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Parafacial zone

The parafacial zone (PZ) is a brain structure located in the brain stem within the medulla oblongata. Due to a high presence of GABAergic neurons, as well as its involvement in slow-wave sleep, the parafacial zone is believed to be heavily responsible for non-rapid eye movement (non-REM) sleep regulation.[1][2][3][4]

Parafacial zone
Part ofBrainstem (Medulla oblongata)
Anatomical terms of neuroanatomy

It is one of several GABAergic sleep-promoting nuclei in the brain, which include the ventrolateral preoptic area of the hypothalamus, the nucleus accumbens core (specifically, the D2-type medium spiny neurons in the core which co-express adenosine A2A receptors), and a GABAergic nucleus in the lateral hypothalamus which co-releases melanin-concentrating hormone.[2][3][4][5][6]


Function and LocationEdit

The parafacial zone promotes slow-wave sleep by inhibiting the glutamatergic parabrachial nucleus (a component of the ascending reticular activating system that mediates wakefulness and arousal) via the release of the inhibitory neurotransmitter GABA onto those neurons.[1][2]

Optogenetic activation of GABAergic PZ neurons induces cortical slow-wave activity and slow-wave sleep in awake animals.[1] In cases of genetic disruption of GABAergic transmizzion from PZ in mice, the mice were observed to go through periods of significantly longer, sustained wakefulness.[7] PZ neurons are also believed to be sleep active, as they express activity after sleep but not after wakefulness.[1]

The parafacial is located within the medulla oblongata, lateral and dorsal to the facial nerve.[8] It overlaps with the alpha part of the parvocellular reticular formation (PCRt), which is thought to govern states of consciousness as well as have some control over sleep-wake sensory signals and mechanisms. However, PZ and PCRt activity are believed to be of separate nature.


The parafacial zone receives inputs mainly from three areas: the hypothalamus, the midbrain, and the pons and medulla.[9]

From the hypothalamus, the PZ receives inputs from the hypothalamic area, zona incerta, and the parasubthalamic nucleus; while the zona incerta and parasubthalamic nucleus functions remain largely unknown, several of their functions have been proposed to deal with action selection and limbic-motor integration.

From the midbrain, the PZ receives input from the substantia nigra, pars reticulata, and deep mesencephalic nucleus. These brain structures are believed to deal heavily with movement, as well as reward and unconscious reflex; additionally, the par reticulata especially has been documented to project nearly all GABAergic inhibitory neurons. And from the pons and medulla, the PZ receives input from the intermediate reticular nucleus and medial vestibular nucleus (parvocellular), areas that are thought to be involved in expiration and respiratory rhythm generation.

  • From the hypothalamus
    • Hypothalamic area
    • Zona incerta
    • Parasubthalamic nucleus
    • Substantia nigra
  • From the midbrain
    • Substantia nigra
    • Pars reticular
    • Mesenphalic nucleus


PZ neurons project to the medial parabrachial nucleus,[1] a wake promoting neuron cluster that is part of the ascending reticular activating system.

Thirty-four various nuclei also share strong reciprocal projections with PZ GABAergic neurons, including various nuclei of the stria terminalis, the lateral hypothalamic area, the substantia nigra, the zona incerta, and the central amygdaloid nucleus.[9] These strong reciprocal projections suggest feedback control and the ability to regulate specific functions.

Clinical significanceEdit


  1. ^ a b c d e f Anaclet C, Ferrari L, Arrigoni E, Bass CE, Saper CB, Lu J, Fuller PM (September 2014). "The GABAergic parafacial zone is a medullary slow wave sleep-promoting center" (PDF). Nat. Neurosci. 17 (9): 1217–1224. doi:10.1038/nn.3789. PMC 4214681. PMID 25129078. In the present study we show, for the first time, that activation of a delimited node of GABAergic neurons located in the medullary PZ can potently initiate SWS and cortical SWA in behaving animals. ... For now however it remains unclear if the PZ is interconnected with other sleep– and wake–promoting nodes beyond the wake–promoting PB. ... The intensity of cortical slow–wave–activity (SWA: 0.5–4Hz) during SWS is also widely accepted as a reliable indicator of sleep need ... In conclusion, in the present study we demonstrated that all polygraphic and neurobehavioral manifestation of SWS, including SWA, can be initiated in behaving animals by the selective activation of a delimited node of GABAergic medullary neurons.
  2. ^ a b c Schwartz MD, Kilduff TS (December 2015). "The Neurobiology of Sleep and Wakefulness". The Psychiatric Clinics of North America. 38 (4): 615–644. doi:10.1016/j.psc.2015.07.002. PMC 4660253. PMID 26600100. This ascending reticular activating system (ARAS) is comprised of cholinergic laterodorsal and pedunculopontine tegmentum (LDT/PPT), noradrenergic locus coeruleus (LC), serotonergic (5-HT) Raphe nuclei and dopaminergic ventral tegmental area (VTA), substantia nigra (SN) and periaqueductal gray projections that stimulate the cortex directly and indirectly via the thalamus, hypothalamus and BF.6, 12-18 These aminergic and catecholaminergic populations have numerous interconnections and parallel projections which likely impart functional redundancy and resilience to the system.6, 13, 19 ... More recently, the medullary parafacial zone (PZ) adjacent to the facial nerve was identified as a sleep-promoting center on the basis of anatomical, electrophysiological and chemo- and optogenetic studies.23, 24 GABAergic PZ neurons inhibit glutamatergic parabrachial (PB) neurons that project to the BF,25 thereby promoting NREM sleep at the expense of wakefulness and REM sleep. ... Sleep is regulated by GABAergic populations in both the preoptic area and the brainstem; increasing evidence suggests a role for the melanin-concentrating hormone cells of the lateral hypothalamus and the parafacial zone of the brainstem
  3. ^ a b Brown RE, McKenna JT (June 2015). "Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal". Front. Neurol. 6: 135. doi:10.3389/fneur.2015.00135. PMC 4463930. PMID 26124745. The sleep-promoting action of GABAergic neurons located in the preoptic hypothalamus (6–8) is now well-known and accepted (9). More recently, other groups of sleep-promoting GABAergic neurons in the lateral hypothalamus (melanin-concentrating hormone neurons) and brainstem [parafacial zone; (10)] have been identified.
  4. ^ a b Cherasse Y, Urade Y (November 2017). "Dietary Zinc Acts as a Sleep Modulator". International Journal of Molecular Sciences. 18 (11): 2334. doi:10.3390/ijms18112334. PMC 5713303. PMID 29113075. More recently, Fuller’s laboratory also discovered that sleep can be promoted by the activation of a gamma-aminobutyric acid-ergic (GABAergic) population of neurons located in the parafacial zone [11,12], while the role of the GABAergic A2AR-expressing neurons of the nucleus accumbens [13] and the striatum has just been revealed [14,15].
  5. ^ Oishi Y, Xu Q, Wang L, Zhang BJ, Takahashi K, Takata Y, Luo YJ, Cherasse Y, Schiffmann SN, de Kerchove d'Exaerde A, Urade Y, Qu WM, Huang ZL, Lazarus M (September 2017). "Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice". Nature Communications. 8 (1): 734. doi:10.1038/s41467-017-00781-4. PMC 5622037. PMID 28963505. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound.
  6. ^ Yuan XS, Wang L, Dong H, Qu WM, Yang SR, Cherasse Y, Lazarus M, Schiffmann SN, d'Exaerde AK, Li RX, Huang ZL (October 2017). "Striatal adenosine A2A receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus". eLife. 6: e29055. doi:10.7554/eLife.29055. PMC 5655138. PMID 29022877.
  7. ^ Borbély, Alexander A.; Achermann, Peter (2005), "Sleep Homeostasis and Models of Sleep Regulation", Principles and Practice of Sleep Medicine, Elsevier, pp. 405–417, doi:10.1016/b0-72-160797-7/50040-9, ISBN 9780721607979
  8. ^ Anaclet, C.; Lin, J.-S.; Vetrivelan, R.; Krenzer, M.; Vong, L.; Fuller, P. M.; Lu, J. (2012-12-12). "Identification and Characterization of a Sleep-Active Cell Group in the Rostral Medullary Brainstem". Journal of Neuroscience. 32 (50): 17970–17976. doi:10.1523/jneurosci.0620-12.2012. ISSN 0270-6474. PMC 3564016. PMID 23238713.
  9. ^ a b Su, Yun-Ting; Gu, Meng-Yang; Chu, Xi; Feng, Xiang; Yu, Yan-Qin (2018-03-20). "Whole-Brain Mapping of Direct Inputs to and Axonal Projections from GABAergic Neurons in the Parafacial Zone". Neuroscience Bulletin. 34 (3): 485–496. doi:10.1007/s12264-018-0216-8. ISSN 1673-7067. PMC 5960452. PMID 29557546.