Rhesus Monkey Brain Research Articles

Upregulation of Aβ42 in the Brain and Bodily Fluids of Rhesus Monkeys with Aging.

The cerebral accumulation of amyloid beta (Aβ) is one of the key pathological hallmarks of Alzheimer's disease (AD). Aβ is also found in bodily fluids such as the cerebrospinal fluid (CSF) and plasma. However, the significance of Aβ accumulation in the brain and different bodily pools, as well as its correlation with aging and cerebral amyloid pathology, is not completely understood. To better understand this question, we selected the rhesus monkey, which is phylogenetically and physiologically highly similar to the human, as a model to study. We quantified the levels of the two main Aβ isoforms (Aβ42 and Aβ40) in different sections of the brain (frontal cortex, temporal cortex, and hippocampus) and bodily fluids (CSF and plasma) of rhesus monkeys at different developmental phases (young, 5-9years of age; mature, 10-19years of age; and old, 21-24years of age). We found that the levels of neuronal and insoluble Aβ42 increased significantly in the brain with aging, suggesting that this specific isoform might be directly involved in aging and AD-like pathophysiology. There was no significant change in the Aβ40 level in the brain with aging. In addition, the Aβ42 level, but not the Aβ40 level, in both the CSF and plasma increased with aging. We also identified a positive correlation between Aβ42 in the CSF and plasma and Aβ42 in the brain. Taken collectively, our results indicate that there is an association between Aβ accumulation and age. These results support the increased incidence of AD with aging.

A comprehensive transcriptional map of primate brain development.

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny.

The intercalated nuclear complex of the primate amygdala

The organization of the inhibitory intercalated cell masses (IM) of the primate amygdala is largely unknown despite their key role in emotional processes. We studied the structural, topographic, neurochemical and intrinsic connectional features of IM neurons in the rhesus monkey brain. We found that the intercalated neurons are not confined to discrete cell clusters, but form a neuronal net that is interposed between the basal nuclei and extends to the dorsally located anterior, central, and medial nuclei of the amygdala. Unlike the IM in rodents, which are prominent in the anterior half of the amygdala, the primate inhibitory net stretched throughout the antero-posterior axis of the amygdala, and was most prominent in the central and posterior extent of the amygdala. There were two morphologic types of intercalated neurons: spiny and aspiny. Spiny neurons were the most abundant; their somata were small or medium size, round or elongated, and their dendritic trees were round or bipolar, depending on location. The aspiny neurons were on average slightly larger and had varicose dendrites with no spines. There were three non-overlapping neurochemical populations of IM neurons, in descending order of abundance: (1) Spiny neurons that were positive for the striatal associated dopamine- and cAMP-regulated phosphoprotein (DARPP-32+); (2) Aspiny neurons that expressed the calcium-binding protein calbindin (CB+); and (3) Aspiny neurons that expressed nitric oxide synthase (NOS+). The unique combinations of structural and neurochemical features of the three classes of IM neurons suggest different physiological properties and function. The three types of IM neurons were intermingled and likely interconnected in distinct ways, and were innervated by intrinsic neurons within the amygdala, or by external sources, in pathways that underlie fear conditioning and anxiety.

621. Widespread Gene Delivery to the Nonhuman Primate Brain for the Treatment of Huntington's Disease

Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG-trinucleotide repeat expansion in a coding exon of a single allele in the HTT locus. In HD, the resulting polyglutamine (polyQ) expansion confers a toxic gain-of-function to the mutant huntingtin protein (mHTT). Reduction of expression of mHTT using gene silencing by RNA interference (RNAi) may confer transformative disease modifying therapeutic approach for HD. Adeno associated vectors (AAV) provide an ideal delivery system for nucleic acid therapeutics and have the potential to allow for long lasting and continuous expression of these huntingtin lowering RNAi in the brain. Despite this promise, global delivery of AAV to the adult brain remains an elusive goal. Furthermore, the appropriate brain areas to target for achieving transformative therapeutic benefit in HD patients remain to be defined. Postmortem analyses of HD patient brains reveal extensive medium spiny neuronal loss in the striatum, in addition to loss of pyramidal neurons in the cerebral cortex and hippocampus. Recent studies in rodent models suggest that simultaneous targeting of striatum and cortex is more efficacious than targeting either individually. Thus, available evidence suggests that delivery of Htt-lowering therapeutics to both striatal and cortical regions may provide optimal therapeutic efficacy. The current study demonstrate for the first time the successful use of an AAV targeting strategy that leads to viral transduction in key brain areas considered to be important for HD pathology. The study compared the efficiency of transduction of AAV1 and AAV2 vectors in the rhesus monkey brain following intra-striatal injection. Both vectors encoded green fluorescent protein (GFP) under control of a hybrid CMV enhancer/chicken beta-actin promoter. One month following injection, brains were analyzed for distribution of GFP-positive cells. We found that the AAV1 vector provided extensive delivery to the majority of the primate striatum, and additionally transduced large numbers of cells within the cerebral cortex, thalamus, and hippocampus. In summary, the data suggest that intrastriatal delivery maybe sufficient for the delivery of nucleic acid-based therapeutics to multiple areas of the human brain relevant in HD.

Quantitative proteomics reveals the novel co-expression signatures in early brain development for prognosis of glioblastoma multiforme.

Although several researches have explored the similarity across development and tumorigenesis in cellular behavior and underlying molecular mechanisms, not many have investigated the developmental characteristics at proteomic level and further extended to cancer clinical outcome. In this study, we used iTRAQ to quantify the protein expression changes during macaque rhesus brain development from fetuses at gestation 70 days to after born 5 years. Then, we performed weighted gene co-expression network analysis (WGCNA) on protein expression data of brain development to identify co-expressed modules that highly expressed on distinct development stages, including early stage, middle stage and late stage. Moreover, we used the univariate cox regression model to evaluate the prognostic potentials of these genes in two independent glioblastoma multiforme (GBM) datasets. The results showed that the modules highly expressed on early stage contained more reproducible prognostic genes, including ILF2, CCT7, CCT4, RPL10A, MSN, PRPS1, TFRC and APEX1. These genes were not only associated with clinical outcome, but also tended to influence chemoresponse. These signatures identified from embryonic brain development might contribute to precise prediction of GBM prognosis and identification of novel drug targets in GBM therapies. Thus, the development could become a viable reference model for researching cancers, including identifying novel prognostic markers and promoting new therapies.

Severe dopaminergic neuron loss in rhesus monkey brain impairs morphine-induced conditioned place preference.

It is well known that dopamine (DA) is critical for reward, but the precise role of DA in reward remains uncertain. The aim of this study was to determine what percentage of dopaminergic neurons in the primate brain is required for the expression of conditioned reward by measuring the performance of DA-deficient rhesus monkeys in a morphine-induced conditioned place preference (CPP) paradigm. Animals with mild Parkinsonian symptoms successfully developed and retained a morphine preference that was equivalent to control monkeys. However, these monkeys could not maintain the preference as well as controls when they retained severe Parkinsonian symptoms. On the other hand, monkeys initially in a severe Parkinsonian state developed a preference for morphine, but this preference was weaker than that of the controls. Histological results showed that the loss of dopaminergic neurons in monkeys that had severe Parkinsonian symptoms was about 80% in comparison to the control monkeys. All these data suggest that a severely impaired DA system alters rewarding-seeking behavior in non-human primates.

Longitudinal analysis of the developing rhesus monkey brain using magnetic resonance imaging: birth to adulthood.

We have longitudinally assessed normative brain growth patterns in naturalistically reared Macaca mulatta monkeys. Postnatal to early adulthood brain development in two cohorts of rhesus monkeys was analyzed using magnetic resonance imaging. Cohort A consisted of 24 rhesus monkeys (12 male, 12 female) and cohort B of 21 monkeys (11 male, 10 female). All subjects were scanned at 1, 4, 8, 13, 26, 39, and 52 weeks; cohort A had additional scans at 156 weeks (3 years) and 260 weeks (5 years). Age-specific segmentation templates were developed for automated volumetric analyses of the T1-weighted magnetic resonance imaging scans. Trajectories of total brain size as well as cerebral and subcortical subdivisions were evaluated over this period. Total brain volume was about 64 % of adult estimates in the 1-week-old monkey. Brain volume of the male subjects was always, on average, larger than the female subjects. While brain volume generally increased between any two imaging time points, there was a transient plateau of brain growth between 26 and 39 weeks in both cohorts of monkeys. The trajectory of enlargement differed across cortical regions with the occipital cortex demonstrating the most idiosyncratic pattern of maturation and the frontal and temporal lobes showing the greatest and most protracted growth. A variety of allometric measurements were also acquired and body weight gain was most closely associated with the rate of brain growth. These findings provide a valuable baseline for the effects of fetal and early postnatal manipulations on the pattern of abnormal brain growth related to neurodevelopmental disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-015-1076-x) contains supplementary material, which is available to authorized users.

A diffusion tensor MRI atlas of the postmortem rhesus macaque brain

The rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate for modeling the structure and function of the brain. Brain atlases, and particularly those based on magnetic resonance imaging (MRI), have become important tools for understanding normal brain structure, and for identifying structural abnormalities resulting from disease states, exposures, and/or aging. Diffusion tensor imaging (DTI)-based MRI brain atlases are widely used in both human and macaque brain imaging studies because of the unique contrasts, quantitative diffusion metrics, and diffusion tractography that they can provide. Previous MRI and DTI atlases of the rhesus brain have been limited by low contrast and/or low spatial resolution imaging. Here we present a microscopic resolution MRI/DTI atlas of the rhesus brain based on 10 postmortem brain specimens. The atlas includes both structural MRI and DTI image data, a detailed three-dimensional segmentation of 241 anatomic structures, diffusion tractography, cortical thickness estimates, and maps of anatomic variability among atlas specimens. This atlas incorporates many useful features from previous work, including anatomic label nomenclature and ontology, data orientation, and stereotaxic reference frame, and further extends prior analyses with the inclusion of high-resolution multi-contrast image data.

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome

Developmental changes in the temporal and spatial regulation of gene expression drive the emergence of normal mature brain function, while disruptions in these processes underlie many neurodevelopmental abnormalities. To solidify our foundational knowledge of such changes in a primate brain with an extended period of postnatal maturation like in human, we investigated the whole-genome transcriptional profiles of rhesus monkey brains from birth to adulthood. We found that gene expression dynamics are largest from birth through infancy, after which gene expression profiles transition to a relatively stable state by young adulthood. Biological pathway enrichment analysis revealed that genes more highly expressed at birth are associated with cell adhesion and neuron differentiation, while genes more highly expressed in juveniles and adults are associated with cell death. Neocortex showed significantly greater differential expression over time than subcortical structures, and this trend likely reflects the protracted postnatal development of the cortex. Using network analysis, we identified 27 co-expression modules containing genes with highly correlated expression patterns that are associated with specific brain regions, ages or both. In particular, one module with high expression in neonatal cortex and striatum that decreases during infancy and juvenile development was significantly enriched for autism spectrum disorder (ASD)-related genes. This network was enriched for genes associated with axon guidance and interneuron differentiation, consistent with a disruption in the formation of functional cortical circuitry in ASD.

477. Three-Dimensional Imaging of Multiple AAV Serotype/Mutant Vector Transductions in the Non-Human Primate Brain By Massively Parallel Sequencing

Global therapeutic gene delivery to the central nervous system (CNS) offers a promising approach to treat CNS diseases and preclinical studies using rodents have shown AAV9 as a potential candidate to achieve this goal. However, recent work has highlighted the existence of nonhuman primate (NHP)-rodent differences in AAV vector biology and transduction profiles in the CNS after gene delivery, making imperative a more rigorous evaluation of various AAV serotype and capsid mutant vectors in NHPs. It is of particular importance to understand how each AAV strain (serotype or mutant) is distributed and transduces cells in the brain of a primate species closely related to humans when injected into the bloodstream or cerebrospinal fluids (CSF). Here we report a novel approach to generate three-dimensional (3D) vector transduction heat maps of more than one hundred of AAV strains in the rhesus monkey brain when vectors are delivered via the cisterna magna. In this approach, we integrate the vector transduction data obtained by AAV Barcode-Seq (an Illumina sequencing-based high-throughput vector transduction analysis) into an MRI image. To show proof-of-principle of the method, a barcoded-AAV library containing 145 different AAV strains was directly injected into CSF via the cisterna magna of three rhesus macaques (4×1012 vg/kg) and their brains were subjected to MRI analysis before collection of the organ 6 weeks post-injection. Six mm-thick coronal sections of the brain were made and photographed, and the right half of each section slice was diced into 6 × 7 × 7 mm3 cubes using a matrix, generating more than 100 cubes from a cerebral hemisphere. Total DNA was then extracted from each cube using an automated magnetic particle processor and subjected to AAV Barcode-Seq analysis to determine transduction efficiency of each AAV strain in each cube by multiplexed Illumina sequencing. The coordinates of each cube were determined by aligning the photo images of each coronal section to the corresponding MRI images using an image alignment algorithm. This strategy allowed us to create 3D heat maps showing distribution and transduction of each AAV strain in the entire NHP brain. A preliminary analysis using one of the three monkeys revealed that AAV1 vector spreads globally and transduces all brain regions including the cerebral cortex while the distribution of AAV2 was limited locally. Unexpectedly, we found that many other serotypes and mutants transduced the NHP brain better than AAV9 when delivered into CSF. Thus, imaging of AAV vector distribution and transduction throughout the NHP brain by AAV Barcode-Seq combined with MRI provides a powerful approach to comprehensively study AAV vector-mediated CNS gene delivery in clinically relevant animal models. Our results emphasize the large difference in AAV distribution and transduction efficiency that exists in the brain of higher primates compared to rodent models.

Model for Aging and Cognitive Decline

A population of neurons in the cerebral cortex of humans and other mammals organize themselves into vertical microcolumns perpendicular to the pial surface. Anatomical changes to these microcolumns have been correlated with neurological diseases and normal aging, and in particular in area 46 of the rhesus monkey brain the strength of microcolumns was shown to decrease with age. We have previously developed a model to simulate aging brains by constructing a microcolumnar network of neurons and allowing the neurons to undergo Brownian motion while being constrained by a harmonic force that weakens as a function of age. Now, we expand on this model by constructing and simulating the generated neural networks. By generating a young neural network from strong restorative forces, one can create an initial distant dependent connectivity. Then, we age these networks and presume that connectivity between neurons either weakens or severs as a function of neural displacement from initial neuronal positions. We aim to show that older networks are unable to efficiently shift between different firing regimes, providing a potential mechanism for loss of information processing in relation to microcolumnar structure.

Improved Automated Radiosynthesis of [(11)C]PBR28.

Microglial activation is commonly identified by elevated levels of the 18 kDa translocator protein (TSPO) in response to several inflammatory processes. [11C]PBR28 is one of the most promising PET tracers to image TSPO in both human and non-human primates. In this study, we optimized the radiolabeling procedure of [11C]PBR28 for higher radiochemical yield, radiochemical purity, and specific activity, which can be easily translated to any automated module for clinical trials. Time-activity curves (TACs) derived from the dynamic PET imaging of male rhesus monkey brains demonstrated that [11C]PBR28 had suitable kinetics with radiotracer accumulation observed in the caudate, putamen, cerebellum, and frontal cortex region.

Transcallosal connectivity changes from infancy to late adulthood: an ex vivo diffusion spectrum imaging study of macaque brains.

Interhemispheric communication plays a critical role to ensure normal brain functions in cognition and behavior. Since non-human primate (NHP) brains resemble most aspects of the human brain, a thorough knowledge of interhemispheric cortical connectivity changes in NHP brains throughout the developmental and aging periods may provide valuable insights for translational and clinical research. In this study, formalin-fixed rhesus monkey brains aged from 1 to 24 years were utilized to examine transcallosal connectivity changes using diffusion spectrum imaging (DSI). It was found that the transcallosal connectivity for most frontal cortical areas, including dorso- and ventro-lateral prefrontal, premotor, and motor cortices, demonstrated pronounced age-related alterations. However, such a pattern was less obvious in temporal, posterior parietal, and visual cortices. The DSI results reveal the age-related evolution pattern of transcallosal connectivity in various cortical areas of macaque brains from infancy to late adulthood, and may have implications for assessing the functional defects or alterations in the associated cortical areas during brain development and aging in humans.

Rhesus monkey brain development during late infancy and the effect of phencyclidine: A longitudinal MRI and DTI study

Early brain development is a complex and rapid process, the disturbance of which may cause the onset of brain disorders. Based on longitudinal imaging data acquired from 6 to 16months postnatal, we describe a systematic trajectory of monkey brain development during late infancy, and demonstrate the influence of phencyclidine (PCP) on this trajectory. Although the general developmental trajectory of the monkey brain was close to that of the human brain, the development in monkeys was faster and regionally specific. Gray matter volume began to decrease during late infancy in monkeys, much earlier than in humans in whom it occurs in adolescence. Additionally, the decrease of gray matter volume in higher-order association regions (the frontal, parietal and temporal lobes) occurred later than in regions for primary functions (the occipital lobe and cerebellum). White matter volume displayed an increasing trend in most brain regions, but not in the occipital lobe, which had a stable volume. In addition, based on diffusion tensor imaging, we found an increase in fractional anisotropy and a decrease in diffusivity, which may be associated with myelination and axonal changes in white matter tracts. Meanwhile, we tested the influence of 14-day PCP treatment on the developmental trajectories. Such treatment tended to accelerated brain maturation during late infancy, although not statistically significant. These findings provide comparative information for the understanding of primate brain maturation and neurodevelopmental disorders.

A thin film polyimide mesh microelectrode for chronic epidural electrocorticography recording with enhanced contactability

Objective. Epidural electrocorticography (ECoG) activity may be more reliable and stable than single-unit-activity or local field potential. Invasive brain computer interface (BCI) devices are limited by mechanical mismatching and cellular reactive responses due to differences in the elastic modulus and the motion of stiff electrodes. We propose a mesh-shaped electrode to enhance the contactability between surface of dura and electrode. Approach. We designed a polyimide (PI) electrode with a mesh pattern for more conformal contact with a curved surface. We compared the contact capability of mesh PI electrodes with conventionally used sheet PI electrode. The electrical properties of the mesh PI electrode were evaluated for four weeks. We recorded the epidural ECoG (eECoG) activity on the surface of rhesus monkey brains while they performed a saccadic task for four months. Main results. The mesh PI electrode showed good contact with the agarose brain surface, as evaluated by visual inspection and signal measurement. It was about 87% accurate in predicting the direction of saccade eye movement. Significance. Our results indicate that the mesh PI electrode was flexible and good contact on the curved surface and can record eECoG activity maintaining close contact to dura, which was proved by in vivo and in vitro test.

A thermostable bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates.

A long-acting, thermostable bacterial cocaine esterase (CocE) has been identified that rapidly degrades cocaine with a KM of 1.33+0.085 μM. In vivo evaluation of CocE has shown protection against convulsant and lethal effects of cocaine in rodents, confirming the therapeutic potential of CocE against cocaine overdose. However, the current study is the first to evaluate the effects of CocE on cocaine brain levels. Positron emission tomogrpahy neuroimaging of [11C]cocaine was used to evaluate the time course of cocaine elimination from brain in the presence and absence of CocE in nonhuman primates. Systemic administration of CocE eliminated cocaine from the rhesus-monkey brain approximately three times faster than control conditions via peripheral actions through attenuating the input function from blood plasma. The efficiency of this process is sufficient to alleviate or prevent adverse central nervous system effects induced by cocaine. Although the present study used tracer doses of cocaine to access brain clearance, these findings further support the development of CocE for the treatment of acute cocaine toxicity.

A Computational Model for the Loss of Neuronal Organization in Microcolumns

A population of neurons in the cerebral cortex of humans and other mammals organize themselves into vertical microcolumns perpendicular to the pial surface. Anatomical changes to these microcolumns have been correlated with neurological diseases and normal aging; in particular, in area 46 of the rhesus monkey brain, the strength of microcolumns was shown to decrease with age. These changes can be caused by alterations in the spatial distribution of the neurons in microcolumns and/or neuronal loss. Using a three-dimensional computational model of neuronal arrangements derived from thin tissue sections and validated in brain tissue from rhesus monkeys, we show that neuronal loss is inconsistent with the findings in aged individuals. In contrast, a model of simple random neuronal displacements, constrained in magnitude by restorative harmonic forces, is consistent with observed changes and provides mechanistic insights into the age-induced loss of microcolumnar structure. Connection of the model to normal aging and disease are discussed.

Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Sites in Rhesus Brain

The development of a PET radioligand selective for I2-imidazoline binding sites (I2BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiology. BU99008 was identified as the most promising I2BS radioligand candidate and radiolabeled with (11)C via methylation. The in vivo binding properties of (11)C-BU99008 were assessed in rhesus monkeys to determine brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic model for analyzing data generated with this PET radioligand. (11)C-BU99008 was demonstrated to readily enter the brain, resulting in a heterogeneous distribution (globus pallidus > cortical regions > cerebellum) consistent with the reported regional I2BS densities as determined by human tissue section autoradiography and preclinical in vivo PET studies in the pig. In vivo competition studies revealed that (11)C-BU99008 displayed reversible kinetics specific for the I2BS. The multilinear analysis (MA1) model was the most appropriate analysis method for this PET radioligand in this species. The selective I2BS blocker BU224 was shown to cause a saturable, dose-dependent decrease in (11)C-BU99008 binding in all regions of the brain assessed, further demonstrating the heterogeneous distribution of I2BS protein in the rhesus brain and binding specificity for this radioligand. These data demonstrate that (11)C-BU99008 represents a specific and selective PET radioligand for imaging and quantifying the I2BS, in vivo, in the rhesus monkey. Further work is under way to translate the use of (11)C-BU99008 to the clinic.

Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors.

A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [(125)I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [(3)H]BMS-728300. The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [(3)H]BMS-728300 and the two (18)F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [(18)F]BMS-721313, [(18)F]BMS-732098 and [(11)C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.

Low‐ and high‐frequency transcutaneous electrical acupoint stimulation induces different effects on cerebral μ‐opioid receptor availability in rhesus monkeys

Although systematic studies have demonstrated that acupuncture or electroacupuncture (EA) analgesia is based on their accelerating endogenous opioid release to activate opioid receptors and that EA of different frequencies is mediated by different opioid receptors in specific areas of the central nervous system, there is little direct, real-time evidence to confirm this in vivo. The present study was designed to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS), an analogue of EA, at low and high frequencies on μ-opioid receptor (MOR) availability in the brain of rhesus monkeys. Monkeys underwent 95-min positron emission tomography (PET) with (11) C-carfentanil three times randomly while receiving 0, 2, or 100 Hz TEAS, respectively. Each TEAS was administered in the middle 30 min during the 95-min PET scan, and each session of PET and TEAS was separated by at least 2 weeks. The results revealed that 2 Hz but not 100 Hz TEAS evoked a significant increase in MOR binding potential in the anterior cingulate cortex, the caudate nucleus, the putamen, the temporal lobe, the somatosensory cortex, and the amygdala compared with 0 Hz TEAS. The effect remained after the end of TEAS in the anterior cingulate cortex and the temporal lobe. The selective increase in MOR availability in multiple brain regions related to pain and sensory processes may play a role in mediating low-frequency TEAS efficacy.