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Dietary fat modulates neuronal health and contributes to age-related nervous system disorders. However, the complex interaction between dietary fat and supplementation and its consequences on neurotoxic pathophysiology has been sparsely explored. The indigenous Alaskan bog blueberry (BB), Vaccinum uliginosum, is known to have anti-inflammatory properties, mostly attributed to its rich polyphenolic content. Here, we evaluate the interplay between dietary fat and BB supplementation on sub-chronic manganese (Mn) exposure that inflicts neurotoxicity and behavioral impairments. In both low-fat and normal-fat diets, BB supplementation attenuated the behavioral and the molecular hallmarks of Mn-induced neurotoxicity. On the contrary, a high-fat diet was found to exacerbate these Mn-induced pathological features. Furthermore, BB supplementation failed to recover the behavioral deficits in mice subjected to a high fat diet in Mn-treated mice. Overall, our results demonstrate the importance of including a dietary regimen comprised of polyphenolic rich supplements with low-fat content in combating age-related neurodegenerative disorders.

Inflammation is a key physiological phenomenon that can be pervasive when dysregulated. Persistent chronic inflammation precedes several pathophysiological conditions forming one of the critical cellular homeostatic checkpoints. With a steady global surge in inflammatory diseases, it is imperative to delineate underlying mechanisms and design suitable drug molecules targeting the cellular partners that mediate and regulate inflammation. Nicotinic acetylcholine receptors have a confirmed role in influencing inflammatory pathways and have been a subject of scientific scrutiny underlying drug development in recent years. Drugs designed to target allosteric sites on the nicotinic acetylcholine receptors present a unique opportunity to unravel the role of the cholinergic system in regulating and restoring inflammatory homeostasis. Such a therapeutic approach holds promise in treating several inflammatory conditions and diseases with inflammation as an underlying pathology. Here, we briefly describe the potential of cholinergic allosterism and some allosteric modulators as a promising therapeutic option for the treatment of neuroinflammation.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurring intrusive thoughts and repetitive compulsive behaviors, ultimately interfering with their quality of life. The complex heterogeneity of symptom dimensions across OCD patient subgroups impedes diagnosis and treatment. The core and comorbid symptomologies of OCD are thought to be modulated by common environmental exposures such as consumption of the psychostimulant caffeine. The effect of caffeine on the expression of obsessions and compulsions are unexplored. The current study utilized mouse strains (HA) with a spontaneous, predictable, and stable compulsive-like phenotype that have face, predictive, and construct validity for OCD. We demonstrate that an acute high dose (25 mg/kg) of caffeine decreased compulsive-like nest-building behavior in the HA strains in the first hour after injection. However, nest-building scores increased in hours 3, 4, and 5 after administration finally decreasing over a 24 h period. In contrast, a high dose of chronic caffeine (25 mg/kg/d) increased nest-building behavior. Interestingly for compulsive-like digging behavior, acute exposure to a high dose of caffeine decreased the number of marbles buried, while chronic exposure had little effect. An acute high dose of caffeine decreased anxiety-like and motor activity in open field behaviors whereas chronic caffeine administration did not have any overall effect on open field activity. The results, therefore, suggest a complex role of caffeine on compulsive-like, anxiety-like, and locomotor behaviors that is dependent on the duration of exposure.

There is ample evidence that obsessive-compulsive disorder (OCD) is based on reduced serotonergic function. Replicated bidirectional selection for thermoregulatory nest-building behavior in the laboratory house mouse (Mus musculus) resulted in compulsive-like, non-compulsive-like and randomly bred control mice that represent a non-induced animal model of OCD. The present study aimed at investigating the neurochemical patterns in specific brain regions of compulsive-like (HA) versus non-compulsive-like (LA) and normal (CA) mice. The neurochemical investigation of several brain regions of the corticostriato-thalamocortical circuity, i.e., nucleus caudatus (CPU), nucleus accumbens (NAc), globus pallidus (GP), hippocampus (HPC), amygdala (AM), ventral tegmental area (VTA) and substantia nigra (SN) was performed by electrochemical (serotonin and dopamine) and fluorescence (glutamate and GABA) HPLC detection. HA mice displayed significantly decreased 5-HT concentrations in the mPFC and LA mice displayed a significant increase in GABA concentrations in the mPFC. This supports the pathophysiological relevance of serotonin in the manifestation of OCD and adding to the construct validity of the non-induced mouse model of OCD.

There is currently a lack of understanding how genetic background and sex differences attribute to the heterogeneity of obsessive-compulsive disorder (OCD). An animal model of compulsive-like behaviors has been developed through bidirectional selection of house mice (Mus musculus) for high (big cotton nests; BIG mice) and low levels (small nests; SMALL mice) of nest-building behavior. The BIG male strains have predictive and face validity as a spontaneous animal model of OCD. Here, we evaluated compulsive-, anxiety-, cognitive-, and depression-like behaviors among male and proestrus female replicate strains each of BIG (BIG1, BIG2) and SMALL (SML1, SML2) nest-builders, and randomly-bred Controls (C1, C2). BIG1 and BIG2 males and females had higher nesting scores when compared to SMALL and Control strains. Male BIG1 and BIG2 strains showed more compulsive-like nesting than BIG1 and BIG2 proestrus females, which was not observed among the other strains. Nesting scores were also different between BIG replicate male strains. A similar pattern was observed in the compulsive-like marble burying behavior with BIG strains burying more marbles than SMALL and Control strains. Significant replicate and sex differences were also observed in marble burying among the BIG strains. The open field test revealed replicate effects while the BIG strains showed less anxiety-like behavior in the elevated plus maze test compared to the SMALL strains. For novel object recognition only the Control strains showed replicate and sex differences. In the depression-like forced swim test proestrus females demonstrated less depression-like behavior than males. BIG and SMALL nest-building strains had a higher corticosterone stress response than the Control strains. Together these results indicate a strong interplay of genetic background and sex in influencing expression of behaviors in our compulsive-like mouse model. These results are in congruence with the clinical heterogeneity of OCD.

Misfolding and accumulation of cellular protein aggregates are pathological hallmarks of aging and neurodegeneration. One such protein is α-synuclein, which when misfolded, forms aggregates and disrupts normal cellular functions of the neurons causing Parkinson’s disease. Nutritional interventions abundant in pharmacologically potent polyphenols have demonstrated a therapeutic role for combating protein aggregation associated with neurodegeneration. The current study hypothesized that Alaskan bog blueberry (Vaccinum uliginosum), which is high in polyphenolic content, will reduce α-synuclein expression in a model of Caenorhabditis elegans (C. elegans). We observed that blueberry extracts attenuated α-synuclein protein expression, improved healthspan in the form of motility and restored lipid content in the transgenic strain of C. elegans expressing human α-synuclein. We also found reduced gene expression levels of sir-2.1 (ortholog of mammalian Sirtuin 1) in blueberry treated transgenic animals indicating that the beneficial effects of blueberries could be mediated through partial reduction of sirtuin activity. This therapeutic effect of the blueberries was attributed to its xenohormetic properties. The current results highlight the role of Alaskan blueberries in mediating inhibition of sir-2.1 as a novel therapeutic approach to improving pathologies of protein misfolding diseases. Finally, our study warrants further investigation of the structure, and specificity of such small molecules from indigenous natural compounds and its role as sirtuin regulators.

The current study evaluated the role of strain and compulsive trait differences in response to fluvoxamine, a common obsessive-compulsive disorder (OCD) drug, in two different mouse strains (BIG1 and BIG2) with a spontaneous compulsive-like phenotype. For compulsive-like nest-building behavior, dose-dependent attenuation of nesting by fluvoxamine was observed for the BIG1 compulsive-like strain during the first hour after administration. No significant differences were found for the BIG2 strain during the first hour, although a dose-dependent trend similar to that in the BIG1 strain was observed. Fluvoxamine dose dependently decreased the number of marbles buried in both strains 1 h after administration. For anxiety-like behaviors in the open field, no significant drug effects were found for the latency to leave the center and the number of line crossings. Significant strain differences were observed, with the BIG2 strain showing higher anxiety-like behaviors and reduced locomotor activity compared with the BIG1 strain. Consequently, this study adds predictive validity to our mouse model of OCD, whereas the anxiety-like differences between the strains add heterogeneity to our mouse model, similar to the heterogeneity observed in OCD.

Using a spontaneous mouse model of obsessive–compulsive disorder (OCD), the current study evaluated the influence of postpartum lactation on the expression of compulsive-like behaviors, SSRI effectiveness, and the putative role of oxytocin and dopamine in mediating these lactation specific behavioral outcomes. Compulsive-like lactating mice were less compulsive-like in nest building and marble burying and showed enhanced responsiveness to fluoxetine (50 mg/kg) in comparison to compulsive-like nonlactating and nulliparous females. Lactating mice exhibited more anxiety-like behavior in the open field test compared to the nulliparous females, while chronic fluoxetine reduced anxiety-like behaviors. Blocking the oxytocin receptor with L368-899 (5 mg/kg) in the lactating mice exacerbated the compulsive-like and depression-like behaviors. The dopamine D2 receptor (D2R) agonist bromocriptine (10 mg/kg) suppressed marble burying, nest building, and central entries in the open field, but because it also suppressed overall locomotion in the open field, activation of the D2R receptor may have inhibited overall activity nonspecifically. Lactation- and fluoxetine-mediated behavioral outcomes in compulsive-like mice, therefore, appear to be partly regulated by oxytocinergic mechanisms. Serotonin immunoreactivity and serum levels were higher in lactating compulsive-like mice compared to nonlactating and nulliparous compulsive-like females. Together, these results suggest behavioral modulation, serotonergic alterations, and changes in SSRI effectiveness during lactation in compulsive-like mice. This warrants further investigation of postpartum events in OCD patients.

Nicotinic α4β2 receptors are the most abundant subtypes of nicotinic acetylcholine receptors (nAChRs) expressed in brain regions implicated in obsessive compulsive disorder (OCD). These receptors are known to modify normal and addictive behaviors by modulating neuronal excitability. Desformylflustrabromine (dFBr) is a novel, positive allosteric modulator (PAM) of high acetylcholine sensitivity (HS) and low acetylcholine sensitivity (LS) α4β2 nAChRs. The present study tested the hypothesis that positive allosteric modulation of α4β2 receptors by dFBr will attenuate compulsive-like behavior in a non-induced compulsive-like mouse model. Male mice (Mus musculus) selected for compulsive-like nesting behavior (NB; 48 animals; 12 per group) received acute (once) and chronic (every day for 32 days) subcutaneous injection of dFBr at 2, 4 and 6 mg/kg doses. Saline was used as a control (0 mg/kg). Compulsive-like NB was assessed after 1, 2, 3, 4, 5 and 24 h, while compulsive-like marble burying (MB) and anxiety-like open field (OF) behaviors were performed 2 h after dFBr administration. In the acute administration protocol, dFBr dose dependently attenuated NB and MB. Rapid effects (1–2 h after drug administration) of dFBr on MB and NB were observed for the chronic administration which was in congruence with the acute study. Chronic administration also revealed sustained suppression of NB by dFBr following 5 weeks of treatment. In both the acute and chronic regimen dFBr did not modulate OF behaviors. This research demonstrates the novel role of positive allosteric modulation of α4β2 nicotinic receptors by dFBr as a translational potential for OCD.

Hibernation is a natural model of neuroprotection and adult synaptic plasticity. NMDA receptors (NMDAR), which play key roles in excitotoxicity and synaptic plasticity, have not been characterized in a hibernating species. Tolerance to excitotoxicity and cognitive enhancement in Arctic ground squirrels (AGS, Spermophilus parryii) suggests that NMDAR expression may decrease in hibernation and increase upon arousal. NMDAR consist of at least one NMDAR1 (NR1) subunit, which is required for receptor function. Localization of NR1 reflects localization of the majority, if not all, NMDAR complexes. The purpose of this study, therefore, was to characterize the distribution of NR1 subunits in AGS central nervous system using immunohistochemistry. In addition, we compare NR1 expression in hippocampus of hibernating AGS (hAGS) and inter-bout euthermic AGS (ibeAGS) and assess changes in cell somata size using NR1 stained sections in three hippocampal sub-regions (CA1, CA3, and dentate gyrus). For the first time, we report that immunoreactivity of anti-NR1 is widely distributed throughout the central nervous system in AGS and is similar to other species. No differences exist in the expression and distribution of NR1 in hAGS and ibeAGS. However, we report a significant decrease in size of hippocampal CA1 and dentate gyrus NR1-expressing neuronal somata during hibernation torpor.

The suprachiasmatic nucleus (SCN) of the hypothalamus houses the main mammalian circadian clock. This clock is reset by light–dark cues and stimuli that evoke arousal. Photic information is relayed directly to the SCN via the retinohypothalamic tract (RHT) and indirectly via the geniculohypothalamic tract, which originates from retinally innervated cells of the thalamic intergeniculate leaflet (IGL). In addition, pathways from the dorsal and median raphe (DR and MR) convey arousal state information to the IGL and SCN, respectively. The SCN regulates many physiological events in the body via a network of efferent connections to areas of the brain such as the habenula (Hb) in the epithalamus, subparaventricular zone (SPVZ) of the hypothalamus and locus coeruleus of the brainstem—areas of the brain associated with arousal and behavioral activation. Substance P (SP) and the neurokinin-1 (NK-1) receptor are present in the rat SCN and IGL, and SP acting via the NK-1 receptor alters SCN neuronal activity and resets the circadian clock in this species. However, the distribution and role of SP and NK-1 in the circadian system of other rodent species are largely unknown. Here we use immunohistochemical techniques to map the novel distribution of SP and NK-1 in the hypothalamus, thalamus and brainstem of the Alaskan northern red-backed vole, Clethrionomys rutilus, a species of rodent currently being used in circadian biology research. Interestingly, the pattern of immunoreactivity for SP in the red-backed vole SCN was very different from that seen in many other nocturnal and diurnal rodents

The circadian rhythm of core body temperature (Tb) was examined in two mouse lines bidirectionally selected for nest-building behavior (small (SNB) and big nest-builders (BNB)). This selection also resulted in more robust circadian organization of wheel-running activity in the SNB compared to the BNB mice. Tb was measured by an e-mitter implanted in the abdominal cavity. The circadian Tb rhythm of the SNB was more robust compared to the BNB regardless of whether the animals had access to a running wheel or not and regardless of the lighting conditions, i.e., 12 h:12 h light:dark (LD) cycle or constant dark (DD). Wheel-running activity rhythms of SNB were more robust in LD and DD compared to BNB. The amplitude of the circadian Tb rhythm increased significantly in response to wheel access in both mouse lines, but was not significantly different between the BNB and SNB. However, BNB tended to have lower amplitudes of circadian Tb rhythm in the absence of running wheels and a larger increase in the amplitude upon access to a running wheel compared to SNB. No differences were found in LD and DD between the lines in mean Tb and wheel-running activity levels. In addition, no differences between the two mouse lines were found in the free-running period of the Tb or wheel-running activity rhythms in DD. Overall, our findings reveal a more robust circadian phenotype of the SNB compared to the BNB.

The master circadian clock, located in the mammalian suprachiasmatic nuclei (SCN), generates and coordinates circadian rhythmicity, i.e., internal organization of physiological and behavioral rhythms that cycle with a near 24-h period. Light is the most powerful synchronizer of the SCN. Although other nonphotic cues also have the potential to influence the circadian clock, their effects can be masked by photic cues. The purpose of this study was to investigate the ability of scheduled feeding to entrain the SCN in the absence of photic cues in four lines of house mouse ( Mus domesticus). Mice were initially housed in 12:12-h light/dark cycle with ad libitum access to food for 6 h during the light period followed by 4–6 mo of constant dark under the same feeding schedule. Wheel running behavior suggested and circadian PER2 protein expression profiles in the SCN confirmed entrainment of the master circadian clock to the onset of food availability in 100% (49/49) of the line 2 mice in contrast to only 4% (1/24) in line 3 mice. Mice from line 1 and line 4 showed intermediate levels of entrainment, 57% (8/14) and 39% (7/18), respectively. The predictability of entrainment vs. nonentrainment in line 2 and line 3 and the novel entrainment process provide a powerful tool with which to further elucidate mechanisms involved in entrainment of the SCN by scheduled feeding.

House mouse lines bidirectionally selected for nest-building behavior show a correlation between number of AVP cells in the suprachiasmatic nuclei (SCN), the master circadian clock in mammals, and level of nest-building behavior as well as a correlation between wheel-running activity and SCN AVP content. Similar genetic correlations between wheel-running activity and nest-building behavior have been reported in house mouse lines selected for increased voluntary wheel-running behavior. These similarities in genetic correlation structure in independently selected mouse lines allowed us to test whether AVP in the SCN and wheel running activity are truly correlated traits under identical testing procedures. In the mouse lines selected for voluntary wheel-running, no difference was found between the lines selected for high levels of voluntary wheel-running and randomly-bred control lines in the number of AVP immunoreactive neurons in the SCN ( F1,6 = 0.09, NS; replicate line effect: F1,22 = 0.05, NS). This finding was confirmed at the level of individual variation, which revealed no relationship between number of AVP neurons in the SCN and total daily activity ( R = -0.086, NS, n = 24), or circadian organization (i.e., the chi-squared periodogram waveform amplitude; R = -0.071, NS). Therefore our data do not support the hypothesis that differences in activity level and the circadian expression of activity in young adult mice are related to differences in the number of AVP-immunoreactive cells in the SCN.

In mammals, circadian rhythms controlled by the suprachiasmatic nuclei are entrained by photic stimuli. To investigate the molecular mechanism of photic entrainment, we examined light-induced behavioral phase delays and associated changes in mPer1 and mPer2 gene expression in the suprachiasmatic nuclei of two mouse lines artificially selected for nest-building behavior. Big nest-builders show larger phase delays than small nestbuilders. Light-induced mPer1 and mPer2 expression was examined in individual mice previously tested for phase shifting at circadian time 16. Light-induced mPer2 expression was significantly higher in big compared to small nest-builders. No difference was found between lines in light-induced mPer1 expression. The results suggest a more important role for mPer2 than for mPer1 gene expression in behavioral phase delays. NeuroReport 14:1247‐1251 & 2003 Lippincott Williams & Wilkins.

The endogenous circadian clock of the mammalian suprachiasmatic nucleus (SCN) can be reset by light to synchronize the biological clock of the brain with the external environment. This process involves induction of immediate-early genes such as the circadian clock gene Period1 (Per1) and results in a stable shift in the timing of behavioral and physiological rhythms on subsequent days. The mechanisms by which gene activation permanently alters the phase of clock neuron activity are unknown. To study the relationship between acute gene activation and persistent changes in the neurophysiology of SCN neurons, we recorded from SCN neurons marked with a dynamic green fluorescent protein (GFP) reporter of Per1 gene activity. Phase-resetting light pulses resulted in Per1 induction in a distinct subset of SCN neurons that also exhibited a persistent increase in action potential frequency 3‐5 hr after a light pulse. By simultaneously quantifying Per1 gene activation and spike frequency in individual neurons, we found that the degree of Per1 induction was highly correlated with neuronal spike frequency on a cell-by-cell basis. Increased neuronal activity was mediated by membrane potential depolarization as a result of a reduction in outward potassium current. Double-label immunocytochemistry revealed that vasoactive intestinal peptide (VIP)-expressing cells, but not arginine vasopressin (AVP)-expressing cells, exhibited significant Per1 induction by light pulses. Rhythmic GFP expression occurred in both VIP and AVP neurons. Our results indicate that the steps that link acute molecular events to permanent changes in clock phase involve persistent suppression of potassium current, downstream of Per1 gene induction, in a specific subset of Per1-expressing neurons enriched for VIP.

A key to advancing the understanding of obsessive-compulsive disorder (OCD)-like symptoms is the development of spontaneous animal models. Over 55 generations of bidirectional selection for nest-building behavior in house mice, Mus musculus, resulted in a 40-fold difference in the amount of cotton used for a nest in high (BIG) and low (SMALL) selected lines. The nesting behavior of BIG mice appears to be compulsive-like and has initial face validity as an animal model for OCD in humans. Compulsive-like digging behavior was assessed: BIG male mice buried about three times as many marbles as SMALL male mice, strengthening face validity. Using the open field and elevated plus maze, SMALL male mice showed higher levels of anxiety/fear-like behavior than BIG male mice, indicating that compulsive-like and not anxiety-like behavior was measured. To establish predictive validity, chronic (4 weeks) oral administration of fluoxetine (30,50 and 100 mg/kg/day) and clomipramine (80 mg/kg/day), both effective in treating OCD, significantly reduced compulsive-like nest-building behavior in BIG male mice. Compulsive-like digging behavior was also significantly reduced by chronic oral fluoxetine (30 and 80 mg/kg/day) treatment in BIG male mice. General locomotor activity was not affected by chronic oral fluoxetine (30 and 80 mg/kg/day) treatment; chronic oral treatment with desipramine (30 mg/kg/day), an antidepressant not effective in treating OCD, had no effect on nesting behavior of BIG male mice, strengthening predictive validity. Together, the results indicate that these mice have good face and predictive validity as a non-induced mouse model of compulsive-like behavior relevant to OCD. (C) 2011 Elsevier B.V. All rights reserved.

OBJECTIVES: Arctic and northern peoples are spread across Alaska, Canada, Russia and the Scandinavian countries. Inhabiting a variety of ecosystems, these 4 million residents include Indigenous populations who total about 10% of the population. Although Arctic peoples have very diverse cultural and social systems, they have health issues related to environmental impacts and knowledge/treatment disparities that are common to other minority and Indigenous peoples around the world. Research that explores the neuroscience and behavioural aspects of these health disparities offers challenges and significant opportunities. As the next generation of neuroscientists enter the field, it is imperative that they view their contributions in terms of translational medicine to address health disparities. STUDY DESIGN: A workshop was designed to bring neuroscientists together to report on the current directions of neuroscience research and how it could impact health disparities in the North. This workshop produced research recommendations for the growth of neuroscience in the North. METHODS: On May 31, 2006 the National Institute of Neurological Disorders and Stroke, the Burroughs Wellcome Foundation, the Arctic Division of AAAS and the University of Alaska co-sponsored a workshop entitled "Arctic Peoples and Beyond: Decreasing Health Disparities through Basic and Clinical Research." Also, the role and goals of the International Union for Circumpolar Health (IUCH) were presented at the meeting. RESULTS: A set of recommendations related to research opportunities in neuroscience and behaviour research and ways to facilitate national and international partnerships were developed. CONCLUSIONS: These recommendations should help guide the development of future health research in circumpolar neuroscience and behaviour. They provide ideas about research support and informational exchange that will address health challenges. Keywords: behaviour; brain disease; health disparity research; international collaboration; SIDS; stroke (Int J Circumpolar Health 2007; 66(3):264-275)

Arctic and subarctic environments are exposed to extreme light: dark (LD) regimes, including periods of constant light (LL) and constant dark (DD) and large daily changes in day length, but very little is known about circadian rhythms of mammals at high latitudes. The authors investigated the circadian rhythms of a subarctic population of northern red-backed voles ( Clethrionomys rutilus). Both wild-caught and third-generation laboratory-bred animals showed predominantly nocturnal patterns of wheel running when exposed to a 16:8 LD cycle. In LL and DD conditions, animals displayed large phenotypic variation in circadian rhythms. Compared to wheel-running rhythms under a 16:8 LD cycle, the robustness of circadian activity rhythms decreased among all animals tested in LLand DD (i.e., decreased chi-squared periodogram waveform amplitude). A large segment of the population became noncircadian (60% in DD, 72% in LL) within 8 weeks of exposure to constant lighting conditions, of which the majority became ultradian, with a few individuals becoming arrhythmic, indicating highly labile circadian organization. Wild-caught and laboratory-bred animals that remained circadian in wheel running displayed free-running periods between 23.3 and 24.8 h. A phase-response curve to light pulses in DD showed significant phase delays at circadian times 12 and 15, indicating the capacity to entrain to rapidly changing day lengths at high latitudes. Whether this phenotypic variation in circadian organization, with circadian, ultradian, and arrhythmic wheel-running activity patterns in constant lighting conditions, is a novel adaptation to life in the arctic remains to be elucidated.