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Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior.

Common efferent projections of the dorsolateral prefrontal cortex and posterior parietal cortex were examined in 3 rhesus monkeys by placing injections of tritiated amino acids and HRP in frontal and parietal cortices, respectively, of the same hemisphere. Terminal labeling originating from both frontal and parietal injection sites was found to be in apposition in 15 ipsilateral cortical areas: the supplementary motor cortex, the dorsal premotor cortex, the ventral premotor cortex, the anterior arcuate cortex (including the frontal eye fields), the orbitofrontal cortex, the anterior and posterior cingulate cortices, the frontoparietal operculum, the insular cortex, the medial parietal cortex, the superior temporal cortex, the parahippocampal gyrus, the presubiculum, the caudomedial lobule, and the medial prestriate cortex. Convergent terminal labeling was observed in the contralateral hemisphere as well, most prominently in the principal sulcal cortex, the superior arcuate cortex, and the superior temporal cortex. In certain common target areas, as for example the cingulate cortices, frontal and parietal efferents terminate in an array of interdigitating columns, an arrangement much like that observed for callosal and associational projections to the principal sulcus (Goldman-Rakic and Schwartz, 1982). In other areas, frontal and parietal terminals exhibit a laminar complementarity: in the depths of the superior temporal sulcus, prefrontal terminals are densely distributed within laminae I, III, and V, whereas parietal terminals occupy mainly laminae IV and VI directly below the prefrontal bands. Subcortical structures also receive apposing or overlapping projections from both prefrontal and parietal cortices. The dorsolateral prefrontal and posterior parietal cortices project to adjacent, longitudinal domains of the neostriatum, as has been described previously (Selemon and Goldman-Rakic, 1985); these projections are also found in close apposition in the claustrum, the amygdala, the caudomedial lobule, and throughout the anterior medial, medial dorsal, lateral dorsal, and medial pulvinar nuclei of the thalamus. In the brain stem, both areas of association cortex project to the intermediate layers of the superior colliculus and to the midline reticular formation of the pons.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Behavioral microanalysis of spatial delayed alternation performance: rehearsal through overt behavior, and effects of scopolamine and chlordiazepoxide.

Rats were trained in an operant spatial delayed alternation task utilizing retention intervals from 2 to 32 s. In addition to response accuracy, operations of the levers during the retention intervals were recorded and analyzed. Animals were tested following the administration of the muscarinic antagonists scopolamine hydrobromide and methylbromide, and the benzodiazepine receptor agonist chlordiazepoxide. In vehicle-treated animals, the relative number of correct responses and correct rehearsal operations (operation of the forthcoming correct lever during retention intervals) varied with the length of the retention intervals, and these measures were correlated. The response rate for rehearsal operations increased with the length of the retention intervals. It is speculated that the delay-dependent increase in response rate reflects an effect of delayed reward that was also associated with a delay-dependent increase in the tendency to alternate between levers. The effects of delay on the accuracy of rehearsal operations may have contributed to the delay-dependent correct responding. Scopolamine hydrobromide (0.01, 0.03, 0.1, 0.3 mg/kg) and methylbromide (0.1, 0.3 mg/kg) impaired correct responding, but did not seem to interfere with the relative number of correct rehearsal operations. As only the presentation of the panel light indicated trial onset, it is speculated that the cholinergic receptor blockade resulted in an increase in the probability of a repositioning response that was triggered by light onset. Chlordiazepoxide (1, 3, 5, 10 mg/kg) did not affect behavioral performance. These results suggest that in tasks that allow the development of rehearsal operations, delay-dependent response accuracy does not represent a sufficient condition for conclusions on task demands on memory.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

DPAS-Graph: adaptive spatial-feature relation learning for spatial RNA-to-protein prediction and virtual protein profiling.

Paired spatial multi-omics provides a supervised basis for learning RNA-protein correspondence in situ, but predicting protein abundance from spatial transcriptomic data alone remains challenging across tissue contexts and protein panels. Here, we present DPAS-Graph, an adaptive relation-learning framework for spatial RNA-to-protein prediction. Rather than directly merging spatial proximity and transcriptomic similarity as fixed graph priors, DPAS-Graph represents them as two relation channels on a shared edge support and updates their contributions during representation learning for protein prediction. Its Niche-Coupled Field Encoder combines layer-wise edge-relation modeling, intra-branch relation refinement, and cross-branch residual correction to learn spot representations for protein abundance prediction. In a leave-one-dataset-out benchmark across seven paired spatial multi-omics datasets, DPAS-Graph achieved lower aggregate prediction errors and improved spot-level agreement of protein expression profiles, with gains mainly reflected in error-based metrics and PCC-Spot. Spatial autocorrelation and protein-derived domain agreement analyses were further used to characterize the spatial behavior of the predicted protein maps. When applied to external RNA-only spatial sections, DPAS-Graph generated qualitatively interpretable marker-level virtual protein maps, illustrating its use as a complementary tool for protein-level interpretation of transcriptomics-only spatial data.

RNA

Structural complexity effects on transverse propagation in a two-dimensional model of myocardium.

A thin sheet of cardiac tissue was modeled as a set of resistively coupled excitable cables with membrane dynamics described by the modified Beeler Reuter model. Transverse connections have a resistance Rn and are regularly distributed with a spacing delta on any given cable, to provide alternating input and output junctions. Flat wave longitudinal propagation corresponds to propagation along a single continuous cable since all units of the network are functionally isolated due to the absence of transverse current flow. Events on a given cable during flat transverse propagation include electrotonic spread of potential from input to output junctions, action potential initiation at input junctions, and collision at output junctions. The propagating two-dimensional transverse wavefront is an undulating transmembrane potential surface with highs at the input junctions and lows at the output junctions. The action potential upstroke is also modulated in a periodic manner with minimum and maximum Vmax at the input and output junctions respectively. Thus, the network is capable of a diversity of dynamic behavior spatially distributed in relation to the specific pattern of transverse connections chosen. Overall, the behavior of the network model is in good agreement with available structural and electrophysiological data on myocardium. In addition, this network topology allows to handle more easily parameters governing propagation and to avoid very large matrices which are costly in computational effort and overall computer time.

Computer Simulation

Immediate and long-lasting effects of MK-801 on motor activity, spatial navigation in a swimming pool and EEG in the rat.

In a series of experiments, rats received the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and measures were made of motor behavior, spatial navigation in a swimming pool, and electroencephalographic (EEG) activity. High doses (0.25-10 mg/kg IV) produced somnolence and akinesia, impaired food consumption, locomotion and swimming, and also impaired navigation to a hidden platform but complete recovery on all measures was obtained between 3 and 5 days postinjection. Lower doses (0.05-0.10 mg/kg, IV) impaired acquisition of a new place response in a swimming pool and produced hyperactivity but did not impair performance on a new cue response or on a well-learned place response. Two forms of hippocampal EEG activity, atropine-sensitive and atropine-resistant EEG were present with the low doses. The results demonstrate that a single dose of MK-801 causes changes in motor behavior and learning lasting a few days, but complete recovery occurs within 5 days of administration of even very high doses of MK-801. They further demonstrate that low doses of the drug selectively impair acquisition of new place responses. Although the general changes in behavior produced by MK-801 suggest that NMDA receptors are involved in many aspects of the control of behavior, the results additionally suggest that NMDA receptors are important for place learning.

Animals

Proteomic and Phosphoproteomic Signatures Link Molecular Remodeling to Behavioral Outcomes Following Elderberry and DHA Supplementation in Aging Mice.

Background: Aging is a risk factor for Alzheimer's disease and related dementias, which are associated with synaptic dysfunction and cognitive decline. Elderberry (Sambucus spp.) is rich in anthocyanins with antioxidant and anti-inflammatory properties. Docosahexaenoic acid (DHA), an essential fatty acid, plays a key role in neuronal membrane integrity during brain aging. However, it remains unclear whether elderberry and DHA exert overlapping or distinct effects on brain aging and how these relate to molecular signaling. This study aimed to characterize molecular signatures induced by dietary supplementation and to determine their relationships with behavioral outcomes. Methods: 44-week-old male C57BL/6J mice were randomly assigned to control, elderberry, DHA, or combined diets for 12 weeks. Behavioral testing assessed anxiety-like behavior, spatial learning and memory. Brain tissues underwent proteomic and phosphoproteomic profiling and fatty-acid analysis. Data were analyzed using Ingenuity Pathway Analysis to identify enriched pathways, upstream regulators, and functional associations. Results: Elderberry as well as DHA supplementation induced targeted remodeling of the proteome and phosphoproteome, with pathway enrichment involving synaptogenesis, glutamatergic signaling, and long-term potentiation. Upstream-regulator analysis predicted elderberry-associated CDK5 signaling, accompanied by reduced MAPT/Tau phosphorylation at selected sites, whereas DHA supplementation was associated with CAMK-related signaling. DHA supplementation altered fatty-acid composition, increasing the n-3/n-6 ratio. Elderberry reduced anxiety-like behavior and improved target-directed search during the Barnes maze probe test. Molecular signatures were examined in relation to the measured behavioral outcomes. Conclusions: Elderberry and DHA are associated with distinct molecular networks related to synaptic function and behavioral outcomes in the aging male mouse brain. These findings support further investigation of elderberry and DHA as dietary interventions targeting molecular and behavioral features of brain aging.

Animals

Morphological, neurochemical, and behavioral studies on serotonergic denervation and graft-induced reinnervation of the rat hippocampus.

A procedure was developed to conduct simultaneously immunocytochemical and neurochemical studies on the serotonergic system in adjacent 300-micron-thick slices of rat hippocampus. This procedure was applied to correlate morphological (innervation pattern and density), neurochemical (5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake and release) and behavioral (spatial learning) effects of neurotoxin-induced denervation and reinnervation by grafting fetal mesencephalic raphe cells. Intracerebroventricular injections of a low dose of 5,7-dihydroxytryptamine caused a discrete serotonergic denervation of the hippocampus. Eleven months after lesioning, 5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake capacity were decreased by 50-60%. By this time, the residual fibers displayed an enhanced vulnerability towards K(+)-induced depolarization. Grafting of a fetal raphe cell suspension resulted in a reinnervation of the host hippocampus. The pattern of reinnervation was comparable to control innervation and the density was supranormal at the level of the graft. As observed semiquantitatively, the innervation density decreased with distance from the core of the graft. Neurochemical studies showed that the fibers were capable of synthesizing, metabolizing and releasing 5-hydroxytryptamine. The turnover of 5-hydroxytryptamine in both the denervated and the reinnervated hippocampus was comparable to that in control tissue. Previous behavioral testing of the denervated and of the denervated and implanted animals did not reveal any effect on spatial learning, either in an individual or in a social test paradigm. The latter data substantiate the notion that interference with the hippocampal serotonergic innervation does not hamper adequate spatial learning.

5,7-Dihydroxytryptamine

Cerebral lateralization as a source of interindividual differences in behavior.

Cerebral laterality can no longer be considered an exclusively human trait, as over the last 15 years there has been an emergence of data to suggest that animal brains are also lateralized. Morphologic, chemical and behavioral indices of brain asymmetry in the rodent have been reported, and it is suggested that variations in the magnitude and direction of these indices are determined by a complex interaction of genetic, hormonal and experiential factors. Interindividual differences in cerebral laterality have been shown to covary with, or predict, individual differences in spatial behavior and stress reactivity, as well as susceptibility to stress pathology and drug sensitivity. Such findings suggest that it is possible to study individual differences in lateralized brain function through the use of animal models.

Animals

Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex.

Studies of spatial behavior in both the human and non-human primate have generally focused on the role of the posterior parietal and prefrontal cortices and have indicated that destruction of these regions produce allocentric and egocentric deficits, respectively. The present study examined the role of the rodent analogs of these regions, the posterior parietal (PPC) and medial agranular (AGm) cortices, in egocentric and allocentric spatial processing, and whether spatial processing in rodents is organized in a hemispatial and/or lateralized manner as has been found in the primate. Eighty male rats receiving either a unilateral or bilateral lesion of AGm or PPC were examined on an egocentric (adjacent arm) or an allocentric (cheeseboard) maze task. The results indicated that PPC and AGm have dissociable spatial functions. Bilateral AGm destruction resulted in egocentric spatial deficits, and unilateral AGm operates demonstrated an intermediate deficit. In contrast, bilateral PPC operates demonstrated a severe deficit in allocentric processing. In addition, there were lateralized differences in the performance of unilateral PPC operates. While right PPC lesions resulted in a significant deficit on the allocentric task, no such deficit was seen in left PPC operates. In addition, neither unilateral AGm nor unilateral PPC operates demonstrated a hemispatial impairment on either the egocentric or allocentric tasks.

Animals

Effects of genetic vestibular defects on behavior related to spatial orientation and emotionality.

A large battery of behavioral tests was administered to normal mice and to mice with varying degrees of otoconial agenesis due to genes affecting vestibular development. Many significant differences were found, but a factor analysis revealed that the variance on the 11 best tests could be accounted for in terms of two underlying variables. Factor I, the more important of the two, was associated with activity, habituation, and spontaneous alternation. Factor II appeared to represent a fear of new stimuli or situations. In both cases factor scores were highly related to the degree of otoconial deficiency. One subgroup of mice with severe otoconial agenesis displayed hyperactivity and a total absence of either habituation or spontaneous alternation. In these animals, brain and body development were stunted, and the reactions to amphetamine and physostigmine were opposite to those seen in normal mice. The results support the idea that the static organs contribute importantly to spatial orientation and suggest that early-onset vestibular defects can result in profound alterations of emotionality.

Acetylcholine

Physiological aspects of visual perception. I. Functional aspects of visual cortex.

The first part of the Bennett Lecture for 1975 is a description of the dissociation of visual perception in the macaque monkey by ablation of area 17 on the one hand, and of areas 18 and 19 on the other. Bilateral removal of area 17, with careful preservation of a great part of areas 18 and 19, and of the inferior pulvinar, resulted in loss of binocular fixation, loss of visual recognition of still objects, and loss of visuosocial behavior such as grimacing and vocalization. There remained excellent visuospatial orientation and reaching for moving peripheral visual targets. Removal of areas 18 and 19, with isolation of area 17 from the remainder of cortex, was accomplished in two animals and left intact the ability to distinguish and sort out still objects by vision, with intact fixation, and visuosocial behavior. Spatial orientation was then easily confused by movement.

Animals

Inkblot content and interpersonal distance.

Four Ht content scales were related to a projective and a live measure of interpersonal distance. Based on previour research, negative correlations between human and barrier content and interpersonal distance were predicted, with positive correlations predicted between anxiety and hostility content and distance behavior. All four content scales were found to relate significantly to projective distance, but only anxiety and hostility correlated significantly with distance behavior. The content scales also were combined in regression equations to predict interpersonal distance. The projective measure of interpersonal distance correlated signifiantly with the live measure of distance. The results were interpreted as support for the construct validity of the inkblot scales.

Anxiety

Monkey motor stimulation and altered social behavior during chronic methadone administration.

To assess the effects of chronic methadone administration on locomotor, social, and eating behavior od drug-native individuals under circumstances approximating those of methadone "maintenance" clinics, we gave single, daily oral doses of methadone to 5 Macaca radiata monkeys living in a social group. We obtained motor activity counts automatically during 6 weeks of baseline, 10 weeks of drug administration, and 3 weeks of post-drug abstinence. Social behaviors of association, dominance, submission, and sexuality were counted 5 days per week, and animal weights, food eaten and food-reinforced work were recorded. Plasma methadone levels were near those achieved in mechadone clincs. Methadone produced mixed stimulation and sedation in the daytime, with stimulation predominating for 4 hrs following administration. At night the subjects moved less while taking the drug. Associative behaviors were reduced by methadone, but dominance, submission, and sexual behaviors were not altered. The monkeys ate less while taking the drug, losing weight and working less for food. In these primates methadone had significant stimulant properties, impaired important social behaviors, and reduced the potency of food as a reinforcer of work. The results are compared with methadone's effects upon humans.

Animals

The influence of the social thermoregulation on the cold-adaptive growth of BAT in hairless and furred mice.

When mice were living in groups they developed less brown adipose tissue (BAT) during cold adaptation as compared with single mice. This effect of social aggregation was more pronounced in genetically hairless mice than in furred mice. In both races of mice the most significant difference in BAT growth was found between single mice and pairs of mice, indicating that the formation of pairs causes the relatively most effective improvement of thermal balance.

Adaptation, Physiological

The sociability of two-year-olds with their mothers and fathers.

Twenty-one two-year-olds were observed interacting with their parents in a laboratory playroom. Previously reported analyses had found that they displayes no preferencd for interaction with either parent. The present analysis found that there was a high degree of correlation between the sociability of the cild with his mother and his sociability with his father. Possible implications of this finding are discussed.

Adult

Spatial performance correlates with in vitro potentiation in young and aged Fischer 344 rats.

Young adult (2-4 months old) and aged (24-26 months old) Fischer 344 (F344) rats were trained for spatial behavior (locating a hidden escape platform) in a circular water maze. The aged rats showed deficits in both the acquisition and retention of the learned response. Following the behavioral training, hippocampal slices from the rats were prepared. Potentiation of CA1 extracellular, somatic field potentials was studied in vitro following either a short stimulus train (4 pulses) or a longer train (50 pulses). Slices from the aged rats showed less short-term potentiation (124.8 +/- 4.9% baseline, mean +/- S.E.M.) at 1 min following the short train in comparison to slices from the young rats (151.8 +/- 7.5%, P less than 0.05). However, following the longer train, no differences were found between the groups in the degree of either short-term (measured at 1 min after stimulation) or long-term potentiation (measured at 60 min). The amount of potentiation seen at various time points after either train correlated with the behavioral measure of retention. These results indicate that F344 rats exhibit age-related behavioral deficits, and age-related synaptic potentiation deficits in response to short stimulation trains. The correlation between the degree of potentiation (both short-term and long-term) and retention of a behavioral task adds strength to the hypothesis that potentiation mechanisms may underlie memory processes.

Aging