Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation

Insulin resistance and diabetes might promote neurodegenerative disease, but a molecular link between these disorders is unknown. Many factors are responsible for brain growth, patterning, and survival, including the insulin-insulin-like growth factor (IGF)-signaling cascades that are mediated by tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. Irs2 signaling mediates peripheral insulin action and pancreatic beta-cell function, and its failure causes diabetes in mice. In this study, we reveal two important roles for Irs2 signaling in the mouse brain. First, disruption of the Irs2 gene reduced neuronal proliferation during development by 50%, which dissociated brain growth from Irs1-dependent body growth. Second, neurofibrillary tangles containing phosphorylated tau accumulated in the hippocampus of old Irs2 knock-out mice, suggesting that Irs2 signaling is neuroprotective. Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease.

An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.

Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M₄ allosteric potentiators. VU10010, the lead compound, potentiates the M₄ response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M₄ with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M₄ knockout mice. Selective regulation of excitatory transmission by M₄ suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.

Effects of intrahippocampal NAC(61-95) injections on memory in the rat and attenuation with vitamin E

Parkinson's disease (PD)-related dementia affects approximately 40% of PD patients and the severity of this dementia correlates significantly with the density of Lewy body (LB) deposition in the PD brain. Aggregated alpha-synuclein protein is the major component of LB's and the non-amyloid component (NAC) region of alpha-synuclein, residues 61-95, is essential for the aggregation and toxicity of this protein. The current study evaluated the effect of pre-aggregated NAC(61-95) injected into the CA3 area of the dorsal hippocampus of the brain on memory in the rat. Previous research has suggested that oxidative stress processes may play a role in the neuropathology of PD, therefore the effect of treatment with vitamin E, an antioxidant, was also evaluated. Male Sprague-Dawley rats were trained in two-lever operant chambers under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement. When responding showed no trends, subjects were divided into four groups. Two groups were injected bilaterally into the dorsal hippocampus with aggregated NAC(61-95) (5 mu l suspension), and two groups were injected bilaterally into the dorsal hippocampus with sterile water (5 mu l). Subgroups were treated with either vitamin E (150 mg/kg in Soya oil) or vehicle (Soya oil) daily. Injection of NAC(61-95) induced memory deficits and vitamin E treatment alleviated these. In addition, NAC(61-95) injections induced activated astrocytes and chronic treatment with vitamin E reduced the numbers of activated astrocytes. These results suggest that aggregated NAC(61-95) and associated oxidative stress, may play a role in the pathogenesis of cognitive deficits seen in PD-induced dementia. (C) 2009 Elsevier Inc. All rights reserved.

Using time-to-contact information to assess potential collision modulates both visual and temporal prediction networks

Accurate estimates of the time-to-contact (TTC) of approaching objects are crucial for survival. We used an ecologically valid driving simulation to compare and contrast the neural substrates of egocentric (head-on approach) and allocentric (lateral approach) TTC tasks in a fully factorial, event-related fMRI design. Compared to colour control tasks, both egocentric and allocentric TTC tasks activated left ventral premotor cortex/frontal operculum and inferior parietal cortex, the same areas that have previously been implicated in temporal attentional orienting. Despite differences in visual and cognitive demands, both TTC and temporal orienting paradigms encourage the use of temporally predictive information to guide behaviour, suggesting these areas may form a core network for temporal prediction. We also demonstrated that the temporal derivative of the perceptual index tau (tau-dot) held predictive value for making collision judgements and varied inversely with activity in primary visual cortex (V1). Specifically, V1 activity increased with the increasing likelihood of reporting a collision, suggesting top-down attentional modulation of early visual processing areas as a function of subjective collision. Finally, egocentric viewpoints provoked a response bias for reporting collisions, rather than no-collisions, reflecting increased caution for head-on approaches. Associated increases in SMA activity suggest motor preparation mechanisms were engaged, despite the perceptual nature of the task.

Echinostoma caproni: Differential tegumental responses to growth in compatible and less compatible hosts

The topography of the tegument of Echinostoma caproni adults collected from high (mice) and low (rats) compatible hosts was compared by SEM. In the oral (OS) and the ventral sucker (VS) areas, a worm age-host species interaction was found with regard to the density of spines. There was a decrease in the density of spines in the adults collected from mice, whereas an increase occurred in the OS area in worms from rats over time. The tegumentary spines in adults from mice became larger and blunter. Some spines from the VS area in adults from mice at 4 wpi were multipointed. The spines of adults from rats were sharper, not covered by the tegument and no multipointed spines were observed. We detected a greater level of actin gene expression in the adults collected from rats. These facts suggest that the low compatible host induces an increased turnover of tegumentary spines. (C) 2010 Elsevier Inc. All rights reserved.

How information guides movement: Intercepting curved free kicks in soccer

Previous studies have shown that balls subjected to spin induce large errors in perceptual judgements (Craig et al, 2006; Craig et al 2009) due to the additional accelerative force that causes the ball’s flight path to deviate from a standard parabolic trajectory. A recent review however, has suggested that the findings from such experiments may be imprecise due to the decoupling of perception and action and the reliance on the ventral system (Van der Kamp et al, 2008). The aim of this study was to present the same curved free kick trajectory simulations from the perception only studies (Craig et al, 2006; Craig et al, 2009) but this time allow participants to move to intercept the ball. By using immersive, interactive virtual reality technology participants were asked to control the movement of a virtual effector presented in a virtual soccer stadium so that it would make contact with a virtual soccer ball as it crossed the goal-line. As in the perception only studies the direction of spin had a significant effect on the participants’ responses (F(2,12)=222.340; p

The biology and functional anatomy of Modiolarca tumida (Musculus marmoratus) Bivalvia: Mytilidae

Modiolarca tumida (Hanley, 1843) is a member of the sub-family Crenellinae (Mytilidae). The preferred habitat of the species is the test of certain ascidians. The shell is dorsally flattened, which prevents it from cutting into the test during dorso-ventral contraction of the byssal retractors. The use of the byssus enables it to surround itself completely with host tissue. Adoption of the feeding posture involves the anterior-posterior contraction of the byssal retractors, which elevates the posterior margin above the host's surface using the anterior margin as the fulcrum against the host. Modiolarca tumida are attracted by the tunicin of the host, a process probably facilitated by the host's feeding currents. The smallest individuals are found round the oral aperture. Colonization of other parts of the host may result from surface migration as M. tumida can be highly mobile, crawling by means of the very extensible foot. It is during this process that individuals may be swept away in local currents and be forced to adopt a free-living existence.

A voxel based morphometry study investigating brain structural changes in first episode psychosis.

Schizophrenia (SCZ) and bipolar disorder (BP) are associated with neuropathological brain changes, which are believed to disrupt connectivity between brain processes and may have common properties. Patients at first psychotic episode are unique, as one can assess brain alterations at illness inception, when many confounders are reduced or absent. SCZ (N=25) and BP (N=24) patients were recruited in a regional first episode psychosis MRI study. VBM methods were used to study gray matter (GM) and white matter (WM) differences between patient groups and case by case matched controls. For both groups, deficits identified are more discrete than those typically reported in later stages of illness. SCZ patients showed some evidence of GM loss in cortical areas but most notable were in limbic structures such as hippocampus, thalamus and striatum and cerebellum. Consistent with disturbed neural connectivity WM alterations were also observed in limbic structures, the corpus callosum and many subgyral and sublobar regions in the parietal, temporal and frontal lobes. BP patients displayed less evidence of volume changes overall, compared to normal healthy participants, but those changes observed were primarily in WM areas which overlapped with regions identified in SCZ, including thalamus and cerebellum and subgyral and sublobar sites. At first episode of psychosis there is evidence of a neuroanatomical overlap between SCZ and BP with respect to brain structural changes, consistent with disturbed neural connectivity. There are also important differences however in that SCZ displays more extensive structural alteration.

FMRFamide-like peptides in root knot nematodes and their potential role in nematode physiology

FMRFamide-like peptides (FLPs) are a diverse group of neuropeptides that are expressed abundantly in nematodes. They exert potent physiological effects on locomotory, feeding and reproductive musculature and also act as neuromodulators. However, little is known about the specific expression patterns and functions of individual peptides. The current study employed rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR) to characterize flp genes from infective juveniles of the root knot nematodes, Meloidogyne incognita and Meloidogyne minor. The peptides identified from these transcripts are sequelogs of FLPs from the free-living nematode, Caenorhabditis elegans; the genes have therefore been designated as Mi-flp-1, Mi-flp-7, Mi-flp-12, Mm-flp-12 and Mi-flp-14. Mi-flp-1 encodes five FLPs with the common C-terminal moiety, NFLRFamide. Mi-flp-7 encodes two copies of APLDRSALVRFamide and APLDRAAMVRFamide and one copy of APFDRSSMVRFamide. Mi-flp-12 and Mm-flp-12 encode the novel peptide KNNKFEFIRFamide (a longer version of RNKFEFIRFamide found in C. elegans). Mi-flp-14 encodes a single copy of KHEYLRFamide (commonly known as AF2 and regarded as the most abundant nematode FLP), and a single copy of the novel peptide KHEFVRFamide. These FLPs share a high degree of conservation between Meloidogyne species and nematodes from other clades, including those of humans and animals, perhaps suggesting a common neurophysiological role which may be exploited by novel drugs. FLP immunoreactivity was observed for the first time in Meloidogyne, in the circumpharyngeal nerve ring, pharyngeal nerves and ventral nerve cord. Additionally, in situ hybridization revealed Mi-flp-12 expression in an RIR-like neuron and Mi-flp-14 expression in SMB-like neurons, respectively. These localizations imply physiological roles for FLP-12 and FLP-14 peptides, including locomotion and sensory perception.

Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils.

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus.

A chiton without a foot

The palaeoloricate ‘polyplacophorans’ are an extinct paraphyletic group of basal chiton-like organisms known primarily from their fossilized valves. Their phylo- genetic placement remains contentious, but they are likely to include both stem-group Polyplacophora and stem- group Aplacophora. Candidates for the latter position include ‘Helminthochiton’ thraivensis from the Ordovician of Scotland, which we redescribe here through a combined optical and micro-CT (XMT) restudy of the type material. The 11 specimens in the type series are all articulated, presenting partial or complete valve series as well as moul- dic preservation of the girdle armature; they demonstrate a vermiform body plan. The valves are typically palaeolori- cate in aspect, but differ in detail from all existing palaeol- oricate genera; we hence erect Phthipodochiton gen. nov. to contain the species. The most notable feature of the fossils is the spicular girdle; this is impersistently preserved, but demonstrably wraps entirely around the ventral surface of the animal, implying that a ‘true’ (i.e. polyplacophoran like) foot was absent, although we do not exclude the pos- sibility of a narrow solenogastre-like median pedal groove having been present. Phthipodochiton thraivensis presents an apparent mosaic of aplacophoran and polyplacophoran features and as such will inform our understanding of the relationship between these groups of extant molluscs. An inference may also be drawn that at least some other pal- aeoloricates possessed an ‘armoured aplacophoran’ body plan, in contrast to the ‘limpet-like’ body plan of extant Polyplacophora.

mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold theta-burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function. Neuropsychopharmacology (2009) 34, 2057-2071; doi:10.1038/npp.2009.30; published online 18 March 2009

Ultrastructural features of the epidermis of the planarian Artioposthia triangulata (Dendy)

The epidermis of the land planarian Arthioposthia triangulata was examined by scanning and transmission electron microscopy. This investigation revealed that the flatworm was covered entirely with cilia and was especially densely populated on the ventral surface. In all regions the epidermis consisted of a one-layered columnar epithelium resting on a prominent basement membrane, but lacking a terminal web. Various secretions were found in the epidermis together with epidermal rhabdoids. Below the basement membrane other secretory material was visible and this included the cytoplasmic lamellated granules and adenal rhabdites. The basement membrane consisted of fibrils with a beaded appearance and these were arranged parallel to the epidermal layer but did not display cross-banding. The secretory cells above and below the basement membrane were compared and their products characterized on the basis of shape, size and location. Their possible function is discussed.

Immunocytochemical localization of glutamate-like immunoreactivity within the nervous system of the cestode Mesocestoides corti and the trematode Fasciola hepatica

The localization and distribution of glutamate-like immunoreactivity (IR) in the nervous system of both the cestode Mesocestoides corti and the trematode Fasciola hepatica has been determined by an indirect immunofluorescent technique, in conjunction with confocal scanning laser microscopy (CSLM). Immunostaining was widespread in the central (CNS) and peripheral (PNS) nervous systems of both species examined. In the CNS, IR was evident in nerve cells and fibres in the cerebral ganglia, the cerebral commissure and the dorsal, ventral and longitudinal nerve cords. In the peripheral nervous system (PNS) of M. corti, IR was apparent in nerve plexuses associated with the subtegmental musculature and the musculature associated with the anteriorly positioned suckers. In F. hepatica, IR was evident in the innervation of both the oral and the ventral suckers, In the reproductive system of F. hepatica, glutamate-IR was observed around the ootype/Mehlis' gland complex.

FASCIOLA-HEPATICA - ULTRASTRUCTURAL-CHANGES TO THE TEGUMENT OF JUVENILE FLUKES FOLLOWING INCUBATION IN-VITRO WITH THE DEACETYLATED (AMINE) METABOLITE OF DIAMPHENETHIDE

Ultrastructural changes to the tegument of 5-week-old, 3-week-old and freshly-excysted Fasciola hepatica following in vitro incubation with the deacetylated (amine) metabolite of diamphenethide (DAMD, 10 mu gml(-1)) were examined by transmission electron microscopy, A similar sequence of tegumental changes occurred in all three age groups of fluke, although, with increasing fluke age, the time before onset increased and the damage became more extensive. The 5-week-old flukes showed an initial stress response after 3 h, typified by blebbing of the apical plasma membrane, formation of microvilli and an accumulation and accelerated release of secretory bodies at the tegumental apex, as well as swelling of the basal infolds, The swelling increased in extent with progressively longer periods of incubation in DAMD, leading to extreme edema and sloughing of the tegument after 9 h. The 3-week-old flukes showed a stress response and swelling of the basal infolds after only 1.5 h, although sloughing of the tegument did not occur until after 9 h. In the freshly-excysted metacercaria, a stress response and some sloughing of the tegument were evident after only 0.5 h. At all stages of development, the ventral tegument was more severely affected than the dorsal, Changes also occurred to the tegumental cells which were indicative of a disruption in the synthesis and release of tegumental secretory bodies: the amount of GER became reduced, the cisternae became swollen and their ribosomal covering decreased, the Golgi complexes disappeared from the cells and the numbers of secretory bodies in the cells also decreased, The heterochromatin content of the nuclei increased and eventually the tegumental cells began to break down, Again, the changes became apparent more rapidly at the earlier stages of development. The ultrastructural changes to the tegument are linked to a possible mode of action for diamphenethide as an inhibitor of protein synthesis. In turn, the results may help to explain the drug's high efficacy against juvenile stages of F. hepatica.