Michael J. Raleigh’s research while affiliated with University of California, Los Angeles and other places

We propose that a control system will address the causal dynamics of the neural network that Depue & Collins regard as underlying extraversion. We briefly describe a control system approach and articulate the notion of integration. The integration of goals and regards is achieved by subcortical assessment of reward in the nucleus accumbens and VTA (ventral tegmental area) transmission of this information largely by dopaminergic systems and representation of reward in the MOC (medial orbital cortex). Thus reward information is collected, integrated, and evaluated in the MOC. Such control decisions rely on constraining processes, a functional property of the MOC mediated largely by serotonergic neurons.

This chapter validates an FDG-PET protocol in conscious infant monkeys to demonstrate reproducibility of adult monkey local-cerebral metabolic rates of glucose (ICMRGlc) data, and to present absolute CMRGIc values in conscious neonatal and infant vervet monkeys. The protocol used in this chapter is designed to avoid factors (sedation and stress) that are known to affect CMRGIc. Results indicate that instrumentation and analysis provide reliable and reproducible data and that this method is sensitive to changes in CMRGIc. Therefore, the chapter concludes that this method may be used to determine the normal metabolic development of the brain in nonhuman primates.

A combination of ketamine and midazolam (K/M) produce a safer, shorter-acting anesthesia than pentobarbital (PB) in both vervet and squirrel monkeys. (18F) Fluorodopa positron emission tomography kinetics were examined in 23 vervet and 18 squirrel monkeys using PB and K/M. Relative to PB, K/M reduced recovery times by 32% in squirrel monkeys and 48% in vervets. Systemic metabolism of (18F)fluorodopa was unchanged in both species. KI, a measure of the blood-brain barrier transport rate of (18F) fiuorodopa, was slightly lower with K/M compared to PB in vervet (10%, p = 0.05), and significantly lower in squirrel monkeys (32%, p < 0.01). Ki, the (18F) fluorodopa uptake constant, was unchanged in vervet and slightly lower with K/M in squirrel monkeys (19%, p = 0.10). K/M produced effective immobilization, was suitable for measuring (18F) fluorodopa kinetics, and significantly reduced the time needed for animal recovery.

Cellular distribution of the Glut1 glucose transporter in normal primate brains was analyzed by immunogold electron microscopy. Two configurations of endothelial Glut1 glucose transporter (high and low density capillaries) have been found in resections of traumatically injured and epileptogenic human brain; the objective of the present study was to ascertain whether these same 2 capillary populations, expressing high and low glucose transporter densities, were the common configuration in normal brain. The relative numbers of Glut1 glucose transporter-associated gold particles on luminal and abluminal endothelial cell membranes were determined within the cerebral cortex of several normal, nonhuman primates. Low Glut1 densities were seen in brain endothelia of both the rhesus and squirrel monkey cortex, with slightly greater quantities of Glut1 in vervet monkey cortices. The Glut1 transporter was most highly expressed in the baboon cortex, approaching the concentrations seen in human brains. In the rhesus, squirrel, and vervet monkeys, Glut1 concentrations were greater on the abluminal than luminal capillary membranes. In contrast, mean luminal membrane Glut1 concentrations were greater in baboons, resembling the distribution seen in the human brain. Brain regional differences in transporter concentration were seen in comparing membrane densities in the baboon cortex (approximately 15 Glut1-gold particles per micrometer), hippocampus (approximately 12 Glut1 gold particles per micrometer), cerebellum (approximately 6 Glut1-gold particles per micrometer), and retinal microvasculature (approximately 20 Glut1-gold particles per micrometer). We conclude that a single, uniform Glut1 distribution characterizes brain capillaries of normal nonhuman primates, and hypothesize that the presence of high and low density glucose transporter endothelial cells (seen in human traumatic injury and seizure resections) represents a pathologic response to brain insult.

Clinical and animal studies suggest that brain serotonergic systems may regulate aggressive behavior; however, the serotonin/violence hypothesis has not been assessed at the epidemiological level. For study of an epidemiological sample we examined blood serotonin, because certain physiological and behavioral findings suggested that it might serve as an analog marker for serotonergic function. Whole blood serotonin was measured in a representative birth cohort of 781 21-year-old women (47%) and men (53%). Violence was measured using cumulative court conviction records and participants' self-reports. Potential intervening factors addressed were: gender, age, diurnal variation, diet, psychiatric medications, illicit drug history, season of phlebotomy, plasma tryptophan, platelet count, body mass, suicide attempts, psychiatric diagnoses, alcohol, tobacco, socioeconomic status, IQ, and overall criminal offending. Whole blood serotonin related to violence among men but not women. Violent men's mean blood serotonin level was 0.48 SD above the male population norm and 0.56 SD above the mean of nonviolent men. The finding was specific to violence, as opposed to general crime, and it was robust across two different methods of measuring violence. Together, the intervening variables accounted for 25% of the relation between blood serotonin and violence. To our knowledge, this is the first demonstration that an index of serotonergic function is related to violence in the general population.

6-[F-18]Fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) has been used to measure the central dopaminergic function in many species, including humans and monkeys. For transport across the blood brain barrier (BBB), FDOPA competes with plasma large neutral amino acids (LNAA). In this article we evaluate the effects of normal physiological LNAA concentration variation on BBB transport (K1) and the FDOPA uptake measurement, Ki. We also investigate a method for reducing the dependency of FDOPA quantitation on LNAA. Adult vervet monkeys (Cercopithecus aethiops sabaeus, n = 19) were fasted overnight before FDOPA positron emission tomography scans. Blood samples were drawn for LNAA determination, metabolite analysis, and compartmental modeling. The estimated K1 and Ki were both negatively correlated with LNAA concentrations (r2 = 0.51 and 0.62, respectively). Using an adjustment to K1 and Ki based on these correlations, the LNAA dependency was reduced (SD of the data for K1 was reduced by 33%, for Ki by 40%). Experiments with amino acid loading on an additional six animals indicate that BBB transport can be described using Michaelis-Menten kinetics. Results show a clear dependence of FDOPA uptake on plasma LNAA concentrations, which can be removed to increase the precision of FDOPA quantitation.

The objective of the present study was to examine the apparent work capacity of one of the two separate membrane systems (the blood-cerebrospinal fluid barrier) that isolate the mammalian brain extracellular fluid (and cerebrospinal fluid, CSF) from plasma. Digitized analyses of electron-microscopic images provided estimates of mitochondrial volumes, which were expressed as a percentage of the cell cytoplasm. We recorded a high mitochondrial content of 12-15% in the cuboidal epithelium of primate choroid plexus, which was consistent in vervet, rhesus, and squirrel monkeys, as well as in baboons. Similarly high mitochondrial contents were observed in the rabbit, rat, and mouse choroid plexus. It has been postulated that the high mitochondrial content of brain endothelium is associated with maintaining the ionic gradients within the central nervous system. We observed that the mitochondrial content of the choroid plexus (where CSF is produced) was slightly higher than in (prior measurements of) the blood-brain barrier (BBB). In addition, surface areas at the apical borders of the choroid plexus epithelia (where the Na+K+ATPase activity has been localized) were increased 7- to 13-fold over the basal borders, in the primate species examined. The observation of high mitochondrial volumes in choroid plexus cells is consistent with the suggestion that increased mitochondrial densities seen in choroidal epithelia and BBB capillaries provide a metabolic work capability for both secretory activities and maintaining ionic gradients across blood-CSF barriers.

In six vervet monkeys, presynaptic striatal dopamine function was assessed longitudinally by [18F]fluoro-L-DOPA (FDOPA)-positron emission tomography (PET) after administration (2 x 2 mg/kg, i.m., 4 h apart) of either amphetamine (Amp), n = 3, or methamphetamine (MeAmp), n = 3. At 1-2 weeks postdrug, both Amp and MeAmp exposure effected similar decreases (60-70%) in the FDOPA influx rate constant (FDOPA Ki), an index of striatal dopamine synthesis capacity. Subsequent studies in these subjects showed that FDOPA Ki values were decreased by 45-67% at 3-6 weeks, by 25% at 10-12 weeks and by 16% in one Amp-treated subject at 32 weeks. Biochemical analysis showed that striatal dopamine concentrations were decreased by 75% at 3-4 weeks and by 55% at 10-12 weeks. These results indicate that in vervet monkey striatum, an acute Amp or MeAmp drug dosage produces extensive striatal dopamine system neurotoxicity. However, these effects were reversible; observed time-dependent recovery in both FDOPA Ki and dopamine concentrations indicates that neurochemical plasticity remains active in the adult primate striatum. At 3-4 and 10-12 weeks postdrug, the concurrent characterization of the striatal FDOPA Ki and dopamine concentrations for individual subjects showed that Ki decreases between 24 and 67% corresponded to dopamine depletions of 55-85%. These relatively larger postdrug decrements in steady-state striatal dopamine concentrations suggest that compensatory increases in dopamine synthesis capacity develop in the partially lesioned striatum. In contrast to the dopamine depletion in striatum, substantia nigra concentrations remained unchanged from referent values at both 3-4 and 10-12 weeks postdrug. Thus, the integrity of the substantia nigra could not be inferred from decreases in the striatal FDOPA Ki parameter. This disparity between striatum and substantia nigra reactivity to systemic administration of amphetamines suggests that each has unique dopamine system regulatory mechanisms.