Region Of Monkey Research Articles

Effective nose-to-brain drug delivery using a combination system targeting the olfactory region in monkeys

The nose-to-brain (N2B) pathway has garnered attention because it transports drugs directly into the brain. Although recent studies have suggested the necessity of selective drug administration to the olfactory region for effective N2B drug delivery, the importance of delivering the formulation to the olfactory region and the detailed pathway involved in drug uptake in primates brain remain unclear. Here, we developed a combination system for N2B drug delivery comprising a proprietary mucoadhesive powder formulation and a dedicated nasal device (N2B-system) and evaluated it for nasal drug delivery to the brain in cynomolgus monkeys. This N2B-system demonstrated a much greater formulation distribution ratio in the olfactory region in an in vitro experiment using a 3D-printed nasal cast and in vivo experiment using cynomolgus monkeys, as compared to that in other nasal drug delivery systems that comprise of a proprietary nasal powder device developed for nasal absorption and vaccination and a commercially available liquid spray. Additionally, Texas Red-labeled dextran (TR-DEX, 3 kDa) was administered using the N2B-system to estimate the drug transition pathway from the nasal cavity to the brain. TR-DEX preferentially localized to the olfactory epithelium and reached the olfactory bulb through the cribriform foramina. Moreover, domperidone, a model drug with poor blood-brain barrier permeability, was administered to assess the brain uptake of medicine after olfactory region-selective administration by using the N2B-system. Domperidone accumulation in the brain was evaluated using positron emission tomography with intravenously administered [18F]fallypride based on competitive inhibition of the dopamine D2 receptor (D2R). Compared to other systems, the N2B-system significantly increased D2R occupancy and domperidone uptake in the D2R-expressing brain regions. The current study reveals that the olfactory region of the nasal cavity is a suitable target for efficient nasal drug delivery to the brain in cynomolgus monkeys. Thus, the N2B-system, which targets the olfactory region, provides an efficient approach for developing effective technology for nasal drug delivery to the brain in humans.

Individual Neurons in the Cingulate Cortex Encode Action Monitoring, Not Selection, during Adaptive Decision-Making.

The cingulate cortex contributes to complex, adaptive behaviors, but the exact nature of its contributions remains unresolved. Proposals from previous studies, including evaluating past actions or selecting future ones, have been difficult to distinguish in part because of an incomplete understanding of the task-relevant variables that are encoded by individual cingulate neurons. In this study, we recorded from individual neurons in parts of both the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) in 2 male rhesus monkeys performing a saccadic reward task. The task required them to use adaptive, feedback-driven strategies to infer the spatial location of a rewarded saccade target in the presence of different forms of uncertainty. We found that task-relevant, spatially selective feedback signals were encoded by the activity of individual neurons in both brain regions, with stronger selectivity for spatial choice and reward-target signals in PCC and stronger selectivity for feedback in ACC. Moreover, neurons in both regions were sensitive to sequential effects of feedback that partly reflected sequential behavioral patterns. However, neither brain region exhibited systematic modulations by the blockwise conditions that governed the reliability of the trial-by-trial feedback and drove adaptive behavioral patterns. There was also little evidence that single-neuron responses in either brain region directly predicted the extent to which feedback and contextual information were used to inform choices on the subsequent trial. Thus, certain cingulate neurons encode diverse, evaluative signals needed for adaptive, feedback-driven decision-making, but those signals may be integrated elsewhere in the brain to guide actions.SIGNIFICANCE STATEMENT Effective decision-making in dynamic environments requires adapting to changes in feedback and context. The anterior and posterior cingulate cortex have been implicated in adaptive decision-making, but the exact nature of their respective roles remains unresolved. Here we compare patterns of task-driven activity of subsets of individual neurons from parts of the two brain regions in monkeys performing a saccadic task with dynamically changing reward locations. We find evidence for regional specializations in neural representations of choice and feedback, including task-relevant modulations of activity that could be used for performance monitoring. However, we find little evidence that these neural representations are used directly to adjust choice behavior, which thus likely requires integration of these signals elsewhere in the brain.

Functional Similarity of Medial Superior Parietal Areas for Shift-Selective Attention Signals in Humans and Monkeys.

We continually shift our attention between items in the visual environment. These attention shifts are usually based on task relevance (top-down) or the saliency of a sudden, unexpected stimulus (bottom-up), and are typically followed by goal-directed actions. It could be argued that any species that can covertly shift its focus of attention will rely on similar, evolutionarily conserved neural substrates for processing such shift-signals. To address this possibility, we performed comparative fMRI experiments in humans and monkeys, combining traditional, and novel, data-driven analytical approaches. Specifically, we examined correspondences between monkey and human brain areas activated during covert attention shifts. When "shift" events were compared with "stay" events, the medial (superior) parietal lobe (mSPL) and inferior parietal lobes showed similar shift sensitivities across species, whereas frontal activations were stronger in monkeys. To identify, in a data-driven manner, monkey regions that corresponded with human shift-selective SPL, we used a novel interspecies beta-correlation strategy whereby task-related beta-values were correlated across voxels or regions-of-interest in the 2 species. Monkey medial parietal areas V6/V6A most consistently correlated with shift-selective human mSPL. Our results indicate that both species recruit corresponding, evolutionarily conserved regions within the medial superior parietal lobe for shifting spatial attention.

Neurophysiological Organization of the Middle Face Patch in Macaque Inferior Temporal Cortex.

The underlying organization of neurons that give rise to the large spatial regions of activity observed with fMRI is not well understood. Neurophysiological studies that have targeted the fMRI identified face patches in monkeys have provided evidence for both large-scale clustering and a heterogeneous spatial organization. Here we used a novel x-ray imaging system to spatially map the responses of hundreds of sites in and around the middle face patch. We observed that face-selective signal localized to the middle face patch was characterized by a gradual spatial enrichment. Furthermore, strongly face-selective sites were ∼40 times more likely to be found inside the patch than outside of the patch.

How monkeys see in 3D

Visual Neuroscience The primate brain uses two major visual systems to represent the three-dimensional (3D) shape of objects. A number of heavily interacting cortical areas make up these two systems. To better understand how these systems interact, Van Dromme et al. used a drug to reversibly silence one of these regions in monkeys. In psychophysical tests and functional MRI investigations, this caused not only deficits in the system to which this region belonged but also in the second major system. Using microelectrodes to selectively stimulate the same region indicated complex indirect effects that used a number of interconnected circuits. These data help reveal how several regions in the primate visual system required for 3D object vision functionally interact. PLOS Biol. 10.1371/journal. pbio.1002445 (2016).

The pattern of c-Fos expression and its refractory period in the brain of rats and monkeys.

Intense activation of neurons triggers the appearance of immediate expression genes, including c-Fos. This gene is related to various signal cascades involved in biochemical processes such as neuronal plasticity, cell growth and mitosis. Here we investigate the expression pattern and the refractory period of c-Fos in rats and monkey’s brains after stimulation with pentylenetetrazol. Rats and monkeys were sacrificed at various times after PTZ-induced seizure. Here we show that rats and monkeys already showed c-Fos expression at 0.5 h after seizure. Yet, the pattern of protein expression was longer in monkeys than rats, and also was not uniform (relative intensity) across different brain regions in monkeys as opposed to rats. In addition monkeys had a regional brain variation with regard to the temporal profile of c-Fos expression, which was not seen in rats. The refractory period after a second PTZ stimulation was also markedly different between rats and monkeys with the latter even showing a summatory effect on c-Fos expression after a second stimulation. However, assessment of c-Fos mRNA in rats indicated a post-transcriptional control mechanism underlying the duration of the refractory period. The difference in the protein expression pattern in rodents and primates characterizes a functional aspect of brain biochemistry that differs between these mammalian orders and may contribute for the more developed primate cognitive complexity as compared to rodents given c-Fos involvement in cognitive and learning tasks.

Comparison of Human Ventral Frontal Cortex Areas for Cognitive Control and Language with Areas in Monkey Frontal Cortex

Human ventrolateral frontal cortex (vlFC) is identified with cognitive processes such as language and cognitive flexibility. The relationship between it and the vlFC of other primates has therefore been the subject of particular speculation. We used a combination of structural and functional neuroimaging methods toidentify key components of human vlFC. We compared how vlFC areas interacted with other brain areas in 25 humans and 25 macaques using the same methods. We identified a core set of 11 vlFC components that interacted in similar ways with similar distributed circuits in both species and, in addition, one distinctively human component in ventrolateral frontal pole. Fundamental differences in interactions with posterior auditory association areas in the two species were also present-these were ubiquitous throughout posterior human vlFC but channeled todifferent frontal regions in monkeys. Finally, there were some differences in interregional interactions within vlFC in the two species.

Neural correlates of auditory recognition memory in primate lateral prefrontal cortex

The neural underpinnings of working and recognition memory have traditionally been studied in the visual domain and these studies pinpoint the lateral prefrontal cortex (lPFC) as a primary region for visual memory processing (Miller et al., 1996; Ranganath et al., 2004; Kennerley and Wallis, 2009). Herein, we utilize single-unit recordings for the same region in monkeys (Macaca mulatta) but investigate a second modality examining auditory working and recognition memory during delayed matching-to-sample (DMS) performance. A large portion of neurons in the dorsal and ventral banks of the principal sulcus (area 46, 46/9) show DMS event-related activity to one or more of the following task events: auditory cues, memory delay, decision wait time, response, and/or reward portions. Approximately 50% of the neurons show evidence of auditory-evoked activity during the task and population activity demonstrated encoding of recognition memory in the form of match enhancement. However, neither robust nor sustained delay activity was observed. The neuronal responses during the auditory DMS task are similar in many respects to those found within the visual working memory domain, which supports the hypothesis that the lPFC, particularly area 46, functionally represents key pieces of information for recognition memory inclusive of decision-making, but regardless of modality.

Ventromedial and Orbital Prefrontal Neurons Differentially Encode Internally and Externally Driven Motivational Values in Monkeys

The value of events that predict future rewards, thereby driving behavior, is sensitive to information arising from external (environmental) and internal factors. The ventral prefrontal cortex, an anatomically heterogeneous area, has information related to this value. We designed experiments to compare the contribution of two distinct subregions, orbital and ventromedial, of the ventral prefrontal cortex to the encoding of internal and external factors controlling the perceived motivational value. We recorded the activity of single neurons in both regions in monkeys while manipulating internal and external factors that should affect the perceived value of task events. Neurons in both regions encoded the value of task events, with orbitofrontal neurons being more sensitive to external factors such as visual cues and ventromedial neurons being more sensitive to internal factors such as satiety. Thus, the orbitofrontal cortex emphasizes signals for evaluating environment-centered, externally driven motivational processes, whereas ventromedial prefrontal cortex emphasizes signals more suited for subject-centered, internally driven motivational processes.

Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety

The ventral hippocampus, unlike its dorsal counterpart, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta-frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.

Monkey brain activity modulated by reward preferences: A positron emission tomography study

Motivation, depending on the relative preference and magnitudes of rewards, can influence our goal-directed action. Reward preferences can modulate neurons in the striatum (ventral and dorsal portions), lateral prefrontal and orbitofrontal cortex, but it remains unclear where in the brain and how any motivational change affects subsequent rewarding action. The present study sought to test whether the lateral prefrontal and other regions in monkeys during a visuo-motor task may change the activities in response to the reward preferences. After defining the rating of reward preference in a choice test, we measured regional cerebral blood flow of two Japanese monkeys during the task where the cognitive requirement was always the same, but the motivational significance varied by different rewards (raisin, banana flavored pellet, plain pellet, and banana), using positron emission tomography with H 2 15O. We showed that lateral prefrontal, orbitofrontal, parietal, striatal (ventral and dorsal), and cerebellar activities may be modulated depending on the reward preferences. The present results may include the brain regions subserving motivational changes by subjective reward significances.

Object Representations in the Temporal Cortex of Monkeys and Humans as Revealed by Functional Magnetic Resonance Imaging

Increasing evidence suggests that the neural processes associated with identifying everyday stimuli include the classification of those stimuli into a limited number of semantic categories. How the neural representations of these stimuli are organized in the temporal lobe remains under debate. Here we used functional magnetic resonance imaging (fMRI) to identify correlates for three current hypotheses concerning object representations in the inferior temporal (IT) cortex of monkeys and humans: representations based on animacy, semantic categories, or visual features. Subjects were presented with blocked images of faces, body parts (animate stimuli), objects, and places (inanimate stimuli), and multiple overlapping contrasts were used to identify the voxels most selective for each category. Stimulus representations appeared to segregate according to semantic relationships. Discrete regions selective for animate and inanimate stimuli were found in both species. These regions could be further subdivided into regions selective for individual categories. Notably, face-selective regions were contiguous with body-part-selective regions, and object-selective regions were contiguous with place-selective regions. When category-selective regions in monkeys were tested with blocks of single exemplars, individual voxels showed preferences for visually dissimilar exemplars from the same category and voxels with similar preferences tended to cluster together. Our results provide some novel observations with respect to how stimulus representations are organized in IT cortex. In addition, they further support the idea that representations of complex stimuli in IT cortex are organized into multiple hierarchical tiers, encompassing both semantic and physical properties.

Effect of ovarian hormones on survival genes in laser captured serotonin neurons from macaques

We sought the effect of estradiol (E) and progesterone (P) on survival gene expression in laser captured serotonin neurons and in the dorsal raphe region of monkeys with cDNA array analysis. Spayed rhesus macaques were treated with either placebo, E or E + P via Silastic implant for 1 month prior to killing. First, RNA from a small block of midbrain containing the dorsal raphe was hybridized to Rhesus Gene Chips (n = 3/treatment). There was a significant change in 854 probe sets with E +/- P treatment (anova, p < 0.05); however, only 151 probes sets exhibited a twofold or greater change. Twenty-five genes related to cell survival changed significantly. The expression of vascular endothelial growth factor, superoxide dismutase (SOD1), and the caspase inhibitor, BIRC4, was confirmed with quantitative RT-PCR. Then, RNA from laser captured serotonin neurons (n = 2/treatment) was hybridized to Rhesus Gene Chips. There was a significant change in 744 probe sets, but 10 493 probe sets exhibited a twofold or greater change. Pivotal changes in apoptosis and cell cycle pathways included twofold or greater increases in SOD1, IkappaBalpha, Fas apoptotic inhibitory molecule, fibroblast growth factor-receptor 2 (FGFR2), neurotrophic tyrosine kinase receptor 2 (NTRK2), phosphoinositide-3-kinase (p85 subunit), cyclic AMP dependent protein kinase (PKA) (catalytic subunit), calpain 2, and ataxia telangectasia mutated (ATM). Twofold or greater decreases occurred in TNF receptor interacting serine-threonine kinase 1 (RIP1), BH3 interacting domain death agonist (BID), apoptotic peptidase activating factor 1 (Apaf1), caspase recruitment domain 8 (CARD8), apoptosis inducing factor (AIF), Diablo and Cyclins A, B, D, and E. The regulation of SOD1, calpain 2, Diablo, and Cyclin D was confirmed with quantitative RT-PCR (n = 3/treatment). The data indicate that ovarian steroids target the cytokine-signaling pathway, caspase-dependent and -independent pathways and cell cycle proteins to promote serotonin neuron survival.

Functional dissociation of saccade and hand reaching control with bilateral lesions of the medial wall of the intraparietal sulcus: Implications for optic ataxia

The posterior parietal cortex (PPC) is essential for the integration of visuomotor information during visually guided reaching. Studies in macaque monkeys have demonstrated a functional specialisation around the intraparietal sulcus (IPS) with a more medial representation of hand movements (“parietal reach region”) and a more lateral representation of saccadic eye movements (lateral intraparietal area, LIP). Here we present evidence for the validity of this concept with respect to the human parietal cortex. We recorded isolated and combined goal-directed eye–hand movements in normal control subjects and in a patient with bilateral parieto-occipital lesions and incomplete Balint's syndrome including severe optic ataxia (misreaching to visual targets). Brain lesions in the patient were caused by acute posterior leucoencephalopathy in association with aortic surgery because of Takayasu's arteritis. MRI scans showed bilateral line-shaped hemorrhagic lesions, restricted to the cortex at the medial banks of the intraparietal sulcus, but leaving its lateral banks largely intact. In the patient visually guided reaching was significantly dysmetric, whereas the metrics of visually guided saccades were within normal limits. Dysmetria was more pronounced for the right visual field, with a gross hypermetria. Variability of the movement improved when a delay of 5 or 10 s was introduced between target presentation and movement execution. Lesion data support the concept of a functional specialisation around the human IPS: The cortex medial to the IPS predominantly controls rapid goal-directed reaching movements, comparable to the parietal reach region in monkeys, whereas saccadic eye movements appear to be controlled rather by the cortex lateral to the IPS.

Different degrees of right-to-left shunting predict migraine and stroke: Data from 420 patients

The authors analyzed the extent of right-to-left shunting in patients with migraine, patients with cryptogenic stroke, and controls. Patients with both migraine and stroke had larger shunts than did patients with migraine without stroke (p = 0.038), patients with no migraine with stroke (p = 0.007), and control patients (p < 0.0001). Patients with migraine have overall larger shunts than nonmigraineurs, particularly if they have had a stroke. Right-to-left shunting may be causally related to migraine and to the increased stroke risk of migraine.

Effects of Chymase on the Macular Region in Monkeys and Porcine Müller Cells: Probable Involvement of Chymase in the Onset of Idiopathic Macular Holes

Objectives: To investigate chymase involvement in idiopathic macular hole onset, the effects of chymase on monkey eyes and cultured Müller cells were investigated. Methods: Immunohistochemistry using antinestin and antiglial fibrillary acidic protein antibodies was performed in a normal monkey eye. After chymase was injected into the monkey vitreous, histological changes in the retina were evaluated using the TdT-mediated dUTP nick-end labeling (TUNEL) assay. Expression of c-kit, a stem cell factor receptor, and nestin was examined in porcine Müller cells cultured with basic fibroblast growth factor. The effects of chymase on proliferation and TUNEL staining in Müller cells were also examined. Results: The number of nestin and glial fibrillary acidic protein-positive cells was higher in the macula than in other regions. Thickening of the posterior hyaloid membrane and some apoptotic cells were found in the macula of chymase-treated eyes. The expression of c-kit and nestin in Müller cells was shown and enhanced when cultured with basic fibroblast growth factor. Exposure to chymase inhibited Müller cell proliferation and produced TUNEL-positive cells. Conclusions: There might be Müller cells possessing atypical properties near the macular region and chymase might cause fibrosis and apoptosis through these cells. These findings suggest that increased chymase activity may result in idiopathic macular hole onset.

Sequence and genetic arrangement of the U(S) region of the monkey B virus (cercopithecine herpesvirus 1) genome and comparison with the U(S) regions of other primate herpesviruses.

The sequence of the unique short (U(S)) region of monkey B virus (BV) was determined. The 13 genes identified are arranged in the same order and orientation as in herpes simplex virus (HSV). These results demonstrate that the BV U(S) region is entirely colinear with that of HSV type 1 (HSV-1), HSV-2, and simian agent 8 virus.

Examination of a CYP2E1 Repeat Polymorphism in a Monkey Model of Alcohol Abuse

Background: Cytochrome P-450 2E1 (CYP2E1) is involved in alcohol metabolism, and the expression of this enzyme displays wide phenotypic variability in humans. It has been proposed that some of this variability in expression may be a consequence of the size of a repeat polymorphism in the 5″ regulatory region of the gene and that the polymorphism may segregate with alcoholism. This study examined whether the repeat polymorphism exists in macaque monkeys and whether it associates with excessive alcohol consumption in this animal model. Methods: Ten outbred cynomolgus monkeys (Macaca fascicularis) that displayed a voluntary alcohol consumption ranging from 1.0 to 3.6 g/kg/day were genotyped for a CYP2E1 repeat polymorphism. This polymorphism has been documented in the region from −2519 base pair (bp) to −1953 bp of the human CYP2E1 gene 5″ distal promoter. Results: Individual polymerase chain reaction amplification of genomic DNA from each of the 10 monkey samples revealed a single band of approximately 400 bp in the region corresponding to the human CYP2E1 polymorphism. Polymerase chain reaction amplicons from the 10 individuals were sequenced, and each one generated a 370 bp sequence that is 90% identical to the human gene sequence. However, unlike human alleles that contain five to eight repeats, the cynomolgus monkey is homozygous for a single copy of the repeat most closely resembling repeat 8 (88% identical) in the human gene. Conclusions: These data demonstrate that the CYP2E1 distal promoter region in monkeys is very similar to the human sequence yet lacks the extensive repeated DNA found in humans. This includes the rare repeats 3 and 4, which have been postulated to play a role in transcription regulation and to associate with alcohol abuse liability in humans. These data suggest that the CYP2E1 polymorphism arose late in evolution and that the regulation of the gene by this genetic region is not associated with a heavy alcohol drinking phenotype in the cynomolgus monkey.

Examination of a CYP2E1 Repeat Polymorphism in a Monkey Model of Alcohol Abuse

Cytochrome P-450 2E1 (CYP2E1) is involved in alcohol metabolism, and the expression of this enzyme displays wide phenotypic variability in humans. It has been proposed that some of this variability in expression may be a consequence of the size of a repeat polymorphism in the 5" regulatory region of the gene and that the polymorphism may segregate with alcoholism. This study examined whether the repeat polymorphism exists in macaque monkeys and whether it associates with excessive alcohol consumption in this animal model. Ten outbred cynomolgus monkeys (Macaca fascicularis) that displayed a voluntary alcohol consumption ranging from 1.0 to 3.6 g/kg/day were genotyped for a CYP2E1 repeat polymorphism. This polymorphism has been documented in the region from -2519 base pair (bp) to -1953 bp of the human CYP2E1 gene 5" distal promoter. Individual polymerase chain reaction amplification of genomic DNA from each of the 10 monkey samples revealed a single band of approximately 400 bp in the region corresponding to the human CYP2E1 polymorphism. Polymerase chain reaction amplicons from the 10 individuals were sequenced, and each one generated a 370 bp sequence that is 90% identical to the human gene sequence. However, unlike human alleles that contain five to eight repeats, the cynomolgus monkey is homozygous for a single copy of the repeat most closely resembling repeat 8 (88% identical) in the human gene. These data demonstrate that the CYP2E1 distal promoter region in monkeys is very similar to the human sequence yet lacks the extensive repeated DNA found in humans. This includes the rare repeats 3 and 4, which have been postulated to play a role in transcription regulation and to associate with alcohol abuse liability in humans. These data suggest that the CYP2E1 polymorphism arose late in evolution and that the regulation of the gene by this genetic region is not associated with a heavy alcohol drinking phenotype in the cynomolgus monkey.

The parahippocampal region and object identification.

The hippocampus has long been thought to be critical for memory, including memory for objects. However, recent neuropsychological studies in nonhuman primates have indicated that other regions within the medial temporal lobe, specifically, structures in the parahippocampal region, are primarily responsible for object recognition and object identification. This article reviews the behavioral effects of removal of structures within the parahippocampal region in monkeys, and cites relevant work in rodents as well. It is argued that the perirhinal cortex, in particular, contributes to object identification in at least two ways: (i) by serving as the final stage in the ventral visual cortical pathway that represents stimulus features, and (ii) by operating as part of a network for associating together sensory inputs within and across sensory modalities.