Explore the vast range of titles available.

Transient receptor potential melastatin 7 (TRPM7) contributes to a variety of physiological and pathological processes in many tissues and cells. With a widespread distribution in the nervous system, TRPM7 is involved in animal behaviors and neuronal death induced by ischemia. However, the physiological role of TRPM7 in central nervous system (CNS) neuron remains unclear. Here, we identify endocytic defects in neuroendocrine cells and neurons from TRPM7 knockout (KO) mice, indicating a role of TRPM7 in synaptic vesicle endocytosis. Our experiments further pinpoint the importance of TRPM7 as an ion channel in synaptic vesicle endocytosis. Ca 2+ imaging detects a defect in presynaptic Ca 2+ dynamics in TRPM7 KO neuron, suggesting an importance of Ca 2+ influx via TRPM7 in synaptic vesicle endocytosis. Moreover, the short-term depression is enhanced in both excitatory and inhibitory synaptic transmissions from TRPM7 KO mice. Taken together, our data suggests that Ca 2+ influx via TRPM7 may be critical for short-term plasticity of synaptic strength by regulating synaptic vesicle endocytosis in neurons.

Synaptotagmin 7 (Syt7), a presynaptic calcium sensor, has a significant role in the facilitation in short-term synaptic plasticity: Syt7 knock out mice show a significant reduction in the facilitation. The functional importance of short-term synaptic plasticity such as facilitation is not well understood. In this study, we attempt to investigate the potential functional relationship between the short-term synaptic plasticity and postsynaptic response by developing a mathematical model that captures the responses of both wild-type and Syt7 knock-out mice. We then studied the model behaviours of wild-type and Syt7 knock-out mice in response to multiple input action potentials. These behaviors could establish functional importance of short-term plasticity in regulating the postsynaptic response and related synaptic properties. In agreement with previous modeling studies, we show that release sites are governed by non-uniform release probabilities of neurotransmitters. The structure of non-uniform release of neurotransmitters makes short-term synaptic plasticity to act as a high-pass filter. We also propose that Syt7 may be a modulator for the long-term changes of postsynaptic response that helps to train the target frequency of the filter. We have developed a mathematical model of short-term plasticity which explains the experimental data.

Short-term plasticity plays a key role in synaptic transmission and has been extensively investigated for excitatory synapses. Much less is known about inhibitory synapses. Here we analyze the performance of glycinergic connections between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO) in the auditory brainstem, where high spike rates as well as fast and precise neurotransmission are hallmarks. Analysis was performed in acute mouse slices shortly after hearing onset (postnatal day (P)11) and 8 days later (P19). Stimulation was done at 37°C with 1-400 Hz for 40 s. Moreover, in a novel approach named marathon experiments, a very prolonged stimulation protocol was employed, comprising 10 trials of 1-min challenge and 1-min recovery periods at 50 and 1 Hz, respectively, thus lasting up to 20 min and amounting to >30,000 stimulus pulses. IPSC peak amplitudes displayed short-term depression (STD) and synaptic attenuation in a frequency-dependent manner. No facilitation was observed. STD in the MNTB-LSO connections was less pronounced than reported in the upstream calyx of Held-MNTB connections. At P11, the STD level and the failure rate were slightly lower within the ms-to-s range than at P19. During prolonged stimulation periods lasting 40 s, P19 connections sustained virtually failure-free transmission up to frequencies of 100 Hz, whereas P11 connections did so only up to 50 Hz. In marathon experiments, P11 synapses recuperated reproducibly from synaptic attenuation during all recovery periods, demonstrating a robust synaptic machinery at hearing onset. At 26°C, transmission was severely impaired and comprised abnormally high amplitudes after minutes of silence, indicative of imprecisely regulated vesicle pools. Our study takes a fresh look at synaptic plasticity and stability by extending conventional stimulus periods in the ms-to-s range to minutes. It also provides a framework for future analyses of synaptic plasticity.

Generating a comprehensive description of cortical networks requires a large-scale, systematic approach. To that end, we have begun a pipeline project using multipatch electrophysiology, supplemented with two-photon optogenetics, to characterize connectivity and synaptic signaling between classes of neurons in adult mouse primary visual cortex (V1) and human cortex. We focus on producing results detailed enough for the generation of computational models and enabling comparison with future studies. Here, we report our examination of intralaminar connectivity within each of several classes of excitatory neurons. We find that connections are sparse but present among all excitatory cell classes and layers we sampled, and that most mouse synapses exhibited short-term depression with similar dynamics. Synaptic signaling between a subset of layer 2/3 neurons, however, exhibited facilitation. These results contribute to a body of evidence describing recurrent excitatory connectivity as a conserved feature of cortical microcircuits. The outer sheet of brain tissue, the neocortex, is composed of circuits formed from trillions of connections among billions of neurons, of which there are about one hundred different neuron types. The scale and complexity of cortical circuitry pose experimental challenges, leading to an incomplete understanding of how cortical cell types are connected and the computations that take place at the connections. About half of the cell types in the brain are excitatory, which means they can activate other cells. The cortex consists of several distinct layers of cells, within which excitatory cells cooperate to process the signals they receive from other cortical layers and brain areas. Using recordings of electrical activity arising from the connections between pairs of excitatory neurons, Seeman, Campagnola et al. measured the likelihood and strength of connectivity among related groups of excitatory cell types in slices of cortex taken from human and mouse brains. The initial results confirm previous findings that individual layers of human cortex can have more and stronger excitatory connections than the same layers of mouse cortex. In most layers of mouse cortex, repeatedly activating the excitatory cells leads to progressively weaker responses. However, in the upper layers of mouse cortex, the opposite effect is sometimes seen: more excitatory activity causes the connections to generate stronger responses. By feeding these data into a computer model, Seeman, Campagnola et al. described and compared the activity of the groups of related excitatory cell types. These results are the first of a new, large-scale project where findings can be integrated across experiments to gain a more detailed picture of cortical circuitry and computation. Neuroscientists will be able to use the results to build advanced computer models of cortical circuits. Such models will, for example, generate predictions for how the attributes of excitatory connectivity revealed by Seeman, Campagnola et al. influence how information is processed in the cortex. In so doing, the models will add to our understanding of how the human brain works both in health and in disease.

We propose several modifications to an existing computational model of stochastic vesicle release in inner hair cell ribbon synapses, with the aim of producing simulated auditory nerve fiber spiking data that more closely matches empirical data. Specifically, we studied the inter-spike-interval (ISI) distribution, and long and short term ISI correlations in spontaneous spiking in post-synaptic auditory nerve fibers. We introduced short term plasticity to the pre-synaptic release probability, in a manner analogous to standard stochastic models of cortical short term synaptic depression. This modification resulted in a similar distribution of vesicle release intervals to that estimated from empirical data. We also introduced a biophysical stochastic model of calcium channel opening and closing, but showed that this model is insufficient for generating a match with empirically observed spike correlations. However, by combining a phenomenological model of channel noise and our short term depression model, we generated short and long term correlations in auditory nerve spontaneous activity that qualitatively match empirical data.

Continuous attractor models of working-memory store continuous-valued information in continuous state-spaces, but are sensitive to noise processes that degrade memory retention. Short-term synaptic plasticity of recurrent synapses has previously been shown to affect continuous attractor systems: short-term facilitation can stabilize memory retention, while short-term depression possibly increases continuous attractor volatility. Here, we present a comprehensive description of the combined effect of both short-term facilitation and depression on noise-induced memory degradation in one-dimensional continuous attractor models. Our theoretical description, applicable to rate models as well as spiking networks close to a stationary state, accurately describes the slow dynamics of stored memory positions as a combination of two processes: (i) diffusion due to variability caused by spikes; and (ii) drift due to random connectivity and neuronal heterogeneity. We find that facilitation decreases both diffusion and directed drifts, while short-term depression tends to increase both. Using mutual information, we evaluate the combined impact of short-term facilitation and depression on the ability of networks to retain stable working memory. Finally, our theory predicts the sensitivity of continuous working memory to distractor inputs and provides conditions for stability of memory.

The cerebellum has been implicated as a major player in producing temporal acuity. Theories of cerebellar timing typically emphasize the role of the cerebellar cortex while overlooking the role of the deep cerebellar nuclei (DCN) that provide the sole output of the cerebellum. Here we review anatomical and electrophysiological studies to shed light on the DCN's ability to support temporal pattern generation in the cerebellum. Specifically, we examine data on the structure of the DCN, the biophysical properties of DCN neurons and properties of the afferent systems to evaluate their contribution to DCN firing patterns. In addition, we manipulate one of the afferent structures, the inferior olive (IO), using systemic harmaline injection to test for a network effect on activity of single DCN neurons in freely moving animals. Harmaline induces a rhythmic firing pattern of short bursts on a quiescent background at about 8 Hz. Other neurons become quiescent for long periods (seconds to minutes). The observed patterns indicate that the major effect harmaline exerts on the DCN is carried indirectly by the inhibitory Purkinje cells (PCs) activated by the IO, rather than by direct olivary excitation. Moreover, we suggest that the DCN response profile is determined primarily by the number of concurrently active PCs, their firing rate and the level of synchrony occurring in their transitions between continuous firing and quiescence. We argue that DCN neurons faithfully transfer temporal patterns resulting from strong correlations in PCs state transitions, while largely ignoring the timing of simple spikes from individual PCs. Future research should aim at quantifying the contribution of PC state transitions to DCN activity, and the interplay between the different afferent systems that drive DCN activity.

In addition to the known link between cholecystectomy and depression, the risk of developing short-term and long-term depression after surgery and whether such mental health issues leads to suicide were not known. Therefore, this study aimed to address these questions. Using data from the National Health Insurance Service of Korea (2002–2019), we conducted a retrospective cohort study including 6,688 cholecystectomy patients matched with 66,880 individuals without a history of cholecystectomy for suicide analysis and 6,694 cholecystectomy patients matched with 66,940 individuals for depression analysis. The non-cholecystectomy group was matched at a 1:10 ratio for sex and age. The incidence of depression and suicide were followed from the day of cholecystectomy to December 31, 2019. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards regression. Short-term depression risk within three years of cholecystectomy was significantly elevated (aHR 1.38, 95% CI 1.19–1.59), while the long-term depression risk beyond three years was not significantly greater (aHR 1.09, 95% CI 0.98–1.22). Cholecystectomy was not associated with an increased risk of suicide in any period. These findings highlight the importance of monitoring and providing postoperative mental health support for patients at risk of short-term depression after cholecystectomy. However, no association was observed with long-term depression or suicide risk.

Improving our ability to accurately predict individual risk for depression would have profound public health benefits. While there has been growing interest in understanding the relation between measures of positive emotion, such as well-being, and depression, it is not clear whether low well-being is an independent predictor of short term depression risk. We assessed whether low well-being is a risk factor for depressive symptoms. Medical internship is a well-established period of stress when levels of depressive symptoms increase dramatically. 1621 individuals beginning medical internship were assessed for well-being, depressive symptoms, and a set of psychological and demographic traits prior to starting internship year and again for depressive symptoms at 3 month intervals during the year. Low subjective well-being significantly predicted increased depression symptom scores during the stress of medical internship and accounted for individual level inter-variability in depression symptom trends across time. Assessing well-being may have utility in predicting future depression risk.

Sustained neuronal activity demands a rapid resupply of synaptic vesicles to maintain reliable synaptic transmission. Such vesicle replenishment is accelerated by submicromolar presynaptic Ca 2+ signals by an as-yet unidentified high-affinity Ca 2+ sensor 1 , 2 . Here we identify synaptotagmin-3 (SYT3) 3 , 4 as that presynaptic high-affinity Ca 2+ sensor, which drives vesicle replenishment and short-term synaptic plasticity. Synapses in Syt3 knockout mice exhibited enhanced short-term depression, and recovery from depression was slower and insensitive to presynaptic residual Ca 2+ . During sustained neuronal firing, SYT3 accelerated vesicle replenishment and increased the size of the readily releasable pool. SYT3 also mediated short-term facilitation under conditions of low release probability and promoted synaptic enhancement together with another high-affinity synaptotagmin, SYT7 (ref. 5 ). Biophysical modelling predicted that SYT3 mediates both replenishment and facilitation by promoting the transition of loosely docked vesicles to tightly docked, primed states. Our results reveal a crucial role for presynaptic SYT3 in the maintenance of reliable high-frequency synaptic transmission. Moreover, multiple forms of short-term plasticity may converge on a mechanism of reversible, Ca 2+ -dependent vesicle docking. Synaptotagmin-3 is identified as the presynaptic high-affinity calcium sensor to rapidly replenish synaptic vesicles to maintain steady synaptic transmission.