Wake-sleep, thermoregulatory, and autonomic effects of cholinergic activation of the lateral hypothalamus in the rat: a pilot study

Alessia Di Cristoforo, Matteo Cerri, Flavia Del Vecchio, Timna Hitrec, Marco Luppi, Emanuele Perez, Giovanni Zamboni, Roberto Amici


A major role in the wake-promoting effects of the activation of the lateral hypothalamus (LH) has been ascribed to a population of orexin (ORX)-containing neurons that send projections to central areas which regulate Wake-Sleep and autonomic function. Since, in the rat, a substantial amount of ORX neurons receive cholinergic projections from cells involved in Wake-Sleep regulation, the aim of this study was to assess the role played by LH cholinoceptive cells in Wake-Sleep and autonomic regulations. To this end, the effects of a microinjection of the cholinergic agonist Carbachol (CBL) into the LH were compared to those obtained through the activation of a wider cell population by the microinjection of the GABAA antagonist GABAzine (GBZ). The results of this pilot study showed that both drugs elicited the same behavioral and autonomic effects, those caused by GBZ being larger and longer-lasting than those following administration of CBL. Briefly, wakefulness was enhanced and sleep was depressed, and brain temperature and heart rate consistently increased, while mean arterial pressure showed only a mild increment. Surprisingly, the administration of the drug vehicle (SAL) elicited a similar pattern of Wake-Sleep effects which, although much smaller, were sufficient to mask any statistical significance between treatment and control data. In conclusion, the results of this work show that the arousal elicited by LH disinhibition by GABAzine is concomitant with autonomic responses set by the intervention of cold-defense mechanisms. Since the same response is elicited at a lower level by CBL administration, the hypothesis of an involvement of cholinoceptive ORX neurons in its generation is discussed.


Lateral hypothalamus; Cholinergic system; Wake-Sleep states; Thermoregulation; Autonomic function

Full Text:



- Alexandre C., Andermann M.L., Scammell T.E. Control of arousal by the orexin neurons. Curr. Opin. Neurobiol., 23: 752-9, 2013.

- Amici R., Cerri M., and Parmeggiani P.L. Overview of Physiological Processes During Sleep, pp. 385-389. In: Kushida C.A. (Ed.) The Encyclopedia of Sleep. Waltham - MA, Academic Press, 2013.

- Berthoud H.R. and Munzberg H. The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics. Physiol. Behav., 104: 29–39, 2011.

- Bowman B.R., Kumar N.N., Hassan S.F., McMullan S., Goodchild A.K. Brain sources of inhibitory input to the rat rostral ventrolateral medulla. J. Comp. Neurol., 521: 213-232, 2013.

- Cerri M., Morrison S.F. Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis. Neuroscience, 135: 627–638, 2005

- Cerri M., Ocampo-Garces A., Amici R., Baracchi F., Capitani P., Jones C.A., Luppi M., Perez E., Parmeggiani P.L., Zamboni G. Cold exposure and sleep in the rat: effects on sleep architecture and the electroencephalogram. Sleep, 28: 694-705, 2005.

- Cerri M., Zamboni G., Tupone D., Dentico D., Luppi M., Martelli D., Perez E., Amici R. Cutaneous vasodilation elicited by disinhibition of the caudal portion of the rostral ventromedial medulla of the free-behaving rat. Neuroscience. 165: 984-95, 2010.

- Cerri M., Del Vecchio F., Mastrotto M., Luppi M., Martelli D., Perez E., Tupone D., Zamboni G., Amici R. Enhanced slow-wave EEG activity and thermoregulatory impairment following the inhibition of the lateral hypothalamus in the rat, PLoS One, 9: e112849, 2014.

- Clement O., Sapin E., Libourel P.A., Arthaud S., Brischoux F., Fort P., Luppi P.H. The lateral hypothalamic area controls paradoxical (REM) sleep by means of descending projections to brainstem GABAergic neurons. J. Neurosci., 32: 16763-16774, 2012.

- Dampney R.A., Goodchild A.K., Tan E. Identification of cardiovascular cell groups in the brain stem. Clin. Exp. Hypertens. A., 6: 205-20,1984.

- Eggermann E., Serafin M., Bayer L., Machard D., Saint-Mleux B., Jones B.E., Mühlethaler M. Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience, 108:177-81, 2001.

- Henny, P., and Jones, B.E. Innervation of orexin/hypocretin neurons by GABAergic, glutamatergic or cholinergic basal forebrain terminals evidenced by immunostaining for presynaptic vesicular transporter and postsynaptic scaffolding proteins. J. Comp. Neurol., 499: 645-61, 2006.

- Holm S. A simple sequentially rejective multiple test procedure. Scand. J. Stat., 6: 65–70, 1979.

- Lee M.G., Hassani O.K., Alonso A., Jones B.E. Cholinergic basal forebrain neurons burst with theta during waking and paradoxical sleep. J. Neurosci., 25: 4365-9, 2005.

- Li F.W., Deurveilher S., Semba K. Behavioural and neuronal activation after microinjections of AMPA and NMDA into the perifornical lateral hypothalamus in rats. Behav. Brain. Res., 224: 376–386, 2011.

- Lin J.S., Anaclet C., Sergeeva O.A., Haas H.L. The waking brain: an update. Cell. Mol. Life Sci., 68: 2499-2512, 2011.

- Morrison S.F., Madden C.J., Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell. Metab., 19: 741-756, 2014.

- Parmeggiani P.L. Thermoregulation and sleep. Front. Biosci., 8: s557-567, 2003.

- Paxinos, G and Watson , C. The rat brain in stereotaxic coordinates. 2007, San Diego: Elsevier.

- Reddi B.A. Why is saline so acidic (and does it really matter?). Int. J. Med. Sci.,10: 747-750, 2013.

- Shirasaka T., Kunitake T., Takasaki M., Kannan H. Neuronal effects of orexins: relevant to sympathetic and cardiovascular functions. Regul. Pept., 104: 91-5, 2002.

- Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S, Takahashi S, Goto K, Koyama Y, Shioda S, Yanagisawa M. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron, 46: 297-308, 2005.

- Tupone D., Madden C.J., Cano G. and Morrison S.F. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J. Neurosci., 31: 15944-15955, 2011.

- Yoshida K., McCormack S., España R.A., Crocker A., Scammell T.E. Afferents to the orexin neurons of the rat brain. J. Comp. Neurol., 494: 845-61, 2006.

- Williams R.H., Jensen L.T., Verkhratsky A., Fugger L., Burdakov D. Control of hypothalamic orexin neurons by acid and CO2. Proc. Natl. Acad. Sci. U S A, 104: 10685–10690, 2007.

DOI: https://doi.org/10.4449/aib.v153i2-3.4046


  • There are currently no refbacks.