Synaptic mechanisms of top-down control in the non-lemniscal inferior colliculus

Corticofugal projections to evolutionarily ancient, subcortical structures are ubiquitous across mammalian sensory systems. These ‘descending’ pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here, we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from mouse auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity, and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor-dependent, supralinear excitatory postsynaptic potential summation, indicating that descending signals can nonlinearly amplify IC neurons’ moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway’s role in plasticity and perceptual learning.

How synaptic strength, short-term plasticity, and temporal factors contribute to neuronal spike output

To compute spiking responses, neurons integrate inputs from thousands of synapses whose strengths span an order of magnitude. Intriguingly, in mouse neocortex, the small minority of 'strong' synapses is found predominantly between similarly tuned cells, suggesting they are the synapses that determine a neuron's spike output. This raises the question of how other computational primitives, such as 'background' activity from the majority of synapses, which are 'weak', short-term plasticity, and temporal synchrony contribute to spiking. First, we combined extracellular stimulation and whole-cell recordings in mouse barrel cortex to map the distribution of excitatory postsynaptic potential (EPSP) amplitudes and paired-pulse ratios of excitatory synaptic connections converging onto individual layer 2/3 (L2/3) neurons. While generally net short-term plasticity was weak, connections with EPSPs > 2 mV displayed pronounced paired-pulse depression. EPSP amplitudes and paired-pulse ratios of connections converging onto the same neurons spanned the full range observed across L2/3 and there was no indication that strong synapses nor those with particular short-term plasticity properties were associated with particular cells, which critically constrains theoretical models of cortical filtering. To investigate how different computational primitives of synaptic information processing interact to shape spiking, we developed a computational model of a pyramidal neuron in the rodent L2/3 circuitry: firing rates and pairwise correlations of presynaptic inputs were constrained by in vivo observations, while synaptic strength and short-term plasticity were set based on our experimental data. Importantly, we found that the ability of strong inputs to evoke spiking critically depended on their high temporal synchrony and high firing rates observed in vivo and on synaptic background activity - and not primarily on synaptic strength, which in turn further enhanced information transfer. Depression of strong synapses was critical for maintaining a neuron's responsivity and prevented runaway excitation. Our results provide a holistic framework of how cortical neurons exploit complex synergies between temporal coding, synaptic properties, and noise in order to transform synaptic inputs into output firing.

Corticothalamic Projections Gate Alpha Rhythms in the Pulvinar

Two types of corticothalamic (CT) terminals reach the pulvinar nucleus of the thalamus, and their distribution varies according to the hierarchical level of the cortical area they originate from. While type 2 terminals are more abundant at lower hierarchical levels, terminals from higher cortical areas mostly exhibit type 1 axons. Such terminals also evoke different excitatory postsynaptic potential dynamic profiles, presenting facilitation for type 1 and depression for type 2. As the pulvinar is involved in the oscillatory regulation between intercortical areas, fundamental questions about the role of these different terminal types in the neuronal communication throughout the cortical hierarchy are yielded. Our theoretical results support that the co-action of the two types of terminals produces different oscillatory rhythms in pulvinar neurons. More precisely, terminal types 1 and 2 produce alpha-band oscillations at a specific range of connectivity weights. Such oscillatory activity is generated by an unstable transition of the balanced state network’s properties that it is found between the quiescent state and the stable asynchronous spike response state. While CT projections from areas 17 and 21a are arranged in the model as the empirical proportion of terminal types 1 and 2, the actions of these two cortical connections are antagonistic. As area 17 generates low-band oscillatory activity, cortical area 21a shifts pulvinar responses to stable asynchronous spiking activity and vice versa when area 17 produces an asynchronous state. To further investigate such oscillatory effects through corticothalamo-cortical projections, the transthalamic pathway, we created a cortical feedforward network of two cortical areas, 17 and 21a, with CT connections to a pulvinar-like network with two cortico-recipient compartments. With this model, the transthalamic pathway propagates alpha waves from the pulvinar to area 21a. This oscillatory transfer ceases when reciprocal connections from area 21a reach the pulvinar, closing the CT loop. Taken together, results of our model suggest that the pulvinar shows a bi-stable spiking activity, oscillatory or regular asynchronous spiking, whose responses are gated by the different activation of cortico-pulvinar projections from lower to higher-order areas such as areas 17 and 21a.

A stable proportion of Purkinje cell inputs from parallel fibers are silent during cerebellar maturation

Cerebellar Purkinje neurons integrate information transmitted at excitatory synapses formed by granule cells. Although these synapses are considered essential sites for learning, most of them appear not to transmit any detectable electrical information and have been defined as silent. It has been proposed that silent synapses are required to maximize information storage capacity and ensure its reliability, and hence to optimize cerebellar operation. Such optimization is expected to occur once the cerebellar circuitry is in place, during its maturation and the natural and steady improvement of animal agility. We therefore investigated whether the proportion of silent synapses varies over this period, from the third to the sixth postnatal week in mice. Selective expression of a calcium indicator in granule cells enabled quantitative mapping of presynaptic activity, while postsynaptic responses were recorded by patch clamp in acute slices. Through this approach and the assessment of two anatomical features (the distance that separates adjacent planar Purkinje dendritic trees and the synapse density), we determined the average excitatory postsynaptic potential per synapse. Its value was four to eight times smaller than responses from paired recorded detectable connections, consistent with over 70% of synapses being silent. These figures remained remarkably stable across maturation stages. According to the proposed role for silent synapses, our results suggest that information storage capacity and reliability are optimized early during cerebellar maturation. Alternatively, silent synapses may have roles other than adjusting the information storage capacity and reliability.

Increased Signal Delays and Unaltered Synaptic Input Pattern Recognition in Layer III Neocortical Pyramidal Neurons of the rTg4510 Mouse Model of Tauopathy: A Computer Simulation Study With Passive Membrane

Abnormal tau proteins are involved in pathology of many neurodegenerative disorders. Transgenic rTg4510 mice express high levels of human tau protein with P301L mutation linked to chromosome 17 that has been associated with frontotemporal dementia with parkinsonism. By 9 months of age, these mice recapitulate key features of human tauopathies, including presence of hyperphosphorylated tau and neurofibrillary tangles (NFTs) in brain tissue, atrophy and loss of neurons and synapses, and hyperexcitability of neurons, as well as cognitive deficiencies. We investigated effects of such human mutant tau protein on neuronal membrane, subthreshold dendritic signaling, and synaptic input pattern recognition/discrimination in layer III frontal transgenic (TG) pyramidal neurons of 9-month-old rTg4510 mice and compared these characteristics to those of wild-type (WT) pyramidal neurons from age-matched control mice. Passive segmental cable models of WT and TG neurons were set up in the NEURON simulator by using three-dimensionally reconstructed morphology and electrophysiological data of these cells. Our computer simulations predict leakage resistance and capacitance of neuronal membrane to be unaffected by the mutant tau protein. Computer models of TG neurons showed only modest alterations in distance dependence of somatopetal voltage and current transfers along dendrites and in rise times and half-widths of somatic Excitatory Postsynaptic Potential (EPSPs) relative to WT control. In contrast, a consistent and statistically significant slowdown was detected in the speed of simulated subthreshold dendritic signal propagation in all regions of the dendritic surface of mutant neurons. Predictors of synaptic input pattern recognition/discrimination remained unaltered in model TG neurons. This suggests that tau pathology is primarily associated with failures/loss in synaptic connections rather than with altered intraneuronal synaptic integration in neurons of affected networks.

Corticothalamic Projections Gate Alpha Rhythms in the Pulvinar

Two types of corticothalamic (CT) terminals reach the pulvinar nucleus of the thalamus, and their distribution varies according to the hierarchical level of the cortical area they originate from. While type 2 terminals are more abundant at lower hierarchical levels, terminals from higher cortical areas mostly exhibit type 1 axons. Such terminals also evoke different excitatory postsynaptic potential dynamic profiles, presenting facilitation for type 1 and depression for type 2. As the pulvinar is involved in the oscillatory regulation between intercortical areas, fundamental questions about the role of these different terminal types in the neuronal communication throughout the cortical hierarchy are yielded. Our theoretical results support that the co-action of the two types of terminals produces different oscillatory rhythms in pulvinar neurons. More precisely, terminal types 1 and 2 produce alpha-band oscillations at a specific range of connectivity weights. Such oscillatory activity is generated by an unstable transition of the balanced state network’s properties that it is found between the quiescent state and the stable asynchronous spike response state. While CT projections from areas 17 and 21a are arranged in the model as the empirical proportion of terminals types 1 and 2, the actions of these two cortical connections are antagonistic. As area 17 generates low-band oscillatory activity, cortical area 21a shifts pulvinar responses to stable asynchronous spiking activity and vice-versa when area 17 produces an asynchronous state. To further investigate such oscillatory effects through corticothalamo-cortical projections, the transthalamic pathway, we created a cortical feedforward network of two cortical areas, 17 and 21a, with CT connections to a pulvinar-like network. With this model, the transthalamic pathway propagates alpha waves from the pulvinar to area 21a. This oscillatory transfer ceases when reciprocal connections from area 21a reach the pulvinar, closing the cortico-thalamic loop. Taken together, results of our model suggest that the pulvnar shows a bi-stable spiking activity, oscillatory or regular asynchronous spiking, whose responses are gated by the different activation of cortico-pulvinar projections from lower to higher-order areas such as areas 17 and 21a.

Asymptotic Input-Output Relationship Predicts Electric Field Effect on Sublinear Dendritic Integration of AMPA Synapses

An extracellular electric field (EF) induces transmembrane polarizations on extremely inhomogeneous spaces Evidence shows that EF-induced somatic polarization in pyramidal cells can modulate the neuronal input-output (I/O) function. However, it remains unclear whether and how dendritic polarization participates in the dendritic integration and contributes to the neuronal I/O function. To this end, we built a computational model of a simplified pyramidal cell with multi-dendritic tufts, one dendritic trunk, and one soma to describe the interactions among EF, dendritic integration, and somatic output, in which the EFs were modeled by inserting inhomogeneous extracellular potentials. We aimed to establish the underlying relationship between dendritic polarization and dendritic integration by analyzing the dynamics of subthreshold membrane potentials in response to AMPA synapses in the presence of constant EFs. The model-based singular perturbation analysis showed that the equilibrium mapping of a fast subsystem can serve as the asymptotic subthreshold I/O relationship for sublinear dendritic integration. This allows us to predict the tendency of EF-mediated dendritic integration by showing how EF changes modify equilibrium mapping. EF-induced hyperpolarization of distal dendrites receiving synapses inputs was found to play a key role in facilitating the AMPA receptor-evoked excitatory postsynaptic potential (EPSP) by enhancing the driving force of synaptic inputs. A significantly higher efficacy of EF modulation effect on global AMPA-type dendritic integration was found compared with local AMPA-type dendritic integration. During the generation of an action potential (AP), the relative contribution of EF-modulated dendritic integration and EF-induced somatic polarization was determined to show their collaboration in promoting or inhibiting the somatic excitability, depending on the EF polarity. These findings are crucial for understanding the EF modulation effect on neuronal computation, which provides insight into the modulation mechanism of noninvasive brain modulation.

Protective Effects of Oral Vitamin C on Memory and Learning Impairment and Attenuation of Synaptic Plasticity induced by Intracerebroventricular Injection of Beta-amyloid Peptide in Male Rats

Background: In neurodegenerative diseases, like Alzheimer’s disease (AD), learning and memory, and neural plasticity are impaired. Vitamin C (Vit C), as an antioxidant, protects tissues against oxidative stress. In this study, the neuroprotection and the effectiveness of Vit C in the prevention and treatment of AD in a rat model of AD induced by intracerebroventricular (ICV) injection of amyloid-beta (Aβ) were studied using behavioral tests and electrophysiological methods. Methods: 50 male Wistar rats were randomly assigned to five groups (n=10 rats /group): Control, Sham, AD, Vit C, and AD+Vit C. After treatment (2 months), animals were assessed by learning and memory tests, including the new object recognition (NOR), passive avoidance learning (PAL), and Morris water maze (MWM) tests. Then, using the electrophysiological method, synaptic plasticity in the hippocampus was assessed and Vit C effects on long-term potentiation (LTP) were examined.Results: ICV injection of Aβ to the AD group reduced memory in the NOR, PAL, and MWM behavioral tests. Also, Vit C reduced learning and memory impairment due to Aβ injection in rats. Aβ caused the inhibition of LTP in dentate gyrus (DG) granule cells by reducing the slope of the excitatory postsynaptic potential (EPSP) and the amplitude of the population spike (PS) in the AD group. Conclusions: These results showed that Vit C reduced the impairment in synaptic plasticity induced by Aβ in DG of the hippocampus. Vit C supplementation through its antioxidant properties can improve the impaired synaptic plasticity and memory induced by Aβ and can be applied as a neuroprotective agent.

Basal Synaptic Transmission and Long-Term Plasticity at CA3-CA1 Synapses Are Unaffected in Young Adult PINK1-Deficient Rats

Loss of function mutations in PARK6, the gene that encodes the protein PTEN-induced kinase 1 (PINK1), cause autosomal recessive familial Parkinson’s disease (PD). While PD is clinically diagnosed by its motor symptoms, recent studies point to the impact of non-motor symptoms, including cognitive dysfunction in the early pre-motor stages of the disease (Aarsland et al., 2004; Chaudhuri and Schapira, 2009). As the hippocampus is a key structure for learning and memory, this study aimed to determine whether synaptic transmission is affected at CA3-CA1 excitatory synapses in PINK1 knockout rats at an age when we recently reported a gain of function at excitatory synapses onto spiny projection neurons in the dorsal striatum (Creed et al., 2020) and when motor symptoms are beginning to appear (Dave et al., 2014). Using extracellular dendritic field excitatory postsynaptic potential recordings at CA3-CA1 synapses in dorsal hippocampus 4-to 5- month old PINK1 KO rats and wild-type littermate controls, we observed no detectable differences in the strength of basal synaptic transmission, paired-pulse facilitation, or long-term potentiation. Our results suggest that loss of PINK1 protein does not cause a general dysfunction of excitatory transmission throughout the brain at this young adult age when excitatory transmission is abnormal in the striatum.

Effect of Bone Marrow Stromal Stem Cells (BMSCs) Therapy on the Expression of Sodium Channel, Voltage-Gated, Type I, Alpha Subunit (SCN1A) in Temporal Lobe Epilepsy and Its Mechanism

SCN1A gene plays an indispensable role in several diseases. Bone marrow stromal stem cells (BMSCs) therapy is a potential target for treating epilepsy, but its therapeutic effect and mechanism is unclear. Our study aims to investigate the mechanism by how BMSCs affect epilepsy. Wistar rats were assigned into control group, model group (pilocarpine-induced TLE model), and BMSCs group followed by measuring the latency of field excitatory postsynaptic potential, pathological changes, SCN1A level by Real time PCR, NF-ĸB and TLR4 expression by Western blot, and HGMB1, TLR4, IL-1β and IL-6 secretion by ELISA. In model group, the incubation period of postsynaptic potential generation was significantly shortened and SCN1A level was significantly decreased, along with increased NF-ĸB expression and secretion of HMGB1, TLR-4, IL-1β and IL-6 (P < 0.05). After BMSCs treatment, the incubation period of postsynaptic potentials can be significantly prolonged and SCN1A was significantly upregulated, with ameliorated epilepsy injury and reduced secretion of related factors (P <0.05). Pilocarpine-induced TLE can reduce SCN1A expression and BMSCs therapy can up-regulate SCN1A expression by regulating NF-ĸB/HGMB1/TLR4 signaling pathway, thereby protecting neurons, reducing pathological damage, and ameliorating the development of epilepsy.