Table 1.
Inactivation of brain regions/neurotransmitter systems and effects on sleep-wake behavior
| Brain Area/System Targeted | Inactivation Technique | Effect on Sleep-Wake and EEG |
|---|---|---|
| Brain stem | ||
| Midbrain/pontine reticular formation | Transections in cat (136–138, 580, 730, 1393). | Loss of cortical activation during waking and REM sleep. |
| Cerveau isole mesencephalic transaction immediately caudal to the third nerve nuclei (effects contrast with encephale isole intact sleep-wake with transaction at C1 level of spinal cord). | Loss of forebrain signs of REM sleep. | |
| Brain stem damage in human patients (980). | Coma. | |
| Transection at caudal pontine or prebulbar level (1341, 1393). | Loss of REM sleep and of the ability of pontine carbachol to elicit tonic and phasic REM components. | |
| Electrolytic lesions in cat (730). | Loss of cortical activation (not observed when lateral sensory pathways were interrupted). Coma like state. | |
| Neurotoxic lesions ibotenic acid lesions in cat (302) or rat (758). | Temporary increase in EEG slow waves but no long-term effects (cat). One week coma like state for combined PH/MPRF lesions. Recovery occurred. No effect (rat). | |
| Dorsolateral pons including the dorsal subcoeruleus (=sublaterodorsal nucleus or peri-locus coeruleus alpha) or dorsal pontine nucleus oralis (PnO) | Electrolytic (387, 388, 495, 498, 569, 893, 900, 1111, 1121, 1122). | Very large lesions: |
| Neurotoxic kainic acid (577, 1122, 1394), ibotenic acid (758), NMDA (682, 683), hypocretin 2-saporin (100), quisqualic acid (606). | Loss of REM sleep correlated with loss of cholinergic neurons. | |
| Acute brain stem encephalitis with isolated inflammatory lesion in dorsomedial pontine tegmentum (including DRN, MR, PnO, LC, SubC, LDT, PPT) (810). | Large lesions including the SubC and surrounding areas: | |
| Pharmacological tetrodotoxin (1111, 1114). | REM sleep behavior disorder (RBD) in humans, oneiric (dream-like) behavior in animals. | |
| Idiopathic degeneration in humans (400, 1133). | Smaller discrete lesions (focusing on SLD/SubC area): | |
| REM without atonia in animals, increased limb movements during sleep. | ||
| GABA or muscimol (183, 1112, 1440, 1441) | Wakefulness↑, NREM↓, REM sleep↓. | |
| Norepinephrine (262), noradrenergic α2 agonist clonidine (1300), or dopamine acting on α2 receptors(263). | Decreased REM and/or REM without atonia. | |
| Noradrenergic β antagonist, propanolol (1301). | REM↑ due to increased number of REM episodes. | |
| Inhibition of adenylyl cyclase (799). | REM sleep↑ (increased frequency of episodes). | |
| Peribrachial pons (surrounding brachium conjunctivum): includes PPT/LDT, cuneiform nucleus, subcoeruleus (FTG in cat), medial and lateral parabrachial nucleus. | Cooling, electrolytic or neurotoxic lesion in P-wave generation zone (277, 278, 604, 690, 691, 814, 1100). | Loss of pontine component of PGO waves (P-waves). Reduced expression of learning related genes and proteins following active avoidance training. Reduced frequency of hippocampal theta and reduced synchronization between hippocampus and amygdala. |
| M2 receptor antagonist, methoctramine (283). | Block of enhanced PGO-wave activity and REM-sleep like state induced by carbachol in the cat. | |
| Serotonin (279) | Inhibition of P-waves when injected into P-wave generator in dorsal subcoeruleus. | |
| Medial parabrachial nucleus | Neurotoxic: ibotenic acid (758). | Wake 21%↓ |
| Precoeruleus | Neurotoxic: ibotenic acid (758). | Loss of theta rhythm during REM |
| Ventral medulla (gigantocellular and magnocellular tegmental fields) | Neurotoxic quisqualic acid in cat (514) or neonatal rat (606). | Muscle tone↑ during NREM and REM sleep. Increased movements during REM sleep. Reduction in REM sleep and atonia duration during first postlesion week followed by recovery in weeks 2 and 3. Amount of remaining REM sleep correlated positively with ratio of remaining cholinergic or GABA neurons to serotonergic neurons. |
| Transection at ponto-medullary junction in decerebrate cat (1179) or injection of lidocaine into pontine reticular formation (652). | Abolition of muscle atonia produced by electrical stimulation of medial medulla. | |
| Brain stem cholinergic (PPT) | Ibotenic acid (758). | Wake 30%↓ |
| Locus coeruleus (LC) | Electrolytic lesion (576). | No effect on REM sleep generation. |
| Scopolamine, minipump perfusion (1168). | REM sleep↓ during the daytime (inactive period) in the rat. | |
| GABAA agonist muscimol (959, 1303); | Increased REM sleep with muscimol (due to increase in number of REM bouts) Possibly due to preferential inhibition of local GABAergic neurons. | |
| GABAB receptor agonist baclofen into PPT/DpMe (370). | Decreased REM sleep and memory consolidation with baclofen. | |
| α2 Agonist, clonidine, α1 antagonist prazosin or β antagonist (958). | REM sleep↑. | |
| Adenylyl cyclase or protein kinase A inhibition (67, 282). | REM sleep ↓ (due to decrease in number of episodes). | |
| Serotonin (279, 1113). | No effect on PGO waves. | |
| Brain stem cholinergic (LDT) | Ibotenic acid (758). | LDT: increased fragmentation but no effect on amount of sleep. |
| Neurotoxic lesion: kainic acid (1394), ibotenic acid (758), dopamine-β- hydroxylase saporin (100). | ||
| Cooling (201) | REM sleep ↑ | |
| RNAi knockdown of orexin 1 receptor (219). | REM sleep during dark period↑ | |
| Microdialysis of α2 agonist clonidine (1096). | Decreased activity of LC neurons. Waking ↓, NREM sleep ↑. | |
| DSP-4 lesion (238, 244, 881). | Reduced immediate-early and synaptic plasticity related gene expression. | |
| Either no change in baseline sleep-wake (238, 244) or increase in REM (881). | ||
| Dorsal raphe nucleus (DRN) | Electrolytic lesion (1451). | No effect. |
| Neurotoxic lesion: ibotenic acid (758), 5,7-dihydroxytryptamine (757). | No effect on amounts of sleep-wake. | |
| GABAA receptor agonist, muscimol (926). | REM sleep ↑. | |
| Median raphe (MR) | Electrolytic:(1451) | Hippocampal theta rhythm ↑. |
| Pharmacological glutamatergic antagonists (629); GABAA agonist, muscimol (630), 5-HT1A receptor agonists (1364). | ||
| Dopamine- vPAG/DRN | 6-OHDA or ibotenic acid (757). | Marked decrease in waking (>20%), concomitant increase in sleep. |
| Ventrolateral periaqueductal gray (vlPAG) | Electrolytic lesion in encephale isole cats (730). | Cortical activation preserved. |
| Neurotoxic lesion: orexin 2-Saporin (612, 758) | REM sleep ↑ in both normal and orexin KO animals. | |
| Pharmacological muscimol in the cat (1120), rat (1118), and guinea pig (1336). | Increased REM bouts and REM bout duration during dark period. | |
| Lateral pontine tegmentum (LPT) = deep mesencephalic nucleus (DpMe) | Electrolytic lesion in encephale isole cats (730). | Cortical activation preserved. |
| Neurotoxic lesion orexin 2-saporin in the rat (758) and mouse (612). | REM sleep ↑. Increased REM bouts during light period and occasional bouts of cataplexy. | |
| Pharmacological muscimol in the cat (1120), rat (1118), and guniea pig (1336). | ||
| Superior colliculus/pretectum | Aspiration (857) | Abolition of lights off-induced increase in REM sleep. |
| Hypothalamus | ||
| Preoptic area/anterior hypothalamus | Viral insult in humans (1378). | Prolonged (>3 wk) and large suppression of sleep (both NREM and REM). |
| Electrolytic lesions in the cat (761, 840, 911) and neonatal rat (873). | ||
| Neurotoxic lesions in the cat: ibotenic (1105) or kainic acid (1255). | ||
| Lateral preoptic area/bed nucleus of the stria terminalis (BNST) | Neurotoxic lesions in the rat. Ibotenic acid (1138) or NMDA (1201). | Reduction in number of erections during REM sleep (1138). NREM sleep ↓ (1201). |
| Ventrolateral preoptic area (VLPO, core) | Neurotoxic (rats). ibotenic acid (756). | NREM 50–60%↓, REM sleep 59%↓, EEG delta power 60–70% ↓lasting at least 3 wk. Extent of lesion correlated with loss of NREM sleep. Sleep-wake fragmentation. |
| GABA/galanin-positive neurons | ||
| Extended VLPO (dorsomedial) | Neurotoxic (rat). ibotenic acid (756). | REM sleep 35% ↓, NREM sleep,15%↓, 25% loss of delta mainly during light period. Extent of lesion correlated with loss of REM sleep. |
| Ventromedial preoptic area | Neurotoxic (rat). ibotenic acid (756), NMDA (563, 1201). | No effect on sleep-wake (756). Reduced NREM and REM sleep (563, 1201). Disrupted body temperature regulation. |
| Median preoptic area | Pharmacological: muscimol perfusion (1251) | Prolonged waking state |
| Suprachiasmatic nucleus (SCN) | Electrolytic: rat (1439). | Loss of circadian rhythms. Reduced REM sleep during the rest (light) phase. |
| Dorsomedial hypothalamus (DMH) | Neurotoxic: ibotenic acid (52, 224). | Loss of circadian rhythms of sleep-wakefulness. |
| Posterior/lateral hypothalamus (PH/LH) | Viral insult (1378) | Hypersomnolence in human patients following influenza pandemic. |
| Orexin/hypocretin (perifornical hypothalamus; PFH) | Damage to PH/LH including perifornical hypothalamus due to tumor (43) or stroke (1129). | Narcolepsy. |
| Electrolytic/transection: (730, 840, 911, 1046) | Reduction or abolition of cortical activation. Hypersomnolence for several days followed by recovery (cat). | |
| Neurotoxic: | PH/LH: no long-term effects (cat) | |
| LH: hypocretin 2-saporin (411, 413) | TMN area: minor changes. | |
| Orexin KO or orexin receptor doubleknockouts (29, 214, 598, 640). | Narcolepsy with cataplexy in mice. Unchanged 24 h wake amount but sleep-wake fragmentation, cataplexy, loss of circadian control of REM sleep. Reduced voluntary motor activity (wheel running). | |
| Orexin receptor 2 mutations (727). | Inherited narcolepsy in dogs. | |
| Loss (degeneration) of >90% of orexin neurons and reduced CSF orexin (999, 1284). | Idiopathic narcolepsy-cataplexy in humans. | |
| Partial (33%) loss of orexin neurons (1285). | Idiopathic narcolepsy without cataplexy in humans. | |
| Mutation in preproorexin (999). | Early onset narcolepsy in humans. | |
| Orexin postnatal genetic (ataxin-3) lesion (96, 479) | Narcolepsy with cataplexy in mice and rats. | |
| Knockdown of orexin in PFH with siRNA (221). | REM sleep during dark period in rats↑. | |
| Orexin receptor 1 KO mice (640). | Mild effects on sleep-wake. No cataplexy or sleep-onset REM episodes. | |
| Orexin receptor 2 KO mice (1415). | Milder form of narcolepsy-cataplexy (less cataplexy or sleep onset REM episodes). | |
| Orexin receptor (1 and 2) antagonist (140). | Increased sleep, especially REM sleep in rat, dogs, and humans. No cataplexy. | |
| Melanin concentrating hormone (MCH) | MCH knockout mice (5). | NREM and REM sleep ↓. |
| Perifornical hypothalamus | MCH 1 receptor antagonist (12) | |
| Histamine (tuberomammillary nucleus) | Reduced CSF histamine in narcolepsy and idiopathic hypersomnia (597). | Excessive daytime sleepiness in humans. |
| HDC (synthetic enzyme) knockout mice (29, 978). | No change in 24 h wake amount. Increased fragmentation. Decreased θ-power during waking increased δ during sleep. Increased REM during light period. Decreased sleep latency in novel environment. | |
| α-FMH (histamine decarboxylase inhibitor) in cat (724), mice (978), and rat (551, 1152). | Wake ↓ (cat, mice). No effect on 24 h values (rat). | |
| Systemic H1R antagonists crossing the blood-brain barrier: human (1402), cat (724), mice (528). | Reduced wakefulness and alertness ↓ (human, cat). No change (mice), decreased fragmentation. | |
| H1R knockout mice (528) | No change in 24 h wake amount or diurnal rhythms of sleep-wake. Decreased fragmentation. | |
| Systemic H3R (autoreceptor) agonist in cat (725), rat (686, 885) | Cat: wake ↓ NREM sleep↑ | |
| Rat: no effect. | ||
| Mammillary body (MB) | Pharmacological inhibition: local anesthetic procaine (639). | Abolition of hippocampal theta in urethane-anesthetized animals. Reduced frequency (1 Hz less) of hippocampal theta in awake animals. |
| Supramammillary nucleus (SuM)/posterior hypothalamus | Pharmacological inhibition local anesthetic procaine (639). | Abolition of hippocampal theta in urethane-anesthetized rats. Reduced frequency (1 Hz less) of hippocampal theta in awake rats. |
| Basal forebrain | ||
| Rostral basal forebrain (MS, vDB) | Electrolytic lesions rabbits (30, 1090). | Hippocampal theta rhythm reduced (neurotoxic) or abolished (electrolytic). |
| Neurotoxic lesions: rat: kainic acid (preferential loss of noncholinergic neurons) (1463), Orexin-saporin (415). | No other change in sleep-wake. | |
| Rostral BF cholinergic | Pharmacological: AP5 (NMDA receptor antagonist) (104); muscimol (106); procaine(945). | Reduced power of hippocampal theta. |
| Neurotoxic lesion IgG192 saporin or orexin-saporin (80, 415, 600, 697, 1463). | Reduced amplitude of hippocampal theta rhythm and theta-gamma coupling. No change in sleep-wake. | |
| Rostral BF GABAergic (mainly PV-Pos) | Pharmacological inhibition of H-current with ZD7288 in rat (1343, 1446). | Reduced hippocampal theta (1446) or minor effects (1343). |
| Caudal basal forebrain (SI, HDB, MCPO) | Neurotoxic ibotenic acid or quisqualate (177, 611, 1064). | No effect on 24 h sleep-wake. Increased delta power in all states. Reduced recovery sleep and delta power after ±SD. |
| Caudal BF cholinergic | Pharmacological procaine (190), adenosine (1247). | Increased sleep, delta wave activity. |
| IgG192-saporin (94, 102, 103, 592, 611). | No or minor effects on baseline sleep-wake. Reduced EEG gamma. Reduced recovery sleep and delta power after sleep deprivation (611). | |
| Caudal BF, TMN, LC | Triple lesions using saporin-conjugated neurotoxins (101). | No changes in daily amounts of wake. More sleep during light-to dark transition period. More stable sleep architecture. |
| Forebrain | ||
| Thalamus | Electrolytic: monkey (1046). | No effect on sleep-wake or EEG except abolition of high-voltage spindles (sharp-wave/ripples). |
| Neurotoxic ibotenic acid in rat (177, 397). | ||
| Basal ganglia | Ibotenic acid lesion (1029). | Rostral striatum: |
| Wake 15 %↓ | ||
| Sleep fragmentation, slowing of EEG during waking (theta→delta). | ||
| Globus pall.: wake 46 % ↑ Increased fragmentation. | ||
| Slowing of EEG. | ||
| NAcc core: wake 27 % ↑ NREM bout duration ↓. | ||
| Slowing of EEG. | ||
| STN: minor changes. | ||
| SNr: minor changes. | ||
| Substantia nigra | Hypocretin-2 saporin (412). | Insomnia. |
| SN/VTA | NMDA lesion (683). | No decrease in wakefulness. |
| Neurotransmitters/neuromodulators (Systemic or icv effects) | ||
| Acetylcholine | Systemic muscarinic antagonists (177, 555, 744). | Increase in EEG delta waves. Increased high-voltage spindles (sharp waves/ ripples). Block of PGO waves. |
| M2/M4 double knockouts (434). | No effect on sleep-wake | |
| M3 receptor knockouts (434). | REM 22% ↓ | |
| Rats reared on a diet lacking choline (1256). | Reduced NREM and REM sleep | |
| Serotonin | Depletion of serotonin (363, 555, 582, 1080). | Increased PGO waves in all states of sleep-wake. |
| Norepinephrine | Dopamine-β-hydroxylase knockout mice (539, 956). | Either no change in baseline sleep-wake or decrease in REM. Shorter sleep latency after mild stress. |