Red raspberry (Rubus ideaus) supplementation mitigates the effects of a high-fat diet on brain and behavior in mice.

OBJECTIVES: Research has shown that berries may have the ability to reverse, reduce, or slow the progression of behavioral dysfunction associated with aging and neurodegenerative disease. In contrast, high-energy and high-fat diets (HFD) may result in behavioral deficits like those seen in aging animals. This research examined whether red raspberry (Rubus ideaus) mitigates the effects of HFD on mouse brain and behavior. METHODS: Eight-week-old mice consumed a HFD (60% calories from fat) or a control diet (CD) with and without 4% freeze-dried red raspberry (RB). Behavioral tests and biochemical assays of brain tissue and serum were conducted. RESULTS: After 12 weeks on the diets, mice fed CD and HFD had impaired novel object recognition, but mice on the RB-supplemented diets did not. After approximately 20 weeks on the diets, mice fed HFD + RB had shorter latencies to find the escape hole in the Barnes maze than the HFD-fed mice. Interleukin (IL)-6 was significantly elevated in the cortex of mice fed HFD; while mice fed the CD, CD + RB, and HFD + RB did not show a similar elevation. There was also evidence of increased brain-derived neurotrophic factor (BDNF) in the brains of mice fed RB diets. This reduction in IL-6 and increase in BDNF may contribute to the preservation of learning and memory in HFD + RB mice. CONCLUSION: This study demonstrates that RB may protect against the effects HFD has on brain and behavior; however, further research with human subjects is needed to confirm these benefits.

Blueberry supplementation attenuates microglia activation and increases neuroplasticity in mice consuming a high-fat diet.

OBJECTIVES: Consuming a high-fat diet (HFD) may result in behavioral deficits similar to those observed in aging animals. Blueberries may prevent and even reverse age-related alterations in neurochemistry and behavior. It was previously demonstrated that middle-aged mice fed HFD had impaired memory; however, supplementation of HFD with blueberry reduced these memory deficits. As a follow-up to that study, the brain tissue from HFD-fed mice with and without blueberry supplementation was assessed to determine the neuroprotective mechanism(s) by which blueberry allayed cognitive dysfunction associated with HFD. METHODS: Mice were fed HFDs (60% calories from fat) or low-fat diets (LFD) with and without 4% blueberry (freeze-dried, U.S. Highbush Blueberry Council). Microglia activation was assessed ex vivo and in vitro. The hippocampus was assessed for brain-derived neurotrophic factor (BDNF) and neurogenesis by measuring doublecortin (DCX). RESULTS: There was significantly less microglia ionized calcium binding adaptor molecule 1 staining and fewer microglia in the brains of mice fed HFD + blueberry compared to mice fed LFD and HFD. BV-2 microglial cells treated with serum collected from the mice fed the diets supplemented with blueberry produced less nitric oxide compared to cells treated with serum from mice fed HFD. BDNF levels were higher and the number of DCX-positive cells was greater in the hippocampus of mice fed HFD + blueberry compared to mice fed HFD. DISCUSSION: This study demonstrated that supplementation of a HFD with blueberry reduced indices of microglia activation and increased neuroplasticity, and these changes may underlie the protection against memory deficits in HFD-fed mice supplemented with blueberry.

Dietary supplementation with the polyphenol-rich açaí pulps (Euterpe oleracea Mart. and Euterpe precatoria Mart.) improves cognition in aged rats and attenuates inflammatory signaling in BV-2 microglial cells.

OBJECTIVES: The present study was carried out to determine if lyophilized açaí fruit pulp (genus, Euterpe), rich in polyphenols and other bioactive antioxidant and anti-inflammatory phytochemicals, is efficacious in reversing age-related cognitive deficits in aged rats. METHODS: The diets of 19-month-old Fischer 344 rats were supplemented for 8 weeks with 2% Euterpe oleracea (EO), Euterpe precatoria (EP), or a control diet. Rats were tested in the Morris water maze and then blood serum from the rats was used to assess inflammatory responses of BV-2 microglial cells. RESULTS: After 8 weeks of dietary supplementation with 2% EO or EP, rats demonstrated improved working memory in the Morris water maze, relative to controls; however, only the EO diet improved reference memory. BV-2 microglial cells treated with blood serum collected from EO-fed rats produced less nitric oxide (NO) than control-fed rats. Serum from both EO- and EP-fed rats reduced tumor necrosis factor-alpha (TNF-α). There is a relationship between performance in the water maze and the production of NO and TNF-α by serum-treated BV-2 cells, such that serum from rats with better performance was more protective against inflammatory signaling. DISCUSSION: Protection of memory during aging by supplementation of lyophilized açaí fruit pulp added to the diet may result from its ability to influence antioxidant and anti-inflammatory signaling.

The beneficial effects of berries on cognition, motor behaviour and neuronal function in ageing.

Previously, it has been shown that strawberry (SB) or blueberry (BB) supplementations, when fed to rats from 19 to 21 months of age, reverse age-related decrements in motor and cognitive performance. We have postulated that these effects may be the result of a number of positive benefits of the berry polyphenols, including decreased stress signalling, increased neurogenesis, and increased signals involved in learning and memory. Thus, the present study was carried out to examine these mechanisms in aged animals by administering a control, 2 % SB- or 2 % BB-supplemented diet to aged Fischer 344 rats for 8 weeks to ascertain their effectiveness in reversing age-related deficits in behavioural and neuronal function. The results showed that rats consuming the berry diets exhibited enhanced motor performance and improved cognition, specifically working memory. In addition, the rats supplemented with BB and SB diets showed increased hippocampal neurogenesis and expression of insulin-like growth factor 1, although the improvements in working memory performance could not solely be explained by these increases. The diverse polyphenolics in these berry fruits may have additional mechanisms of action that could account for their relative differences in efficacy.

Stress-induced increases in depression-like and cocaine place-conditioned behaviors are reversed by disruption of memories during reconsolidation.

Maladaptive behavioral responses characteristic of post-traumatic stress disorders are notably resistant to treatment. We hypothesized that the pharmacological disruption of memories activated during reconsolidation might reverse established stress-induced increases in depression-like behaviors and cocaine reward. C57BL/6J mice were subjected to repeated social defeat stress (SDS), and examined for time spent immobile in a subsequent forced swim test (FST). An additional set of SDS-exposed mice were place-conditioned with cocaine, and tested for cocaine-conditioned place preference (CPP). All stress-exposed mice were then subjected to a single additional trial of SDS while under the influence of propranolol or cycloheximide to disrupt memory reconsolidation, then given one additional FST or CPP test the next day. Mice subjected to repeated SDS subsequently demonstrated increases in time spent immobile in the FST or in the cocaine-paired chamber. Vehicle-treatment followed by additional SDS exposure did not alter these behaviors, but propranolol or cycloheximide treatment reversed each of the potentiated responses in a dose-dependent manner. Overall, these results demonstrate that while repeated exposure to a social defeat stressor subsequently increased depression-like behavior and cocaine-CPP, disruption of traumatic memories made labile by re-exposure to SDS during reconsolidation may have therapeutic value in the treatment of established post-traumatic stress disorder-related behaviors.

Inhibition of Gßγ-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward.

Inhibition of Gßγ-subunit signaling to phospholipase C ß3 has been shown to potentiate morphine-mediated antinociception while attenuating the development of tolerance and dependence in mice. The objective of this study was to determine the effect of Gßγ-subunit inhibition on antinociception and other pharmacological effects, such as respiratory depression, constipation, and hyperlocomotion, mediated by the µ-opioid receptor. The Gßγ-subunit inhibitor, gallein, was administered to C57BL/6J mice by intraperitoneal injection before morphine, and data were compared with mice treated with vehicle, morphine, or gallein alone. Morphine-induced antinociception was measured using the 55°C warm-water tail-withdrawal test. Pretreatment with gallein produced a dose-dependent potentiation of morphine-mediated antinociception, producing up to a 10-fold leftward shift in the morphine dose-response curve and extending the duration of antinociception induced by a single dose of morphine. Gallein pretreatment also prevented acute antinociceptive tolerance induced by morphine. In contrast, the dose-dependent respiratory depression and hyperlocomotion induced by morphine were not potentiated by gallein pretreatment. Similarly, gallein pretreatment did not potentiate morphine-conditioned place preference responses or morphine-induced constipation, as measured as a reduction in excreta. These results suggest that selectively inhibiting Gßγ-mediated signaling may selectively increase µ-opioid receptor-mediated antinociception without matching increases in adverse physiological effects.

The ability of walnut extract and fatty acids to protect against the deleterious effects of oxidative stress and inflammation in hippocampal cells.

UNLABELLED: Previous research from our lab has demonstrated that dietary walnut supplementation protects against age-related cognitive declines in rats; however, the cellular mechanisms by which walnuts and polyunsaturated fatty acids (PUFAs) may affect neuronal health and functioning in aging are undetermined. OBJECTIVES: We assessed if pretreatment of primary hippocampal neurons with walnut extract or PUFAs would protect cells against dopamine- and lipopolysaccharide-mediated cell death and calcium dysregulation. METHODS: Rat primary hippocampal neurons were pretreated with varying concentrations of walnut extract, linoleic acid, alpha-linolenic acid, eicosapentaenoic acid, or docosahexaenoic acid prior to exposure to either dopamine or lipopolysaccharide. Viability was assessed using the Live/Dead Cellular Viability/Cytotoxicity Kit. Also, the ability of the cells to return to baseline calcium levels after depolarization was measured with fluorescent imaging. RESULTS: Results indicated that walnut extract, alpha-linolenic acid, and docosahexaenoic acid provided significant protection against cell death and calcium dysregulation; the effects were pretreatment concentration dependent and stressor dependent. Linoleic acid and eicosapentaenoic acid were not as effective at protecting hippocampal cells from these insults. DISCUSSION: Walnut extract and omega-3 fatty acids may protect against age-related cellular dysfunction, but not all PUFAs are equivalent in their beneficial effects.

Endogenous kappa opioid activation mediates stress-induced deficits in learning and memory.

We hypothesized that mice subjected to prolonged stress would demonstrate decreased performance in a learning and memory task attributable to the endogenous activation of the kappa opioid receptor (KOR). C57BL/6J mice were tested using the novel object recognition (NOR) assay at various time points after exposure to repeated forced swim stress (FSS). Unstressed mice demonstrated recognition of the novel object at the end of a procedure using three 10-min object interaction phases, with a recognition index (RI) for the novel object of 71.7+/-3.4%. However, 1 h after exposure to FSS, vehicle-pretreated mice displayed a significant deficit in performance (RI=58.2+/-4.1%) compared with unstressed animals. NOR was still significantly reduced 4 but not 24 h after FSS. Treatment with the KOR-selective antagonist norbinaltorphimine (10 mg/kg, i.p.) prevented the decline in learning and memory performance. Moreover, direct activation of the KOR induced performance deficits in NOR, as exogenous administration of the KOR agonist U50,488 [(+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide] (0.3 mg/kg, i.p.) suppressed NOR (RI=56.0+/-3.9%). The effect of FSS on NOR performance was further examined in mice lacking the gene for the endogenous KOR agonist dynorphin (Dyn). Dyn gene-disrupted mice exposed to FSS did not show the subsequent learning and memory deficits (RI=66.8+/-3.8%) demonstrated by their wild-type littermates (RI=49.7+/-2.9%). Overall, these results suggest that stress-induced activation of the KOR may be both necessary and sufficient to produce subsequent deficits in novel object recognition.

Walnut-Associated Fatty Acids Inhibit LPS-Induced Activation of BV-2 Microglia.

Walnuts have high levels of the omega-3 fatty acid alpha-linolenic acid (C18:3n-3, ALA) and the omega-6 fatty acid linoleic acid (C18:2n-6, LA). Previous research has demonstrated that pre-treatment of BV-2 microglia with walnut extract inhibited lipopolysaccharide (LPS)-induced activation of microglia. As an extension of that study, the effects of walnut-associated fatty acids on BV-2 microglia were assessed. BV-2 murine microglia cells were treated with LA, ALA, or a combination of LA+ALA prior to or after exposure to LPS. Nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) were measured in cell-conditioned media. Cyclooxeganse-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression were assessed in BV-2 microglia. Both LA and ALA protected against LPS-induced increases in NO, iNOS, COX-2, and TNF-alpha when used before LPS exposure. When BV-2 microglia were treated with fatty acids after LPS, only COX-2 and TNF-alpha were significantly attenuated by the fatty acids. There was no synergism of LA+ALA, as the LA+ALA combination was no more effective than LA or ALA alone. Fatty acids, like those found in walnuts, may protect against production of cytotoxic intermediates and cell-signaling molecules from microglia and may prove beneficial for preventing age- or disease-related neurodegeneration.

Blueberries Improve Neuroinflammation and Cognition differentially Depending on Individual Cognitive baseline Status.

Daily supplementation of blueberries (BBs) reverses age-related deficits in behavior in aged rats. However, it is unknown whether BB is more beneficial to one subset of the population dependent on baseline cognitive performance and inflammatory status. To examine the effect of individual differences on the efficacy of BB, aged rats (17 months old) were assessed for cognition in the radial arm water maze (RAWM) and divided into good, average, and poor performers based on navigation errors. Half of the rats in each cognitive group were then fed a control or a 2% BB diet for 8 weeks before retesting. Serum samples were collected, pre-diet and post-diet, to assess inflammation. Latency in the radial arm water maze was significantly reduced in the BB-fed poor performers (p < .05) and preserved in the BB-fed good performers. The control-fed good performers committed more working and reference memory errors in the post-test than pretest (p < .05), whereas the BB-fed good performers showed no change. An in vitro study using the serum showed that BB supplementation attenuated lipopolysaccharide (LPS)-induced nitrite and tumor necrosis factor-alpha, and cognitive performance was associated with innate anti-inflammatory capability. Therefore, consumption of BB may reverse some age-related deficits in cognition, as well as preserve function among those with intact cognitive ability.

Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus.

Cognitive impairment in age-related neurodegenerative diseases such as Alzheimer's disease may be partly due to long-term exposure and increased susceptibility to inflammatory insults. In the current study, we investigated whether polyphenols in blueberries can reduce the deleterious effects of inflammation induced by central administration of kainic acid by altering the expression of genes associated with inflammation. To this end, 4-month-old male Fischer-344 (F344) rats were fed a control, 0.015% piroxicam (an NSAID) or 2% blueberry diet for 8 weeks before either Ringer's buffer or kainic acid was bilaterally micro-infused into the hippocampus. Two weeks later, following behavioral evaluation, the rats were killed and total RNA from the hippocampus was extracted and used in real-time quantitative RT-PCR (qRT-PCR) to analyze the expression of inflammation-related genes. Kainic acid had deleterious effects on cognitive behavior as kainic acid-injected rats on the control diet exhibited increased latencies to find a hidden platform in the Morris water maze compared to Ringer's buffer-injected rats and utilized non-spatial strategies during probe trials. The blueberry diet, and to a lesser degree the piroxicam diet, was able to improve cognitive performance. Immunohistochemical analyses of OX-6 expression revealed that kainic acid produced an inflammatory response by increasing the OX-6 positive areas in the hippocampus of kainic acid-injected rats. Kainic acid up-regulated the expression of the inflammatory cytokines IL-1beta and TNF-alpha, the neurotrophic factor IGF-1, and the transcription factor NF-kappaB. Blueberry and piroxicam supplementations were found to attenuate the kainic acid-induced increase in the expression of IL-1beta, TNF-alpha, and NF-kappaB, while only blueberry was able to augment the increased IGF-1 expression. These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions, perhaps via alteration of gene expression.

Protective Effects of Foods Containing Flavonoids on Age-Related Cognitive Decline.

PURPOSE OF REVIEW: Evidence suggests that flavonoids, polyphenolic compounds found in many plant-derived foods, such as berries, may allay cognitive impairment. We review recent research exploring the protective effects of flavonoids on age-related cognitive decline and neurodegenerative disorders in humans and animals. We also address the mechanisms by which flavonoids may exert their effects and promising avenues of future research. RECENT FINDINGS: Flavonoids have been found to decrease neuroinflammation, reduce oxidative stress, and mediate neuroplasticity in animal models of neurodegeneration and aging. Injecting flavonoids encased in metal nanoparticles may further enhance the efficacy of flavonoids. Animal studies also demonstrate that flavonoid supplementation may alleviate neurodegenerative cognitive and memory impairments. Limited human studies, however, demonstrate the need for further clinical research investigating flavonoids. Flavonoid supplementation, as well as dietary modification to include whole foods high in flavonoids, may provide therapeutic potential for aging individuals experiencing cognitive deficits resulting from neurodegeneration.

Mitigating the effects of high fat diet on the brain and behavior with berry supplementation.

Research on the potential of berries to modulate the effects of high fat diets on the brain and behavior is a relatively small and growing field. This review provides an overview of current findings from animal studies assessing the impact of high fat diets supplemented with blueberries, blackberries, grapes and jaboticaba berries on cognitive performance and neuroprotection. High fat diets are demonstrated to increase brain markers of oxidative stress and inflammation and result in other neural alterations that can contribute to impairments in learning and memory. Berries are rich in bioactive polyphenols and show promise for mitigating the effects of high fat diet. Challenges to systematic research include variability in diet composition and regimens, limitations of predominantly male animal models, and other factors. Links between peripheral inflammation and CNS dysfunction have implications for the understanding of underlying mechanisms and directions for future research.

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice.

Human immunodeficiency virus (HIV) infection is associated with mood disorders and behavioral disinhibition. Impairments in sensorimotor gating and associated neurocognitive disorders are reported, but the HIV-proteins and mechanisms involved are not known. The regulatory HIV-1 protein, Tat, is neurotoxic and its expression in animal models increases anxiety-like behavior concurrent with neuroinflammation and structural changes in limbic and extra-limbic brain regions. We hypothesized that conditional expression of HIV-1 Tat1-86 in the GT-tg bigenic mouse model would impair sensorimotor gating and increase microglial reactivity in limbic and extralimbic brain regions. Conditional Tat induction via doxycycline (Dox) treatment (0-125 mg/kg, i.p., for 1-14 days) significantly potentiated the acoustic startle reflex (ASR) of GT-tg mice and impaired prepulse inhibition (PPI) of this response in a dose-dependent manner when Dox (100mg/kg) was administered for brief (1 day) or prolonged (daily for 7 days) intervals. A greater proportion of active/reactive Iba1-labeled microglia was seen in the anterior cingulate cortex (ACC), dentate gyrus, and nucleus accumbens core when Tat protein was induced under either brief or prolonged expression conditions. Other subregions of the medial prefrontal cortex, amygdala, hippocampal formation, ventral tegmental area, and ventral pallidum also displayed Tat-induced microglial activation, but only the activation observed in the ACC recapitulated the pattern of ASR and PPI behaviors. Tat exposure also increased frontal cortex GFAP. Pretreatment with indomethacin attenuated the behavioral effects of brief (but not prolonged) Tat-exposure. Overall, exposure to HIV-1 Tat protein induced sensorimotor deficits associated with acute and persistent neuroinflammation in limbic/extralimbic brain regions.

Conditional Tat protein brain expression in the GT-tg bigenic mouse induces cerebral fractional anisotropy abnormalities.

Cerebral white matter changes including tissue water diffusion abnormalities detected with diffusion tensor magnetic resonance imaging (DTI) are commonly found in humans with Human Immunodeficiency Virus (HIV) infection, as well as in animal models of the disorder. The severities of some of these abnormalities have been reported to correlate with measures of disease progression or severity, or with the degree of cognitive dysfunction. Accordingly, DTI may be a useful translational biomarker. HIV-Tat protein appears to be an important factor in the viral pathogenesis of HIV-associated neurotoxicity. We previously reported cerebral gray matter density reductions in the GT-tg bigenic mouse treated with doxycycline (Dox) to conditionally induce Tat protein expression. Presently, we administered intraperitoneal (i.p.) Dox (100 mg/kg/day) for 7 days to GT-tg mice to determine whether induction of conditional Tat expression led to the development of cerebral DTI abnormalities. Perfused and fixed brains from eight GT-tg mice administered Dox and eight control mice administered saline i.p. were extracted and underwent DTI scans on a 9.4 Tesla scanner. A whole brain analysis detected fractional anisotropy (FA) reductions in several areas including insular and endopiriform regions, as well as within the dorsal striatum. These findings suggest that exposure to Tat protein is sufficient to induce FA abnormalities, and further support the use of the GT-tg mouse to model some effects of HIV.

Fruit extracts antagonize Abeta- or DA-induced deficits in Ca2+ flux in M1-transfected COS-7 cells.

Evidence suggests that there is a selective sensitivity to oxidative stress (OSS) among muscarinic receptor (MAChR) subtypes with M1, M2 and M4 showing > OSS than M3 or M5 subtypes in transfected COS-7 cells. This may be important in determining the regional specificity in neuronal aging and Alzheimer disease (AD). We assessed the effectiveness of blueberry (BB) and other high antioxidant (HA) fruit extracts (boysenberry, BY; cranberry, CB; black currant, BC; strawberry, SB; dried plums, DP; and grape, GR) on the toxic effects of Abeta 25-35 (100 microM, 24 hrs) and DA (1 mM, 4 hrs) on calcium buffering (Recovery) following oxotremorine (750 microM) -induced depolarization in M1AChR-transfected COS-7 cells, and on cell viability following DA (4 hrs) exposure. The extracts showed differential levels of Recovery protection in comparisons to the non-supplemented controls that was dependent upon whether DA or Abeta was used as the pretreatment. Interestingly, assessments of DA-induced decrements in viability revealed that all of the extracts had some protective effects. These findings suggest that the putative toxic effects of Abeta or DA might be reduced by HA fruit extracts.

Blueberry supplementation improves memory in middle-aged mice fed a high-fat diet.

Consuming a high-fat diet may result in behavioral deficits similar to those observed in aging animals. It has been demonstrated that blueberry supplementation can allay age-related behavioral deficits. To determine if supplementation of a high-fat diet with blueberries offers protection against putative high-fat diet-related declines, 9-month-old C57Bl/6 mice were maintained on low-fat (10% fat calories) or high-fat (60% fat calories) diets with and without 4% freeze-dried blueberry powder. Novel object recognition memory was impaired by the high-fat diet; after 4 months on the high-fat diet, mice spent 50% of their time on the novel object in the testing trial, performing no greater than chance performance. Blueberry supplementation prevented recognition memory deficits after 4 months on the diets, as mice on this diet spent 67% of their time on the novel object. After 5 months on the diets, mice consuming the high-fat diet passed through the platform location less often than mice on low-fat diets during probe trials on days 2 and 3 of Morris water maze testing, whereas mice consuming the high-fat blueberry diet passed through the platform location as often as mice on the low-fat diets. This study is a first step in determining if incorporating more nutrient-dense foods into a high-fat diet can allay cognitive dysfunction.

Effects of conditional central expression of HIV-1 tat protein to potentiate cocaine-mediated psychostimulation and reward among male mice.

As a major neuropathogenic factor associated with human immunodeficiency virus (HIV) infection, HIV-1 Tat protein is known to synergize with psychostimulant drugs of abuse to cause neurotoxicity and exacerbate the progression of central nervous system pathology. However, the functional consequences of the interaction between HIV-1 Tat and abused drugs on behavior are little known. We tested the hypothesis that HIV-1 Tat expression in brain would modulate the psychostimulant effects of cocaine. Using the GT-tg bigenic mouse model, where brain-selective Tat expression is induced by activation of a doxycycline (Dox) promotor, we tested the effects of Tat on cocaine (10 mg/kg, s.c.) induced locomotion and conditioned place preference (CPP). Compared with uninduced littermates or C57BL/6J controls, cocaine-induced hyperlocomotion was sustained for a significantly longer duration among Tat-induced mice. Moreover, although all groups displayed similar saline-CPP, Tat-induced GT-tg mice demonstrated a three-fold increase in cocaine-CPP over the response of either uninduced littermates or Dox-treated C57BL/6J control mice. Induction of Tat also increased the magnitude of a previously established cocaine-CPP after an additional cycle of cocaine place-conditioning. Despite Tat-induced potentiation, extinction of place preference occurred within 21 days, commensurate with cocaine-extinction among saline-treated littermates and C57BL/6J controls. Re-exposure to cocaine produced reinstatement of an equivalent place preference in Tat-induced GT-tg or C57BL/6J mice; however, induction of Tat protein after the extinction of CPP also produced reinstatement without additional exposure to cocaine. Together, these data suggest that central HIV-1 Tat expression can potentiate the psychostimulant behavioral effects of cocaine in mice.

Stilbenes and anthocyanins reduce stress signaling in BV-2 mouse microglia.

Blueberries contain an array of phytochemicals that may decrease both inflammatory and oxidative stress. This study determined if pterostilbene, resveratrol, and two anthocyanins commonly found in blueberries, delphinidin-3-O-glucoside and malvidin-3-O-glucoside, would be efficacious in protecting microglia from inflammatory-induced stress signaling. Microglia that were pretreated with blueberry extract (0.25, 0.5, 1, 2 mg/mL) or its components (1, 10, 20, 30 µM pterostilbene, resveratrol, delphinidin-3-O-glucoside, or malvidin-3-O-glucoside) prior to exposure to lipopolysaccharide (100 ng/mL) demonstrated concentration-dependent reductions in nitric oxide and tumor necrosis factor-alpha release and decreased expression of inducible nitric oxide synthase and cyclooxygenase-2. However, much higher concentrations of the individual components than those found in blueberries were needed to demonstrate the effects. For example, 1 mg/mL blueberry extract significantly reduced LPS-induced nitric oxide release; this concentration of blueberry extract contains 2.6 µM malvidin-3-O-glucoside, but when malvidin-3-O-glucoside was tested individually, 20 µM was necessary to observe a significant reduction in nitric oxide release. Therefore the protective effects of blueberries may not be due to any one component, but rather a synergism of the activity of the compounds tested and/or other blueberry compounds not tested here. These results lend further support that blueberry and its active components are able to combat some of the inflammatory mediators of aging at the cellular level.

Conditional Tat protein expression in the GT-tg bigenic mouse brain induces gray matter density reductions.

Tat (Trans-activator of transcription) is implicated in the neuropathogenesis of HIV-1 infection and known to contribute to neuronal damage and learning and memory impairments. However, direct neuroanatomical demonstration of Tat pathobiology is limited. GT-tg bigenic mice with a doxycycline (Dox)-inducible and brain-selective tat gene were used to test the hypothesis that conditional induction of Tat activity in brain can induce gray matter density abnormalities. Ultra high spatial resolution ex vivo magnetic resonance imaging (MRI) combined with a voxel based morphometry (VBM) analysis revealed gray matter density reductions in the sublenticular extended amygdala, the amygdala, the amygdala-hippocampal area, piriform and peri-/entorhinal cortices, and hypothalamus, in Tat-expressing GT-tg mice compared to Dox-treated C57Bl/6J mice. These neuroanatomical abnormalities are consistent with regions expected to be abnormal based on behavioral deficits exhibited by Tat-expressing mice (Carey et al., 2012). These experiments provide the first neuroimaging evidence that conditional Tat protein expression in the GT-tg bigenic mouse model alters brain structure. The findings warrant future studies to further characterize effects of conditional Tat expression on brain structure. Such studies may improve our understanding of the neurological underpinnings of neuroAIDS and the neurodegeneration associated with HIV-1 infection, potentially leading to new treatments.