While cognitive decline is observed in the normal aging monkey, neurons are not lost with age. Instead, frontal white matter is lost as myelin degenerates and both correlate with age-related cognitive decline. As age-related myelin damage increases, there should be an increase in clearance of damaged myelin by microglial phagocytosis. In this study, brains of behaviorally tested rhesus monkeys were assessed using unbiased stereology to quantify the density of activated microglia (LN3 antibody positive) and phagocytic microglia (galectin-3 (Gal-3) antibody positive) in three white matter regions: the corpus callosum, cingulum bundle (CGB), and frontal white matter (FWM). LN3 cell density was significantly increased in the CGB, whereas Gal-3 cell density was significantly increased in all regions. Increases in Gal-3 cell density in the FWM were associated with cognitive impairment. In the FWM of old animals, Gal-3-positive microglia were classified by morphological subtype as ramified, hypertrophic, or amoeboid. The densities of hypertrophic and amoeboid microglia significantly correlated with cognitive impairment. Finally, microglia were double-labeled with LN3 and Gal-3 showing that 91% of Gal-3 cells were also LN3 positive, thus expressing an Bactivated^phenotype. Furthermore, 15% of all double-labeled cells formed phagocytic cups. Overall, these results suggest that microglia become activated in white matter with age where the majority express a phagocytic phenotype. We hypothesize that age-related phagocytic activation of microglia is a response to accumulating myelin pathology. The association of Gal-3 in the FWM with cognitive impairment may reflect regional differences in damage or dysfunction of normal clearance mechanisms.

Cannabinoid modulation of dopaminergic transmission is suggested by the ability of delta9-tetrahydrocanabinoid to affect motor and motivated behaviors in a manner similar to that produced by pharmacological manipulation of the nigrostriatal and mesocorticolimbic dopamine systems. These behavioral effects as well as analogous effects of endocannabinoids are largely mediated through the cannabinoid type 1 receptor (CB1R). This receptor is located within the substantia nigra and ventral tegmental area, which respectively house the somata of nigrostriatal and mesocorticolimbic dopaminergic neurons. The CB1R is also abundantly expressed in brain regions targeted by the efferent terminals of these dopaminergic neurons. In this review we present the accumulating anatomical and electrophysiological evidence indicating that in each of these systems cannabinoids modulate dopamine transmission largely if not exclusively through indirect mechanisms. The summarized mechanisms include presynaptic release of amino acid transmitters onto midbrain dopamine neurons and onto both cortical and striatal neurons that express dopamine D1-like or D2-like receptors functionally affiliated with the CB1 receptor. The review concludes with a consideration of the psychiatric and neurological implications of cannabinoid modulation of dopamine transmission within these networks.

Studies of both humans and non-human primates have demonstrated that aging is typically characterized by a decline in cognition that can occur as early as the fifth decade of life. Age-related changes in working memory are particularly evident and mediated, in part, by the prefrontal cortex, an area known to evidence age-related changes in myelin that is attributed to inflammation. In recent years, several nutraceuticals, including curcumin, by virtue of their anti-inflammatory and antioxidant effects, have received considerable attention as potential treatments for age-related cognitive decline and inflammation. Accordingly, we assessed for the first time in a non-human primate model of normal aging the efficacy of dietary intervention using the natural phenol curcumin to ameliorate the effects of aging on spatial working and recognition memory. Results revealed that monkeys receiving daily administration of curcumin over 14-18 months demonstrated a greater improvement in performance on repeated administration of a task of spatial working memory compared to monkeys that received a control substance.

The ventral pallidum (VP) is a major recipient of inhibitory projections from nucleus accumbens (Acb) neurons that differentially express the reward (enkephalin) and aversion (dynorphin) associated opioid peptides. The cannabinoid-1 receptor (CB1R) is present in Acb neurons expressing each of these peptides, but its location in the VP is not known. To address this question, we used electron microscopic dual immunolabeling of the CB1R and either dynorphin 1-8 (Dyn) or Met5-enkephalin (ME) in the VP of C57BL/6J mice, a species in which CB1R gene deletion produces a reward deficit. We also used similar methods to determine the relationship between the CB1R and N-acylphosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D (NAPE-PLD), an anandamide-synthesizing enzyme located presynaptically in other limbic brain regions. CB1R-immunogold was principally localized to cytoplasmic endomembranes and synaptic or extrasynaptic plasma membranes of axonal profiles, but was also affiliated with postsynaptic membrane specializations in dendrites. The axonal profiles included many single CB1R-labeled axon terminals as well as terminals containing CB1R-immunogold and either Dyn or ME immunoreactivity. Dually labeled terminals comprised 26% of all Dyn- and 17% of all ME-labeled axon terminals. Both single and dual labeled terminals formed mainly inhibitory-type synapses, but almost 16% of these terminals formed excitatory synapses. Approximately 60% of the CB1R-labeled axonal profiles opposed or converged with axon terminals containing NAPE-PLD immunoreactivity. We conclude that CB1Rs in the mouse VP have subcellular distributions consistent with on demand activation by endocannabinoids that can regulate the release of functionally opposed opioid peptides and also modulate inhibitory and excitatory transmission.

Cortical injury elicits long‐term cytotoxic and cytoprotective mechanisms within the brain and the balance of these pathways can determine the functional outcome for the individual. Cytotoxicity is exacerbated by production of reactive oxygen species, accumulation of iron, and peroxidation of cell membranes and myelin. There are currently no neurorestorative treatments to aid in balancing the cytotoxic and cytoprotective mechanisms following cortical injury. Cell based therapies are an emerging treatment that may function in immunomodulation, reduction of secondary damage, and reorganization of surviving structures. We previously evaluated human umbilical tissue‐derived cells (hUTC) in our non‐human primate model of cortical injury restricted to the hand area of primary motor cortex. Systemic hUTC treatment resulted in significantly greater recovery of fine motor function compared to vehicle controls. Here we investigate the hypothesis that hUTC treatment reduces oxidative damage and iron accumulation and increases the extent of the microglial response to cortical injury. To test this, brain sections from these monkeys were processed using immunohistochemistry to quantify oxidative damage (4‐HNE) and activated microglia (LN3), and Prussian Blue to quantify iron. hUTC treated subjects exhibited significantly reduced oxidative damage in the sublesional white matter and iron accumulation in the perilesional area as well as a significant increase in activated microglia along downstream white matter. Increased perilesional iron accumulation was associated with greater perilesional oxidative damage and larger reconstructed lesion volume. These findings support the hypothesis that systemic hUTC administered 24 hours after cortical damage decreases the cytotoxic response while increasing the extent of microglial activation. Support or Funding Information This study was supported by a contract from Advanced Technologies and Regenerative Medicine (ATRM), LLC. [RR# 101115‐PR] who provided the cell therapy product and the vehicle control and by the National Institutes of Health [NIH‐NINDS R21NS081261]. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.