An Anatomical and Physiological Basis for Coincidence Detection Across Time Scales in the Auditory System.

Coincidence detection is a common neural computation that identifies co-occurring stimuli by integration of inputs. In the auditory system, octopus cells act as coincidence detectors for complex sounds that include both synchronous and sequenced combinations of frequencies. Octopus cells must detect coincidence on both the millisecond and submillisecond time scale, unlike the average neuron, which integrates inputs over time on the order of tens of milliseconds. Here, we show that octopus cell computations in the cell body are shaped by inhibition in the dendrites, which adjusts the strength and timing of incoming signals to achieve submillisecond acuity. This mechanism is crucial for the fundamental process of integrating the synchronized frequencies of natural auditory signals over time.

Characterization of primary visual cortex input to specific cell types in the superior colliculus.

The superior colliculus is a critical brain region involved in processing visual information. It receives visual input directly from the retina, as well as via a projection from primary visual cortex. Here we determine which cell types in the superficial superior colliculus receive visual input from primary visual cortex in mice. Neurons in the superficial layers of the superior colliculus were classified into four groups - Wide-field, narrow-field, horizontal and stellate - based on their morphological and electrophysiological properties. To determine functional connections between V1 and these four different cell types we expressed Channelrhodopsin2 in primary visual cortex and then optically stimulated these axons while recording from different neurons in the superficial superior colliculus using whole-cell patch-clamp recording in vitro. We found that all four cell types in the superficial layers of the superior colliculus received monosynaptic (direct) input from V1. Wide-field neurons were more likely than other cell types to receive primary visual cortex input. Our results provide information on the cell specificity of the primary visual cortex to superior colliculus projection, increasing our understanding of how visual information is processed in the superior colliculus at the single cell level.

High synaptic threshold for dendritic NMDA spike generation in human layer 2/3 pyramidal neurons.

Neurons receive synaptic input primarily onto their dendrites. While we know much about the electrical properties of dendrites in rodents, we have only just started to describe their properties in the human brain. Here, we investigate the capacity of human dendrites to generate NMDA-receptor-dependent spikes (NMDA spikes). Using dendritic glutamate iontophoresis, as well as local dendritic synaptic stimulation, we find that human layer 2/3 pyramidal neurons can generate dendritic NMDA spikes. The capacity to evoke NMDA spikes in human neurons, however, was significantly reduced compared with that in rodents. Simulations in morphologically realistic and simplified models indicated that human neurons have a higher synaptic threshold for NMDA spike generation primarily due to the wider diameter of their dendrites. In summary, we find reduced NMDA spike generation in human compared with rodent layer 2/3 pyramidal neurons and provide evidence that this is due to the wider diameter of human dendrites.

Voltage Clamp Errors During Estimation of Concurrent Excitatory and Inhibitory Synaptic Input to Neurons with Dendrites.

The whole-cell voltage clamp technique is commonly used to estimate synaptic conductances. While previous work has shown how these estimates are affected by series resistance and space clamp errors during isolated synaptic events, how voltage clamp errors impact on synaptic conductance estimates during concurrent excitation and inhibition is less clear. This issue is particularly relevant given that many studies now use the whole-cell voltage clamp technique to estimate synaptic conductances in vivo, where both excitation and inhibition are intact. Using both simplistic and morphologically realistic models, we investigate how imperfect voltage clamp conditions distort estimates of excitatory and inhibitory synaptic conductance estimated using the Borg-Graham method during concurrent synaptic input onto dendrites. These simulations demonstrate that dendritically located conductances are underestimated even when dynamic clamp reinjection faithfully reproduces the voltage response at the soma to the actual conductances. Inhibitory conductances are underestimated more than excitatory conductances, leading to errors in the excitatory to inhibitory conductance ratio and negative inhibitory conductance estimates during distal inhibition. Interactions between unclamped dendritic excitatory and inhibitory conductances also introduce correlations when the actual conductances are uncorrelated, as well as distortions in the time course of estimated excitatory and inhibitory conductances. Finally, we show that space clamp errors are exacerbated by the inclusion of dendritic voltage-activated conductances. In summary, we highlight issues with the interpretation of synaptic conductance estimates obtained using somatic whole-cell voltage clamp during concurrent excitatory and inhibitory input to neurons with dendrites.

Superior colliculus modulates cortical coding of somatosensory information.

The cortex modulates activity in superior colliculus via a direct projection. What is largely unknown is whether (and if so how) the superior colliculus modulates activity in the cortex. Here, we investigate this issue and show that optogenetic activation of superior colliculus changes the input-output relationship of neurons in somatosensory cortex, enhancing responses to low amplitude whisker deflections. While there is no direct pathway from superior colliculus to somatosensory cortex, we found that activation of superior colliculus drives spiking in the posterior medial (POm) nucleus of the thalamus via a powerful monosynaptic pathway. Furthermore, POm neurons receiving input from superior colliculus provide monosynaptic excitatory input to somatosensory cortex. Silencing POm abolished the capacity of superior colliculus to modulate cortical whisker responses. Our findings indicate that the superior colliculus, which plays a key role in attention, modulates sensory processing in somatosensory cortex via a powerful di-synaptic pathway through the thalamus.

Conditioning by subthreshold synaptic input changes the intrinsic firing pattern of CA3 hippocampal neurons.

Unlike synaptic strength, intrinsic excitability is assumed to be a stable property of neurons. For example, learning of somatic conductances is generally not incorporated into computational models, and the discharge pattern of neurons in response to test stimuli is frequently used as a basis for phenotypic classification. However, it is increasingly evident that signal processing properties of neurons are more generally plastic on the timescale of minutes. Here we demonstrate that the intrinsic firing patterns of CA3 neurons of the rat hippocampus in vitro undergo rapid long-term plasticity in response to a few minutes of only subthreshold synaptic conditioning. This plasticity on the spike timing could also be induced by intrasomatic injection of subthreshold depolarizing pulses and was blocked by kinase inhibitors, indicating that discharge dynamics are modulated locally. Cluster analysis of firing patterns before and after conditioning revealed systematic transitions toward adapting and intrinsic burst behaviors, irrespective of the patterns initially exhibited by the cells. We used a conductance-based model to decide appropriate pharmacological blockade and found that the observed transitions are likely due to recruitment of low-voltage calcium and Kv7 potassium conductances. We conclude that CA3 neurons adapt their conductance profile to the subthreshold activity of their input, so that their intrinsic firing pattern is not a static signature, but rather a reflection of their history of subthreshold activity. In this way, recurrent output from CA3 neurons may collectively shape the temporal dynamics of their embedding circuits.NEW & NOTEWORTHY Although firing patterns are widely conserved across the animal phyla, it is still a mystery why nerve cells present such diversity of discharge dynamics upon somatic step currents. Adding a new timing dimension to the intrinsic plasticity literature, here we show that CA3 neurons rapidly adapt through the space of known firing patterns in response to the subthreshold signals that they receive from their embedding circuit, potentially adjusting their network processing to the temporal statistics of their circuit.

Paradoxical Excitatory Impact of SK Channels on Dendritic Excitability.

Dendritic excitability regulates how neurons integrate synaptic inputs and thereby influences neuronal output. As active dendritic events are associated with significant calcium influx they are likely to be modulated by calcium-dependent processes, such as calcium-activated potassium channels. Here we investigate the impact of small conductance calcium-activated potassium channels (SK channels) on dendritic excitability in male and female rat cortical pyramidal neurons in vitro and in vivo Using local applications of the SK channel antagonist apamin in vitro, we show that blocking somatic SK channels enhances action potential output, whereas blocking dendritic SK channels paradoxically reduces the generation of dendritic calcium spikes and associated somatic burst firing. Opposite effects were observed using the SK channel enhancer NS309. The effect of apamin on dendritic SK channels was occluded when R-type calcium channels were blocked, indicating that the inhibitory impact of apamin on dendritic calcium spikes involved R-type calcium channels. Comparable effects were observed in vivo Intracellular application of apamin via the somatic whole-cell recording pipette reduced the medium afterhyperpolarization and increased action potential output during UP states. In contrast, extracellular application of apamin to the cortical surface to block dendritic SK channels shifted the distribution of action potentials within UP states from an initial burst to a more distributed firing pattern, while having no impact on overall action potential firing frequency or UP and DOWN states. These data indicate that somatic and dendritic SK channels have opposite effects on neuronal excitability, with dendritic SK channels counter-intuitively promoting rather than suppressing neuronal output.SIGNIFICANCE STATEMENT Neurons typically receive input from other neurons onto processes called dendrites, and use electrical events such as action potentials for signaling. As electrical events in neurons are usually associated with calcium influx they can be regulated by calcium-dependent processes. One such process is through the activation of calcium-dependent potassium channels, which usually act to reduce action potential signaling. Although this is the case for calcium-dependent potassium channels found at the cell body, we show here that calcium-dependent potassium channels in dendrites of cortical pyramidal neurons counter-intuitively promote rather than suppress action potential output.

A calcium-dependent plasticity rule for HCN channels maintains activity homeostasis and stable synaptic learning.

Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles for experimentally observed plasticity in HCN channels accompanying synaptic plasticity in hippocampal neurons, and uncover potential links between HCN-channel plasticity and calcium influx, dynamic gain control and stable synaptic learning.