The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand.

Background: Paedocypris, a highly developmentally truncated fish from peat swamp forests in Southeast Asia, comprises the world's smallest vertebrate. Although clearly a cyprinid fish, a hypothesis about its phylogenetic position among the subfamilies of this largest teleost family, with over 2400 species, does not exist. Here we present a phylogenetic analyses of 227 cypriniform taxa, including 213 cyprinids, based upon complete mitochondrial DNA cytochrome b nucleotide sequences in order to determine the phylogenetic position of Paedocypris and to study the evolution of miniaturization among cyprinids.

AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal graymatter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis. IntroductionDopaminergic abnormalities have long served as a major framework for understanding the pathophysiology as well as pharmacology of psychosis, such as schizophrenia, and also associated cognitive deficits, particularly those affecting executive function and working memory. Classically, D1 receptors, implicated in the maintenance of relevant information during the working memory delay period (1), couple through Gα s protein to stimulate the production of cAMP and the activity of PKA (2). Conversely, D2 receptors, which in neural models play critical roles marking salience, prediction errors, and updating and manipulating new information (3), couple through Gα i/o protein to reduce cAMP production and PKA activity (2). Downstream from PKA, dopamine-(DA-) and cAMPregulated phosphoprotein of molecular weight 32 (DARPP-32) is a key signaling integrator that regulates an array of subsequent neurophysiological processes (2). Genetic variation in DARPP-32 has recently been found to have an impact on normal human variation in frontostriatal cognitive performance, neostriatal volume and physiologic activation, and functional connectivity between striatum and prefrontal cortex; DARPP-32 has also been implicated in risk for schizophrenia (4). The cAMP/PKA/DARPP-32 pathway, however, is not the only molecular network that transduces DA signals in dopaminoceptive neurons (2).

Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that these genes influence prefrontal physiological signalto-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontalparietal coupling on the background of COMT Val-homozygous genotype. Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.dopamine ͉ functional MRI ͉ genetics ͉ schizophrenia D opaminergic and glutamatergic abnormalities have long served as major theoretical frameworks for understanding the pathophysiology as well as pharmacology of schizophrenia and its cognitive deficits, particularly working memory (1-4). They are also central in the neural dynamics mediating sustained activity of prefrontal neurons during working memory, and in optimizing cortical signal-to-noise (5-10). Locally sustained activity of prefrontal neurons crucial in the maintenance of information during the delay period of working memory tasks (11) seems to be protected against distracters and instability by dopamine-mediated mechanisms (12). This mechanism is likely to be through dopamine D1-receptors (9) and through their role in enhancing NMDA receptor-mediated postsynaptic currents in prefrontal pyramidal neurons active during the delay period (7, 10, 13). Concurrently, D1-receptors seem to cause a tonic increase in the firing of GABAergic inhibitory interneurons, allowing a focused increase in task-relevant activity while reducing that which is not, thus optimizing signal-to-noise (14). Therefore, dopaminergic and glutamatergic (and GABAergic) systems act together in signal-to-noise tuning critical for information processing and should have important interactions of relevance at the in vivo systems level.Less is known, however, about how these molecular and singleneuron paradigms resonate in vivo during prefrontally mediated human executive and cognitive control processes (15, 16). Biophysically based neural network models suggest that the reverberatory complement of excitatory and inhibitory NMDA and dopaminergic (and GABA) mechanisms underlie both persistent activity in working memory as well as its ex...