Cancer blues? A promising judgment bias task indicates pessimism in nude mice with tumors.

In humans, affective states can bias responses to ambiguous information: a phenomenon termed judgment bias (JB). Judgment biases have great potential for assessing affective states in animals, in both animal welfare and biomedical research. New animal JB tasks require construct validation, but for laboratory mice (Mus musculus), the most common research vertebrate, a valid JB task has proved elusive. Here (Experiment 1), we demonstrate construct validity for a novel mouse JB test: an olfactory Go/Go task in which subjects dig for high- or low-value food rewards. In C57BL/6 and Balb/c mice faced with ambiguous cues, latencies to dig were sensitive to high/low welfare housing: environmentally-enriched animals responded with relative 'optimism' through shorter latencies. Illustrating the versatility of this validated JB task across different fields of research, it further allowed us to test hypotheses about the mood-altering effects of cancer in male and female nude mice (Experiment 2). Males, although not females, treated ambiguous cues as intermediate; and males bearing subcutaneous lung adenocarcinomas also responded more pessimistically to these than did healthy controls. To our knowledge, this is the first evidence of a valid mouse JB task, and the first demonstration of pessimism in tumor-bearing animals. This task still needs to be refined to improve its sensitivity. However, it has great potential for investigating mouse welfare, the links between affective state and disease, depression-like states in animals, and hypotheses regarding the neurobiological mechanisms that underlie affect-mediated biases in judgment.

Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation.

Inflammation is an essential part of immunity against pathogens and tumors but can promote disease if not tightly regulated. Self and non-self-nucleic acids can trigger inflammation, through recognition by the cyclic GMP-AMP (cGAMP) synthetase (cGAS) and subsequent activation of the stimulator of interferon genes (STING) protein. Here, we show that RNA:DNA hybrids can be detected by cGAS and that the Lysyl-tRNA synthetase (LysRS) inhibits STING activation through two complementary mechanisms. First, LysRS interacts with RNA:DNA hybrids, delaying recognition by cGAS and impeding cGAMP production. Second, RNA:DNA hybrids stimulate LysRS-dependent production of diadenosine tetraphosphate (Ap4A) that in turn attenuates STING-dependent signaling. We propose a model whereby these mechanisms cooperate to buffer STING activation. Consequently, modulation of the LysRS-Ap4A axis in vitro or in vivo interferes with inflammatory responses. Thus, altogether, we establish LysRS and Ap4A as pharmacological targets to control STING signaling and treat inflammatory diseases.

PET study of the human foveal fixation system.

Positron emission tomography (PET) was used to investigate the functional anatomy of the foveal fixation system in 10 subjects scanned under three different conditions: at rest (REST), during the fixation of a central point (FIX), and while fixating the same foveal target during the presentation of peripheral visual distractors (DIS). Compared with the REST condition, both FIX and DIS tasks activated a common set of cortical areas. First, in addition to the involvement of the occipital visual cortex, both the frontal eye field (FEF) and the intraparietal sulcus (IPS) were bilaterally activated. Right frontal activation was also found in the dorsolateral prefrontal cortex, the inferior part of the precentral gyrus, and the inferior frontal gyrus. These results suggest that both FEF and IPS may constitute the main cortical regions subserving bilaterally the foveal fixation system in humans. The remaining right frontal activations may be considered as part of the anterior attentional network, supporting a role for the right frontal lobe in the allocation of the attentional mechanisms. Compared with the FIX condition, the DIS task also revealed the perceptual and cognitive processes related to the presence of peripheral visual distractors during foveal fixation. In addition to a bilateral activation of the V5/MT motion-sensitive area, a right FEF-IPS network was activated which may correspond to the engagement of the visuospatial attention. Finally, normalized regional cerebral blood flow (NrCBF) decreases were also observed during both DIS and FIX condition performance. Such NrCBF decreases were centered in the superior and middle temporal gyri, the prefrontal cortex, and the precuneus and the posterior retrosplenial part of the cingulate gyrus.

Neuronal mechanisms of perceptual learning: changes in human brain activity with training in orientation discrimination.

Using 15O-water 3D positron emission tomography, regional cerebral blood flow was measured twice in six human subjects: before and after extensive training in orientation discrimination. In each session subjects performed two orientation discrimination tasks, during which they discriminated the orientation of a grating at either the trained or untrained reference orientation, and a control task, during which they detected a randomly textured pattern. By comparing the discrimination to the detection tasks, we observed a main effect of task bilaterally in the posterior occipital cortex, extending into the left posterior fusiform gyrus and the right inferior occipital gyrus, bilaterally in the intraparietal sulcus, as well as in the cerebellum, thalamus, and brainstem. When we compared the activation pattern before and after the training period, all the changes observed were activity decreases. The nonspecific changes, which were not related to the orientation used during the training, were situated in the cerebellum and bilaterally in the extrastriate visual cortex. The orientation-specific changes, on the other hand, were restricted to the striate and extrastriate visual cortex, more precisely the right calcarine sulcus, the left lingual gyrus, the left middle occipital, and the right inferior occipital gyrus. These findings confirm our hypothesis concerning the existence of learning related changes at early levels of visual processing in human adults and suggest that mechanisms resulting in neuronal activity decreases might be involved in the present kind of learning.

PET study of human voluntary saccadic eye movements in darkness: effect of task repetition on the activation pattern.

Using H2(15)O 3D Positron Emission Tomography (PET), regional cerebral blood flow (rCBF) was measured in six human subjects under two different conditions: at rest and while performing self-paced horizontal saccadic eye movements in darkness. These two conditions were repeated four times each. First, the comparison between the four saccadic and four resting conditions was investigated in a group and a single subject analysis. Saccades elicited bilateral rCBF increases in the medial part of the superior frontal gyrus (supplementary eye field), precentral gyrus (frontal eye field), superior parietal lobule, anterior medial part of the occipital lobe involving striate and extrastriate cortex (lingual gyrus and cuneus), and in the right inferior parietal lobule. At the subcortical level, activations were found in the left putamen. These results mainly replicate previous PET findings on saccadic control. Second, the interaction between the experimental conditions and their repetition was examined. When activations throughout repetition of the same saccadic task are compared, the supplementary eye fields show a progressive increase of activation. On the contrary, the activation in the cerebellum, left superior parietal lobule and left occipital cortex progressively decreases during the scanning session. Given the existence of such an interaction, the pattern of activations must be interpreted as a function of task repetition. This may be a factor explaining some apparent mismatch between different studies.

Biomedical applications of degradable polyphosphazenes.

This article describes the synthesis of biodegradable polyphosphazenes. The rate of degradation can be varied in a controllable manner by the introduction of hydrolysis-sensitive amino acid ester side groups or by blending of polymers. Biodegradable polyphosphazenes can be used for the preparation of drug-containing implants and this is illustrated for devices containing the cytostatic agent mitomycin C. This article reviews data about the degradation characteristics of poly[(amino acid ester)phosphazene] derivatives that have been discussed previously. Some new data about MMC-containing poly[(organo)phosphazene] devices are discussed as well. (c) 1996 John Wiley & Sons, Inc.