Summation Of Inputs Research Articles

Why the whole is more than the sum of its parts: Salience-driven overestimation in aggregated tactile sensations.

Experimental psychology often studies perception analytically, reducing its focus to minimal sensory units, such as thresholds or just noticeable differences in a single stimulus. Here, in contrast, we examine a synthetic aspect: how multiple inputs to a sensory system are aggregated into an overall percept. Participants in three experiments judged the total stimulus intensity for simultaneous electrical shocks to two digits. We tested whether the integration of component somatosensory stimuli into a total percept occurs automatically, or rather depends on the ability to consciously perceive discrepancy among components (Experiment 1), whether the discrepancy among these components influences sensitivity or/and perceptual bias in judging totals (Experiment 2), and whether the salience of each individual component stimulus affects perception of total intensity (Experiment 3). Perceptual aggregation of two simultaneous component events occurred both when participants could perceptually discriminate the two intensities, and also when they could not. Further, the actual discrepancy between the stimuli modulated both participants' sensitivity and perceptual bias: increasing discrepancies produced a systematic and progressive overestimation of total intensity. The degree of this bias depended primarily on the salience of the stronger stimulus in the pair. Overall, our results suggest that important nonlinear mechanisms contribute to sensory aggregation. The mind aggregates component inputs into a coherent and synthetic perceptual experience in a salience-weighted fashion that is not based on simple summation of inputs.

Processing of Paired Click-Tone Stimulation in the Mice Inferior Colliculus.

The inferior colliculus (IC) is known as a neuronal structure involved in the integration of acoustic information in the ascending auditory pathway. However, the processing of paired acoustic stimuli containing different sound types, especially when they are applied closely, in the IC remains poorly studied. We here firstly investigated the IC neuronal response to the paired stimuli comprising click and pure tone with different inter-stimulus (click-tone) intervals using in vivo loose-patch recordings in anesthetized BALB/c mice. It was found that the total acoustic evoked spike counts decreased under certain click-tone interval conditions on some neurons with or without click-induced supra-threshold responses. Application of click could enhance the minimum threshold of the neurons responding to the tone in a pair without changing other characteristics of the neuronal tone receptive fields. We further studied the paired acoustic stimuli evoked excitatory/inhibitory inputs, IC neurons received, by holding the membrane potential at -70/0 mV using in vivo whole-cell voltage-clamp techniques. The curvature and peak amplitude of the excitatory/inhibitory post-synaptic current (EPSC/IPSC) could be almost unchanged under different inter-stimulus interval conditions. Instead of showing the summation of synaptic inputs, most recorded neurons only had the EPSC/IPSC with the amplitude similar as the bigger one evoked by click or tone in a pair when the inter-stimulus interval was small. We speculated that the IC could inherit the paired click-tone information which had been integrated before reaching it.

Nonlinear Processing of Shape Information in Rat Lateral Extrastriate Cortex.

In rodents, the progression of extrastriate areas located laterally to primary visual cortex (V1) has been assigned to a putative object-processing pathway (homologous to the primate ventral stream), based on anatomical considerations. Recently, we found functional support for such attribution (Tafazoli et al., 2017), by showing that this cortical progression is specialized for coding object identity despite view changes, the hallmark property of a ventral-like pathway. Here, we sought to clarify what computations are at the base of such specialization. To this aim, we performed multielectrode recordings from V1 and laterolateral area LL (at the apex of the putative ventral-like hierarchy) of male adult rats, during the presentation of drifting gratings and noise movies. We found that the extent to which neuronal responses were entrained to the phase of the gratings sharply dropped from V1 to LL, along with the quality of the receptive fields inferred through reverse correlation. Concomitantly, the tendency of neurons to respond to different oriented gratings increased, whereas the sharpness of orientation tuning declined. Critically, these trends are consistent with the nonlinear summation of visual inputs that is expected to take place along the ventral stream, according to the predictions of hierarchical models of ventral computations and a meta-analysis of the monkey literature. This suggests an intriguing homology between the mechanisms responsible for building up shape selectivity and transformation tolerance in the visual cortex of primates and rodents, reasserting the potential of the latter as models to investigate ventral stream functions at the circuitry level.SIGNIFICANCE STATEMENT Despite the growing popularity of rodents as models of visual functions, it remains unclear whether their visual cortex contains specialized modules for processing shape information. To addresses this question, we compared how neuronal tuning evolves from rat primary visual cortex (V1) to a downstream visual cortical region (area LL) that previous work has implicated in shape processing. In our experiments, LL neurons displayed a stronger tendency to respond to drifting gratings with different orientations while maintaining a sustained response across the whole duration of the drift cycle. These trends match the increased complexity of pattern selectivity and the augmented tolerance to stimulus translation found in monkey visual temporal cortex, thus revealing a homology between shape processing in rodents and primates.

Limited prefrontal cortical regulation over the basolateral amygdala in adolescent rats

Cognitive regulation of emotion develops from childhood into adulthood. This occurs in parallel with maturation of prefrontal cortical (PFC) regulation over the amygdala. The cellular substrates for this regulation may include PFC activation of inhibitory GABAergic elements in the amygdala. The purpose of this study was to determine whether PFC regulation over basolateral amygdala area (BLA) in vivo is immature in adolescence, and if this is due to immaturity of GABAergic elements or PFC excitatory inputs. Using in vivo extracellular electrophysiological recordings from anesthetized male rats we found that in vivo summation of PFC inputs to the BLA was less regulated by GABAergic inhibition in adolescents (postnatal day 39) than adults (postnatal day 72–75). In addition, stimulation of either prelimbic or infralimbic PFC evokes weaker inhibition over basal (BA) and lateral (LAT) nuclei of the BLA in adolescents. This was dictated by both weak recruitment of inhibition in LAT and weak excitatory effects of PFC in BA. The current results may contribute to differences in adolescent cognitive regulation of emotion. These findings identify specific elements that undergo adolescent maturation and may therefore be sensitive to environmental disruptions that increase risk for psychiatric disorders.

Nonlinear Dynamics, Quasi-Periodic Summation, Self-Oscillating Processes, and Information Coding in Selective Spiking Neural Networks

Nonlinear dynamics, physical processes, and information processing in selective spiking neurons are investigated. Summation of pulse inputs are considered on the basis of the theory of quasi-periodic functions and nonlinear transformation via relaxation of the self-oscillating system of a neuron. A way of encoding input information is also considered in which the information unit is a pulse sequence, and the intensity of the input signal is encoded by a synchronous change in the frequency of the pulse sequences.

Target Interneuron Preference in Thalamocortical Pathways Determines the Temporal Structure of Cortical Responses.

Sensory processing relies on fast detection of changes in environment, as well as integration of contextual cues over time. The mechanisms by which local circuits of the cerebral cortex simultaneously perform these opposite processes remain obscure. Thalamic "specific" nuclei relay sensory information, whereas "nonspecific" nuclei convey information on the environmental and behavioral contexts. We expressed channelrhodopsin in the ventrobasal specific (sensory) or the rhomboid nonspecific (contextual) thalamic nuclei. By selectively activating each thalamic pathway, we found that nonspecific inputs powerfully activate adapting (slow-responding) interneurons but weakly connect fast-spiking interneurons, whereas specific inputs exhibit opposite interneuron preference. Specific inputs thereby induce rapid feedforward inhibition that limits response duration, whereas, in the same cortical area, nonspecific inputs elicit delayed feedforward inhibition that enables lasting recurrent excitation. Using a mean field model, we confirm that cortical response dynamics depends on the type of interneuron targeted by thalamocortical inputs and show that efficient recruitment of adapting interneurons prolongs the cortical response and allows the summation of sensory and contextual inputs. Hence, target choice between slow- and fast-responding inhibitory neurons endows cortical networks with a simple computational solution to perform both sensory detection and integration.

Spontaneously opening GABAA receptors play a significant role in neuronal signal filtering and integration

Continuous (tonic) charge transfer through ionotropic receptors of γ-aminobutyric acid (GABAARs) is an important mechanism of inhibitory signalling in the brain. The conventional view has been that tonic GABA-ergic inhibitory currents are mediated by low concentrations of ambient GABA. Recently, however, it was shown that the GABA-independent, spontaneously opening GABAARs (s-GABAARs), may contribute significantly to the tonic GABAAR current. One of the common approaches to temporal lobe epilepsy (TLE) therapy is an increase of GABA concentration in the cerebrospinal fluid to augment tonic current through GABAARs. Such an increase, however, generates multiple side effects, which impose significant limitations on the use of correspondent drugs. In contrast, activation/deactivation of s-GABAARs in a GABA-independent manner may provide a mechanism of regulation of tonic conductance without modification of extracellular GABA concentration, thus avoiding connected side effects. Although s-GABAARs have been detected in our earlier work, it is unclear whether they modulate neural signalling, or, due to their independence from the neurotransmitter, they provide just a stable background effect without much impact on neural crosstalk dynamics. Here, we focused on the causal relationship between s-GABAAR activity and signal integration in the rat’s dentate gyrus granule cells to find that s-GABAARs play an important role in neural signal transduction. s-GABAARs shape the dynamics of phasic inhibitory responses, regulate the action potential generation machinery and control the coincidence detection window pertinent to excitatory input summation. Our results demonstrate that tonic inhibition delivered by s-GABAARs contributes to the key mechanisms that ensure implementation of neural signal filtering and integration, in a GABA-independent manner. This makes s-GABAAR a new and important actor in the regulation of long-term neural plasticity and a perspective target for TLE therapy.

Wind-up in lamina I spinoparabrachial neurons: a role for reverberatory circuits.

Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is believed to underlie temporal summation of nociceptive input. However, whether spinoparabrachial neurons, which likely contribute to the affective component of pain, undergo wind-up was unknown. Here, we addressed this question and investigated the underlying neural circuit. We show that one-fifth of lamina I spinoparabrachial neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain's unpleasantness.

Feedforward Inhibition Allows Input Summation to Vary in Recurrent Cortical Networks.

Brain computations depend on how neurons transform inputs to spike outputs. Here, to understand input-output transformations in cortical networks, we recorded spiking responses from visual cortex (V1) of awake mice of either sex while pairing sensory stimuli with optogenetic perturbation of excitatory and parvalbumin-positive inhibitory neurons. We found that V1 neurons’ average responses were primarily additive (linear). We used a recurrent cortical network model to determine whether these data, as well as past observations of nonlinearity, could be described by a common circuit architecture. Simulations showed that cortical input-output transformations can be changed from linear to sublinear with moderate (∼20%) strengthening of connections between inhibitory neurons, but this change away from linear scaling depends on the presence of feedforward inhibition. Simulating a variety of recurrent connection strengths showed that, compared with when input arrives only to excitatory neurons, networks produce a wider range of output spiking responses in the presence of feedforward inhibition.

Energy Efficient Reconfigurable Threshold Logic Circuit with Spintronic Devices

A Threshold Logic Gate (TLG) performs weighted summation of multiple binary inputs and compares the summation with a threshold. Different logic functions can be implemented by reconfiguring the weights and threshold of the same TLG circuit. This paper introduces a novel design of reconfigurable Spintronic Threshold Logic Gate (STLG), which employs spintronic weight devices to perform current-mode weighted summation of binary inputs, whereas, the low voltage fast switching spintronic threshold device carries out the threshold operation in an energy efficient manner. The proposed STLG operates at a small terminal voltage of 50 mV, resulting in ultra-low energy consumption. A bottom-up cross-layer simulation framework is developed to synthesize and map large scale digital logic functions to the proposed STLG circuits. The simulation results of ISCAS-85 benchmarks show that the proposed STLG based reconfigurable logic hardware can achieve two orders lower Energy-Delay Product (EDP) compared with state-of-the-art CMOS Field Programmable Gate Arrays (FPGA), and smaller EDP compared to large scale Memristive Threshold Logic (MTL) based FPGA. Moreover, the ultra-low programming energy of spintronic weight device also leads to three orders lower reconfiguration energy of STLG compared to MTL design.

Temporal summation and motor function modulation during repeated jaw movements in patients with temporomandibular disorder pain and healthy controls.

Temporal summation of nociceptive inputs may be an important pathophysiological mechanism in temporomandibular disorders (TMD) pain; however, it remains unknown how natural jaw function relates to underlying pain mechanisms. This study evaluated changes in pain and movement patterns during repeated jaw movements in patients with painful temporomandibular joints (TMJ) compared with healthy controls. Twenty patients with TMD with TMJ pain, and an anterior disk displacement without reduction and 20 age- and gender-matched healthy volunteers were included. Participants performed 20 trials (4 × 5 sessions) of standardized and repeated mandibular movements, and scored the movement-associated pain intensity on 0 to 10 numeric rating scale in addition to measurements of jaw movements. Patients with TMJ pain reported higher baseline pain compared to the control group for all types of jaw movements (P = 0.001) and significant increases in numeric rating scale pain scores by repetition of jaw movements (P < 0.001), which was not observed in the control group (P > 0.05). Jaw total opening distance (P = 0.030), maximum opening velocity (P = 0.043) and average closing velocity (P = 0.044) in the TMJ pain group were significantly reduced during the repeated movements. In the control group, however, total opening distance (P = 0.499), maximum opening velocity (P = 0.064), and average closing velocity (P = 0.261) remained unchanged, whereas average opening velocity (P = 0.040) and maximum closing velocity (P = 0.039) increased. The study demonstrates that repeated jaw movements constitute a sufficient and adequate stimulation for triggering temporal summation effects associated with significant inhibition of motor function in painful TMJs. These findings have practical implications for diagnosis of TMD pain and for more mechanism-driven management protocols in the future.

POm Thalamocortical Input Drives Layer-Specific Microcircuits in Somatosensory Cortex.

Higher-order thalamic nuclei, such as the posterior medial nucleus (POm) in the somatosensory system or the pulvinar in the visual system, densely innervate the cortex and can influence perception and plasticity. To systematically evaluate how higher-order thalamic nuclei can drive cortical circuits, we investigated cell-type selective responses to POm stimulation in mouse primary somatosensory (barrel) cortex, using genetically targeted whole-cell recordings in acute brain slices. We find that ChR2-evoked thalamic input selectively targets specific cell types in the neocortex, revealing layer-specific modules for the summation and processing of POm input. Evoked activity in pyramidal neurons from deep layers is fast and synchronized by rapid feedforward inhibition from GABAergic parvalbumin-expressing neurons, and activity in superficial layers is weaker and prolonged, facilitated by slow inhibition from GABAergic neurons expressing the 5HT3a receptor. Somatostatin-expressing GABAergic neurons do not receive direct input in either layer and their spontaneous activity is suppressed during POm stimulation. This novel pattern of weak, delayed, thalamus-evoked inhibition in layer 2 suggests a longer integration window for incoming sensory information and may facilitate stimulus detection and plasticity in superficial pyramidal neurons.

Neuronify: An Educational Simulator for Neural Circuits.

Educational software (apps) can improve science education by providing an interactive way of learning about complicated topics that are hard to explain with text and static illustrations. However, few educational apps are available for simulation of neural networks. Here, we describe an educational app, Neuronify, allowing the user to easily create and explore neural networks in a plug-and-play simulation environment. The user can pick network elements with adjustable parameters from a menu, i.e., synaptically connected neurons modelled as integrate-and-fire neurons and various stimulators (current sources, spike generators, visual, and touch) and recording devices (voltmeter, spike detector, and loudspeaker). We aim to provide a low entry point to simulation-based neuroscience by allowing students with no programming experience to create and simulate neural networks. To facilitate the use of Neuronify in teaching, a set of premade common network motifs is provided, performing functions such as input summation, gain control by inhibition, and detection of direction of stimulus movement. Neuronify is developed in C++ and QML using the cross-platform application framework Qt and runs on smart phones (Android, iOS) and tablet computers as well personal computers (Windows, Mac, Linux).

Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials.

Key points We establish experimental preparations for optogenetic investigation of glutamatergic input to the inferior olive.Neurones in the principal olivary nucleus receive monosynaptic extra‐somatic glutamatergic input from the neocortex.Glutamatergic inputs to neurones in the inferior olive generate bidirectional postsynaptic potentials (PSPs), with a fast excitatory component followed by a slower inhibitory component.Small conductance calcium‐activated potassium (SK) channels are required for the slow inhibitory component of glutamatergic PSPs and oppose temporal summation of inputs at intervals ≤ 20 ms.Active integration of synaptic input within the inferior olive may play a central role in control of olivo‐cerebellar climbing fibre signals. The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long‐range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABAA independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance calcium‐activated potassium channels with iberiotoxin, and is abolished by blocking small conductance calcium‐activated potassium channels with apamin. Summation of excitatory components of synaptic responses to inputs at intervals ≤ 20 ms is increased by apamin, suggesting a role for the inhibitory component of glutamatergic responses in temporal integration. Our results indicate that neurones in the inferior olive implement novel rules for synaptic integration and suggest new principles for the contribution of inferior olive neurones to coordinated motor behaviours.

More than meets the eye

Orientation selectivity in visual cortex is not simply the result of linear input summation. Instead, selectivity is enhanced by nonlinear dendritic transformation of spatially clustered, cotuned synaptic inputs.

Medial cerebellar nucleus projects to feeding-related neurons in the ventromedial hypothalamic nucleus in rats.

The cerebellum, a hindbrain motor center, also participates in regulating nonsomatic visceral activities such as feeding control. However, the underlying neural mechanism is largely unknown. Here, we investigate whether the cerebellar medial nucleus (MN), one of the final outputs of the cerebellum, could directly project to and modulate the feeding-related neurons in the ventromedial hypothalamic nucleus (VMN), which has been traditionally implicated in feeding behavior, energy balance, and body weight regulation. The retrograde tracing results show that both GABAergic and glutamatergic projection neurons in the cerebellar MN send direct projections to the VMN. Electrical stimulation of cerebellar MN elicits an inhibitory, excitatory or biphasic response of VMN neurons. Interestingly, the VMN neurons modulated by cerebellar MN afferents not only receive phasic and tonic inputs from the gastric vagal nerves, but also are sensitive to peripheral glycemia and ghrelin signals. Moreover, a summation of inputs from the cerebellar MN and gastric vagal afferents occurs on single glycemia/ghrelin-sensitive neurons in the VMN, and the immunostaining result show that the axons from the cerebellar MN and the projections from the nucleus tractus solitarius, which conveys the gastric vagal inputs to hypothalamus, converge on single VMN glycemia/ghrelin-sensitive neurons. These results demonstrate that the somatic information forwarded by the cerebellar MN, together with the feeding signals from periphery, converge onto single VMN neurons, suggesting that a somatic-visceral integration related to feeding may occur in the VMN and the cerebellum may actively participate in the feeding regulation through the direct cerebellar MN-VMN projections.

NMDA receptors amplify mossy fiber synaptic inputs at frequencies up to at least 750 Hz in cerebellar granule cells.

Neuronal integration of high-frequency signals is important for rapid information processing. Cerebellar mossy fiber axons (MFs) can fire action potentials (APs) at frequencies of more than one kilohertz. However, it is unclear whether and how the postsynaptic cerebellar granule cells (GCs) are able to process these high-frequency MF inputs. Here, we measured AP firing in GCs during high-frequency MF stimulation and show that GC firing frequency increased non-linearly when MF stimulation frequency was increased from 100 to 750 Hz. To investigate the mechanisms enabling such high-frequency signaling, we analyzed the role of N-methyl-d-aspartate receptors (NMDARs), which have been implicated in synaptic signaling at lower frequencies. Application of D-2-amino-5-phosphonopentanoic acid (APV), a potent inhibitor of NMDARs, strongly impaired the GC firing frequency during high-frequency MF stimulation. APV had no significant effect on single excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) evoked at 1 Hz at resting membrane potentials. However, the time course of EPSCs evoked at 1 Hz at depolarized potentials or following high-frequency MF stimulation was accelerated by APV. Thus, our results show that NMDAR-mediated currents amplify high-frequency MF inputs by prolonging the time courses of synaptic inputs, thereby causing greater synaptic summation of inputs. Hence, NMDARs support the integration of MF synaptic input at frequencies up to at least 750 Hz. Synapse 70:269-276, 2016. © 2016 Wiley Periodicals, Inc.

Curvature of dendritic nonlinearities modulates higher-order spiking correlations

Characterizing neural spiking covariability is essential for understanding the collective activity of neural populations. Recent experiments have provided evidence of statistical dependencies among groups of neurons beyond that expected by the firing rates and pairwise alone [1-3]. These correlations (HOCs) can be generated by common input [4] or motifs within the network architecture [5], yet a complete mechanistic understanding is lacking. We explore a novel mechanism through which higher-order can be modulated: dendritic nonlinearities. We simulated the spiking activity of a simple exponential integrate-and-fire model neuron in response to two correlated presynaptic spike trains and background noise. The synaptic conductances were either summed linearly at the soma or were filtered through a nonlinear dendritic transfer function (see Figure ​Figure1),1), which was chosen to have a similar magnitude of effect on nonlinear EPSP summation as observed by active dendritic properties in pyramidal cells [6]. Using maximum entropy techniques, correlations in the circuit were quantified as the probability of synchronous triplet spiking between the postsynaptic cell and its two presynaptic inputs beyond what could be captured by the firing rates and pairwise alone, normalized by the product of the standard deviations. We found that superlinear dendrites significantly increased the level of triplet. On the other hand, saturating dendrites decorrelated triplets. These results reveal that HOCs in spiking activity are modulated by the curvature of the dendritic transfer function. Finally, this study demonstrates how intrinsic single-cell properties can tune spiking covariability in neural populations. Figure 1 A. Transfer functions depicting the summation of synaptic inputs for linear dendrites. B. Transfer function for saturating dendritic nonlinearities (solid line), as well as the identity (dotted line). C. Same as B for superlinear dendrites. D-F. Triplet ...

Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration after Status Epilepticus.

In this paper, we describe a novel mechanism that causes increased dendritic persistent Na(+) current. We demonstrate using a combination of electrophysiology and molecular approaches that the upregulation of persistent Na(+) currents is due to a relief from polyamine-dependent inhibition. The polyamine deficit in hippocampal neurons is likely caused by an upregulation of the degrading enzyme spermidine/spermine acetyltransferase. Multiphoton glutamate uncaging experiments revealed that the increase in dendritic persistent Na current causes augmented dendritic summation of excitatory inputs. We believe that these results establish a novel post-transcriptional modification of ion channels in chronic epilepsy.

Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

BackgroundRecent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes. MethodsWe applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants. ResultsWe present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. ConclusionSOur results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior.