Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs.

Activity-driven modifications in synaptic connections between neurons in the neocortex may occur during development and learning. In dual whole-cell voltage recordings from pyramidal neurons, the coincidence of postsynaptic action potentials (APs) and unitary excitatory postsynaptic potentials (EPSPs) was found to induce changes in EPSPs. Their average amplitudes were differentially up- or down-regulated, depending on the precise timing of postsynaptic APs relative to EPSPs. These observations suggest that APs propagating back into dendrites serve to modify single active synaptic connections, depending on the pattern of electrical activity in the pre- and postsynaptic neurons.

Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex.

A puzzling feature of the neocortex is the rich array of inhibitory interneurons. Multiple neuron recordings revealed numerous electrophysiological-anatomical subclasses of neocortical gamma-aminobutyric acid-ergic (GABAergic) interneurons and three types of GABAergic synapses. The type of synapse used by each interneuron to influence its neighbors follows three functional organizing principles. These principles suggest that inhibitory synapses could shape the impact of different interneurons according to their specific spatiotemporal patterns of activity and that GABAergic interneuron and synapse diversity may enable combinatorial inhibitory effects in the neocortex.

Caries Detection with Near-Infrared Transillumination Using Deep Learning.

Dental caries is the most prevalent chronic condition worldwide. Early detection can significantly improve treatment outcomes and reduce the need for invasive procedures. Recently, near-infrared transillumination (TI) imaging has been shown to be effective for the detection of early stage lesions. In this work, we present a deep learning model for the automated detection and localization of dental lesions in TI images. Our method is based on a convolutional neural network (CNN) trained on a semantic segmentation task. We use various strategies to mitigate issues related to training data scarcity, class imbalance, and overfitting. With only 185 training samples, our model achieved an overall mean intersection-over-union (IOU) score of 72.7% on a 5-class segmentation task and specifically an IOU score of 49.5% and 49.0% for proximal and occlusal carious lesions, respectively. In addition, we constructed a simplified task, in which regions of interest were evaluated for the binary presence or absence of carious lesions. For this task, our model achieved an area under the receiver operating characteristic curve of 83.6% and 85.6% for occlusal and proximal lesions, respectively. Our work demonstrates that a deep learning approach for the analysis of dental images holds promise for increasing the speed and accuracy of caries detection, supporting the diagnoses of dental practitioners, and improving patient outcomes.

Synchrony generation in recurrent networks with frequency-dependent synapses.

Throughout the neocortex, groups of neurons have been found to fire synchronously on the time scale of several milliseconds. This near coincident firing of neurons could coordinate the multifaceted information of different features of a stimulus. The mechanisms of generating such synchrony are not clear. We simulated the activity of a population of excitatory and inhibitory neurons randomly interconnected into a recurrent network via synapses that display temporal dynamics in their transmission; surprisingly, we found a behavior of the network where action potential activity spontaneously self-organized to produce highly synchronous bursts involving virtually the entire network. These population bursts were also triggered by stimuli to the network in an all-or-none manner. We found that the particular intensities of the external stimulus to specific neurons were crucial to evoke population bursts. This topographic sensitivity therefore depends on the spectrum of basal discharge rates across the population and not on the anatomical individuality of the neurons, because this was random. These results suggest that networks in which neurons are even randomly interconnected via frequency-dependent synapses could exhibit a novel form of reflex response that is sensitive to the nature of the stimulus as well as the background spontaneous activity.

Regional changes in NGF receptor immunohistochemical labeling in the septum of the aged rat.

A monoclonal antibody to the nerve growth factor receptor (NGFR) (IgG 192) was used to visualize differences in immunohistochemical labeling of young (10 months) and old (35 months) rats. Three parameters were analyzed; cell counts, immunoreactive cross-sectional surface area (SA) and optical density (OD) of labeled cells. Large reductions in all three parameters were recorded in the medial septum (MS). Both OD and immunoreactive SA were reduced in the VDB, while only OD was reduced in the HDB. This observation confirms that NGFR labeling is reduced in the aged rat septum and adds that the loss of labeling is differential, with greater deficits in the MS-VDB complex than in the HDB.

Potential for multiple mechanisms, phenomena and algorithms for synaptic plasticity at single synapses.

Recent experimental evidence indicates that in the neocortex, the manner in which each synapse releases neurotransmitter in response to trains of presynaptic action potentials is potentially unique. These unique transmission characteristics arise because of a large heterogeneity in various synaptic properties that determine frequency dependence of transmission such as those governing the rates of synaptic depression and facilitation. A theoretical analysis was therefore undertaken to explore the phenomenologies of changes in the values of these synaptic parameters. The results illustrate how the change in any one of several synaptic parameters produces a distinctive effect on synaptic transmission and how these distinctive effects can point to the most likely biophysical mechanisms. These results could therefore be useful in studies of synaptic plasticity in order to obtain a full characterization of the phenomenologies of synaptic modifications and to isolate potential biophysical mechanisms. Based on this theoretical analysis and experimental data, it is proposed that there exists multiple mechanisms, phenomena and algorithms for synaptic plasticity at single synapses. Finally, it is shown that the impact of changing the values of synaptic parameters depends on the values of the other parameters. This may indicate that the various mechanisms, phenomena and algorithms are interlinked in a 'synaptic plasticity code'.

Presynaptic cholinergic action in the hippocampus.

The hippocampus is among the regions in the brain richest in M1 cholinergic receptors. Topical application of acetylcholine (ACh) onto hippocampal slices produces a characteristic complex response consisting of a depolarization, an increase in input resistance especially upon depolarization and a blockade of a slow afterhyperpolarization (AHP). The first two of these responses can be recorded also in non-cholinergic septal neurons in an area which contains about 8% of the M1 muscarinic receptors found in the hippocampus. The responses of hippocampal but not septal neurons to ACh involve an increase in the spontaneous synaptic activity and a decrease in evoked responses to afferent stimulation. The dissociated hippocampal culture was used to study these presynaptic effects. The neurons in culture possess muscarinic receptors which develop gradually over a period of several weeks after plating. ACh rarely depolarizes hippocampal neurons in culture. Instead, it causes an increase in spontaneous discharge of small postsynaptic currents (PSC's) and a marked decrease of large, evoked PSC's. In some cultured hippocampal cells ACh reduced ICa without affecting any of several outward K currents studied. It is suggested that ACh reduces evoked activity by reducing Ca currents at presynaptic terminals.

Actions of norepinephrine in the rat hippocampus.

Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action in rat hippocampus. It is currently believed that beta 1-receptor activation enhances excitability of recorded neurons, whereas alpha 1 activation suppresses reactivity to afferent stimulation. These reported effects of alpha-agonists are not consistent with alpha 1 effects found elsewhere in the brain. We have conducted experiments in the anesthetized rat and found that an amphetamine-induced increase in the dentate gyrus population spike can be blocked by a beta-antagonist but also by an alpha 1-antagonist. We have conducted experiments in the brain slide preparation and found that an alpha-agonist, phenylephrine (PHE), selectively enhances responses to N-methyl-D-aspartate (NMDA) but not to quisqualate. We propose that the product of activation of both alpha- and beta-receptor types will enhance reactivity of hippocampal cells to afferent stimulation.

Redistribution of synaptic efficacy: a mechanism to generate infinite synaptic input diversity from a homogeneous population of neurons without changing absolute synaptic efficacies.

Changing the reliability of neurotransmitter release results in a change in the efficacy of low frequency synaptic transmission and in the rate of high frequency synaptic depression thus it can not cause an uniform change in strength of synapses and instead results in a change in the dynamics of synaptic transmission referred to as 'redistribution of synaptic efficacy' (RSE). Since the change in synaptic transmission associated with RSE depends on the history of action potential activity it is concluded that RSE serves as a mechanism to generate a potentially infinite diversity of synaptic input.

Anatomical and functional differentiation of glutamatergic synaptic innervation in the neocortex.

Pyramidal neurons are the principal neurons of the neocortex and their excitatory impact on other pyramidal neurons and interneurons is central to neocortical dynamics. A fundamental principal that has emerged which governs pyramidal neuron excitation of other neurons in the local circuitry of neocortical columns is differential anatomical and physiological properties of the synaptic innervation via the same axon depending on the type of neuron targeted. In this study we derive anatomical principles for divergent innervation of pyramidal neurons of the same type within the local microcircuit. We also review data providing circumstantial and direct evidence for differential synaptic transmission via the same axon from neocortical pyramidal neurons and derive some principles for differential synaptic innervation of pyramidal neurons of the same type, of pyramidal neurons and interneurons and of different types of interneurons. We conclude that differential anatomical and physiological differentiation is a fundamental property of glutamatergic axons of pyramidal neurons in the neocortex.

Calcimycin potentiates responses of rat hippocampal neurons to N-methyl-D-aspartate.

We examined the effect of elevating intracellular calcium ([Ca2+]i) on responses to iontophoretically applied N-methyl-D-aspartate (NMDA), and quisqualate in CA1 neurons of the hippocampal slice. Topical application of calcimycin (A23187), a calcium ionophore, potentiated responses to NMDA but not to quisqualate. This potentiation was prevented by loading cells with the calcium chelator, BAPTA, suggesting that the action of calcimycin on NMDA receptors was mediated by an elevation of [Ca2+]i in the recorded cell. The potentiation was also recorded in voltage-clamped and in cesium-loaded cells, suggesting that it was not mediated by non-specific changes in voltage or input resistance of the cell that may have resulted from the rise in [Ca2+]i. We propose that intracellular calcium plays a crucial role in regulating the activity of the NMDA subtype of L-glutamate receptor.

Electrophysiological characteristics of cholinergic and non-cholinergic neurons in the rat medial septum-diagonal band complex.

We examined the electrophysiological properties of cholinergic and non-cholinergic neurons in the medial septum-diagonal band complex (MSDB) of the rat in the in vitro slice preparation. Cells were identified electrophysiologically, filled with Lucifer yellow, fixed and processed for immunohistochemistry with fluorescent labeled anti-choline acetyltransferase (ChAT) antibody. Cholinergic and non-cholinergic neurons differed in action potential parameters, spike afterpotentials and in current-voltage relationships. In addition, cholinergic neurons expressed a potent transient outward rectification in response to a depolarizing current pulse.

Acetylcholine potentiates responses to N-methyl-D-aspartate in the rat hippocampus.

The effect of acetylcholine (ACh) on intracellular responses to ionophoretic application of N-methyl-D-aspartate (NMDA) was examined in rat hippocampal slice. Recordings were obtained from CA1 neurons under current- and voltage-clamp conditions. Drugs were applied topically by ionophoretic and microdrop techniques. ACh produced an atropine-sensitive potentiation of responses to NMDA. The effect of ACh on NMDA receptor-mediated responses was independent of changes in voltage or potassium conductances caused by ACh. ACh also potentiated responses to L-glutamate but not to kainate or quisqualate. This effect was blocked by DL-2-amino-5-phosphonovalerate (2-APV), an NMDA receptor antagonist. We conclude that ACh, acting on muscarinic receptors, potentiates selectively, the NMDA subclass of L-glutamate receptor.

Nlgn4 knockout induces network hypo-excitability in juvenile mouse somatosensory cortex in vitro.

Neuroligins (Nlgns) are postsynaptic cell adhesion molecules that form transynaptic complexes with presynaptic neurexins and regulate synapse maturation and plasticity. We studied the impact of the loss of Nlgn4 on the excitatory and inhibitory circuits in somatosensory cortical slices of juvenile mice by electrically stimulating these circuits using a multi-electrode array and recording the synaptic input to single neurons using the patch-clamp technique. We detected a decreased network response to stimulation in both excitatory and inhibitory circuits of Nlgn4 knock-out animals as compared to wild-type controls, and a decreased excitation-inhibition ratio. These data indicate that Nlgn4 is involved in the regulation of excitatory and inhibitory circuits and contributes to a balanced circuit response to stimulation.

A network of tufted layer 5 pyramidal neurons.

Tufted layer 5 (TL5) pyramidal neurons are important projection neurons from the cerebral cortex to subcortical areas. Recent and ongoing experiments aimed at understanding the computational analysis performed by a network of synaptically connected TL5 neurons are reviewed here. The experiments employed dual and triple whole-cell patch clamp recordings from visually identified and preselected neurons in brain slices of somatosensory cortex of young (14- to 16-day-old) rats. These studies suggest that a local network of TL5 neurons within a cortical module of diameter 300 microns consists of a few hundred neurons that are extensively inter-connected with reciprocal feedback from at least first-, second- and third-order target neurons. A statistical analysis of synaptic innervation suggests that this recurrent network is not randomly arranged and hence each neuron could be functionally unique. Synaptic transmission between these neurons is characterized by use-dependent synaptic depression which confers novel properties to this recurrent network of neurons. First, a range of rates of depression for different synaptic connections enable each TL5 neuron to receive a unique mixture of information about the average firing rates and the temporally correlated action potential (AP) activity in the population of presynaptic TL5 neurons. Second, each AP generated by any neuron in the network induces a change (defined as an iteration step) in the functional coupling of the neurons in the network (defined as network configuration). It is proposed that the network configuration is iterated during a stimulus to achieve an optimally orchestrated network response. Hebbian, anti-Hebbian and neuromodulatory-induced modifications of neurotransmitter release probability change the rates of synaptic depression and thereby alter the iteration step size. These data may be important to understand the dynamics of electrical activity within the network.

Activation of protein kinase C suppresses responses to NMDA in rat CA1 hippocampal neurones.

1. The effects of 1-oleoyl-2-acetylglycerol (OAG), an activator of protein kinase C (PKC), on NMDA receptor-mediated responses were investigated in CA1 neurones of hippocampal slices using current- and voltage-clamp techniques. 2. Topical application of OAG caused a suppression of the slow, voltage-sensitive, NMDA receptor-mediated component of excitatory postsynaptic potentials (EPSPs) evoked by stimulating the schaffer-collateral commissural afferents and had no effect on the fast, voltage-insensitive, quisqualate/kainate component. 3. OAG suppressed the amplitude of inward current responses to NMDA down to about one-third of control responses. OAG could also increase the duration of the responses to NMDA by up to twofold. The effect of OAG on the duration but not on the amplitude of the response to NMDA was blocked by pre-loading cells with the K+ channel blocker, Cs+. Topical application of OAG had no significant effect on current responses to quisqualate. 4. An OAG isomer, which does not activate PKC, had no effect on responses to NMDA. Intracellular application of the kinase inhibitor, H-7, completely blocked the effect of OAG on the amplitude and duration of responses to NMDA, as well as on the slow EPSP. Finally, topical application of another activator of PKC, phorbol 12-myristate 13-acetate (PMA), also suppressed responses to NMDA. PMA reduced the slow component of synaptic responses in about half of the cells tested. 5. We propose that activation of PKC in CA1 hippocampal neurones suppresses NMDA receptor-mediated responses.

The inositol 1,4,5-trisphosphate pathway mediates cholinergic potentiation of rat hippocampal neuronal responses to NMDA.

1. The cellular mechanism by which acetylcholine (ACh) potentiates neuronal responses to N-methyl-D-aspartate (NMDA) was investigated in CA1 neurones of hippocampal slices using current- and voltage-clamp techniques. 2. Loading cells with 5'-guanylylimidodiphosphate (GppNHp) caused a gradual increase in response to NMDA. Pulses of ACh accelerated this increase. Guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) blocked the potentiating effect of ACh on responses to NMDA. 3. Acute LiCl caused a gradual decrease in the potentiating effect of ACh, while the potentiation was completely prevented by 3 day chronic 6 mequiv/kg (I.P.) LiCl treatment and restored by acute treatment with 10 mM-inositol. 4. Loading cells with a general protein kinase inhibitor, H-7, enhanced the potentiating effect of ACh on responses to NMDA and blocked the effect of ACh on the after-hyperpolarization (AHP). 5. Ultraviolet irradiation of cells loaded with a photolabile inositol 1,4,5-trisphosphate (InsP3) caused a transient increase in responses to NMDA, while penetrating cells with active InsP3-containing pipettes caused a gradual BAPTA-sensitive increase in responses to NMDA. 6. Reducing the rate of InsP3 metabolism, with 2,3-diphosphoglyceric acid (DPG), caused an increase and prolongation of the potentiating effect of ACh, while blocking the InsP3 receptor with heparin prevented the cholinergic potentiation. 7. NMDA, by itself, potentiated subsequent responses to NMDA, an effect that was blocked when [Ca2+]i was chelated with BAPTA. NMDA and ACh were also found to compete in potentiating responses to NMDA. Finally, the cholinergic potentiation was blocked when cells were loaded with BAPTA. 8. We propose that activation of the InsP3 branch of the phosphoinositide pathway potentiated responses to NMDA and that InsP3 exerted this effect by elevating [Ca2+]i.

Redistribution of synaptic efficacy between neocortical pyramidal neurons.

Experience-dependent potentiation and depression of synaptic strength has been proposed to subserve learning and memory by changing the gain of signals conveyed between neurons. Here we examine synaptic plasticity between individual neocortical layer-5 pyramidal neurons. We show that an increase in the synaptic response, induced by pairing action-potential activity in pre- and postsynaptic neurons, was only observed when synaptic input occurred at low frequencies. This frequency-dependent increase in synaptic responses arises because of a redistribution of the available synaptic efficacy and not because of an increase in the efficacy. Redistribution of synaptic efficacy could represent a mechanism to change the content, rather than the gain, of signals conveyed between neurons.

Long-lasting facilitation of excitatory postsynaptic potentials in the rat hippocampus by acetylcholine.

1. The effects of acetylcholine (ACh) on excitatory postsynaptic potentials (EPSPs) evoked by stimulating Schaffer-commissural afferents and on ionophoretically applied L-glutamate ligands, were investigated in CA1 neurones of hippocampal slices using current- and voltage-clamp techniques. 2. ACh produced a transient suppression followed by a long-lasting facilitation of EPSPs. The facilitation was also seen in Cs(+)-filled cells under voltage-clamp conditions. Both suppressing and facilitating effects were blocked by atropine. 3. All components of the EPSP were reduced in the initial phase of ACh action, while only the slow component was enhanced during the later phase. The facilitation was blocked by an N-methyl-D-aspartate (NMDA) receptor antagonist, d-2-amino-5-phosphonovalerate (2-APV) and by hyperpolarization. 4. ACh also facilitated responses to ionophoretically applied NMDA in voltage-clamped, Cs(+)-filled cells in Ba2(+)-treated slices. ACh facilitated responses to L-glutamate which was blocked by 2-APV. ACh failed to affect responses to kainate or quisqualate. 5. We conclude that ACh, acting on muscarinic receptors, exerts a primary effect in the hippocampus to specifically amplify NMDA receptor-mediated synaptic responses and thereby facilitate EPSPs.