Descripción: A core problem of decision theories is that although decisionmakers' preferences depend on learning, their choices could be driven either by learned representations of the physical properties of each alternative (for instance reward sizes) or of the benefit (utility and fitness) experienced from them. Physical properties are independent of the subject's state and context, but utility depends on both. We show that starlings' choices are better explained by memory for context-dependent utility than by representations of the alternatives' physical properties, even when the decisionmakers' state is controlled and they have accurate knowledge about the options' physical properties. Our results support the potential universality of utility-driven preference control.

Descripción: The nature of telencephalic control over premotor and motor circuits is debated. Hypotheses range from complete usurping of downstream circuitry to highly interactive mechanisms of control. We show theoretically and experimentally, that telencephalic song motor control in canaries is consistent with a highly interactive strategy. As predicted from a theoretical model of respiratory control, mild cooling of a forebrain nucleus (HVC) led to song stretching, but further cooling caused progressive restructuring of song, consistent with the hypothesis that respiratory gestures are subharmonic responses to a timescale present in the output of HVC. This interaction between a life-sustaining motor function (respiration) and telencephalic song motor control suggests a more general mechanism of how nonlinear integration of evolutionarily new brain structures into existing circuitry gives rise to diverse, new behavior. © 2013 Goldin et al.

Descripción: The electroencephalogram (EEG) together with electromyogram (EMG) of the ischiocavernosus, bulbocavernosus and levator penis muscles were chronically monitored across behavioral states of the armadillo Chaetophractus villosus. This animal has a very long penis, which exhibits remarkable phenomena during wakefulness (W), slow wave sleep (SWS) and paradoxical sleep (PS). During W it remains retracted within a skin receptacle. During SWS penile protrusion can be observed together with very complex movements. Protrusion is a non erectile event during which the penis remains out of its receptacle but without rigidity. Penile erections are observed only during SWS. Contrasting with other mammals, no erections occur during PS. During this phase the penile muscles share the atonia of the body musculature characteristic of that phase. Some reflections on mechanisms of those penile events are presented.

Descripción: Glucocorticoids are potent regulators of the innate immune response, and alteration in this inhibitory feedback has detrimental consequences for the neural tissue. This study profiled and investigated functionally candidate genes mediating this switch between cell survival and death during an acute inflammatory reaction subsequent to the absence of glucocorticoid signaling. Oligonucleotide microarray analysis revealed that following lipopolysaccharide (LPS) intracerebral administration at striatum level, more modulated genes presented transcription impairment than exacerbation upon glucocorticoid receptor blockage. Among impaired genes we identified ceruloplasmin (Cp), which plays a key role in iron metabolism and is implicated in a neurodegenative disease. Microglial and endothelial induction of Cp is a natural neuroprotective mechanism during inflammation, because Cp-deficient mice exhibited increased iron accumulation and demyelination when exposed to LPS and neurovascular reactivity to pneumococcal meningitis. This study has identified genes that can play a critical role in programming the innate immune response, helping to clarify the mechanisms leading to protection or damage during inflammatory conditions in the CNS. © 2007 Glezer et al.

Descripción: The spontaneous non-obese diabetic (NOD) mouse model of Sjögren's syndrome provides a valuable tool to study the onset and progression of both the autoimmune response and secretory dysfunction. Our purpose was to analyse the temporal decline of salivary secretion in NOD mice in relation to the autoimmune response and alterations in various signalling pathways involved in saliva secretion within each salivary gland. A progressive loss of nitric oxide synthase activity in submandibular and parotid glands started at 12 weeks of age and paralleled the decline in salivary secretion. This defect was associated with a lower response to vasoactive intestinal peptide in salivary flow rate, cAMP and nitric oxide/cGMP production. No signs of mononuclear infiltrates or local cytokine production were detectable in salivary glands in the time period studied (10-16 weeks of age). Our data support a disease model for sialadenitis in NOD mice in which the early stages are characterized by defective neurotransmitter-mediated signalling in major salivary glands that precedes the autoimmune response. © 2005 British Society for Immunology.

Descripción: 1. 1. The present work undertakes a comparative study on the hexachlorobenzene (HCB) porphyria induction in female rats of Wistar and CHBBTHOM strains. The purpose was to characterize the CHBBTHOM strain with respect to the haem metabolic pathway, its regulatory mechanisms and its response to foreign drugs. 2. 2. After 7 weeks of treatment it was observed that the hepatic porphyrins increased 140 times, ALA-synthase 4 times and PCL was 73% inhibited in the Wistar strain. 3. 3. On the other hand the animals of CHBBTHOM strain showed lesser alteration on these parameters; hepatic porphyrins increased only 3-fold, ALA-synthase 1.7-fold and PCL was only 22% inhibited. 4. 4. Total iron liver content was nearly equal in both strains of rats. 5. 5. The results obtained would indicate that the lower susceptibility of the CHBBTHOM strain to acquire porphyria does not seem to be due to either: (1) congenital alterations of any parameters of the haem metabolic pathway, since the behaviour of normal animals from both strains was similar; or (2) a lower hepatic iron content in such animals. 6. 6. These findings would suggest that the differential response to HCB to this strain would be looked for in another metabolic pathway, such as that involved in the metabolization process of the toxic. © 1989.

Descripción: Dendritic cells (DCs) are potent APCs and attractive vectors for cancer immunotherapy. Using the B16 melanoma, a poorly immunogenic experimental tumor that expresses low levels of MHC class I products, we investigated whether DCs loaded ex vivo with apoptotic tumor cells could elicit combined CD4+ and CD8+ T cell dependent, long term immunity following injection into mice. The bone marrow-derived DCs underwent maturation during overnight coculture with apoptotic melanoma cells. Following injection, DCs migrated to the draining lymph nodes comparably to control DCs at a level corresponding to ∼0.5% of the injected inoculum. Mice vaccinated with tumor-loaded DCs were protected against an intracutaneous challenge with B16, with 80% of the mice remaining tumor-free 12 wk after challenge. CD4+ and CD8+ T cells were efficiently primed in vaccinated animals, as evidenced by IFN-γ secretion after in vitro stimulation with DCs loaded with apoptotic B16 or DCs pulsed with the naturally expressed melanoma Ag, tyrosinase-related protein 2. In addition, B16 melanoma cells were recognized by immune CD8 + T cells in vitro, and cytolytic activity against tyrosinase-related protein 2180-188-pulsed target cells was observed in vivo. When either CD4+ or CD8+ T cells were depleted at the time of challenge, the protection was completely abrogated. Mice receiving a tumor challenge 10 wk after vaccination were also protected, consistent with the induction of tumor-specific memory. Therefore, DCs loaded with cells undergoing apoptotic death can prime melanoma-specific helper and CTLs and provide long term protection against a poorly immunogenic tumor in mice.

Descripción: The aim of this work was to test in vitro and in vivo the efficacy of the derivatives of 5-aminolevulinic acid (ALA): hexyl-ALA (He-ALA), undecanoyl-ALA and R,S-2-(hydroximethyl)tetrahydropyranyl-ALA (THP-ALA) as pro-photosensitising agents. The compounds were assayed in a cell line derived from a murine mammary tumour, in tumour explants and after injection of the cells into mice. In vitro, undecanoyl-ALA and THP-ALA did not improve ALA efficacy in terms of porphyrin synthesis. On the other hand, half of the amount of ALA is required to obtain the same plateau amount of photosensitiser from He-ALA. However, this plateau value cannot be surpassed in spite of the four-times higher accumulation of ALA/He-ALA from the ALA derivative. This shows that He-ALA conversion to porphyrins but not He-ALA entry to the cells is limiting. Employing ionic exchange chromatography, we found that 80% of total uptake was He-ALA whereas only 20% was ALA. This suggests that the esterases, probably themselves regulated by the heme pathway, are limiting the conversion of ALA derivatives into porphyrins. A similar situation occurs with THP-ALA. Tumour explant porphyrin results correlate well with cell line data. However, i.p. injection of ALA derivatives to mice resulted in a lower porphyrin concentration in the tumour when compared to the administration of equimolar amounts of ALA, indicating that there should be retention of ALA derivatives either within the blood vessels in the initial phase of distribution and/or within the capillaries of the tumour. © 2004 Cancer Research UK.

Descripción: Galectins control critical pathophysiological processes, including the progression and resolution of central nervous system (CNS) inflammation. In spite of considerable progress in dissecting their role within lymphoid organs, their functions within the inflamed CNS remain elusive. Here, we investigated the role of galectin-glycan interactions in the control of oligodendrocyte (OLG) differentiation, myelin integrity and function. Both galectin-1 and-3 were abundant in astrocytes and microglia. Although galectin-1 was abundant in immature but not in differentiated OLGs, galectin-3 was upregulated during OLG differentiation. Biochemical analysis revealed increased activity of metalloproteinases responsible for cleaving galectin-3 during OLG differentiation and modulating its biological activity. Exposure to galectin-3 promoted OLG differentiation in a dose-and carbohydrate-dependent fashion consistent with the glycosylation signature of immature versus differentiated OLG. Accordingly, conditioned media from galectin-3-expressing, but not galectin-3-deficient (Lgals3/) microglia, successfully promoted OLG differentiation. Supporting these findings, morphometric analysis showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio in the corpus callosum and striatum of Lgals3/compared with wild-type (WT) mice. Moreover, the myelin structure was loosely wrapped around the axons and less smooth in Lgals3/mice versus WT mice. Behavior analysis revealed decreased anxiety in Lgals3/mice similar to that observed during early demyelination induced by cuprizone intoxication. Finally, commitment toward the oligodendroglial fate was favored in neurospheres isolated from WT but not Lgals3/mice. Hence, glial-derived galectin-3, but not galectin-1, promotes OLG differentiation, thus contributing to myelin integrity and function with critical implications in the recovery of inflammatory demyelinating disorders. © 2011 Macmillan Publishers Limited All rights reserved.

Descripción: Experiments with insects and crabs have demonstrated their remarkable capacity to learn and memorize complex visual features (Giurfa et al., 2001; Pedreira and Maldonado, 2003; Chittka and Niven, 2009). Such abilities are thought to require modular brain processing similar to that occurring in vertebrates (Menzel and Giurfa, 2001). Yet, physiological evidence for this type of functioning in the small brains of arthropods is still scarce (Liu et al., 1999, 2006; Menzel and Giurfa, 2001). In the crab Chasmagnathus granulatus, the learning rate as well as the long-term memory of a visual stimulus has been found to be reflected in the performance of identified lobula giant neurons (LGs) (Tomsic et al., 2003). The memory can only be evoked in the training context, indicating that animals store two components of the learned experience, one related to the visual stimulus and one related to the visual context (Tomsic et al., 1998; Hermitte et al., 1999). By performing intracellular recordings in the intact animal, we show that the ability of crabs to generalize the learned stimulus into new space positions and to distinguish it from a similar but unlearned stimulus, two of the main attributes of stimulus memory, is reflected by the performance of the LGs. Conversely, we found that LGs do not support the visual context memory component. Our results provide physiological evidence that the memory traces regarding "what" and "where" are stored separately in the arthropod brain. © 2011 the authors.

Descripción: Spatial familiarization consists of a decrease in the exploratory activity over time after exposure to a place. Here, we show that a 30-min exposure to an open field led to a pronounced decrease in the exploratory behavior of rats, generating context familiarity. This behavioral output is associated with a selective decrease in hippocampal PKMζ levels. A short 5-min exposure did not induce spatial familiarity or a decrease in PKMζ, while inactivation of hippocampal PKMζ by the specific inhibitor ZIP was sufficient to induce spatial familiarity, suggesting that the decrease in PKMζ is involved in setting a given context as a familiar place. © 2008 Cold Spring Harbor Laboratory Press.

Descripción: Background: Olfactory systems create representations of the chemical world in the animal brain. Recordings of odour-evoked activity in the primary olfactory centres of vertebrates and insects have suggested similar rules for odour processing, in particular through spatial organization of chemical information in their functional units, the glomeruli. Similarity between odour representations can be extracted from across-glomerulus patterns in a wide range of species, from insects to vertebrates, but comparison of odour similarity in such diverse taxa has not been addressed. In the present study, we asked how 11 aliphatic odorants previously tested in honeybees and rats are represented in the antennal lobe of the ant Camponotus fellah, a social insect that relies on olfaction for food search and social communication.Results: Using calcium imaging of specifically-stained second-order neurons, we show that these odours induce specific activity patterns in the ant antennal lobe. Using multidimensional analysis, we show that clustering of odours is similar in ants, bees and rats. Moreover, odour similarity is highly correlated in all three species.Conclusion: This suggests the existence of similar coding rules in the neural olfactory spaces of species among which evolutionary divergence happened hundreds of million years ago. © 2010 Dupuy et al; licensee BioMed Central Ltd.

Descripción: Several studies support that stored memories undergo a new period of consolidation after retrieval. It is not known whether this process, termed reconsolidation, requires the same transcriptional mechanisms involved in consolidation. Increasing evidence supports the participation of the transcription factor NF-κB in memory. This was initially demonstrated in the crab Chasmagnathus model of associative contextual memory, in which re-exposure to the training context induces a well characterized reconsolidation process. Here we studied the role of NF-κB in reconsolidation. NF-κB was specifically activated in trained animals re-exposed to the training context but not to a different context. NF-κB was not activated when animals were re-exposed to the context after a weak training protocol insufficient to induce long-term memory. A specific inhibitor of the NF-κB pathway, sulfasalazine, impaired reconsolidation when administered 20 min before re-exposure to the training context but was not effective when a different context was used. These findings indicate for the first time that NF-κB is activated specifically by retrieval and that this activation is required for memory reconsolidation, supporting the view that this molecular mechanism is required in both consolidation and reconsolidation.

Descripción: The molecular mechanisms governing the pathogenesis of ACTH-secreting pituitary adenomas are still obscure. Furthermore, the pharmacological treatment of these tumors is limited. In this study, we report that bone morphogenetic protein-4 (BMP-4) is expressed in the corticotrophs of human normal adenohypophysis and its expression is reduced in corticotrophinomas obtained from Cushing's patients compared with the normal pituitary. BMP-4 treatment of AtT-20 mouse corticotrophinoma cells has an inhibitory effect on ACTH secretion and cell proliferation. AtT-20 cells stably transfected with a dominant-negative form of the BMP-4 signal cotransducer Smad-4 or the BMP-4 inhibitor noggin have increased tumorigenicity in nude mice, showing that BMP-4 has an inhibitory role on corticotroph tumorigenesis in vivo. Because the activation of the retinoic acid receptor has an inhibitory action on Cushing's disease progression, we analyzed the putative interaction of these two pathways. Indeed, retinoic acid induces both BMP-4 transcription and expression and its antiproliferative action is blocked in Smad-4dn- and noggin-transfected Att-20 cells that do not respond to BMP-4. Therefore, retinoic acid induces BMP-4, which participates in the antiproliferative effects of retinoic acid. This new mechanism is a potential target for therapeutic approaches for Cushing's disease. Copyright © 2006 by The Endocrine Society.

Descripción: Ideally, learning-related changes should be investigated while they occur in vivo, but physical accessibility and stability limit intracellular studies. Experiments with insects and crabs demonstrate their remarkable capacity to learn and memorize visual features. However, the location and physiology of individual neurons underlying these processes is unknown. A recently developed crab preparation allows stable intracellular recordings from the optic ganglia to be performed in the intact animal during learning. In the crab Chasmagnathus, a visual danger stimulus (VDS) elicits animal escape, which declines after a few stimulus presentations. The long-lasting retention of this decrement is mediated by an association between contextual cues of the training site and the VDS, therefore, called context-signal memory (CSM). CSM is achieved only by spaced training. Massed training, on the contrary, produces a decline of the escape response that is short lasting and, because it is context independent, is called signal memory (SM). Here, we show that movement detector neurons (MDNs) from the lobula (third optic ganglion) of the crab modify their response to the VDS during visual learning. These modifications strikingly correlate with the rate of acquisition and with the duration of retention of both CSM and SM. Long-term CSM is detectable from the response of the neuron 1 d after training. In contrast to MDNs, identified neurons from the medulla (second optic ganglion) show no changes. Our results indicate that visual memory in the crab, and possibly other arthropods, including insects, is accounted for by functional changes occurring in neurons originating in the optic lobes.

Descripción: Mammalian fertilization is a complex multi-step process mediated by different molecules present on both gametes. Epididymal protein CRISP1, a member of the Cysteine-RIch Secretory Protein (CRISP) family, was identified by our laboratory and postulated to participate in both sperm-zona pellucida (ZP) interaction and gamete fusion by binding to egg-complementary sites. To elucidate the functional role of CRISP1 in vivo, we disrupted the Crisp1 gene and evaluated the effect on animal fertility and several sperm parameters. Male and female Crisp1-/- animals exhibited no differences in fertility compared to controls. Sperm motility and the ability to undergo a spontaneous or progesterone-induced acrosome reaction were neither affected in Crisp1-/- mice. However, the level of protein tyrosine phosphorylation during capacitation was clearly lower in mutant sperm than in controls. In vitro fertilization assays showed that Crisp1-/- sperm also exhibited a significantly reduced ability to penetrate both ZP-intact and ZP-free eggs. Moreover, when ZP-free eggs were simultaneously inseminated with Crisp1+/+ and Crisp1-/- sperm in a competition assay, the mutant sperm exhibited a greater disadvantage in their fusion ability. Finally, the finding that the fusion ability of Crisp1-/- sperm was further inhibited by the presence of CRISP1 or CRISP2 during gamete co-incubation, supports that another CRISP cooperates with CRISP1 during fertilization and might compensate for its lack in the mutant mice. Together, these results indicate that CRISP proteins are players in the mammalian fertilization process. To our knowledge this is the first knockout mice generated for a CRISP protein. The information obtained might have important functional implications for other members of the widely distributed and evolutionarily conserved CRISP family. © 2008 Elsevier Inc.

Descripción: Type 1 diabetes (T1D) is a disease caused by the destruction of the β cells of the pancreas by activated T cells. Dendritic cells (BC) are the APC that initiate the T cell response that triggers T1D. However, DC also participate in T cell tolerance, and genetic engineering of DC to modulate T cell immunity is an area of active research. Galectin-1 (gal-1) is an endogenous lectin with regulatory effects on activated T cells including induction of apoptosis and down-regulation of the Th1 response, characteristics that make gal-1 an ideal transgene to transduce DC to treat T1D. We engineered bone marrow-derived DC to synthesize transgenic gal-1 (gal-1-DC) and tested their potential to prevent T1D through their regulatory effects on activated T cells. NOD-derived gal-1-DC triggered rapid apoptosis of diabetogenic BDC2.5 TCR-transgenic CD4+ T cells by TCR-dependent and -independent mechanisms. Intravenously administered gal-1-DC trafficked to pancreatic lymph nodes and spleen and delayed onset of diabetes and insulitis in the NODrag1 -/- lymphocyte adoptive transfer model. The therapeutic effect of gal-1-DC was accompanied by increased percentage of apoptotic T cells and reduced number of IFN-γ-secreting CD4+ T cells in pancreatic lymph nodes. Treatment with gal-1-DC inhibited proliferation and secretion of IFN-γ of T cells in response to β cell Ag. Unlike other DC-based approaches to modulate T cell immunity, the use of the regulatory properties of gal-1-DC on activated T cells might help to delete β cell-reactive T cells at early stages of the disease when the diabetogenic T cells are already activated. Copyright © 2005 by The American Association of Immunologists, Inc.

Descripción: The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2-/-) mice and in isolated islets from wild-type and Drd2-/- mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2-/- male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2 -/- mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2-/- mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic β-cell mass in Drd2-/-mice and decreasedβ-cell replication in 2-month-old Drd2-/- mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops. Copyright © 2010 by The Endocrine Society.

Descripción: The role of short-chain fatty acids in the host-seeking behaviour of Triatoma infestans larvae was investigated using a locomotion compensator. Several short-chain fatty acids were tested alone over a wide range of doses, or in combination with L-lactic acid (L-LA; 100 μg). Bugs showed no attractive response to single carboxylic acids, but when L-LA was added to airstreams carrying specific intensities of either propionic (C3; 100 μg), butyric (C4; 1 μg) or valeric acid (C5; 1 μg), these mixtures elicited an attractive response, evincing a synergistic effect. No orientation response was observed when caproic acid (C6) was offered with L-LA at the doses tested. Two blends were created: (1) C3, C4 and C5 combined at the effective doses when added with L-LA [C3C4C5 (1)], and (2) C3, C4 and C5 combined at a third of those intensities [C3C4C5 (2)]. Both blends were tested alone, with L-LA (100 μg), with a sub-threshold concentration of CO2 (300 p.p.m. above the ambient level), and combined with both compounds together. Oriented responses of bugs were only observed with the blend (2) added with L-LA and with the combination of this lure with CO2. This last combination evoked a behavioural response similar in intensity to that induced by a live mouse. © Oxford University Press 2004; all rights reserved.