CRYPTOCHROME (CRY) is the primary circadian photoreceptor in Drosophila. We show that CRY binding to TIMELESS (TIM) is light-dependent in flies and irreversibly commits TIM to proteasomal degradation. In contrast, CRY degradation is dependent on continuous light exposure, indicating that the CRY-TIM interaction is transient. A novel cry mutation (cry(m)) reveals that CRY's photolyase homology domain is sufficient for light detection and phototransduction, whereas the carboxyl-terminal domain regulates CRY stability, CRY-TIM interaction, and circadian photosensitivity. This contrasts with the function of Arabidopsis CRY domains and demonstrates that insect and plant cryptochromes use different mechanisms.
Most animals rely on circadian clocks to synchronize their physiology and behavior with the day/night cycle. Light and temperature are the major physical variables that can synchronize circadian rhythms. Although the effects of light on circadian behavior have been studied in detail in Drosophila, the neuronal mechanisms underlying temperature synchronization of circadian behavior have received less attention. Here, we show that temperature cycles synchronize and durably affect circadian behavior in Drosophila in the absence of light input. This synchronization depends on the well characterized and functionally coupled circadian neurons controlling the morning and evening activity under light/dark cycles: the M cells and E cells. However, circadian neurons distinct from the M and E cells are implicated in the control of rhythmic behavior specifically under temperature cycles. These additional neurons play a dual role: they promote evening activity and negatively regulate E cell function in the middle of the day. We also demonstrate that, although temperature synchronizes circadian behavior more slowly than light, this synchronization is considerably accelerated when the M cell oscillator is absent or genetically altered. Thus, whereas the E cells show great responsiveness to temperature input, the M cells and their robust self-sustained pacemaker act as a resistance to behavioral synchronization by temperature cycles. In conclusion, the behavioral responses to temperature input are determined by both the individual properties of specific groups of circadian neurons and their organization in a neural network.
Drosophila cryptochrome (CRY) is a key circadian photoreceptor that interacts with the period and timeless proteins (PER and TIM) in a light-dependent manner. We show here that a heat pulse also mediates this interaction, and heat-induced phase shifts are severely reduced in the cryptochrome loss-of-function mutant cryb. The period mutant perL manifests a comparable CRY dependence and dramatically enhanced temperature sensitivity of biochemical interactions and behavioral phase shifting. Remarkably, CRY is also critical for most of the abnormal temperature compensation of perL flies, because a perL; cryb strain manifests nearly normal temperature compensation. Finally, light and temperature act together to affect rhythms in wild-type flies. The results indicate a role for CRY in circadian temperature as well as light regulation and suggest that these two features of the external 24-h cycle normally act together to dictate circadian phase.
Fast and accurate segmentation of deep gray matter regions in the brain is important for clinical applications such as surgical planning for the placement of deep brain stimulation implants. Mapping anatomy from stereotactic atlases to patient data is problematic because of individual differences in subject anatomy that are not accounted for by commonly used atlases. We present a segmentation method for individual subject diffusion tensor MR data that is based on local diffusion information to identify subregions of the thalamus. We show the correspondence of our segmentation results to anatomy by comparison with stereotactic atlas data. Importantly, we verify the consistency of our segmentation by evaluating the method on 63 healthy volunteers. Our method is fast, reliable, and independent of any segmentation before the classification of regions within the thalamus. Many illnesses, including Parkinson's disease, schizophrenia, and chronic pain syndrome, are associated with changes in the thalamus (1-4). Dissection or stimulation of certain regions in the thalamus can reduce symptoms of some of these illnesses (5,6). Currently, surgical planning is based on MR imaging and anatomical predictions created by mapping a stereotactic brain atlas onto visually identifiable landmarks in the patient's brain (7). However, anatomical variability of deep gray matter structures relative to currently used atlases can make such techniques challenging (8). Therefore, development of more accurate and efficient segmentation techniques for deep gray matter regions, such as the thalamus, is of increasing clinical importance. Unfortunately, the thalamus has a mostly homogeneous signal value in standard anatomical MR images (see Fig. 1a). Segmentation of thalamic nuclei is therefore not possible on these kinds of data sets. Although some substructures of the thalamus are visible on higher resolution anatomical MR images or magnetization transfer images (see for example (9-11)), high-resolution imaging also increases the measurement time, which is a disadvantage for clinical applications. Deoni et al. (9) successfully used modified k-means clustering to segment thalamic nuclei in high-resolution quantitative MR images. The results of this method were very promising, however the technique required manual segmentation of the whole thalamus and prior information from stereotactic atlases (12) to reduce the computational cost of the segmentation.Other approaches use diffusion tensor MR-imaging (DTI) to segment individual regions in the thalamus. DTI measures the direction of water molecular diffusion to detect the dominant orientation of fibers in living tissue (for details on DTI see for example (13,14)). It therefore has a high potential to be useful in the segmentation of the thalamus because individual thalamic nuclei have wellstructured fiber connections to defined cortical and subcortical areas. Figure 1b shows an example of how diffusion information can aid in distinguishing thalamic substructures. Indeed, there have been several r...
Damage to the optic radiations or primary visual cortex leads to blindness in all or part of the contralesional visual field. Such damage disconnects the retina from its downstream targets and, over time, leads to trans-synaptic retrograde degeneration of retinal ganglion cells. To date, visual ability is the only predictor of retinal ganglion cell degeneration that has been investigated after geniculostriate damage. Given prior findings that some patients have preserved visual cortex activity for stimuli presented in their blind field, we tested whether that activity explains variability in retinal ganglion cell degeneration over and above visual ability. We prospectively studied 15 patients (four females, mean age = 63.7 years) with homonymous visual field defects secondary to stroke, 10 of whom were tested within the first two months after stroke. Each patient completed automated Humphrey visual field testing, retinotopic mapping with functional magnetic resonance imaging, and spectral-domain optical coherence tomography of the macula. There was a positive relation between ganglion cell complex (GCC) thickness in the blind field and early visual cortex activity for stimuli presented in the blind field. Furthermore, residual visual cortex activity for stimuli presented in the blind field soon after the stroke predicted the degree of retinal GCC thinning six months later. These findings indicate that retinal ganglion cell survival after ischaemic damage to the geniculostriate pathway is activity dependent.
Interfacility ED transfers for IS/TIA more than doubled from 2006 to 2014. Further work should determine the necessity of IS/TIA transfers and seek to optimize the US stroke care system.
Summary Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase-shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM, and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles.
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