Age-related alterations to working memory and to pyramidal neurons in the prefrontal cortex of rhesus monkeys begin in early middle-age and are partially ameliorated by dietary curcumin.

Layer 3 (L3) pyramidal neurons in aged rhesus monkey lateral prefrontal cortex (LPFC) exhibit significantly elevated excitability in vitro and reduced spine density compared to neurons in young subjects. The time-course of these alterations, and whether they can be ameliorated in middle age by the powerful anti-oxidant curcumin is unknown. We compared the properties of L3 pyramidal neurons from the LPFC of behaviorally characterized rhesus monkeys over the adult lifespan using whole-cell patch clamp recordings and neuronal reconstructions. Working memory (WM) impairment, neuronal hyperexcitability, and spine loss began in middle age. There was no significant relationship between neuronal properties and WM performance. Middle-aged subjects given curcumin exhibited better WM performance and less neuronal excitability compared to control subjects. These findings suggest that the appropriate time frame for intervention for age-related cognitive changes is early middle age, and points to the efficacy of curcumin in delaying WM decline. Because there was no relationship between excitability and behavior, the effects of curcumin on these measures appear to be independent.

Mesenchymal derived exosomes enhance recovery of motor function in a monkey model of cortical injury.

BACKGROUND: Exosomes from mesenchymal stromal cells (MSCs) are endosome-derived vesicles that have been shown to enhance functional recovery in rodent models of stroke. OBJECTIVE: Building on these findings, we tested exosomes as a treatment in monkeys with cortical injury. METHODS: After being trained on a task of fine motor function of the hand, monkeys received a cortical injury to the hand representation in primary motor cortex. Twenty-four hours later and again 14 days after injury, monkeys received exosomes or vehicle control. Recovery of motor function was followed for 12 weeks. RESULTS: Compared to monkeys that received vehicle, exosome treated monkeys returned to pre-operative grasp patterns and latency to retrieve a food reward in the first three-five weeks of recovery. CONCLUSIONS: These results provide evidence that in monkeys exosomes delivered after cortical injury enhance recovery of motor function.

Specificity in inhibitory systems associated with prefrontal pathways to temporal cortex in primates.

The prefrontal cortex selects relevant signals and suppresses irrelevant stimuli for a given task through mechanisms that are not understood. We addressed this issue using as a model system the pathways from the functionally distinct prefrontal areas 10 and 32 to auditory association cortex, and investigated their relationship to inhibitory neurons labeled for calbindin (CB) or parvalbumin (PV), which differ in mode of inhibition. Projection neurons in area 10 originated mostly in layers 2-3 and were intermingled with CB inhibitory neurons. In contrast, projections from area 32 originated predominantly in layers 5-6 among PV inhibitory neurons. Prefrontal axonal boutons terminating in layers 2-3 of auditory association cortex were larger than those terminating in layer 1. Most prefrontal axons synapsed on spines of excitatory neurons but a significant number targeted dendritic shafts of inhibitory neurons. Axons from area 10 targeted CB and PV inhibitory neurons, whereas axons from area 32 targeted PV inhibitory neurons. The preferential association of the 2 prefrontal pathways with distinct classes of inhibitory neurons at their origin and termination may reflect the specialization of area 10 in working memory functions and area 32 in emotional communication. These findings suggest diversity in inhibitory control by distinct prefrontal pathways.

Diversity of laminar connections linking periarcuate and lateral intraparietal areas depends on cortical structure.

Lateral prefrontal and intraparietal cortices have strong connectional and functional associations but it is unclear how their common visuomotor, perceptual and working memory functions arise. The hierarchical scheme of cortical processing assumes that prefrontal cortex issues 'feedback' projections to parietal cortex. However, the architectonic heterogeneity of these cortices raises the question of whether distinct areas have laminar-specific interconnections underlying their complex functional relationship. Using quantitative procedures, we showed that laminar-specific connections between distinct prefrontal (areas 46 and 8) and lateral intraparietal (LIPv, LIPd and 7a) areas in Macaca mulatta, studied with neural tracers, varied systematically according to rules determined by the laminar architecture of the linked areas. We found that axons from areas 46 and rostral 8 terminated heavily in layers I-III of all intraparietal areas, as did caudal area 8 to area LIPv, suggesting 'feedback' communication. However, contrary to previous assumptions, axons from caudal area 8 terminated mostly in layers IV-V of LIPd and 7a, suggesting 'feedforward' communication. These laminar patterns of connections were highly correlated with consistent differences in neuronal density between linked areas. When neuronal density in a prefrontal origin was lower than in the intraparietal destination, most terminations were found in layer I with a concomitant decrease in layer IV. The opposite occurred when the prefrontal origin had a higher neuronal density than the target. These findings indicate that the neuronal density of linked areas can reliably predict their laminar connections and may form the basis of understanding the functional complexity of prefrontal-intraparietal interactions in cognition.

Relationship of prefrontal connections to inhibitory systems in superior temporal areas in the rhesus monkey.

The prefrontal cortex selects relevant signals and suppresses irrelevant signals in behavior, as exemplified by its functional interaction with superior temporal cortices. We addressed the structural basis of this process by investigating quantitatively the relationship of prefrontal pathways to inhibitory interneurons in superior temporal cortices. Pathways were labeled with neural tracers, and two neurochemical classes of inhibitory interneurons were labeled with parvalbumin (PV) and calbindin (CB), which differ in mode of inhibitory control. Both markers varied significantly and systematically across superior temporal areas. Calbindin neurons were more prevalent than PV neurons, with the highest densities found in posterior high-order auditory association cortices. Axons from anterior lateral, medial prefrontal and orbitofrontal areas terminated in the anterior half of the superior temporal gyrus, targeting mostly the superficial layers (I to upper III), where CB neurons predominated. Reciprocal projection neurons were intermingled with PV neurons, and emanated mostly from the deep part of layer III and to a lesser extent from layers V-VI, in proportions matching the laminar density of inhibitory interneurons. In marked contrast, prefrontal connections in temporal polar cortex were found mostly in the deep layers, showing mismatch with the predominant upper laminar distribution of interneurons. Differences in the relationship of connections to inhibitory neurons probably affect the dynamics in distinct superior temporal cortices. These findings may help explain the reduced efficacy of inhibitory control in superior temporal areas after prefrontal cortical damage.