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Purpose: Oxidative and inflammatory processes play a major role in stress-induced neural atrophy. There is a wide body of literature linking oxidative and inflammatory stress with reductions in neurotrophic factors, stress resilience, and cognitive function. Based on their antioxidant and anti-inflammatory capacity, we investigated the effect of the dietary carotenoids lutein and zeaxanthin, along with the zeaxanthin isomer meso-zeaxanthin (collectively the "macular xanthophylls" [MXans]) on systemic brain-derived neurotrophic factor (BDNF) and anti-oxidant capacity (AOC), and the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. To investigate higher-order effects, we assessed cognitive performance., Methods: 59 young (18-25 yrs.), healthy subjects participated in a 6-month, double-blind, placebo-controlled trial to evaluate the effects of MXan supplementation on the aforementioned serum parameters and cognitive performance. Subjects were randomly assigned to one of three groups: placebo, 13 mg, or 27 mg/day total MXans; all measures were taken at baseline and 6 months. Blood was obtained via fasting blood draw, and MXan concentration in the retina (termed macular pigment optical density [MPOD]) was measured via customized heterochromatic flicker photometry. Serum BDNF and cytokines were assessed via ELISA. Serum antioxidant capacity (AOC) and serum MXan concentrations were quantified via colorimetric microplate assay, and high-performance liquid chromatography, respectively. Cognitive performance was measured via a computer-based assessment tool (CNS Vital Signs)., Results: BDNF, MPOD, serum MXans, and AOC all increased significantly versus placebo in both treatment groups over the 6-month study period (p < .05 for all). IL-1β decreased significantly versus placebo in both treatment groups (p = .0036 and p = .006, respectively). For cognitive measures, scores for composite memory, verbal memory, sustained attention, psychomotor speed, and processing speed all improved significantly in treatment groups (p < .05 for all) and remained unchanged in the placebo group. Several measures were found to be significantly associated in terms of relational changes over the course of the study. Notably, change in BDNF was related to change in IL-1β (r = -0.47; p < .001) and MPOD (r = 0.44; p = .0086). Additionally, changes in serum MXans were strongly related to AOC (r = 0.79 & 0.61 for lutein and zeaxanthin isomers respectively; p < .001). For cognitive scores, change in BDNF was correlated to change in composite memory (r = 0.32; p = .014) and verbal memory (r = 0.35; p = .007), whereas change in MPOD was correlated with change in both psychomotor speed (r = 0.38; p = .003), and processing speed (r = 0.35; p = .007). Change in serum lutein was found to be significantly correlated to change in verbal memory (r = 0.41; p < .001), composite memory (r = 0.31; p = .009), and sustained attention (r = 0.28; p = .036). Change in serum zeaxanthin isomers was significantly correlated with change in verbal memory (r = 0.33; p = .017). Lastly, change in AOC was significantly associated with verbal memory (r = 0.34; p = .021), composite memory (r = 0.29; p = .03), and sustained attention (r = 0.35; p = .016). No significant relational changes in any cognitive parameter were found for the placebo group., Conclusions: Six months of daily supplementation with at least 13 mg of MXans significantly reduces serum IL-1β, significantly increases serum MXans, BDNF, MPOD, and AOC, and improves several parameters of cognitive performance. Findings suggest that increased systemic antioxidant/anti-inflammatory capacity (and not necessarily deposition of the carotenoids in neural tissues), may explain many of the effects determined in this study. The significant relationship between change in BDNF and IL-1β over the course of the study suggests that regular consumption of MXans interrupts the inflammatory cascade that can lead to reduction of BDNF. Changes in MPOD and BDNF appear to account for enhancement in cognitive parameters that involve speed of processing and complex processing, respectively. ISRCTN Clinical Trial Registration: ISRCTN16156382., (Copyright © 2019. Published by Elsevier Inc.)

I. J. Scherer, P. V. Holmes, R. B.S. Harris. The importance of corticosterone in mediating restraint-induced weight loss in rats. PHYSIOL BEHAV 00 (0) 000-000, 2010. Rats restrained for 3 h/day for 3d ays (RR) lose weight and do not return to the weight of non-restrained controls once restraint has ended. This study tested the importance of restraint-induced corticosterone release in mediating the change in body weight by injecting ADX rats with 2.0mg corticosterone/kg before each restraint to replicate the restraint-induced surge in circulating corticosterone. Restrained adrenalectomized (ADX) rats injected with corticosterone had the same initial weight loss as intact restrained rats, whereas corticosterone injection in non-restrained ADX rats and restraint of ADX rats injected with saline each produced only half as much initial weight loss. Sustained weight loss, measured for 14 days after the end of RR, was the same for restrained intact rats and restrained ADX rats injected with corticosterone whereas restrained ADX rats injected with saline achieved the same weight gain as their controls. Corticosterone injections had no effect on weight gain of non-restrained intact rats. In situ hybridization showed that corticotropin releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) was increased by the same degree in ADX rats and restrained intact rats and was not modified by corticosterone injections. There was no significant effect of restraint, ADX or corticosterone injection on PVN arginine vasopressin (AVP) mRNA expression. These data indicate that a surge in corticosterone causes sustained weight loss in ADX rats through a mechanism that can be compensated for in intact rats and is independent of changes in PVN CRF or AVP mRNA expression., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Unlabelled: Chronic activity-wheel running enhances male copulation and is associated with brain noradrenergic adaptations that may be modulated by the neuropeptide galanin (GAL). When injected into the medial pre-optic area (MPOA) of the hypothalamus, norepinephrine facilitates, and the beta-adrenoreceptor antagonist propranolol inhibits, male copulation. The present experiment tested whether chronic exercise mitigates copulatory decrements induced by adrenergic blockade in the MPOA. It was hypothesized that 3 weeks of activity-wheel running would (1) reverse deficits in male copulatory performance and (2) increase GAL mRNA in the MPOA after beta-adrenoreceptor blockade with propranolol., Materials and Methods: Long-Evans male rats were randomly assigned to three experimental groups: sedentary/propranolol, activity-wheel/propranolol, and home-cage control. Animals were chronically administered propranolol in saline vehicle (6 microm/day) via an osmotic mini-pump connected to a cannula implanted into the third ventricle. After 3 weeks of activity-wheel running, rats underwent copulatory testing. After rapid decapitation 24h later, rat brains were analyzed utilizing in situ hybridization histochemistry for GAL mRNA in the MPOA., Results: Chronic exercise mitigated reductions in the percentage of males that intromitted and ejaculated after propranolol treatment, but there was no effect of exercise on GAL mRNA., Conclusion: The findings are consistent with noradrenergic adaptations in the MPOA that facilitate male copulation after wheel running independently of GAL mRNA expression.

We examined the effects of chronic activity wheel running and imipramine administration on appetitive behavior after olfactory bulbectomy (OBX). Male Long-Evans rats were randomly assigned to the following conditions using a 2 x 2 x 2 design: (1) bilateral OBX or sham surgery, (2) voluntary activity wheel running or sedentary home cage, and (3) daily imipramine or saline injections. After 21 days of treatment, animals underwent behavioral testing for copulatory activity and sucrose preference. Bulbectomized animals exhibited decrements in copulatory performance and reductions in sucrose intake compared to sham animals. Within the bulbectomized groups, imipramine-treated rats either did not copulate or had reduced ejaculation frequencies. However, activity wheel running attenuated the copulatory deficits induced by OBX. The findings encourage studies of physical activity and male sexual dysfunction among depressed men being treated by pharmacotherapy., (Copyright 2004 Elsevier Inc.)

Olfactory bulbectomy (OBX) in rats produces behavioral, physiological, and neurochemical changes that resemble symptoms of depression in humans. The procedure thus serves as a rodent model of affective disorder. Many of the behavioral effects of OBX resemble psychomotor agitation. The possible role of dysregulation of ventral striatal dopamine (DA) systems in this phenomenon was investigated. Basal levels of DA, norepinephrine (NE), homovanillic acid, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were examined in the striatum of OBX and sham-operated controls using in vivo microdialysis. OBX rats exhibited significantly higher basal DA levels (192%) and lower NE levels (12%) than sham-operated controls. Locomotor activity in response to novelty and footshock stress was elevated in OBX rats. The finding of higher DA levels in striatum may explain this "agitation-like" behavior, a commonly observed phenomenon in the OBX model.

Intracerebroventricular administration of neuropeptide Y (NPY) has been shown to reduce anxiety-like effects in rodents and also profoundly alter feeding. The area postrema-lesioned (APX) rat model of food motivated behavior overconsumes palatable foods and expresses significantly higher levels of NPY in the hypothalamus than sham-lesioned control rats. For this reason, we examined APX rats in the open field test, which is a standard measure of anxiety- or fear-related behavior and also investigated NPY mRNA levels in the hippocampus, amygdala and hypothalamus. We found that APX rats display reduced anxiety-like behavior in the open field test as indicated by spending increased time in the center of the field as opposed to the perimeter of the field. NPY mRNA levels were also found to be significantly elevated in the amygdala, hippocampus and arcuate nucleus of the hypothalamus of APX rats when compared to sham-lesioned rats. These results support the action of limbic NPY to reduce anxiety-like behavior in a rodent model that appears to express higher than normal NPY levels., (Copyright 2002 Elsevier Science Inc.)

The effects of neuropeptide-Y were examined in the forced swim model of depression in rats. Following a 15-min preswim, four groups of rats were given three intracerebroventricular (i.c.v.) injections of neuropeptide-Y (0.5, 5, or 10 microg) or saline over a 24-h period. Several behaviors were subsequently measured during a 5-min forced swim. Neuropeptide-Y treatment dose dependently increased swimming and decreased immobility. The pattern of results is consistent with that produced by serotonergic antidepressant drugs in this model.

The aim of the present studies was to determine the extent to which changes in defensive behaviors could account for some of the behavioral effects of bilateral olfactory bulbectomy (OBX) in rats. Four tests of aversively-motivated behavior were conducted in bulbectomized and sham-operated rats: activity in a dimly lit or brightly lit open field, passive avoidance, foot shock-induced freezing, and defensive withdrawal. OBX reduced the duration of immobility in the open field. Bulbectomized rats exhibited less freezing in response to foot shock than sham-operated rats. In the defensive-withdrawal test, bulbectomized rats made more transitions into and spent less time inside the covered enclosure than sham-operated rats. The experiments thus reveal two novel paradigms for assessing the behavioral effects of OBX. The results also suggest that deficits in aversively-motivated behavior, specifically defensive freezing, may comprehensively explain the putative "hyperactivity" and "passive-avoidance learning deficits" widely associated with the OBX behavioral syndrome.

Bilateral olfactory bulbectomy in the rat produces a well-characterized syndrome that is independent of anosmia. This syndrome is reversed by chronic antidepressant administration, which provides the basis for the olfactory bulbectomy model of depression. The present experiments focused on neuropeptide plasticity in central olfactory/limbic structures following olfactory bulbectomy in rats. Male Sprague-Dawley rats received bilateral surgical ablation of the olfactory bulbs, sham surgery, or no surgery and were killed either three, seven, 14 or 28 days later. Relative levels of messenger RNA encoding neuropeptide Y, somatostatin, thyrotropin-releasing hormone, and corticotropin-releasing factor precursors in the forebrain were measured by quantitative in situ hybridization histochemistry using oligonucleotide probes. Prepro-neuropeptide Y messenger RNA levels in the piriform cortex and dentate gyrus were significantly elevated in bulbectomized rats 14 and 28 days after surgery compared to sham-operated and surgically naive rats. Prepro-somatostatin messenger RNA levels in the piriform cortex were marginally increased in bulbectomized rats at these time-points. Thyrotropin-releasing hormone and corticotropin-releasing factor precursor messenger RNA levels were not altered in the brain regions studied. The results indicate that olfactory bulbectomy causes long-term increases in the expression of the neuropeptide Y gene. These findings suggest that neuropeptide Y plasticity in the olfactory/limbic system may contribute to the olfactory bulbectomy syndrome in rats, and they provide further evidence of a role for neuropeptide Y in the pathophysiology of depression.

The effects of acute exposure to angiotensin II (AII) on the renal peripheral benzodiazepine receptor were studied in rats. As little as 37.5 micrograms of AII injected s.c. over an 80 min period caused immediate reductions in [3H]Ro5-4864 binding. Scatchard analysis revealed that the reduction in [3H]Ro5-4864 binding induced by AII was due to a drop in receptor density or Bmax. The influence of AII on the peripheral benzodiazepine receptor is similar to that of stress.