% VLPO 3V MPO ed MPO VLPOc VLPOc VLPOem VLPOem EEG/EMG OC OC Unilateral MPO, PVPO c 830–47% mCherry ChR2 1061–47% 1141–38% AC Fiber tract Bilateral MPO, PVPO OC 833–94% 887–70% 1092–47% 1142–68% Bregma: +0.26 mm +0.14 mm Fig. 1 Expression of AAV-ChR2 in VLPOGAL neurons in GAL-IRES-Cre mice.
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