During sleep, the widespread coordination of neuronal oscillations across both cortical and subcortical brain regions is thought to support various physiological functions. However, how sleep-related ...activity within the brain's largest sensorimotor structure, the cerebellum, is multiplexed with well-described sleep-related mechanisms in regions such as the hippocampus remains unknown. We therefore simultaneously recorded from the dorsal hippocampus and three distinct regions of the cerebellum (Crus I, lobule VI, and lobules II/III) in male mice during natural sleep. Local field potential (LFP) oscillations were found to be coordinated between these structures in a sleep stage-specific manner. During non-REM sleep, prominent δ frequency coherence was observed between lobule VI and hippocampus, whereas non-REM-associated hippocampal sharp-wave ripple activity evoked discrete LFP modulation in all recorded cerebellar regions, with the shortest latency effects in lobule VI. We also describe discrete phasic sharp potentials (PSPs), which synchronize across cerebellar regions and trigger sharp-wave ripple suppression. During REM, cerebellar δ phase significantly modulated hippocampal theta frequency, and this effect was greatest when PSPs were abundant. PSPs were phase-locked to cerebellar δ oscillation peak and hippocampal theta oscillation trough, respectively. Within all three cerebellar regions, prominent LFP oscillations were observed at both low (δ, <4 Hz) and very high frequencies (∼250 Hz) during non-REM and REM sleep. Intracerebellar cross-frequency analysis revealed that δ oscillations modulate those in the very high-frequency range. Together, these results reveal multiple candidate physiological mechanisms to support "offline," bidirectional interaction within distributed cerebello-hippocampal networks.
Sleep is associated with widespread coordination of activity across a range of brain regions. However, little is known about how activity within the largest sensorimotor region of the brain, the cerebellum, is both intrinsically organized and links with higher-order structures, such as the hippocampus, during sleep. By making multisite local field potential recordings in naturally sleeping mice, we reveal and characterize multiple sleep stage-specific physiological mechanisms linking three distinct cerebellar regions with the hippocampus. Central to these physiological mechanisms is a prominent δ (<4 Hz) oscillation, which temporally coordinates both intracerebellar and cerebello-hippocampal network dynamics. Understanding this distributed network activity is important for gaining insight into cerebellar contributions to sleep-dependent processes, such as memory consolidation.
Achalasia is a disease for which treatments are palliative in nature. Success of therapy is judged by a number of metrics, the most important being relief of symptoms, such as dysphagia and ...regurgitation. Patients often compensate for symptoms though a variety of dietary and lifestyle modifications, making symptomatic assessment of therapeutic outcome unreliable. Given this fact, and the progressive nature of the condition if left inadequately treated, patients not infrequently present with the disabling manifestations of end-stage disease for which esophagectomy is the best option. In appropriately selected patients, and when performed in experienced centers, esophagectomy with foregut reconstruction can be undertaken successfully with acceptable rates of morbidity and mortality, as well as a good long-term symptomatic outcome, in cases of end-stage achalasia.
Melanopsin-expressing photosensitive retinal ganglion cells (pRGCs) represent a third class of retinal photoreceptor 1–3. These cells are intrinsically photosensitive, but also receive inputs from ...rod and cone photoreceptors 4–7, acting as the primary sensory conduit mediating non-image-forming responses to light 8–11. Multiple subtypes of pRGC have been described in the mouse retina with characteristic morphologies and functional properties, and which perform distinct physiological roles 12–15. Here, we examine the levels of melanopsin expression and distribution of pRGC subtypes across the mouse retina, identifying a previously unreported anatomical and functional specialization of the melanopsin system. Our results show a dorsal-ventral gradient in the expression of melanopsin and the distribution of pRGCs, which, combined with dorsal-ventral gradients in ultraviolet-sensitive and medium-wavelength-sensitive cone opsin expression, produce dramatic variations in the ratio of cone opsins and pRGCs across the retina. Using c-fos expression as a marker of light activation in vivo 16–18, we show that the responses of pRGCs are spectrally tuned by gradients in cone opsin expression depending on their location in the retina. These data illustrate the importance of classical photoreceptors in providing spectral tuning of pRGC light responses and have important implications for the complexity of non-image-forming responses to light.
•Melanopsin-expressing pRGCs show a nonuniform distribution across the mouse retina•Different pRGC subtypes show distinct patterns of distribution•Gradients in cone opsin expression lead to a spectral tuning of pRGC light responses
Background
Esophageal perforation is a serious and potentially life-threatening medical emergency. Given multiple etiologies and varying clinical presentations of the perforated esophagus, the ...diagnosis is commonly delayed, complicating expeditious and optimal intervention.
Methods
We thoroughly reviewed the latest literature on the subject and herein describe the various treatment strategies in varying settings.
Results
Treatment depends on multiple factors including the cause and location of the perforation, the time interval between the inciting event and presentation to the managing clinician, the overall medical stability of the patient, comorbidities including pre-existent esophageal pathology or prior foregut operations, and both the location and extent of extra-esophageal fluid collections. Because of these various considerations, determining the best diagnostic and therapeutic approach requires considerable clinical experience and judgment on the part of the physician. Management principles include (1) adequate fluid resuscitation; (2) expeditious administration of appropriate broad-spectrum antibiotics; (3) repair, occlusion, exclusion, diversion, or exteriorization of the perforation site; (4) drainage of extraluminal fluid collections; (5) relief of distal obstruction; and (6) nutritional support.
Conclusions
For decades, operative intervention has been the mainstay of therapy for esophageal perforation. More recently, endoscopic therapies, including stenting, clipping, suturing, or endoscopic vacuum therapy, have been introduced, expanding the clinician’s therapeutic armamentarium while supplanting surgical approaches in many cases. With further experience and introduction of novel therapies, the management of esophageal perforation undoubtedly will continue to evolve.
The molecular mechanisms that produce the full array of neuronal subtypes in the vertebrate nervous system are incompletely understood. Here, we provide evidence of a global temporal patterning ...program comprising sets of transcription factors that stratifies neurons based on the developmental time at which they are generated. This transcriptional code acts throughout the central nervous system, in parallel to spatial patterning, thereby increasing the diversity of neurons generated along the neuraxis. We further demonstrate that this temporal program operates in stem cell-derived neurons and is under the control of the TGFβ signaling pathway. Targeted perturbation of components of the temporal program, Nfia and Nfib, reveals their functional requirement for the generation of late-born neuronal subtypes. Together, our results provide evidence for the existence of a previously unappreciated global temporal transcriptional program of neuronal subtype identity and suggest that the integration of spatial and temporal patterning mechanisms diversifies and organizes neuronal subtypes in the vertebrate nervous system.
The dorsal and ventral periaqueductal gray (dPAG and vPAG, respectively) are embedded in distinct survival networks that coordinate, respectively, innate and conditioned fear-evoked freezing. ...However, the information encoded by the PAG during these survival behaviors is poorly understood. Recordings in the dPAG and vPAG in rats revealed differences in neuronal activity associated with the two behaviors. During innate fear, neuronal responses were significantly greater in the dPAG compared with the vPAG. After associative fear conditioning and during early extinction (EE), when freezing was maximal, a field potential was evoked in the PAG by the auditory fear conditioned stimulus (CS). With repeated presentations of the unreinforced CS, animals displayed progressively less freezing accompanied by a reduction in event-related field potential amplitude. During EE, the majority of dPAG and vPAG units increased their firing frequency, but spike-triggered averaging showed that only ventral activity during the presentation of the CS was significantly coupled to EMG-related freezing behavior. This PAG-EMG coupling was only present for the onset of freezing activity during the CS in EE. During late extinction, a subpopulation of units in the dPAG and vPAG continued to show CS-evoked responses; that is, they were extinction resistant. Overall, these findings support roles for the dPAG in innate and conditioned fear and for the vPAG in initiating but not maintaining the drive to muscles to generate conditioned freezing. The existence of extinction-susceptible and extinction-resistant cells also suggests that the PAG plays a role in encoding fear memories.
The periaqueductal gray (PAG) orchestrates survival behaviors, with the dorsal (dPAG) and ventral (vPAG) PAG concerned respectively with innate and learnt fear responses. We recorded neural activity from dPAG and vPAG in rats during the expression of innate fear and extinction of learned freezing. Cells in dPAG responded more robustly during innate fear, but dPAG and vPAG both encoded the time of the conditioned stimulus during early extinction and displayed extinction sensitive and resistant characteristics. Only vPAG discharge was correlated with muscle activity, but this was limited to the onset of conditioned freezing. The data suggest that the roles of dPAG and vPAG in fear behavior are more complex than previously thought, including a potential role in fear memory.
Seizures can emerge from multiple or large foci in temporal lobe epilepsy, complicating focally targeted strategies such as surgical resection or the modulation of the activity of specific ...hippocampal neuronal populations through genetic or optogenetic techniques. Here, we evaluate a strategy in which optogenetic activation of medial septal GABAergic neurons, which provide extensive projections throughout the hippocampus, is used to control seizures. We utilized the chronic intrahippocampal kainate mouse model of temporal lobe epilepsy, which results in spontaneous seizures and as is often the case in human patients, presents with hippocampal sclerosis. Medial septal GABAergic neuron populations were immunohistochemically labelled and were not reduced in epileptic conditions. Genetic labelling with mRuby of medial septal GABAergic neuron synaptic puncta and imaging across the rostral to caudal extent of the hippocampus, also indicated an unchanged number of putative synapses in epilepsy. Furthermore, optogenetic stimulation of medial septal GABAergic neurons consistently modulated oscillations across multiple hippocampal locations in control and epileptic conditions. Finally, wireless optogenetic stimulation of medial septal GABAergic neurons, upon electrographic detection of spontaneous hippocampal seizures, resulted in reduced seizure durations. We propose medial septal GABAergic neurons as a novel target for optogenetic control of seizures in temporal lobe epilepsy.
Electron spins confined to phosphorus donors in silicon are promising candidates as qubits because of their long coherence times, exceeding seconds in isotopically purified bulk silicon. With the ...recent demonstrations of initialization, readout and coherent manipulation of individual donor electron spins, the next challenge towards the realization of a Si:P donor-based quantum computer is the demonstration of exchange coupling in two tunnel-coupled phosphorus donors. Spin-to-charge conversion via Pauli spin blockade, an essential ingredient for reading out individual spin states, is challenging in donor-based systems due to the inherently large donor charging energies (∼45 meV), requiring large electric fields (>1 MV m(-1)) to transfer both electron spins onto the same donor. Here, in a carefully characterized double donor-dot device, we directly observe spin blockade of the first few electrons and measure the effective exchange interaction between electron spins in coupled Coulomb-confined systems.
Pontospinal noradrenergic neurons are thought to form part of a descending endogenous analgesic system that exerts inhibitory influences on spinal nociception. Using optogenetic targeting, we tested ...the hypothesis that excitation of the locus ceruleus (LC) is antinociceptive. We transduced rat LC neurons by direct injection of a lentiviral vector expressing channelrhodopsin2 under the control of the PRS promoter. Subsequent optoactivation of the LC evoked repeatable, robust, antinociceptive (+4.7°C ± 1.0, p < 0.0001) or pronociceptive (-4.4°C ± 0.7, p < 0.0001) changes in hindpaw thermal withdrawal thresholds. Post hoc anatomical characterization of the distribution of transduced somata referenced against the position of the optical fiber and subsequent further functional analysis showed that antinociceptive actions were evoked from a distinct, ventral subpopulation of LC neurons. Therefore, the LC is capable of exerting potent, discrete, bidirectional influences on thermal nociception that are produced by specific subpopulations of noradrenergic neurons. This reflects an underlying functional heterogeneity of the influence of the LC on the processing of nociceptive information.
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