Injection parameters and virus dependent choice of promoters to improve neuron targeting in the nonhuman primate brain.

We, like many others, wish to use modern molecular methods to alter neuronal functionality in primates. For us, this requires expression in a large proportion of the targeted cell population. Long generation times make germline modification of limited use. The size and intricate primate brain anatomy poses additional challenges. We surved methods using lentiviruses and serotypes of adeno-associated viruses (AAVs) to introduce active molecular material into cortical and subcortical regions of old-world monkey brains. Slow injections of AAV2 give well-defined expression of neurons in the cortex surrounding the injection site. Somewhat surprisingly we find that in the monkey the use of cytomegalovirus promoter in lentivirus primarily targets glial cells but few neurons. In contrast, with a synapsin promoter fragment the lentivirus expression is neuron specific at high transduction levels in all cortical layers. We also achieve specific targeting of tyrosine hydroxlase (TH)- rich neurons in the locus coeruleus and substantia nigra with a lentvirus carrying a fragment of the TH promoter. Lentiviruses carrying neuron specific promoters are suitable for both cortical and subcortical injections even when injected quickly.

Basic fibroblast growth factor and fibroblast growth factor receptor-1 in the human hippocampal formation.

Basic fibroblast growth factor (bFGF) is an important mitogen and neurotrophic factor that binds and signals through the high-affinity receptor, fibroblast growth factor receptor 1 (FGFR1). However, only a limited amount of information is available concerning the molecular forms and anatomical distribution of fibroblast growth factors (FGFs) in the normal human brain. We found multiple bFGF and FGFR1 mRNA transcripts which vary in expression pattern across human brain regions. Using in situ hybridization and immunohistochemistry, we localized bFGF and FGFR1 mRNA and protein to cells in the normal adult human hippocampus and caudal entorhinal cortex (ERC). The majority of pyramidal neurons contained FGFR1 mRNA and protein in the mesial temporal lobe, with neurons in the CA2/CA3 region demonstrating the highest levels of FGFR1 mRNA. In contrast to FGFR1, bFGF mRNA expression was detected at very low levels in a small fraction of the neurons in the human hippocampus and caudal ERC. While bFGF mRNA may be expressed at low levels in neurons, bFGF-immunopositive cells with astrocytic features were detected throughout the mesial temporal lobe in rats, monkeys and humans. bFGF immunoreactive processes are found traversing the dentate gyrus, and bFGF immunoreactive cells are found in the neurogenic subgranular zone in all three mammalian species studied. The anatomical distribution of these two FGF family members suggests that bFGF is endogenously positioned to be involved in ongoing neurogenesis in the adult hippocampus, and that FGF trophic signaling to differentiated neurons could involve the release of astrocytic bFGF acting on neuronal FGFR1 in the normal adult human hippocampus.

Expression of estrogen receptor alpha exon-deleted mRNA variants in the human and non-human primate frontal cortex.

Although estrogen receptor alpha (ERalpha) mRNA has been detected in the primate frontal cortex, the types of ERalpha transcripts expressed, including exon-deleted variants (Delta), have not been determined in the monkey or human frontal cortex. Because the types of ERalpha mRNA expressed in brain could define neuronal responses to estrogens, we examined the transcript pool of ERalpha mRNAs expressed in normal adult and developing human and macaque frontal cortex. We reverse transcribed total RNA from the postmortem frontal cortex of 29 normal adult humans, 12 rhesus macaques, and 19 people ranging from infants to adults and employed two rounds of nested polymerase chain reaction (PCR) to generate ERalpha products spanning the coding domain. In a third nested PCR, we used primers specific for novel sequences of exon-exon junctions created when whole exons are missing. By sequencing PCR products, we detected 60 instances of 12 distinct DeltaERalpha mRNAs in adult humans and 94 instances of 13 distinct DeltaERalpha mRNAs in monkeys in differing patterns from one individual to another. In adult humans, 83% of individuals expressed at least 1 DeltaERalpha mRNA variant, and 100% of the monkeys expressed at least 1 DeltaERalpha mRNA variant. The single Delta2, Delta5, and Delta7 variants were frequently expressed in both human and monkey frontal cortex, Delta3 variants were rare in both species, and Delta6 variants were more frequently expressed in monkeys. In both species, we detected double, triple and quadruple Deltas, but these were less common than single Deltas. The pattern of human variant expression did not appear to change dramatically as a function of age. These findings imply the potential to produce different ERalpha proteins in frontal cortex, possibly with altered structure and function which may have physiological relevance for gene transcription by virtue of altered functional interactions with each other, other steroid hormone receptors, and genomic DNA.

Anatomical pathways for auditory memory II: information from rostral superior temporal gyrus to dorsolateral temporal pole and medial temporal cortex.

Auditory recognition memory in non-human primates differs from recognition memory in other sensory systems. Monkeys learn the rule for visual and tactile delayed matching-to-sample within a few sessions, and then show one-trial recognition memory lasting 10-20 min. In contrast, monkeys require hundreds of sessions to master the rule for auditory recognition, and then show retention lasting no longer than 30-40 s. Moreover, unlike the severe effects of rhinal lesions on visual memory, such lesions have no effect on the monkeys' auditory memory performance. The anatomical pathways for auditory memory may differ from those in vision. Long-term visual recognition memory requires anatomical connections from the visual association area TE with areas 35 and 36 of the perirhinal cortex (PRC). We examined whether there is a similar anatomical route for auditory processing, or that poor auditory recognition memory may reflect the lack of such a pathway. Our hypothesis is that an auditory pathway for recognition memory originates in the higher order processing areas of the rostral superior temporal gyrus (rSTG), and then connects via the dorsolateral temporal pole to access the rhinal cortex of the medial temporal lobe. To test this, we placed retrograde (3% FB and 2% DY) and anterograde (10% BDA 10,000 mW) tracer injections in rSTG and the dorsolateral area 38 DL of the temporal pole. Results showed that area 38DL receives dense projections from auditory association areas Ts1, TAa, TPO of the rSTG, from the rostral parabelt and, to a lesser extent, from areas Ts2-3 and PGa. In turn, area 38DL projects densely to area 35 of PRC, entorhinal cortex (EC), and to areas TH/TF of the posterior parahippocampal cortex. Significantly, this projection avoids most of area 36r/c of PRC. This anatomical arrangement may contribute to our understanding of the poor auditory memory of rhesus monkeys.

The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia.

BACKGROUND: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development. METHODS: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. RESULTS: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D2 receptor availability in the striatum (n = 14, rho = -.64, p < .01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p < .05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. CONCLUSIONS: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.

Kinetic modeling of [11C]raclopride: combined PET-microdialysis studies.

The in vivo binding of D2 receptor ligands can be affected by agents that alter the concentration of endogenous dopamine. To define a more explicit relation between dopamine and D2 receptor binding, the conventional compartment model for reversible ligands has been extended to account for a time-varying dopamine pulse. This model was tested with [11C]raclopride positron emission tomography and dopamine microdialysis data that were acquired simultaneously in rhesus monkeys. The microdialysis data were incorporated into the model assuming a proportional relation to synaptic dopamine. Positron emission tomography studies used a bolus-plus-infusion tracer delivery with amphetamine given at 40 minutes to induce dopamine release. The extended model described the entire striatal time-activity curve, including the decrease in radioactivity concentration after an amphetamine-induced dopamine pulse. Based on these results, simulation studies were performed using the extended model. The simulation studies showed that the percent decrease in specific binding after amphetamine measured with the bolus-plus-infusion protocol correlates well with the integral of the postamphetamine dopamine pulse. This suggests that changes in specific binding observed in studies in humans can be interpreted as being linearly proportional to the integral of the amphetamine-induced dopamine pulse.

Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion.

Positron emission tomography and single-photon emission computer tomography receptor-binding ligands can be used to measure changes in neurotransmitter levels. In particular, amphetamine-induced dopamine release has been assessed with [11C]raclopride by paired bolus injections and with [123I]iodobenzamide by using a single bolus plus infusion (B/I) study. Here, we measured the change in [11C]raclopride-specific binding in rhesus monkeys after i.v. administration of 0.4 mg/kg amphetamine by using both the bolus and B/I paradigms. Paired bolus studies (control and postamphetamine) were analyzed using compartment modeling and graphical analysis with a new plasma metabolite model to measure the total distribution volume (VT). Specific binding, calculated with three measures linearly proportional to the binding potential, demonstrated a 22-42% reduction in the postamphetamine study. VT values from B/I studies were determined by the tissue-to-plasma ratio at equilibrium, in addition to the bolus methods. There was good agreement between the control VT values between bolus and B/I studies. The amphetamine-induced change in specific binding in B/I studies was 19 +/- 16%, measured directly from tissue radioactivity levels. This study demonstrates that stimulus-induced changes in specific binding can be measured with a single [11C]raclopride study using the B/I method.

In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates.

OBJECTIVE: Studies on brain serotonin metabolism in human and nonhuman primates have indicated that dysfunction of serotonin transmission may play a role in the biological vulnerability to dependence on alcohol. Among young men, low sensitivity to alcohol intoxication predicts subsequent alcohol abuse and dependence. METHOD: The authors used single photon emission computed tomography and the radioligand [(I)123]beta-CIT ([(I)123]methyl 3beta-(4-iodophenyl) tropane-2-carboxylate) to measure the availability of serotonin transporters in 11 male rhesus monkeys, and the monkeys were genotyped for a functional polymorphism of the serotonin transporter gene. The 11 monkeys had experienced parental separation after birth; their behavior and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in CSF had been assessed regularly. RESULTS: In the 5-year-old monkeys, there was a significant negative correlation between beta-CIT binding to serotonin transporters in the brainstem and 5-HIAA concentrations in CSF. Animals with greater beta-CIT binding and low CSF 5-HIAA concentrations displayed greater aggressiveness and were less sensitive to alcohol-induced intoxication. The genetic constitution of the serotonin transporter promoter gene did not significantly contribute to the availability of brainstem serotonin transporters as measured by beta-CIT binding. CONCLUSIONS: In adult nonhuman primates who underwent early developmental stress, variables indicating a low serotonin turnover rate were associated with behavior patterns similar to those predisposing to early-onset alcoholism among humans.

A comparison of the efferents of the amygdala and the hippocampal formation in the rhesus monkey: I. Convergence in the entorhinal, prorhinal, and perirhinal cortices.

This is the first in a series of papers investigating the neuroanatomical basis for the interaction of the amygdala and the hippocampal formation in the rhesus monkey. The present report focuses on the complementary and convergent projections of the amygdala and hippocampal formation to the entorhinal and perirhinal cortices. These results were obtained from complementary experiments using injections of radioactively labeled amino acids to identify the anterograde projection patterns and injections of horseradish peroxidase and fluorescent retrograde tracers to confirm the cytoarchitectonic location of the neurons of origin for each projection. The results of this investigation demonstrate that both the hippocampal formation and the amygdala project to the entorhinal and perirhinal cortices where, with a few exceptions, the major projections of each structure generally are found in different layers of the same cytoarchitecture subdivisions of the entorhinal cortex but overlap in the same layers of the perirhinal cortex. Thus, the lateral and accessory basal nuclei of the amygdala project to layer 3 of areas Pr1, 28I, 28L, and 28S, and the accessory basal nucleus projects strongly to layer 1 of these same areas. In contrast, the subiculum, prosubiculum, and subfield CA1 of the of the hippocampal formation all have a projection to layer 5 of these same areas. In area 28M, the accessory basal nucleus of the amygdala projects to layer 1, while the subiculum, prosubiculum, and subfield CA1 of the hippocampal formation all project to layer 5, and the presubiculum projects to layer 3. In addition to these complementary laminar projections, there are a few areas of laminar overlap. Thus in area 28S, both the presubiculum and the CA1 subfield project to layer 3, where the lateral and accessory basal amygdaloid nuclei also project. Similarly, in 28I there is a major projection from the presubiculum and a lighter projection from the subiculum and CA1 to layer 3, where the lateral and accessory basal nuclei also project. There is also extensive laminar overlap in the perirhinal cortex. From the amygdala, the accessory basal nucleus projects to layers 1 and 3 and the lateral basal nucleus to layers 3, 5, and 6, while from the hippocampal formation, the prosubiculum projects to layers 3, 5, and 6, and the CA1 subfield projects to layer 5. This pattern of hippocampal and amygdaloid projections to the entorhinal and perirhinal cortices indicates that these cortices constitute a region of potentially extensive interaction between the amygdala and the hippocampus.

Comparison of the efferents of the amygdala and the hippocampal formation in the rhesus monkey: II. Reciprocal and non-reciprocal connections.

The pattern of direct connections between the amygdala and the hippocampal formation in the rhesus monkey (Macaca mulatta) was delineated by using both anterograde and retrograde tract-tracing techniques. From the amygdala the accessory basal, medial basal, and the cortical nuclei and the cortical amygdaloid transition area send projections to the hippocampal formation. The efferents from the magnocellular part of the accessory basal nucleus and the cortical nuclei terminate in the molecular layer of subfields CA3, CA2, and CA1', and to a lesser extent in the molecular layer and the superficial part of the pyramidal cell layers of the prosubiculum. In contrast, the projections from the medial basal nucleus and the cortical amygdaloid transition area terminate in the molecular layer and the superficial part of the pyramidal cell layers of the prosubiculum only. From the hippocampal formation, subfield CA1' and the prosubiculum send efferents that terminate in the medial basal nucleus, the cortical transition area, and the ventral part of the cortical nuclei. In addition, the CA1' subfield projects to the ventral, parvicellular part of the accessory basal nucleus. The present data emphasize an important role for the prosubiculum and the CA1' subfield in medial temporal lobe area connections. Both regions, in addition to supporting direct connections between the amygdala and the hippocampal formation, also have extensive connections with the entorhinal cortex. As for the amygdala, the accessory basal nucleus sends efferents to both the hippocampal formation and the entorhinal cortex. The data demonstrate an anatomical means by which the amygdala, hippocampal formation, and the entorhinal cortex may interact. It is proposed that these connections may be important in the limbic memory system.

Hemispheric lateralization in rhesus monkeys can be task-dependent.

Two rhesus monkeys with transection of the forebrain commissures were trained on two grating orientation-discrimination tasks. In one task, the simultaneous orientation identification task, monkeys had to decide which of two simultaneously presented gratings was horizontal. In the other task, the temporal same-different task, the monkey had to decide whether or not two successively presented gratings differed in orientation. Both monkeys showed a statistically significant individual asymmetry in the performance on the same-different task with the left hemisphere supporting superior performance compared with the right hemisphere. No such consistent lateralization was found for the identification task. These results show that the demonstration of a behavioral asymmetry depends on the type of discrimination task performed and suggest that the asymmetry is related to interhemispheric differences in higher order stimulus (cognitive) processing and not to a lateralization of early visual processes.

Further evidence that amygdala and hippocampus contribute equally to recognition memory.

The medial temporal neuropathology found in an amnesic neurosurgical patient [17] was simulated in monkeys in an attempt to determine whether the patient's mnemonic disorder, which had been ascribed to bilateral hippocampal destruction, may have also been due in part to unilateral amygdaloid removal. For this purpose, monkeys were prepared with bilateral hippocampectomy combined with unilateral amygdalectomy, and (as a control) bilateral amygdalectomy combined with unilateral hippocampectomy. The animals were trained both before and after surgery on a one-trial visual recognition task requiring memory of single objects for 10 sec each and then given a postoperative performance test in which their one-trial recognition ability was taxed with longer delays (up to 2 min) and longer lists (up to 10 objects). The two groups, which did not differ reliably at any stage, obtained average scores on the performance test 75 and 80%, respectively. Comparison with the results of an earlier experiment [8] indicates that this performance level lies approximately midway between that of monkeys with amygdaloid or hippocampal removals alone (91%) and that of monkeys with combined amygdalo-hippocampal removals (60%). The results point to a direct quantitative relationship between degree of recognition impairment and amount of conjoint damage to the amygdala and hippocampus irrespective of the specific structure involved. Evidence from neurosurgical cases tested in visual recognition [21] indicates that the same conclusion may apply to man.

Augmentation of prefrontal cortical monoaminergic activity inhibits dopamine release in the caudate nucleus: an in vivo neurochemical assessment in the rhesus monkey.

Prefrontal cortical modulation of caudate nucleus dopamine release was investigated in the rhesus monkey using the in vivo microdialysis technique. Reliable and stable basal caudate nucleus dopamine levels were quickly attained within hours following insertion of the dialysis probes. High-potassium (60 mM) or tetrodotoxin (10 microM) infusions significantly altered caudate nucleus dopamine levels in the dialysate indicating that measured dopamine levels reflected impulse-dependent release from the presynaptic pool. Pharmacological augmentation of monoaminergic transmission in the sulcus principalis region of the prefrontal cortex resulted in significant alterations in caudate nucleus dopamine levels. Increase of monoaminergic activity by infusion of either D-amphetamine (100 microM) or cocaine hydrochloride (100 microM) resulted in a gradual and prolonged decrease in caudate nucleus dopamine levels. Similar decreases were noticed in caudate nucleus dopamine metabolite levels. The present results indicate that in non-human primates modulation of dorsolateral prefrontal cortical monoaminergic transmission results in alterations in dopamine levels in subcortical structures. This observation may have clinical implications for therapeutic management of certain neuropsychiatric disorders, particularly schizophrenia.

Antenatal diagnosis of lethal skeletal dysplasias.

Lethal skeletal dysplasias (LSD) are a heterogeneous group of rare but important genetic disorders characterized by abnormal growth and development of bone and cartilage. We describe the diagnosis and outcome of 29 cases of lethal skeletal dysplasias evaluated between January 1989 and December 1996 at the University of Maryland Medical Center and the Ultrasound Institute of Baltimore. Two cases presented at delivery with no prenatal care while the remaining 27 cases were identified by antenatal sonography. Final diagnoses included thanatophoric dysplasia (14), osteogenesis imperfecta, type II (6), achondrogenesis (2), short rib syndromes (3), campomelic syndrome (2), atelosteogenesis (1), and no evidence of a skeletal dysplasia (1). Twenty out of 27 pregnancies were terminated with an average at detection of 21.6 weeks. The other 7 pregnancies that went on to deliver had an average age at detection of 29.2 weeks. Fetal abnormalities in the terminated pregnancies were identified at a significantly earlier gestational age (P = 0.0016) than the pregnancies that continued. While the identification of LSD by sonography was excellent (26/27), only 13/27 (48%) were given an accurate specific antenatal diagnosis. In 8/14 (57%) cases with an inaccurate or nonspecific diagnosis there was a significant or crucial change in the genetic counseling. Thus, while antenatal sonography is an excellent method for discovering LSD, clinical examination, radiographs, and autopsy are mandatory for making a specific diagnosis.

Monkeys with combined amygdalo-hippocampal lesions succeed in object discrimination learning despite 24-hour intertrial intervals.

Monkeys with combined amygdalo-hippocampal removal show severe impairments on visual memory tasks after delays of only a minute or two, yet they learn visual discrimination habits about as quickly as normal animals with intertrial intervals of the same duration. In an attempt to resolve this discrepancy between abnormally rapid forgetting and successful retention, tests were conducted to determine whether discrimination learning would be prevented in animals with limbic lesions if intertrial intervals lasted 24 hr. The results showed that as long as the lesion did not encroach on inferior temporal cortex, the operated animals could acquire concurrent sets of 20 object discrimination habits at the same rate as normal animals, in an average of about 10 trials per set. The findings suggest that learning and retention processes are divisible into a mechanism for memory formation that is dependent on the limbic system and a mechanism for habit formation that is not.

Neurotoxic lesions of perirhinal cortex impair visual recognition memory in rhesus monkeys.

Recent excitotoxic lesion studies in monkeys have shown that the recognition memory deficits originally attributed to amygdalo-hippocampal damage were due in whole or in part to the accompanying damage to surrounding tissue, including fibers of passage. Here we show that the same conclusion does not apply to the visual recognition impairment produced by aspiration lesions of perirhinal cortex inasmuch as equally severe impairment was found after excitotoxic lesions of this cortex. The finding demonstrates that damage limited to perirhinal neurons is sufficient to impair visual memory and that damage to fibers of passage neither caused nor exacerbated the effect described initially.

Repair of cranial defects with teflon: a method of cranioplasty in monkeys.

Magnetic resonance imaging demonstrated the need for cranioplasty in experimental neurobehavioral studies with non-human primates. Postoperatively temporal lobes showed substantial deformation of the neocortex due to pressure from the overlying muscle. A new method of cranioplasty using teflon to cover a cranial defect has been developed. Teflon is easily shaped and fitted into place. This method is safe, allows for the natural shape of the brain, provides protection, and is compatible with imaging techniques. Cranioplasty with teflon should be considered whenever craniotomy is necessary for accessing the brain.

An improved methodology for routine in vivo microdialysis in non-human primates.

A new method was developed to carry out in vivo microdialysis experiments repetitively and routinely within an individual monkey. We designed and built a dialysis probe guide and holding device ('guide holder') which permits accurate placement of dialysis probes into cortical (e.g., prefrontal, hippocampus, and parietal cortices) and subcortical target areas (e.g., caudate nucleus, amygdala, and nucleus accumbens) of the rhesus monkey brain without extensive and repetitive surgery needed to expose a desired brain region. The guide holder is positioned, using MRI-guided coordinates, and fixed to the skull over an intended targeted region. This design provides an opportunity to conduct several experiments in a single monkey over an extended period and permits placement of several probes accurately into 'fresh' or 'experienced' tissue during repeated microdialysis experiments. In addition, during repeated dialysis experiments tissue trauma is minimized because no surgical procedure is necessary on the day of dialysate collection. This procedure can be readily adapted for use with an awake monkey.

The effects of fornix transection and combined fornix transection, mammillary body lesions and hippocampal ablations on object-pair association memory in the rhesus monkey.

Cynomolgus monkeys were tested on an associative memory task in which they had to remember object-object pairings. Eight animals (4 unoperated monkeys and 4 monkeys with lesions to components of the 'hippocampal-mammillary' circuit) were trained initially on a conditional object-pair association task that was similar to simple discrimination learning, but which involved presentation of object-pairs instead of single objects. Object-pairs were made up from 4 different objects, each with an identical copy. Animals had to learn which pairings of the 4 objects were rewarded (e.g. AB or CD) and which pairings were not (e.g. AC or BD). Objects appeared as a member of both rewarded and non-rewarded pairs. After several stages of training all monkeys reached a high level of performance making greater than 90% correct choices. In a performance test the monkeys had to discriminate between 3 single objects depending on their past associations with the other objects. Animals had to choose the two objects which in initial training were rewarded as an object pair. Monkeys with the 'hippocampal-mammillary' circuit lesions learned the initial object-pair discriminations at the same rate as control monkeys. In the performance test, however, monkeys with the 'hippocampal-mammillary' circuit lesions performed at chance levels, whereas the control monkeys performed significantly better. The results demonstrate a dissociation between the 'habit' and 'mediational' memory systems for ostensibly the same object-pair associations. They also indicate an important contribution of the 'hippocampal-mammillary' circuit in nonspatial association memory.

Opiate receptor avidity is increased in rhesus monkeys following unilateral optic tract lesion combined with transections of corpus callosum and hippocampal and anterior commissures.

Opiate receptor avidity (B(max)'/K(D)) was measured in four rhesus monkeys following unilateral lesioning of the optic tract combined with transection of the corpus callosum and the hippocampal and anterior commissures depriving one hemisphere of visual input (Tract and Split), two animals with transection of commissures only (Split), and nine healthy monkeys with positron emission tomography (PET) and 6-deoxy-6-beta-[(18)F]fluoronaltrexone (cyclofoxy, CF), a mu- and kappa-opiate receptor antagonist. Opiate receptor avidity was found to be significantly higher in the Tract and Split animals, only, bilaterally, throughout the lateral cortex and in the cingulate and posterior putamen (41-117%). Ipsilateral changes were consistently greater than those contralateral, but this asymmetry was of statistical significance only in the parietal and occipital cortices. Cyclofoxy avidity was decreased in the medial cortex of both the Tract and Split and Split animals ( approximately 25%). The results suggest that opiate pathways undergo extensive alteration in response to changes in brain functional activities brought about through hemispheric visual deprivation.