In the rodent primary somatosensory cortex, the configuration of whiskers and sinus hairs on the snout and of receptor-dense zones on the paws is topographically represented as discrete modules of layer IV granule cells (barrels) and thalamocortical afferent terminals 1,2 . The role of neural activity, particularly activity mediated by NMDARs (N-methyl-D-aspartate receptors), in patterning of the somatosensory cortex has been a subject of debate [3][4][5][6] . We have generated mice in which deletion of the NMDAR1 (NR1) gene is restricted to excitatory cortical neurons, and here we show that sensory periphery-related patterns develop normally in the brainstem and thalamic somatosensory relay stations of these mice. In the somatosensory cortex, thalamocortical afferents corresponding to large whiskers form patterns and display critical period plasticity, but their patterning is not as distinct as that seen in the cortex of normal mice. Other thalamocortical patterns corresponding to sinus hairs and digits are mostly absent. The cellular aggregates known as barrels and barrel boundaries do not develop even at sites where thalamocortical afferents cluster. Our findings indicate that cortical NMDARs are essential for the aggregation of layer IV cells into barrels and for development of the full complement of thalamocortical patterns.The rodent somatosensory system is an excellent model to study molecular mechanisms underlying the establishment of patterned topographic connections between the sensory periphery and the brain. Trigeminal and dorsal column pathways convey a somatosensory map from the periphery to the neocortex by relay stations in the brainstem and the ventrobasal thalamus. At each level, pre-synaptic afferents and their target cells establish a patterned array of modules corresponding to the arrangement of whiskers and sinus hairs on the snout (trigeminal pathway), and receptor-dense zones of the paws (dorsal column pathway) 2,7,8 . These patterns are consolidated during the first postnatal week, and are subject to alterations if the sensory periphery is perturbed by nerve or whisker lesions during a critical period 2,7,8 . Thus, early neural activity might be essential in the development and plasticity of central patterns much like that of the vertebrate visual system 9,10 . Within this context, NMDAR activity has attracted much attention 9,11 . Initial studies using pharmacological blockade of NMDARs in postnatal rat somatosensory cortex did not detect effects on thalamocortical patterning, but revealed functional impairment of thalamocortical connectivity and whisker-specific responsiveness of barrel neurons 4,5 . In contrast, genetic manipulations of NMDARs showed an absence of periphery-related patterns in the somatosensory cortex 6 . This result could not be ascribed to direct effects on the neocortex, however, as it could have been a consequence of impaired patterns at the brainstem level 6,12,13 . To delineate the specific role(s) of cortical NMDARs in patterning, here we disrupted the ...
Fifty-one percent of male patients with stable heart failure suffer from sleep-related breathing disorders: 40% from central and 11% from obstructive sleep apnea. Both obstructive and central types of sleep apnea result in sleep disruption and arterial oxyhemoglobin desaturation. Patients with sleep apnea have a high prevalence of atrial fibrillation and ventricular arrhythmias.
Glial cells are traditionally regarded as elements for structural support and ionic homeostasis, but have recently attracted attention as putative integral elements of the machinery involved in synaptic transmission and plasticity. Here, we demonstrate that calcium-binding protein S100B, which is synthesized in considerable amounts in astrocytes (a major glial cell subtype), modulates long-term synaptic plasticity. Mutant mice devoid of S100B developed normally and had no detectable abnormalities in the cytoarchitecture of the brain. These mutant mice, however, had strengthened synaptic plasticity as identified by enhanced longterm potentiation (LTP) in the hippocampal CA1 region. Perfusion of hippocampal slices with recombinant S100B proteins reversed the levels of LTP in the mutant slices to those of the wild-type slices, indicating that S100B might act extracellularly. In addition to enhanced LTP, mutant mice had enhanced spatial memory in the Morris water maze test and enhanced fear memory in the contextual fear conditioning. The results indicate that S100B is a glial modulator of neuronal synaptic plasticity and strengthen the notion that glial-neuronal interaction is important for information processing in the brain.S everal lines of evidence suggest that glial cells play an active role in excitatory neurotransmission in the central nervous system (1, 2). For instance, astrocytes can release glutamate in response to physiological increases in their intracellular calcium concentration, and then evoke substantial glutamatergic currents in neighboring neurons (3). Oligodendrocyte precursor cells directly receive glutamatergic inputs from hippocampal pyramidal neurons (4). These findings, together with earlier studies showing that glial cells express many types of neurotransmitter receptors and respond to neurotransmitter by generating slowly propagating calcium waves (5), suggest that glialneuronal reciprocal signaling may play a role in synaptic plasticity and eventually in information processing in the brain. Indeed, this notion has been supported by the findings that the mice devoid of glial fibrillary acidic protein (GFAP: an intermediate filament specific to astrocytes) showed enhanced longterm potentiation (LTP) in the hippocampal CA1 region and decreased long-term depression in the cerebellum associated with impaired eye-blink conditioning (6, 7). However, the molecular mechanism underlying glial-neuronal interactions is poorly understood.One of the candidates that might be involved in glia-to-neuron signaling is the calcium-binding protein S100B. S100B is a member of the S100 family of proteins containing two EF-handtype calcium-binding domains (8). The highest level of expression of the S100B protein is in the brain and is found primarily in the cytoplasm of astrocytes (9). Results of in vitro studies suggest a variety of intracellular functions of S100B, including cell growth, cell structure, energy metabolism, and calcium homeostasis (8). S100B is secreted from astrocytes, suggesting that it might ...
Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57–1.11) for MACE-4; 0.90 (95% CI, 0.50–1.61) for cardiovascular death; and 0.80 (95% CI, 0.51–1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls.
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