J M Siegel

University of California, Los Angeles, Los Angeles, California, United States

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Publications (149)917.84 Total impact

  • Joshi John, Tohru Kodama, Jerome M Siegel
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    ABSTRACT: Histamine neurons are active during waking and largely inactive during sleep, with minimal activity during rapid-eye movement (REM) sleep. Caffeine, the most widely used stimulant, causes a significant increase of sleep onset latency in rats and humans. We hypothesized that caffeine increases glutamate release in the posterior hypothalamus (PH) and produces increased activity of wake-active histamine neurons. Using in vivo microdialysis, we collected samples from the PH after caffeine administration in freely behaving rats. HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 minutes. Gamma-amino butyric acid (GABA) levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 minutes. Immunostaining showed a significantly elevated number of c-Fos labeled histamine neurons in caffeine treated rats compared to saline treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness.
    American journal of physiology. Regulatory, integrative and comparative physiology. 07/2014;
  • Lalini Ramanathan, Jerome M. Siegel
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    ABSTRACT: Female hypocretin knockout (Hcrt KO) mice have increased body weight despite decreased food intake compared to wild type (WT) mice. In order to understand the nature of the increased body weight, we carried out a detailed study of Hcrt KO and WT, male and female mice. Female KO mice showed consistently higher body weight than WT mice, from 4-20 months (20%-60%). Fat, muscle and free fluid levels were all significantly higher in adult (7-9 months) as well as old (18-20 months) female KO mice compared to age-matched WT mice. Old male KO mice showed significantly higher fat content (150%) compared to age-matched WT mice, but no significant change in body weight. Respiratory quotient (-19%) and metabolic rates (-14%) were significantly lower in KO mice compared to WT mice, regardless of gender or age. Female KO mice had significantly higher serum leptin levels (191%) than WT mice at 18-20 months, but no difference between male mice were observed. Conversely, insulin resistance was significantly higher in both male (73%) and female (93%) KO mice compared to age- and sex-matched WT mice. We conclude that absence of the Hcrt peptide has gender-specific effects. In contrast, Hcrt-ataxin mice and human narcoleptics, with loss of the whole Hcrt cell, show weight gain in both sexes.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; · 3.97 Impact Factor
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    ABSTRACT: To determine whether histamine cells are altered in human narcolepsy with cataplexy, and in animal models of this disease. Immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy were used to detect histamine cells in human narcoleptics, Hcrt receptor-2 mutant dogs and three mouse narcolepsy models: hypocretin (Hcrt, orexin) knockouts (KOs), ataxin-3-orexin and doxycycline-controlled-diphtheria-toxin-A-orexin (DTA). We find an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between narcoleptics and controls. However, we do not see altered numbers of HDC cells in any of the animal models of narcolepsy we examined. Changes in histamine cell numbers are not required for the major symptoms of narcolepsy, since all animal models have these symptoms. The histamine cell changes we saw in humans did not occur in the four animal models of hypocretin dysfunction we examined. Therefore the loss of Hcrt receptor-2, of the Hcrt peptide, or of Hcrt cells is not sufficient to produce these changes. We speculate that the increased histamine cell numbers we see in human narcolepsy may instead be related to the process causing the human disorder. Although research has focused on possible antigens within the Hcrt cells that might trigger their autoimmune destruction, the present findings suggest that the triggering events of human narcolepsy may involve a proliferation of histamine containing cells. We discuss this and other explanations of the difference between human narcoleptics and animal models of narcolepsy, including therapeutic drug use and species differences. ANN NEUROL 2013. © 2013 American Neurological Association.
    Annals of Neurology 07/2013; · 11.19 Impact Factor
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    ABSTRACT: The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.
    Nature Communications 03/2013; 4:1547. · 10.02 Impact Factor
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    ABSTRACT: On land, fur seals predominately display bilaterally synchronized electroencephalogram (EEG) activity during slow-wave sleep (SWS), similar to that observed in all terrestrial mammals. In water, however, fur seals exhibit asymmetric slow-wave sleep (ASWS), resembling the unihemispheric slow-wave sleep of odontocetes (toothed whales). The unique sleeping pattern of fur seals allows us to distinguish neuronal mechanisms mediating EEG changes from those mediating behavioral quiescence. In a prior study we found that cortical acetylcholine release is lateralized during ASWS in the northern fur seal, with greater release in the hemisphere displaying low-voltage (waking) EEG activity, linking acetylcholine release to hemispheric EEG activation (Lapierre et al. 2007). In contrast to acetylcholine, we now report that cortical serotonin release is not lateralized during ASWS. Our data demonstrate that bilaterally symmetric levels of serotonin are compatible with interhemispheric EEG asymmetry in the fur seal. We also find greatly elevated levels during eating and hosing the animals with water, suggesting that serotonin is more closely linked to bilateral variables, such as axial motor and autonomic control, than to the lateralized cortical activation manifested in asymmetrical sleep.
    Journal of Neuroscience 02/2013; 33(6):2555-2561. · 6.91 Impact Factor
  • Ashley M Blouin, Jerome M Siegel
    Sleep 01/2013; 36(12):1777. · 5.10 Impact Factor
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    ABSTRACT: OBJECTIVE: An abnormality in auditory evoked responses localised to the inferior colliculus (IC) has been reported in rapid eye movement (REM) sleep behaviour disorder (RBD) patients. The external cortex of the inferior colliculus (ICX) has been demonstrated not only to be involved in auditory processing, but also to participate in the modulation of motor activity. METHODS: Rats were surgically implanted with electrodes for electroencephalography (EEG) and electromyography (EMG) recording and guide cannulae aimed at the ICX for drug infusions. Drug infusions were conducted after the animals recovered from surgery. Polysomnographic recordings with video were analysed to detect normal and abnormal sleep states. RESULTS: Baclofen, a gamma-aminobutyric acid B (GABA(B)) receptor agonist, infused into the ICX increased phasic motor activity in slow wave sleep (SWS) and REM sleep and tonic muscle activity in REM sleep; it also elicited RBD-like activity during the infusion and post-infusion period. In contrast, saclofen, a GABA(B) receptor antagonist, did not produce significant changes in motor activities in sleep. Baclofen infusions in ICX also significantly increased REM sleep during the post-infusion period, while saclofen infusions did not change the amount of any sleep-waking states. CONCLUSIONS: This study suggests that GABA(B) receptor mechanisms in the ICX may be implicated in the pathology of RBD.
    Sleep Medicine 10/2012; · 3.49 Impact Factor
  • Jerome M Siegel
    Science 09/2012; 337(6102):1610-1. · 31.20 Impact Factor
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    ABSTRACT: Slow wave sleep (SWS) in the northern fur seal (Callorhinus ursinus) is characterized by a highly expressed interhemispheric electroencephalogram (EEG) asymmetry, called 'unihemispheric' or 'asymmetrical' SWS. The aim of this study was to examine the regional differences in slow wave activity (SWA; power in the range of 1.2-4.0 Hz) within one hemisphere and differences in the degree of interhemispheric EEG asymmetry within this species. Three seals were implanted with 10 EEG electrodes, positioned bilaterally (five in each hemisphere) over the frontal, occipital and parietal cortex. The expression of interhemispheric SWA asymmetry between symmetrical monopolar recordings was estimated based on the asymmetry index [AI = (L-R)/(L+R), where L and R are the power in the left and right hemispheres, respectively]. Our findings indicate an anterior-posterior gradient in SWA during asymmetrical SWS in fur seals, which is opposite to that described for other mammals, including humans, with a larger SWA recorded in the parietal and occipital cortex. Interhemispheric EEG asymmetry in fur seals was recorded across the entire dorsal cerebral cortex, including sensory (visual and somatosensory), motor and associative (parietal or suprasylvian) cortical areas. The expression of asymmetry was greatest in occipital-lateral and parietal derivations and smallest in frontal-medial derivations. Regardless of regional differences in SWA, the majority (90%) of SWS episodes with interhemispheric EEG asymmetry meet the criteria for 'unihemispheric SWS' (one hemisphere is asleep while the other is awake). The remaining episodes can be described as episodes of bilateral SWS with a local activation in one cerebral hemisphere.
    Journal of Sleep Research 06/2012; · 3.04 Impact Factor
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    ABSTRACT: The present study describes the organization of the orexinergic (hypocretinergic) neurons in the hypothalamus of the giraffe and harbour porpoise--two members of the mammalian Order Cetartiodactyla which is comprised of the even-toed ungulates and the cetaceans as they share a monophyletic ancestry. Diencephalons from two sub-adult male giraffes and two adult male harbour porpoises were coronally sectioned and immunohistochemically stained for orexin-A. The staining revealed that the orexinergic neurons could be readily divided into two distinct neuronal types based on somal volume, area and length, these being the parvocellular and magnocellular orexin-A immunopositive (OxA+) groups. The magnocellular group could be further subdivided, on topological grounds, into three distinct clusters--a main cluster in the perifornical and lateral hypothalamus, a cluster associated with the zona incerta and a cluster associated with the optic tract. The parvocellular neurons were found in the medial hypothalamus, but could not be subdivided, rather they form a topologically amorphous cluster. The parvocellular cluster appears to be unique to the Cetartiodactyla as these neurons have not been described in other mammals to date, while the magnocellular nuclei appear to be homologous to similar nuclei described in other mammals. The overall size of both the parvocellular and magnocellular neurons (based on somal volume, area and length) were larger in the giraffe than the harbour porpoise, but the harbour porpoise had a higher number of both parvocellular and magnocellular orexinergic neurons than the giraffe despite both having a similar brain mass. The higher number of both parvocellular and magnocellular orexinergic neurons in the harbour porpoise may relate to the unusual sleep mechanisms in the cetaceans.
    Journal of chemical neuroanatomy 06/2012; 44(2):98-109. · 1.75 Impact Factor
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    ABSTRACT: Several behavioral and physiological adaptations have been developed in evolution of Pinnipeds allowing them to sleep both on land and in water. To date sleep has been examined in detail in eared and true seals (the families of Otariidae and Phocidae). The aim of this study was to examine sleep in another semiaquatic mammal - the walrus, which is the only extant representative of the family Odobenidae. Slow wave and paradoxical sleep (SWS and PS) in the examined walrus (2 year old female, weight 130 kg) averaged 19.4 ± 2.0 and 6.9 ± 1.1% of 24-h when on land, and 20.5 ± 0.8% of 24-h and 1.1 ± 0.6% when in water, respectively. The average duration of PS episode was 6.4 ± 0.6 min (maximum 23 min) when on land and 1.8 ± 0.1 min (maximum 3.3 min) when in water. In water, sleep occurred predominantly while the walrus submerged and lay on the bottom of the pool (89% of total sleep time). The walrus usually woke up while emerging to the surface for breathing. Most often EEG slow waves developed synchronously in both cortical hemispheres (90% of SWS time when on land and 97% when in water). Short episodes of interhemispheric EEG asymmetry usually coincided with brief opening of one eye. The pattern of sleep in the walrus was similar to the pattern of sleep in the Otariidae seals while on land (predominantly bilateral SWS, accompanied by regular breathing) and to the pattern of sleep in the Phocidae while in water (sleep during apneas both in depth and at the surface, interrupted by brief arousal when emerging for breathing).
    Doklady Biological Sciences 05/2012; 444:188-91.
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    ABSTRACT: We investigated sleep in therock hyrax, Procavia capensis, a social mammal that typically lives in colonies on rocky outcrops throughout most parts of Southern Africa. The sleep of 5 wild-captured, adult rock hyraxes was recorded continuously for 72 h using telemetric relay of signals and allowing unimpeded movement. In addition to waking, slow wave sleep (SWS) and an unambiguous rapid eye movement (REM) state, a sleep state termed somnus innominatus (SI), characterized by low-voltage, high-frequency electroencephalogram, an electromyogram that stayed at the same amplitude as the preceding SWS episode and a mostly regular heart rate, were identified. If SI can be considered a form of low-voltage non-REM, the implication would be that the rock hyrax exhibits the lowest amount of REM recorded for any terrestrial mammal studied to date. Conversely, if SI is a form of REM sleep, it would lead to the classification of a novel subdivision of this state; however, further investigation would be required. The hyraxes spent on average 15.89 h (66.2%) of the time awake, 6.02 h (25.1%) in SWS, 43 min (3%) in SI and 6 min (0.4%) in REM. The unambiguous REM sleep amounts were on average less than 6 min/day. The most common state transition pathway in these animals was found to be wake → SWS → wake. No significant differences were noted with regard to total sleep time, number of episodes and episode duration for all states between the light and dark periods.Thus, prior classification of the rock hyrax as strongly diurnal does not appear to hold under controlled laboratory conditions.
    Brain Behavior and Evolution 01/2012; 79(3):155-69. · 2.89 Impact Factor
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    ABSTRACT: Hypocretin (Hcrt) has been implicated in the control of motor activity and in respiration and cardiovascular changes. Loss of Hcrt in narcolepsy is linked to sleepiness and to cataplexy, a sudden loss of muscle tone which is triggered by sudden strong emotions. In the current study we have compared the effects of treadmill running, to yard play on cerebrospinal fluid (CSF) Hcrt level in normal dogs. We find that treadmill locomotion, at a wide range of speeds, does not increase Hcrt level beyond baseline, whereas yard play produces a substantial increase in Hcrt, even though both activities produce comparable increases in heart rate, respiration and body temperature. We conclude that motor and cardiovascular changes are not sufficient to elevate CSF levels of Hcrt and we hypothesize that the emotional aspects of yard play account for the observed increase in Hcrt.
    Archives italiennes de biologie 12/2011; 149(4):492-8. · 1.43 Impact Factor
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    ABSTRACT: Hypocretin (Hcrt) cell loss is responsible for narcolepsy, but Hcrt's role in normal behavior is unclear. We found that Hcrt knock-out mice were unable to work for food or water reward during the light phase. However, they were unimpaired relative to wild-type (WT) mice when working for reward during the dark phase or when working to avoid shock in the light or dark phase. In WT mice, expression of Fos in Hcrt neurons occurs only in the light phase when working for positive reinforcement. Expression was seen throughout the mediolateral extent of the Hcrt field. Fos was not expressed when expected or unexpected unearned rewards were presented, when working to avoid negative reinforcement, or when given or expecting shock, even though these conditions elicit maximal electroencephalogram (EEG) arousal. Fos was not expressed in the light phase when light was removed. This may explain the lack of light-induced arousal in narcoleptics and its presence in normal individuals. This is the first demonstration of such specificity of arousal system function and has implications for understanding the motivational and circadian consequences of arousal system dysfunction. The current results also indicate that comparable and complementary specificities must exist in other arousal systems.
    Journal of Neuroscience 10/2011; 31(43):15455-67. · 6.91 Impact Factor
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    ABSTRACT: In the present study, orexinergic cell bodies within the brains of rhythmic and arrhythmic circadian chronotypes from three species of African mole rat (Highveld mole rat-Cryptomys hottentotus pretoriae, Ansell's mole rat--Fukomys anselli and the Damaraland mole rat--Fukomys damarensis) were identified using immunohistochemistry for orexin-A. Immunopositive orexinergic (Orx+) cell bodies were stereologically assessed and absolute numbers of orexinergic cell bodies were determined for the distinct circadian chronotypes of each species of mole rat examined. The aim of the study was to investigate whether the absolute numbers of identified orexinergic neurons differs between distinct circadian chronotypes with the hypothesis of elevated hypothalamic orexinergic neurons in the arrhythmic chronotypes compared with the rhythmic chronotypes. We found statistically significant differences between the circadian chronotypes ofF. anselli, where the arrhythmic group had higher mean numbers of hypothalamic orexin neurons compared with the rhythmic group. These differences were observed when the raw data was compared and when the raw data was corrected for body mass (M(b)) and brain mass (M(br)). For the two other species investigated, no significant differences were noted between the chronotypes, although a statistically significant difference was noted between all rhythmic and arrhythmic individuals of the current study when the counts of orexin neurons were corrected for M(b)--the arrhythmic individuals had larger numbers of orexin cells.
    Neuroscience 10/2011; 199:153-65. · 3.12 Impact Factor
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    Lalini Ramanathan, Jerome M Siegel
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    ABSTRACT: We previously showed that total sleep deprivation increased antioxidant responses in several rat brain regions. We also reported that chronic hypoxia enhanced antioxidant responses and increased oxidative stress in rat cerebellum and pons, relative to normoxic conditions. In the current study, we examined the interaction between these two parameters (sleep and hypoxia). We exposed rats to total sleep deprivation under sustained hypoxia (SDSH) and compared changes in antioxidant responses and oxidative stress markers in the neocortex, hippocampus, brainstem, and cerebellum to those in control animals left undisturbed under either sustained hypoxia (UCSH) or normoxia (UCN). We measured changes in total nitrite levels as an indicator of nitric oxide (NO) production, superoxide dismutase (SOD) activity and total glutathione (GSHt) levels as markers of antioxidant responses, and levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyls as signs of lipid and protein oxidation products, respectively. We found that acute (6h) SDSH increased NO production in the hippocampus and increased GSHt levels in the neocortex, brainstem, and cerebellum while decreasing hippocampal lipid oxidation. Additionally, we observed increased hexokinase activity in the neocortex of SDSH rats compared to UCSH rats, suggesting that elevated glucose metabolism may be one potential source of the enhanced free radicals produced in this brain region. We conclude that short-term insomnia under hypoxia may serve as an adaptive response to prevent oxidative stress.
    Free Radical Biology & Medicine 08/2011; 51(10):1842-8. · 5.27 Impact Factor
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    Jerome M Siegel
    Sleep Medicine Reviews 06/2011; 15(3):139-42. · 8.68 Impact Factor
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    ABSTRACT: Hypocretin receptor-2 (Hcrt-r2)-mutated dogs exhibit all the major symptoms of human narcolepsy and respond to drugs that increase or decrease cataplexy as do narcoleptic humans; yet, unlike narcoleptic humans, the narcoleptic dogs have normal hypocretin levels. We find that drugs that reduce or increase cataplexy in the narcoleptic dogs, greatly increase and decrease, respectively, hypocretin levels in normal dogs. The effects of these drugs on heart rate and blood pressure, which were considerable, were not correlated with their effects on cataplexy. Administration of these drugs to Hcrt-r2-mutated dogs produced indistinguishable changes in heart rate and blood pressure, indicating that neither central nor peripheral Hcrt-r2 is required for these cardiovascular effects. However, in contrast to the marked Hcrt level changes in the normal dogs, these drugs did not alter hypocretin levels in the Hcrt-r2 mutants. We conclude that Hcrt-r2 is a vital element in a feedback loop integrating Hcrt, acetylcholine, and norepinephrine function. In the absence of functional Hcrt-r2, Hcrt levels are not affected by monoaminergic and cholinergic drugs, despite the strong modulation of cataplexy by these drugs. Conversely, strong transient reductions of Hcrt level by these drugs do not produce episodes of cataplexy in normal dogs. The Hcrt-r2 mutation causes drug-induced cataplexy by virtue of its long-term effect on the functioning of other brain systems, rather than by increasing the magnitude of phasic changes in Hcrt level. A similar mechanism may be operative in spontaneous cataplexy in narcoleptic dogs as well as in narcoleptic humans.
    Journal of Neuroscience 04/2011; 31(17):6305-10. · 6.91 Impact Factor
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    ABSTRACT: The giant Zambian mole rat (Fukomys mechowii) is a subterranean Afrotropical rodent noted for its regressed visual system and unusual patterns of circadian rhythmicity--within this species some individuals exhibit distinct regular circadian patterns of locomotor activity while others have arrhythmic circadian patterns. The current study was aimed at understanding whether differences in circadian chronotypes in this species affect the patterns and proportions of the different phases of the sleep-wake cycle. Physiological parameters of sleep (electroencephalogram and electromyogram) and behaviour (video recording) were recorded continuously for 72 h from 6 mole rats (3 rhythmic and 3 arrhythmic) using a telemetric system and a low-light CCTV camera connected to a DVD recorder. The results indicate that the arrhythmic individuals spend more time in waking with a longer average duration of a waking episode, less time in non-rapid eye movement (NREM) with a shorter average duration of an NREM episode though a greater NREM sleep intensity, and similar sleep cycle lengths. The time spent in rapid eye movement (REM) and the average duration of an REM episode were similar between the chronotypes.
    Brain Behavior and Evolution 01/2011; 78(2):162-83. · 2.89 Impact Factor
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    ABSTRACT: A recent publication suggested that hypocretin (Hcrt, orexin) may mediate the neuropathological process leading to Alzheimer's disease (AD) and that antagonism of hypocretin receptors decreases this process. Narcoleptics have an approximately 90% loss of Hcrt neurons and commensurate reductions in the levels of Hcrt in their cerebrospinal fluid beginning at disease onset, usually before the age of 30. If Hcrt mediates the disease process, narcoleptics should be protected against AD. We examined the postmortem neuropathology and clinical records of 12 sequentially encountered cases of human narcolepsy. We found that AD was present in 4 of these narcoleptics, a prevalence that is similar to that of the general population.
    Neurobiology of aging 01/2011; 33(7):1318-9. · 5.94 Impact Factor

Publication Stats

6k Citations
917.84 Total Impact Points

Institutions

  • 1994–2014
    • University of California, Los Angeles
      • • Department of Medicine
      • • Department of Psychiatry and Biobehavioural Sciences
      • • Division of Adult Psychiatry
      • • Brain Research Institute
      Los Angeles, California, United States
    • Palo Alto Research Center
      Palo Alto, California, United States
  • 2013
    • Neuropsychiatric Research Institute
      Fargo, North Dakota, United States
    • The Scripps Research Institute
      La Jolla, California, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2012
    • Severtsov Institute of Ecology and Evolution
      Moskva, Moscow, Russia
  • 2004–2012
    • University of the Witwatersrand
      • School of Anatomical Science
      Johannesburg, Gauteng, South Africa
    • University of Delaware
      Delaware, United States
  • 2001–2012
    • VA Greater Los Angeles Healthcare System
      Los Angeles, California, United States
  • 2011
    • Laureate Institute for Brain Research
      Tulsa, Oklahoma, United States
  • 2009–2011
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, MA, United States
  • 2002–2011
    • University of Southern California
      • • Department of Medicine
      • • Department of Psychiatry and Behavioral Sciences
      Los Angeles, California, United States
  • 1986–2009
    • CSU Mentor
      Long Beach, California, United States
  • 2008
    • Northwestern University
      • Department of Neurobiology
      Evanston, IL, United States
  • 1998–2003
    • Tokyo Metropolitan Institute
      Edo, Tōkyō, Japan
  • 2000–2002
    • Russian Academy of Sciences
      • Institute of Evolutionary Physiology and Biochemistry
      Moscow, Moscow, Russia
  • 1993–1998
    • Stanford University
      • Department of Psychiatry and Behavioral Sciences
      Palo Alto, CA, United States
  • 1996
    • University of California, San Francisco
      San Francisco, California, United States
  • 1992
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States