Effects of monoamine uptake inhibitors on pain-related depression of nesting in mice.

Pain is a significant public health problem, and assessment of pain-related impairment of behavior is a key clinical indicator and treatment target. Similar to opioids and NSAIDs, dopamine (DA) transporter inhibitors block pain-related depression of intracranial self-stimulation (ICSS) in rats. The primary goal of the present study was to determine if the effects of monoamine uptake inhibitors on pain-related depression of ICSS in rats extend to an assay of pain-related depression of nesting in mice. We hypothesized that the DA transporter-selective uptake inhibitor bupropion would block depression of nesting behavior produced by intraperitoneal injection of lactic acid, whereas selective serotonin transporter-selective citalopram, norepinephrine transporter-selective nisoxetine, and the mixed action selective serotonin transporter/norepinephrine transporter inhibitor milnacipran would be ineffective. Effects of the NSAID ketoprofen were also obtained to facilitate interpretation of the effects of the monoamine uptake inhibitors. Consistent with previous findings, ketoprofen blocked pain-related depression of nesting. In contrast, none of the monoamine uptake inhibitors blocked pain-related depression of nesting, although they all blocked pain-related stimulation of stretching. Unlike findings from studies of pain-related depression of ICSS, these results do not support consideration of DA uptake inhibitors for treatment of pain-related depression of behavior.

RCAD/BiP pathway is necessary for the proper synthesis of digestive enzymes and secretory function of the exocrine pancreas.

Alcoholism causes an imbalance of endoplasmic reticulum (ER) homeostasis in pancreatic acini. In those cells, the ER is involved in the synthesis and folding of pancreatic enzymes. Ubiquitin-fold modifier 1 (Ufm1) is part of a novel ubiquitin-like modification system involved in maintaining ER homeostasis. Among the components of the Ufm1 system, Regulator of C53 and DDRGK1 (RCAD) has recently been identified as a Ufm1-specific E3 ligase that promotes ufmylation of DDRGK1, an RCAD-interacting protein. We determined the importance of RCAD in the proper synthesis and secretion of pancreatic enzymes using mice with genetically deleted RCAD. The pancreas of RCAD-deficient mice was of normal size and histology. Using quantitative PCR and Western blotting, we found that amylase was upregulated in pancreas organs from RCAD-knockout (KO) mice. Constitutive amylase secretion was much higher in isolated pancreatic acini from RCAD KO mice, whereas CCK-stimulated amylase secretion was disturbed. RCAD deficiency caused a downregulation in expression of ER chaperone BiP, which affected ER homeostasis and activated both apoptosis and trypsin. We also found that both RCAD and DDRGK1 transcript levels were upregulated in pancreatic acini from alcohol-preferring rats. Elevated expression of RCAD and DDRGK1 was associated with increased ER stress and UPR activation. Because of the lack of BiP expression, caspase 3 and trypsin activation we enhanced in RCAD-deficient pancreatic acini upon treatment with ethanol and CCK. In conclusion, the RCAD/BiP pathway is required for proper synthesis and secretion of pancreatic enzymes. In alcoholism, increased levels of components of the Ufm1 system could prevent the deleterious effects of alcohol in the pancreas by regulating BiP levels.NEW & NOTEWORTHY RCAD/BiP pathway is required for the proper synthesis and secretion of amylase from pancreatic acini, as well as for the maintenance of the ER homeostasis. In alcoholism, the exocrine pancreas could increase the levels of components of the Ufm1 system to protect itself from alcohol's deleterious effects by regulating the expression of ER chaperone BiP.

Functional Segregation of the Entopallium in Pigeons.

In birds, the entopallium is the primary telencephalic target of the major visual ascending route called the tectofugal pathway. Often functionally compared to the primate geniculo-striate pathway and its subsequent telencephalic (cortical) regions, the latter processes visual information in a parallel fashion in terms of anatomy, physiology, and function. Little is known, however, about the exact mechanism of whether or how information is segregated or integrated in the avian tectofugal pathway including the telencephalon. Testing four pigeons, we examined whether or not color, form, and motion information is selectively processed by different portions of the entopallium. Each learned three distinct visual tasks requiring discrimination of different combinations of color, form and motion cues. After learning and pre-lesion testing, two pigeons received lesions to the anterior portion of the entopallium and two received lesions to the posterior entopallium. During post-lesion testing the pigeons with anterior lesions exhibited significant deficits in those tasks most dependent on color and form discrimination, but showed no deficit on a task that had involved discriminating among forms that were moving. Pigeons with posterior lesions showed a different pattern of deficits, exhibiting significant reductions in discriminating both moving and static forms, but little or no deficits in color discrimination. These divergent profiles of effects for each lesion suggest there is a functional segregation of visual information processing in the pigeon telencephalon. This indicates a convergence between birds and primates regarding the parallel processing and separation of information within their phylogenetically distinct major visual pathways.

Avian visual behavior and the organization of the telencephalon.

Birds have excellent visual abilities that are comparable or superior to those of primates, but how the bird brain solves complex visual problems is poorly understood. More specifically, we lack knowledge about how such superb abilities are used in nature and how the brain, especially the telencephalon, is organized to process visual information. Here we review the results of several studies that examine the organization of the avian telencephalon and the relevance of visual abilities to avian social and reproductive behavior. Video playback and photographic stimuli show that birds can detect and evaluate subtle differences in local facial features of potential mates in a fashion similar to that of primates. These techniques have also revealed that birds do not attend well to global configural changes in the face, suggesting a fundamental difference between birds and primates in face perception. The telencephalon plays a major role in the visual and visuo-cognitive abilities of birds and primates, and anatomical data suggest that these animals may share similar organizational characteristics in the visual telencephalon. As is true in the primate cerebral cortex, different visual features are processed separately in the avian telencephalon where separate channels are organized in the anterior-posterior axis roughly parallel to the major laminae. Furthermore, the efferent projections from the primary visual telencephalon form an extensive column-like continuum involving the dorsolateral pallium and the lateral basal ganglia. Such a column-like organization may exist not only for vision, but for other sensory modalities and even for a continuum that links sensory and limbic areas of the avian brain. Behavioral and neural studies must be integrated in order to understand how birds have developed their amazing visual systems through 150 million years of evolution.

Female stimuli trigger gene expression in male pigeons.

The immediate early gene zenk encodes transcriptional regulators and is believed to be one of the first steps in the formation of long-term memories associated with a given stimulus. In this study, we investigated the expression of ZENK protein product in brain regions that are likely involved in the processing of social stimuli, such as a potential mate. Male pigeons (Columba livia) were exposed to one of the following: (1) a live female pigeon, (2) a video playback of a female pigeon, (3) a video playback of a female cockatoo, or (4) an empty stimulus chamber. The brains were then processed immunohistochemically using an antibody against ZENK protein. When the stimulus was a live pigeon compared to all other stimuli, there were more numerous and more darkly-stained ZENK-positive cells in three "association" regions of the telencephalon: the hyperpallium apicale, the lateral portion of the intermediate nidopallium, and the medial nidopallium. There were no significant differences among the video-playback stimuli. The results suggest that the level of ZENK expression in these "association" regions was influenced not only by the visual presence of a potential mate, but by the presence of non-visual signals, the quality of the image, and the real-time interaction with the stimulus.