Atypical neural self-representation in autism

The 'self' is a complex multidimensional construct deeply embedded and in many ways defined by our relations with the social world. Individuals with autism are impaired in both self-referential and other-referential social cognitive processing. Atypical neural representation of the self may be a key to understanding the nature of such impairments. Using functional magnetic resonance imaging we scanned adult males with an autism spectrum condition and age and IQ-matched neurotypical males while they made reflective mentalizing or physical judgements about themselves or the British Queen. Neurotypical individuals preferentially recruit the middle cingulate cortex and ventromedial prefrontal cortex in response to self compared with other-referential processing. In autism, ventromedial prefrontal cortex responded equally to self and other, while middle cingulate cortex responded more to other-mentalizing than self-mentalizing. These atypical responses occur only in areas where self-information is preferentially processed and does not affect areas that preferentially respond to other-referential information. In autism, atypical neural self-representation was also apparent via reduced functional connectivity between ventromedial prefrontal cortex and areas associated with lower level embodied representations, such as ventral premotor and somatosensory cortex. Furthermore, the magnitude of neural self-other distinction in ventromedial prefrontal cortex was strongly related to the magnitude of early childhood social impairments in autism. Individuals whose ventromedial prefrontal cortex made the largest distinction between mentalizing about self and other were least socially impaired in early childhood, while those whose ventromedial prefrontal cortex made little to no distinction between mentalizing about self and other were the most socially impaired in early childhood. These observations reveal that the atypical organization of neural circuitry preferentially coding for self-information is a key mechanism at the heart of both self-referential and social impairments in autism.

Shared neural circuits for mentalizing about the self and others

Although many examples exist for shared neural representations of self and other, it is unknown how such shared representations interact with the rest of the brain. Furthermore, do high-level inference-based shared mentalizing representations interact with lower level embodied/simulation-based shared representations? We used functional neuroimaging (fMRI) and a functional connectivity approach to assess these questions during high-level inference-based mentalizing. Shared mentalizing representations in ventromedial prefrontal cortex, posterior cingulate/precuneus, and temporo-parietal junction (TPJ) all exhibited identical functional connectivity patterns during mentalizing of both self and other. Connectivity patterns were distributed across low-level embodied neural systems such as the frontal operculum/ventral premotor cortex, the anterior insula, the primary sensorimotor cortex, and the presupplementary motor area. These results demonstrate that identical neural circuits are implementing processes involved in mentalizing of both self and other and that the nature of such processes may be the integration of low-level embodied processes within higher level inference-based mentalizing.

Regional response differences across the human amygdaloid complex during social conditioning

The amygdala is consistently implicated in biologically relevant learning tasks such as Pavlovian conditioning. In humans, the ability to identify individual faces based on the social outcomes they have predicted in the past constitutes a critical form of associative learning that can be likened to “social conditioning.” To capture such learning in a laboratory setting, participants learned about faces that predicted negative, positive, or neutral social outcomes. Participants reported liking or disliking the faces in accordance with their learned social value. During acquisition, we observed differential functional magnetic resonance imaging activation across the human amygdaloid complex consistent with previous lesion, electrophysiological, and functional neuroimaging data. A region of the medial ventral amygdala and a region of the dorsal amygdala/substantia innominata showed signal increases to both Negative and Positive faces, whereas a lateral ventral region displayed a linear representation of the valence of faces such that Negative > Positive > Neutral. This lateral ventral locus also differed from the dorsal and medial loci in that the magnitude of these responses was more resistant to habituation. These findings document a role for the human amygdala in social learning and reveal coarse regional dissociations in amygdala activity that are consistent with previous human and nonhuman animal data.

Morphological and molecular characteristics of a new species of Pasteuria parasitic on Meloidogyne ardenensis

A species of the hyper-parasitic bacterium Pasteuria was isolated from the root-knot nematode Meloidogyne ardenensis infecting the roots of ash (Fraxinus excelsior). It is morphologically different from some other Pasteuria pathogens of nematodes in that the spores lack a basal ring on the ventral side of the spore and have a unique clumping nature. Transmission electron microscopy (TEM) showed that the clumps of spores are not random aggregates but result from the disintegration of the suicide cells of the thalli. Sporulation within each vegetative mycelium was shown to be asynchronous. In addition to the novel morphological features 16S rRNA sequence analysis showed this to be a new species of Pasteuria which we have called P. hartismeri. Spores of P. hartismeri attach to juveniles of root-knot nematodes infecting a wide range of plants such as mint (Meloidogyne hapla), rye grass (unidentified Meloidogyne sp.) and potato (Meloidogyne fallax). (c) 2007 Elsevier Inc. All rights reserved.

Restricted expression of NADPH oxidase/peroxidase gene (Duox) in zone VII of the ascidian endostyle

The ascidian Ciona intestinalis, a marine invertebrate chordate, is an emerging model system for developmental and evolutionary studies. The endostyle, one of the characteristic organs of ascidians, is a pharyngeal structure with iodine-concentrating and peroxidase activities and is therefore considered to be homologous to the follicular thyroid of higher vertebrates. We have previously reported that a limited part of the endostyle (zone VII) is marked by the expression of orthologs of the thyroid peroxidase (TPO) and thyroid transcription factor-2 (TTF-2/FoxE) genes. In this study, we have identified the Ciona homolog of NADPH oxidase/peroxidase (Duox), which provides hydrogen peroxide (H2O2) for iodine metabolism by TPO in the vertebrate thyroid. Expression patterns assessed by in situ hybridization have revealed that Ciona Duox (Ci-Duox) is predominantly expressed in the dorsal part of zone VII of the endostyle. Furthermore, two-color fluorescent in situ hybridization with Ci-Duox and Ciona TPO (CiTPO) has revealed that the ventral boundary of the Ci-Duox domain of expression is more dorsal than that of CiTPO. We have also characterized several genes, such as Ci-Fgf8/17/18, 5HT7, and Ci-NK4, which are predominantly expressed in the ventral part of zone VII, in a region complementary to the Ci-Duox expression domain. These observations suggest that, at the molecular level, zone VII has a complex organization that might have some impact on the specification of cell types and functions in this thyroid-equivalent element of the ascidian endostyle.

Plumatella geimermassardi, a newly recognized freshwater bryozoan from Britain, Ireland, and continental Europe (Bryozoa : Phylactolaemata)

Plumatella geimermassardi is a newly recognized species of phylactolaemate bryozoan. Its known range extends from Ireland east through southern Norway and south into Italy. Colonies grow close to the substrate with little free branching; the body wall is mostly transparent and without an obvious raphe. Floatoblasts are broadly oval and relatively small, with distinctively large dorsal fenestra and uniformly narrow ventral annulus. The sessoblast basal valve is low and dish-shaped; the annulus bears tubercles which vary in their prominence. This species brings to 14 the number of phylactolaemate bryozoans known in the region.

Flavonoids and cognition: The molecular mechanisms underlying their behavioural effects

Evidence Suggests that a group of phytochemicals known as flavonoids are highly effective in reversing age-related declines in neuro-cognitive performance through their ability to interact with the cellular and molecular architecture of the brain responsible for memory and by reducing neuronal loss due to neurodegenerative Processes. In particular, they may increase the number of, and strength of, connections between neurons, via their specific interactions with the ERK and Akt signalling pathways, leading to an increase in neurotrophins Such as BDNF. Concurrently, their effects on the peripheral and Cerebral vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Finally, they have also been shown to reduce neuronal damage and losses induced by various neurotoxic species and neuroinflammation. Together, these processes act to maintain the number and quality of synaptic connections in the brain. a factor known to be essential for efficient LTP, synaptic plasticity and ultimately the efficient working of memory. (C) 2009 Elsevier Inc. All rights reserved.

Flavonoids and brain health: multiple effects underpinned by common mechanisms

The neuroprotective actions of dietary flavonoids involve a number of effects within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognitive function. This multiplicity of effects appears to be underpinned by two processes. Firstly, they interact with important neuronal signalling cascades leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and differentiation. These interactions include selective actions on a number of protein kinase and lipid kinase signalling cascades, most notably the PI3K/Akt and MAP kinase pathways which regulate pro-survival transcription factors and gene expression. Secondly, they induce peripheral and cerebral vascular blood flow in a manner which may lead to the induction of angiogenesis, and new nerve cell growth in the hippocampus. Therefore, the consumption of flavonoid-rich foods, such as berries and cocoa, throughout life holds a potential to limit the neurodegeneration associated with a variety of neurological disorders and to prevent or reverse normal or abnormal deteriorations in cognitive performance.

The impact of flavonoids on memory: physiological and molecular considerations

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory acquisition, consolidation, storage and retrieval. These low molecular weight polyphenols are widespread in the human diet, are absorbed to only a limited degree and localise in the brain at low concentration. However, they have been found to be highly effective in reversing age-related declines in memory via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. These interactions include an ability to activate signalling pathways, critical in controlling synaptic plasticity, and a potential to induce vascular effects capable of causing new nerve cell growth in the hippocampus. Their ability to activate the extracellular signal-regulated kinase (ERK1/2) and the protein kinase B (PKB/Akt) signalling pathways, leading to the activation of the cAMP response element-binding protein (CREB), a transcription factor responsible for increasing the expression of a number of neurotrophins important in de. ning memory, will be discussed. How these effects lead to improvements in memory through induction of synapse growth and connectivity, increases in dendritic spine density and the functional integration of old and new neurons will be illustrated. The overall goal of this critical review is to emphasize future areas of investigation as well as to highlight these dietary agents as promising candidates for the design of memory-enhancing drugs with relevance to normal and pathological brain ageing (161 references).

Age-associated changes in protein oxidation and proteasome activities in rat brain: modulation by antioxidants

The free radical theory of ageing postulates that age-associated neurodegeneration is caused by an imbalance between pro-oxidants and antioxidants resulting in oxidative stress. The current study showed regional variation in brain susceptibility to age-associated oxidative stress as shown by increased lipofuscin deposition and protein carbonyl levels in male rats of age 15-16 months compared to control ones (3-5 months). The hippocampus is the area most vulnerable to change compared to the cortex and cerebellum. However, proteasomal enzyme activity was not affected by age in any of the brain regions studied. Treatment with melatonin or coenzyme Q10 for 4 weeks reduced the lipofuscin content of the hippocampus and carbonyl level. However, both melatonin and coenzyme Q10 treatments inhibited beta-glutamyl peptide hydrolase activity. This suggests that these molecules can alter proteasome function independently of their antioxidant actions. (c) 2005 Elsevier Inc. All rights reserved.

Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels

Phytochemical-rich foods have been shown to be effective at reversing age-related deficits in memory in both animals and humans. We show that a supplementation with a blueberry diet (2% w/w) for 12 weeks improves the performance of aged animals in spatial working memory tasks. This improvement emerged within 3 weeks and persisted for the remainder of the testing period. Memory performance correlated well with the activation of cAMP-response element-binding protein (CREB) and increases in both pro- and mature levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. Changes in CREB and BDNF in aged and blueberry-supplemented animals were accompanied by increases in the phosphorylation state of extracellular signal-related kinase (ERK1/2), rather than that of calcium calmodulin kinase (CaMKII and CaMKIV) or protein kinase A. Furthermore, age and blueberry supplementation were linked to changes in the activation state of Akt, mTOR, and the levels of Arc/Arg3.1 in the hippocampus, suggesting that pathways involved in de novo protein synthesis may be involved. Although causal relationships cannot be made among supplementation, behavior, and biochemical parameters, the measurement of anthocyanins and flavanols in the brain following blueberry supplementation may indicate that changes in spatial working memory in aged animals are linked to the effects of flavonoids on the ERK-CREB-BDNF pathway. (c) 2008 Elsevier Inc. All Fights reserved.

Motor brain regions are involved in the encoding of delayed intentions: a fMRI study

In studies of prospective memory, recall of the content of delayed intentions is normally excellent, probably because they contain actions that have to be enacted at a later time. Action words encoded for later enactment are more accessible from memory than those encoded for later verbal report [Freeman, J.E., and Ellis, J.A. 2003a. The representation of delayed intentions: A prospective subject-performed task? Journal of Experimental Psychology: Learning, Memory, and Cognition, 29, 976-992.]. As this higher assessibility is lost when the intended actions have to be enacted during encoding, or when a motor interference task is introduced concurrent to intention encoding, Freeman and Ellis suggested that the advantage of to-be-enacted actions is due to additional preparatory motor operations during encoding. Accordingly, in a fMRI study with 10 healthy young participants, we investigated whether motor brain regions are differentially activated during verbal encoding of actions for later enactment with the right hand in contrast to verbal encoding of actions for later verbal report. We included an additional condition of verbal encoding of abstract verbs for later verbal report to investigate whether the semantic motor information inherent in action verbs in contrast to abstract verbs activates motor brain regions different from those involved in the verbal encoding of actions for later enactment. Differential activation for the verbal encoding of to-be-enacted actions in contrast to to-be-reported actions was found in brain regions known to be involved in covert motor preparation for hand movements, i.e. the postcentral gyrus, the precuneus, the dorsal and ventral premotor cortex, the posterior middle temporal gyrus and the inferior parietal lobule. There was no overlap between these brain regions and those differentially activated during the verbal encoding of actions in contrast to abstract verbs for later verbal report. Consequently, the results of this fMRI study suggest the presence of preparatory motor operations during the encoding of delayed intentions requiring a future motor response, which cannot be attributed to semantic information inherent to action verbs. (c) 2006 Elsevier B.V. All rights reserved.

The roles of perirhinal cortex, postrhinal cortex, and the fornix in memory for objects, contexts, and events in the rat

Investigation of the anatomical substructure of the medial temporal lobe has revealed a number of highly interconnected areas, which has led some to propose that the region operates as a unitary memory system. However, here we outline the results of a number of studies from our laboratories, which investigate the contributions of the rat's perirhinal cortex and postrhinal cortex to memory, concentrating particularly on their respective roles in memory for objects. By contrasting patterns of impairment and spared abilities on a number of related tasks, we suggest that perirhinal cortex and postrhinal cortex make distinctive contributions to learning and memory: for example, that postrhinal cortex is important in learning about within-scene position and context. We also provide evidence that despite the strong connectivity between these cortical regions and the hippocampus, the hippocampus, as evidenced by lesions of the fornix, has a distinct function of its own-combining information about objects, positions, and contexts.

Soya phytoestrogens change cortical and hippocampal expression of BDNF mRNA in male rats

Adult male hooded Lister rats were either fed a diet containing 150 microg/g soya phytoestrogens or a soya-free diet for 18 days. This concentration of phytoestrogens should have been sufficient to occupy the oestrogen-beta, but not the oestrogen-alpha, receptors. Using in situ hybridisation, significant reductions were found in brain-derived neurotrophic factor (BDNF) mRNA expression in the CA3 and CA4 region of the hippocampus and in the cerebral cortex in the rats fed the diet containing phytoestrogens, compared with those on the soya-free diet. No changes in glutamic acid decarboxylase-67 or glial fibrillary acidic protein mRNA were found. This suggests a role for oestrogen-beta receptors in regulating BDNF mRNA expression.

Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting

Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making.