Docosahexaenoic acid (DHA) is the predominant omega-3 (n-3) polyunsaturated fatty acid (PUFA) found in the brain and can affect neurological function by modulating signal transduction pathways, neurotransmission, neurogenesis, myelination, membrane receptor function, synaptic plasticity, neuroinflammation, membrane integrity and membrane organization. DHA is rapidly accumulated in the brain during gestation and early infancy, and the availability of DHA via transfer from maternal stores impacts the degree of DHA incorporation into neural tissues. The consumption of DHA leads to many positive physiological and behavioral effects, including those on cognition. Advanced cognitive function is uniquely human, and the optimal development and aging of cognitive abilities has profound impacts on quality of life, productivity, and advancement of society in general. However, the modern diet typically lacks appreciable amounts of DHA. Therefore, in modern populations, maintaining optimal levels of DHA in the brain throughout the lifespan likely requires obtaining preformed DHA via dietary or supplemental sources. In this review, we examine the role of DHA in optimal cognition during development, adulthood, and aging with a focus on human evidence and putative mechanisms of action.

Nigrostriatal dopaminergic neurons express many nicotinic acetylcholine receptor (nAChR) subunits capable of forming multiple nAChR subtypes. These subtypes are expressed differentially along the neuron and presumably mediate diverse responses. beta3 subunit mRNA has restricted expression but is abundant in the substantia nigra and ventral tegmental areas. To investigate the potential role(s) of nicotinic receptors containing the beta3 subunit in dopaminergic tracts, we generated mice with a null mutation in the beta3 gene. We were thereby able to identify a population of beta3-dependent alpha-conotoxin MII-binding nAChRs that modulate striatal dopamine release. Changes were also observed in locomotor activity and prepulse inhibition of acoustic startle, behaviors that are controlled, in part, by nigrostriatal and mesolimbic dopaminergic activity, respectively, suggesting that beta3-containing nAChRs modulate these behaviors.

BackgroundAngiogenesis appears to be a first-order event in psoriatic arthritis (PsA). Among angiogenic factors, the cytokines vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factors 1 and 2 (FGF1 and FGF2) play a central role in the initiation of angiogenesis. Most of these cytokines have been shown to be upregulated in or associated with psoriasis, rheumatoid arthritis (RA) or ankylosing spondylitis (AS). As these diseases share common susceptibility associations with PsA, investigation of these angiogenic factors is warranted.MethodsTwo hundred and fifty-eight patients with PsA and 154 ethnically matched controls were genotyped using a Sequenom chip-based MALDI-TOF mass spectrometry platform. Four SNPs in the VEGF gene, three SNPs in the EGF gene and one SNP each in FGF1 and FGF2 genes were evaluated. Statistical analysis was performed using Fisher's exact test, and the Cochrane-Armitage trend test. Associations with haplotypes were estimated by using weighted logistic models, where the individual haplotype estimates were obtained using Phase v2.1.ResultsWe have observed an increased frequency in the T allele of VEGF +936 (rs3025039) in control subjects when compared to our PsA patients [Fisher's exact p-value = 0.042; OR 0.653 (95% CI: 0.434, 0.982)]. Haplotyping of markers revealed no significant associations.ConclusionThe T allele of VEGF in +936 may act as a protective allele in the development of PsA. Further studies regarding the role of pro-angiogenic markers in PsA are warranted.

Nicotinic acetylcholine receptor (nAChR) agonists stimulate the release of GABA from GABAergic nerve terminals, but the nAChR subtypes that mediate this effect have not been elucidated. The studies reported here used synaptosomes derived from the cortex, hippocampus, striatum, and thalamus of wildtype and ␣4-, ␣5-, ␣7-, ␤2-, and ␤4-null mutant mice to identify nAChR subtypes involved in acetylcholine (ACh)-evoked GABA release. ]GABA release revealed biphasic concentration-response relationships in the four brain regions examined from all wild-type animals and in ␣5 null mutant mice. Moreover, a selective reduction in the maximum response of the high-affinity component was apparent in ␣5-null mutant mice. The results demonstrate that ␣4␤2-type nAChRs are critical for ACh-stimulated [ 3 H]GABA release from all four brain regions examined. In addition, the results suggest that ␣5-containing receptors on GABAergic nerve terminals comprise a fraction of the high ACh-sensitivity component of the concentration-response curve and contribute directly to the ability of nicotinic agonists to evoke GABA release in these regions.The nicotinic acetylcholine receptor (nAChR) arguably represents one of the most evolutionarily conserved and well characterized neurotransmitter receptors, and the majority of high-resolution structural data have been accumulated from studies of the torpedo-and muscle-type nAChR (Millar and Gotti, 2009). It is generally believed that the structures of neuronal nAChRs are very similar to the muscle-type nAChR subunits because the amino acid sequences of neuronal nAChR subunits are similar to the muscle-type subunits (Lindstrom et al., 1998). Assuming that the neuronal nAChRs are pentameric assemblies that resemble the peripheral-type nAChR, the fact that mammalian neurons express mRNAs for nine nAChR genes (designated ␣2-␣7 and ␤2-␤4) suggests that many different nAChR subtypes might be expressed in the central nervous system.The importance of identifying the sites of expression and subunit compositions of those nAChRs that are actually expressed in brain is demonstrated by observations that the biophysical and pharmacological properties of nAChRs are affected when different subunit combinations are examined in heterologous expression systems (Zwart and Vijverberg, 1998;Moroni et al., 2006;Kuryatov et al., 2008). Of particular importance is the observation that ␣4␣5␤2 nAChRs are more cation-permeable than other high-affinity heteromeric nAChRs, and the calcium-permeability of these ␣4␣5␤2 nAChRs is exceeded only by ␣7-type nAChRs and N-methyl-D-aspartate glutamate receptors (Kuryatov et al., 2008). Indeed, previous studies performed in our laboratory (Brown et al., 2007) showed that deletion of the ␣5 subunit decreased maximal agonist-evoked 86 Rbϩ efflux in several brain re-

Available evidence indicates that common genes influence alcohol and tobacco abuse in humans. The studies reported here used mouse models to evaluate the hypothesis that genetically determined variability in the alpha4beta2* nicotinic receptor modulates genetically determined variability in the intake of both nicotine and alcohol. Data obtained with inbred mouse strains suggested an association between a polymorphism in the mouse alpha4 nAChR subunit gene, Chrna4, and variability in nicotine and ethanol preference. These associations were assessed in F2 animals derived by crossing C57BL/6-super(beta2-/-) mice and A/J mice. The results obtained by the authors indicate that the polymorphism in Chrna4 plays an important role in modulating variability in oral nicotine intake but is linked to a gene that regulates alcohol intake.