Natural Animal Model Research Articles

Characterization of the 10q26-orthologue in rhesus monkeys corroborates a functional connection between ARMS2 and HTRA1

Age-related macular degeneration, which is the leading cause of blindness in industrialized countries, is a multifactorial, degenerative disorder of the macula with strong heritability. For age-related macular degeneration in humans, the genes ARMS2 and HTRA1 in the region 10q26 are both promising candidates for being involved in pathogenesis. However, the associated variants are located in a region of strong linkage disequilibrium and so far, the identification of the causative gene in humans was not yet possible. This dilemma might be solved using an appropriate model organism. Rhesus monkeys suffer from drusen, a major hallmark of age-related macular degeneration, and the drusen-phenotype shares susceptibility factors with human macular degeneration. Thus, the rhesus monkey represents a natural animal model to uncover genetic factors leading to macular degeneration. Moreover, the existence of genetically homogenous cohorts offers an excellent opportunity to determine risk factors. However, the 10q26-orthologue genomic region in rhesus monkeys is not characterized in detail so far. Therefore, the aim of this study is to analyze the rhesus linkage disequilibrium structure and to investigate whether variants in ARMS2 or HTRA1 are associated with the drusen-phenotype as well. We sequenced parts of a 20 kb region around ARMS2 and HTRA1 in a genetically homogeneous cohort of 91 rhesus monkeys descending from the CPRC rhesus cohort on Cayo Santiago and currently housed in the German Primate Centre in Göttingen. Within this group, ophthalmoscopic examinations revealed a naturally high drusen prevalence of about 47% in monkeys >5 years. We detected 56 genetic variants within and around ARMS2 and HTRA1 and, as one deviates from Hardy-Weinberg-Equilibrium, 55 polymorphisms were used to generate a linkage disequilibrium-Plot and to perform association studies. We observed strong linkage disequilibrium between the markers and were able to define two haplotype blocks. One of these blocks spanned the whole ARMS2 locus and the 5′ part of HTRA1 – almost perfectly resembling the situation found in humans. Tests for association revealed a variant in the promoter region of HTRA1 and two variants in the 5′-UTR of ARMS2 to be associated with drusen. The strong linkage disequilibrium inhibits – as in humans – a determination of the risk gene using statistical methods only. However, the conserved linkage disequilibrium structure in humans and macaques goes in line with the recently emerged dual causality model proposing that ARMS2 and HTRA1 are functionally connected and that both genes contribute to the disease pathology. Moreover, the characterization of the 10q26-orthologue genomic region of the rhesus monkey provides a basis for now needed functional investigations in a well-characterized model organism.

Laboratory Opossum (Monodelphis domestica) Model for Melanoma Chemoprevention

Melanoma is the most aggressive form of skin cancer. Developments in melanoma basic research and therapeutic interventions have advanced tremendously with help of animal models of this disease. Transgenic and knockout mice have provided a wide array of melanoma models, which are primarily used for studying molecular pathways and developing treatment strategies. To the best of our knowledge, there has been no natural animal model for research on chemoprevention of melanoma induced by UV light alone. In this editorial, we discuss the potential of the laboratory opossum (Monodelphis domestica) as a natural model for research on chemoprevention of melanoma.

Acute Murine H5N1 Influenza A Encephalitis

Avian influenza A virus H5N1 has the proven capacity to infect humans through cross-species transmission, but to date, efficient human-to-human transmission is limited. In natural avian hosts, animal models and sporadic human outbreaks, H5N1 infection has been associated with neurological disease. We infected BALB/c mice intranasally with H5N1 influenza A/Viet Nam/1203/2004 to study the immune response during acute encephalitis. Using immunohistochemistry and in situ hybridization, we compared the time course of viral infection with activation of immunity. By 5 days postinfection (DPI), mice had lost substantial body weight and required sacrifice by 7 DPI. H5N1 influenza was detected in the lung as early as 1 DPI, whereas infected neurons were not observed until 4 DPI. H5N1 infection of BALB/c mice developed into severe acute panencephalitis. Infected neurons lacked evidence of a perineuronal net and exhibited signs of apoptosis. Whereas lung influenza infection was associated with an early type I interferon (IFN) response followed by a reduction in viral burden concordant with appearance of IFN-γ, the central nervous system environment exhibited a blunted type I IFN response.

Biomarkers and evolution in Alzheimer disease

Brain regions and their highly neuroplastic long axonal connections that expanded rapidly during hominid evolution are preferentially affected by Alzheimer disease. There is no natural animal model with full disease pathology (neurofibrillary tangles and neuritic amyloid plaques of a severity seen in Alzheimer's disease brains). Biomarkers such as reduced glucose metabolism in association neocortex, defects in long white matter tracts, RNA neurochemical changes, and high CSF levels of total and phosphorylated tau protein, which are helpful to identify MCI and preclinical Alzheimer disease patients, may also provide insights into what brain changes led to this disease being introduced during hominid evolution.

Identification of host cell factors common to both mosquito and human cells in response to Dengue virus infection

Dengue virus (DENV) is an enveloped, positive‐stranded RNA virus with four antigenically distinct serotypes. The virus causes dengue fever which is endemic in tropical and subtropical regions of the world. Over 2.5 billion people are at risk for dengue fever with 50 to 100 million annual cases of DENV infection occur worldwide, of which 500,000 cases are life‐threatening dengue hemorrhagic fever and dengue shock syndrome. At present, there are no effective vaccines, specific therapeutics, or natural animal models for DENV. Functional genomics and proteomic analyses have been used to identify the host responses in virus infected cells or hosts providing a better understanding of the molecular basis of pathogenesis of viral infections. In this study, two mosquito cell lines C6/36, CCL‐125 and one human cell line (HUVEC) were used to infect with DENV and identified several factors up‐regulated or down‐regulated in response to virus infection. We used a 2‐DE/MS proteomics approach followed by Western blot analysis to identify differential expression of protein profiles that are common to mosquito and human cell lines following DENV challenge. Further analysis of these data will allow for a greater understanding of DENV pathogenesis and vector‐pathogen interactions.

Dolphins as animal models for type 2 diabetes: Sustained, post-prandial hyperglycemia and hyperinsulinemia

There is currently no known natural animal model that fully complements type 2 diabetes in humans. Criteria for a true natural animal model include the presence of a fasting hyperglycemia, evidence of insulin resistance, and pathologies matching that reported in humans. To investigate the bottlenose dolphin ( Tursiops truncatus) as a comparative model for type 2 diabetes in humans, hourly plasma and urine chemistry changes, including glucose, were analyzed among five healthy, adult dolphins for 24 h following ingestion of 2.5–3.5 kg of mackerel or 2–3 L of 10% dextrose in ionosol. Fasting and 2 h post-prandial insulin levels were also determined among five adult dolphins to assess the presence of hyperinsulinemia. Finally, a case-control study compared insulin and glucagon levels among dolphins with and without iron overload, a condition associated with insulin resistance in humans. Both protein and dextrose meals caused significant increases in plasma glucose during the 0–5 h post-prandial period; dolphins fed dextrose demonstrated a sustained hyperglycemia lasting 5–10 h. Fasting plasma insulin levels among healthy dolphins mimicked those found in humans with some insulin resistance. Dolphins with hemochromatosis had higher post-prandial plasma insulin levels compared to controls. We conclude that bottlenose dolphins can demonstrate metabolic responses consistent with type 2 diabetes, specifically sustained hyperglycemia and hyperinsulinemia. Understanding more about how and why dolphins have a diabetes-like metabolism may provide new research avenues for diabetes in humans.

Effects of Memantine on Convulsive Reactions and the Organization of Sleep in Krushinskii–Molodkina Rats with an Inherited Predisposition to Audiogenic Convulsions

Krushinskii-Molodkina rats, which have a genetic predisposition to audiogenic convulsions, are used as a natural animal model for studies of the actions of anticonvulsants. It is important to understand the extent to which changes in glutamatergic synaptic transmission is involved in the mechanisms producing convulsive states and in the functional organization of the sleep-waking cycle in rats of this strain. The present report describes experiments addressing this, in which i.m. doses of 5 and 10 mg/kg of a noncompetitive NMDA glutamate receptor antagonist of the memantine type were given at different times (30 min, 1, 2, and 3 h) before presentation of sound stimuli (sine-wave tones at 8 kHz, 90 dB). Effects on the latent periods of the initial motor excitation, the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. The greatest attenuation of convulsive seizures, to a level consisting only of motor excitation, was obtained in 60% of the rats between 1 and 2 h after administration. There were no differences between the effects of doses of 5 and 10 mg/kg. When doses were given 3 h before sound provocation, convulsive reactions became more marked than at 2 h, though they were nevertheless more marked than in controls. Krushinskii-Molodkina rats with chronically implanted electrodes for recording brain electrical activity were used to study the effects of memantine on the organization of sleep. These experiments showed that the rats' sleep during the first hour after dosage consisted only of short episodes of superficial slow-wave sleep, and that even this sleep disappeared completely 54.4 +/- 4.9 and 39.9 +/- 5.2 min after administration of the agent at doses of 5 and 7 mg/kg, respectively. Rats showed a complete absence of sleep for 2 and 2.5 h, respectively, after which episodes of slow-wave sleep reappeared. The first episodes of REM sleep was seen in rats only after 3.3 +/- 0.2 and 3.7 +/- 0.2 h after memantine injections. The appearance of these episodes provided evidence that the effects of memantine on the activity of the somnogenic system of the animals' brains were complete and that recovery of the normal organization of the sleep-waking cycle had started. The synchronicity and codirectionality of the blocking action of memantine on sleep organization and measures of audiogenic convulsions in Krushinskii-Molodkina rats is evidence for the involvement of glutamatergic synapses with NMDA receptors in both the regulation of the somnogenic systems and the pathogenesis of epileptiform manifestations in rats.

Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice.

Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS—an already validated animal model of depression—with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression.

Magnetic resonance imaging of cerebral involutional changes in dogs as markers of aging: An innovative tool adapted from a human visual rating scale

The dog is increasingly considered as a natural animal model for the study of normal and pathological human brain aging, because it exhibits anatomical, biochemical and cognitive changes that parallel those seen in humans. This study presents a novel visual semi-quantitative rating scale of canine cerebral magnetic resonance imaging (MRI). Ninety-eight dogs of both sexes from 27 pure breeds, aged 2-15 years, were used. The results suggest that (like in humans) both hippocampal and progressive global atrophy are characteristic features that correlate with aging. When classified according to head shape, cerebral atrophy was highest in mesaticephalic and brachycephalic dogs. This is the first MRI study to characterise a simple, rapid tool for studying age-related canine brain changes that can even be applied by non-experienced observers. The results confirm the possibility of transferring innovative tools developed for human diagnosis to the veterinary field.

Introgression of Brown Norway Chromosome 13 Improves Visual Spatial Memory in the Dahl S Rat

The present study was conducted in an effort to evaluate whether chromosomal substitution can repair impaired exploration learning and memory. It has previously been observed that Dahl salt-sensitive (SS) rodents exhibit impaired cognitive function along with abnormal physiological responses to muscle stimulation. Introgression of Brown Norway chromosome (13(BN)) has been found to restore normal physiological processes in SS animals. However, the effect of chromosomal substitution on cognitive performance has not been explored. It was hypothesized that 13(BN) also rescues cognitive impairments in these animals. Visual spatial learning and cognitive flexibility were evaluated using the Morris water maze (MWM) and the T-maze. This manipulation is effective in rescuing impaired task acquisition, but not perseveration observed in the SS animal. These animals may represent a natural animal model in which to isolate genetic information responsible for learning and memory function.

Different Signaling Pathways Expressed by Chicken Naïve CD4+ T Cells, CD4+ Lymphocytes Activated with Staphylococcal Enterotoxin B, and Those Malignantly Transformed by Marek’s Disease Virus

Proteomics methods, based on liquid chromatography and tandem mass spectrometry, produce large "shotgun" proteomes that are most appropriately compared not at the level of differentially expressed proteins only but at the more comprehensive level of biological networks and pathways. This is now possible with the emergence of functional annotation databases and tools, databases of canonical pathways and molecular interactions and computational text mining tools. Here, we used shotgun proteomics, and the differential proteomics modeling functionalities available in the Pathwaystudio network modeling program to define the cell physiology of Hodgkin's disease antigen-overexpressing (CD30 (hi)) CD4 (+) T cell lymphomas using the unique Marek's disease (MD) natural animal model. CD30 (hi) lymphoma cells have characteristics of activated T cells but are also fundamentally different from their nontransformed healthy counterparts. We compared the cell physiology of naïve, superantigen-activated and MD-transformed CD4 (+) T cell proteomes. While the superantigen-activated cells had signaling pathways associated with cell activation, inflammation, proliferation and cell death, the MD-transformed cells had growth factor, cytokine, adhesion, and transcription factor signaling responses associated with oncogenicity, cell proliferation, angiogenesis, motility, and metastasis.

Functional and Structural Changes in the Retina of Wire-Haired Dachshunds with Early-Onset Cone–Rod Dystrophy

To describe and classify the morphologic changes in a naturally occurring dog model of early-onset cone-rod dystrophy (CRD) and to correlate these with earlier described clinical characteristics of the disease in dogs. Purpose-bred Standard Wire-Haired Dachshunds (SWHDs) derived from a large pedigree of dogs with early-onset CRD were euthanatized at defined ages to characterize morphologic changes in the disease process. Specimens were examined by light microscopy, including morphometric studies, electron microscopy, and immunohistochemistry. Peanut agglutinin (PNA), protein kinase C (PKC), synaptophysin (Syn), rhodopsin (Rho)-63, glial fibrillary acidic protein (GFAP), and short-wavelength cone opsin (OS) were used for immunohistochemical characterization. The photopic cone-system-derived ERG amplitudes were already significantly reduced or nonrecordable in CRD-affected dogs at 5 weeks, the earliest age studied. The outer retina was morphologically most severely affected initially, with a subsequent degeneration of the inner retina. Cone degeneration was more pronounced than rod degeneration in young CRD-affected dogs. There was a marked phenotypic variation based on morphologic findings in the affected dogs. At the earliest time point studied (5-8 weeks) cone photoreceptor and glial cell abnormalities were observed, in accordance with earlier studies based on electrophysiological and clinical findings in which day blindness and abnormal cone ERGs were observed in young affected SWHD puppies. Preliminary genetic studies have indicated an autosomal recessive mode of inheritance for the defect. Through functional and structural characterization, early-onset cone abnormalities were found, consistent with a cone dysplasia at an age when rod structure was normal. Further studies are in progress to identify the gene(s) involved in this retinal disease process. The presently described natural animal model of primary cone dysplasia followed by rod degeneration may provide further insight into the human counterpart. Further studies are needed to ascertain an autosomal recessive mode of inheritance for CRD in the SWHD.

Mouse models of sickle cell disease

In the absence of a natural animal model for sickle cell disease, transgenic mouse models have been generated to better understand the complex pathophysiology of the disease and to evaluate potential specific therapies. In the early nineties, the simple addition of human globin genes induced the expression of hemoglobin S (HbS) or HbS-related human hemoglobins in mice still expressing mouse hemoglobin. To increase the proportion of human hemoglobin and the severity of the mouse sickle cell syndrome, the proportion of mouse hemoglobin could be decreased by a combination of mouse α- and β-thalassemic defects, leading to complex genotypes and mild disease. Following the discovery of gene targeting in the mouse embryonic stem cells (ES cells), it was made possible to knock out all mouse adult globin genes ( 2α and 2β) and to add the human homologous genes elsewhere in the mouse genome. In addition, the human γ gene of fetal hemoglobin was protecting the fetus from HbS polymer formation. Accordingly, the resulting adult mouse models obtained in 1997, expressing human HbS-only, had a very severe anemia (Hb = 5–6 g/dL). In order to survive, these “HbS-only mice” had to reduce the HbS concentration within the red blood cells. The phenotype could be less severe by adding modified human γ genes, still expressed in adult mice. In 2006, a last “S-only” model was obtained by homologous knock in, replacing the mouse globin genes by human genes. This array of models contributes to better understand the role of different interacting factors in the complexity of sickle cell events, such as red cell defects, changes in blood flow and vaso-occlusion, hyperhemolysis, vascular tone dysregulation, oxidations, inflammation, activation and adhesion of cells, ischemia, reperfusion… In addition, each model has an appropriate usefulness to evaluate experimental therapies in vivo and to perform preclinical studies.

Transplacental Infection with Non-Cytopathic Bovine Viral Diarrhoea Virus Types 1b and 2: Viral Spread and Molecular Neuropathology

Infection with bovine viral diarrhoea virus (BVDV) represents a reproducible natural animal model in which to study mechanisms of transplacental viral infection. In the present study, BVDV-seronegative heifers were challenged intranasally with non-cytopathic BVDV of genotype 1b or 2. Fetuses were retrieved by caesarean section 7-114 days post-challenge of the dam and subjected to virological, histopathological and immunohistochemistry(IHC) studies. Gross and histopathological changes were only seen in fetuses infected at gestational age 75-85 days and retrieved at gestational age 190 days. Viral antigen could be detected in most tissues from 14 days post-infection, but the primary target organs for histopathological changes were brain, liver and spleen. In the brain, microscopical changes included leucomalacia and macrophage infiltration of meninges and neuropil. Viral antigen was detected in neurons, oligodendrocyte precursors and infiltrating macrophages. IHC revealed normal to slightly increased expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in the infected fetuses, with evidence of neuronal apoptosis and induction of inducible nitric oxide synthase (iNOS) and phospho-p38alpha mitogen-activated protein kinase (MAPK). These findings suggest that hypoxia may play only a limited role in the pathogenesis of the neural lesions. By contrast, virus-induced cytokine cascades, as part of the fetal innate immune response, and apoptosis of neurons and glial precursor cells may be central to the development of lesions.

An extracellular region of the erythropoietin receptor of the subterranean blind mole rat Spalax enhances receptor maturation

Erythropoietic functions of erythropoietin (EPO) are mediated by its receptor (EPO-R), which is present on the cell surface of erythroid progenitors and induced by hypoxia. We focused on EPO-R from Spalax galili (sEPO-R), one of the four Israeli species of the subterranean blind mole rat, Spalax ehrenbergi superspecies, as a special natural animal model of high tolerance to hypoxia. Led by the intriguing observation that most of the mouse EPO-R (mEPO-R) is retained in the endoplasmic reticulum (ER), we hypothesized that sEPO-R is expressed at higher levels on the cell surface, thus maximizing the response to elevated EPO, which has been reported in this species. Indeed, we found increased cell-surface levels of sEPO-R as compared with mEPO-R by using flow cytometry analysis of BOSC cells transiently expressing HA-tagged EPO-Rs (full length or truncated). We then postulated that unique extracellular sEPO-R sequence features contribute to its processing and cell-surface expression. To map these domains of the sEPO-R that augment receptor maturation, we generated EPO-R derivatives in which parts of the extracellular region of mEPO-R were replaced with the corresponding fragments of sEPO-R. We found that an extracellular portion of sEPO-R, harboring the N-glycosylation site, conferred enhanced maturation and increased transport to the cell surface of the respective chimeric receptor. Taken together, we demonstrate higher surface expression of sEPO-R, attributed at least in part to increased ER exit, mediated by an extracellular region of this receptor. We speculate that these sEPO-R sequence features play a role in the adaptation of Spalax to extreme hypoxia.

Vitamin E deficiency and risk of equine motor neuron disease.

BackgroundEquine motor neuron disease (EMND) is a spontaneous neurologic disorder of adult horses which results from the degeneration of motor neurons in the spinal cord and brain stem. Clinical manifestations, pathological findings, and epidemiologic attributes resemble those of human motor neuron disease (MND). As in MND the etiology of the disease is not known. We evaluated the predisposition role of vitamin E deficiency on the risk of EMND.MethodsEleven horses at risk of EMND were identified and enrolled in a field trial at different times. The horses were maintained on a diet deficient in vitamin E and monitored periodically for levels of antioxidants – α-tocopherols, vitamins A, C, β-carotene, glutathione peroxidase (GSH-Px), and erythrocytic superoxide dismutase (SOD1). In addition to the self-control another parallel control group was included. Survival analysis was used to assess the probability of developing EMND past a specific period of time.ResultsThere was large variability in the levels of vitamins A and C, β-carotene, GSH-Px, and SOD1. Plasma vitamin E levels dropped significantly over time. Ten horses developed EMND within 44 months of enrollment. The median time to develop EMND was 38.5 months. None of the controls developed EMND.ConclusionThe study elucidated the role of vitamin E deficiency on the risk of EMND. Reproducing this disease in a natural animal model for the first time will enable us to carry out studies to test specific hypotheses regarding the mechanism by which the disease occurs.

Random mutagenesis to identify novelHelicobacter mustelaevirulence factors

Helicobacter mustelae is a gastric pathogen of ferrets, where it causes disorders similar to those caused by Helicobacter pylori in humans. The H. mustelae ferret model therefore has potential for the in vivo study of Helicobacter pathogenesis in general. In this study a library of 500 individual H. mustelae mutants was generated using an in vitro random insertion mutagenesis technique. Mutants were subsequently tested for motility and adherence, and 43 of the 500 mutants tested were found to be nonmotile in a soft agar assay. Of these 43 mutants, seven were subsequently identified as deficient in their ability to adhere to AGS cells. Insertion had taken place in different positions in the H. mustelae genome, and included mutants in or near to genes involved in motility and urease activity (e.g. the chemotaxis gene cheV and the urease accessory gene ureH). The development of a mutant library for a natural animal model of Helicobacter infection provides the opportunity to study in vivo the role of candidate Helicobacter virulence genes.

Modeling the proteome of a Marek's disease transformed cell line: a natural animal model for CD30 overexpressing lymphomas

Marek's disease (MD) in the chicken, caused by the highly infectious MD alpha-herpesvirus (MDV), is both commercially important and a unique, naturally occurring model for human T-cell lymphomas overexpressing the Hodgkin's disease antigen, CD30. Here, we used proteomics as a basis for modeling the molecular functions and biological processes involved in MDV-induced lymphomagenesis. Proteins were extracted from an MDV-transformed cell line and were then identified using 2-D LC-ESI-MS/MS. From the resulting 3870 cellular and 21 MDV proteins we confirm the existence of 3150 "predicted" and 12 "hypothetical" chicken proteins. The UA-01 proteome is proliferative, differentiated, angiogenic, pro-metastatic and pro-immune-escape but anti-programmed cell death, -anergy, -quiescence and -senescence and is consistent with a cancer phenotype. In particular, the pro-metastatic integrin signaling pathway and the ERK/MAPK signaling pathways were the two predominant signaling pathways represented. The cytokines, cytokine receptors, and their related proteins suggest that UA-01 has a regulatory T-cell phenotype.

The stem cell and tissue engineering research in Chinese ophthalmology

Much has been considerably developed recently in the ophthalmic research of stem cell (SC) and tissue engineering (TE). They have become closer to the clinical practice, standardized and observable. Leading edge research of SC and TE on the ocular surface reconstruction, neuroregeneration and protection, and natural animal model has become increasingly available. However, challenges remain on the way, especially on the aspects of function reconstruction and specific differentiation. This paper reviews the new developments in this area with an intention of identifying research priorities for the future.

PET Imaging in the Photosensitive Baboon: Case‐controlled Study

The baboon (Papio hamadryas spp) offers a natural primate animal model of photosensitive generalized epilepsy. This study compared changes in cerebral blood flow (CBF) during intermittent light stimulation (ILS) between photosensitive and asymptomatic baboons. Six photosensitive, epileptic (PS) and four nonphotosensitive, asymptomatic (CTL) baboons, matched for age, gender, and weight, were selected based on previous scalp EEG evaluation. Continuous intravenous ketamine (5-13 mg/kg) was used for sedation. Subjects underwent five sequential blood-flow PET studies within 60 min with 20 mCi (15)O-labeled water. Images were acquired in 3D mode (CTI/Siemens HR+ scanner, 63 contiguous slices, 2.4-mm thickness). Three resting scans were alternated with two activation scans during ILS. ILS was performed at 25 Hz for 60 s before to 60 s after the start of an activation scan. PET images were coregistered with MRI (3T Siemens Trio, T(1)-weighted 3D Turboflash sequence; TE/TR/TI, 3.04/2,100/785 ms; flip angle, 13 degrees). PET scans were reviewed and corrected for motion artifact. Resting scans were contrasted with activation scans and averaged independently for both groups. Quantitative CBF analyses were performed for the occipital and motor cortices. The CTL baboons showed greatest ILS-induced activation in the left middle frontal and inferior temporal gyri, left brainstem structures and right postcentral gyrus, bilateral occipital lobes, and in the posterior cingulate gyrus and cerebellum. In contrast, the PS animals showed strongest ILS activation in the right anterior cingulate and medial orbital gyri, amygdala, globus pallidum, and left inferior and superior temporal gyri. A striking finding was the absence of occipital and variable motor cortex activation in the PS animals. Deactivations were noted in the right orbitofrontal and anterior cingulate cortices in the CTL baboons and in the posterior cingulate gyrus, brainstem and cerebellum of the PS animals. The patterns of ILS-induced CBF changes differed between CTL and PS groups. These differences of activations and inhibitions suggest involvement of specific cortical-subcortical or networks in photosensitivity.