Cross-strata co-occurrence of ripples with theta-frequency oscillations in the hippocampus of foraging rats.

Brain rhythms have been postulated to play central roles in animal cognition. A prominently reported dichotomy of hippocampal rhythms links theta-frequency oscillations (4-12 Hz) and ripples (120-250 Hz) exclusively to preparatory and consummatory behaviours, respectively. However, because of the differential power expression of these two signals across hippocampal strata, such exclusivity requires validation through analyses of simultaneous multi-strata recordings. We assessed co-occurrence of theta-frequency oscillations with ripples in multi-channel recordings of extracellular potentials across hippocampal strata from foraging rats. We detected all ripple events from an identified stratum pyramidale (SP) channel. We then defined theta epochs based on theta oscillations detected from the stratum lacunosum-moleculare (SLM) or the stratum radiatum (SR). We found ∼20% of ripple events (in SP) to co-occur with theta epochs identified from SR/SLM channels, defined here as theta ripples. Strikingly, when theta epochs were instead identified from the SP channel, such co-occurrences were significantly reduced because of a progressive reduction in theta power along the SLM-SR-SP axis. Behaviourally, we found most theta ripples to occur during immobile periods, with comparable theta power during exploratory and immobile theta epochs. Furthermore, the progressive reduction in theta power along the SLM-SR-SP axis was common to exploratory and immobile periods. Finally, we found a strong theta-phase preference of theta ripples within the fourth quadrant [3π/2 - 2π] of the associated theta oscillation. The prevalence of theta ripples expands the potential roles of ripple-frequency oscillations to span the continuum of encoding, retrieval and consolidation, achieved through interactions with theta oscillations. KEY POINTS: The brain manifests oscillations in recorded electrical potentials, with different frequencies of oscillation associated with distinct behavioural states. A prominently reported dichotomy assigns theta-frequency oscillations (4-12 Hz) and ripples (120-250 Hz) recorded in the hippocampus to be exclusively associated with preparatory and consummatory behaviours, respectively. Our multi-strata recordings from the rodent hippocampus coupled with cross-strata analyses provide direct quantitative evidence for the occurrence of ripple events nested within theta oscillations. These results highlight the need for an analysis pipeline that explicitly accounts for the specific strata where individual oscillatory power is high, in analysing simultaneously recorded data from multiple strata. Our observations open avenues for investigations involving cross-strata interactions between theta oscillations and ripples across different behavioural states.

Robust emergence of sharply tuned place-cell responses in hippocampal neurons with structural and biophysical heterogeneities.

Hippocampal pyramidal neurons sustain propagation of fast electrical signals and are electrotonically non-compact structures exhibiting cell-to-cell variability in their complex dendritic arborization. In this study, we demonstrate that sharp place-field tuning and several somatodendritic functional maps concomitantly emerge despite the presence of geometrical heterogeneities in these neurons. We establish this employing an unbiased stochastic search strategy involving thousands of models that spanned several morphologies and distinct profiles of dispersed synaptic localization and channel expression. Mechanistically, employing virtual knockout models (VKMs), we explored the impact of bidirectional modulation in dendritic spike prevalence on place-field tuning sharpness. Consistent with the prior literature, we found that across all morphologies, virtual knockout of either dendritic fast sodium channels or N-methyl-D-aspartate receptors led to a reduction in dendritic spike prevalence, whereas A-type potassium channel knockouts resulted in a non-specific increase in dendritic spike prevalence. However, place-field tuning sharpness was critically impaired in all three sets of VKMs, demonstrating that sharpness in feature tuning is maintained by an intricate balance between mechanisms that promote and those that prevent dendritic spike initiation. From the functional standpoint of the emergence of sharp feature tuning and intrinsic functional maps, within this framework, geometric variability was compensated by a combination of synaptic democracy, the ability of randomly dispersed synapses to yield sharp tuning through dendritic spike initiation, and ion-channel degeneracy. Our results suggest electrotonically non-compact neurons to be endowed with several degrees of freedom, encompassing channel expression, synaptic localization and morphological microstructure, in achieving sharp feature encoding and excitability homeostasis.

Active dendrites regulate the spatiotemporal spread of signaling microdomains.

Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in several neuronal computations. Although dendrites, endowed with several voltage-gated ion channels, form a prominent structural substrate for microdomain physiology, it is not known if these channels regulate the spatiotemporal spread of signaling microdomains. Here, we employed a multiscale, morphologically realistic, conductance-based model of the hippocampal pyramidal neuron that accounted for experimental details of electrical and calcium-dependent biochemical signaling. We activated synaptic N-Methyl-d-Aspartate receptors through theta-burst stimulation (TBS) or pairing (TBP) and assessed microdomain propagation along a signaling pathway that included calmodulin, calcium/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1. We found that the spatiotemporal spread of the TBS-evoked microdomain in phosphorylated CaMKII (pCaMKII) was amplified in comparison to that of the corresponding calcium microdomain. Next, we assessed the role of two dendritically expressed inactivating channels, one restorative (A-type potassium) and another regenerative (T-type calcium), by systematically varying their conductances. Whereas A-type potassium channels suppressed the spread of pCaMKII microdomains by altering the voltage response to TBS, T-type calcium channels enhanced this spread by modulating TBS-induced calcium influx without changing the voltage. Finally, we explored cross-dependencies of these channels with other model components, and demonstrated the heavy mutual interdependence of several biophysical and biochemical properties in regulating microdomains and their spread. Our conclusions unveil a pivotal role for dendritic voltage-gated ion channels in actively amplifying or suppressing biochemical signals and their spatiotemporal spread, with critical implications for clustered synaptic plasticity, robust information transfer and efficient neural coding.

Spatially dispersed synapses yield sharply-tuned place cell responses through dendritic spike initiation.

KEY POINTS: The generation of dendritic spikes and the consequent sharp tuning of neuronal responses are together attainable even when iso-feature synapses are randomly dispersed across the dendritic arbor. Disparate combinations of channel conductances with distinct configurations of randomly dispersed place field synapses concomitantly yield similar sharp tuning profiles and similar functional maps of several intrinsic properties. Targeted synaptic plasticity converts silent cells to place cells for specific place fields in models with disparate channel combinations that receive dispersed synaptic inputs from multiple place field locations. Dispersed localization of iso-feature synapses is a strong candidate for achieving sharp feature selectivity in neurons across sensory-perceptual systems, with several degrees of freedom in relation to synaptic locations. Quantitative evidence for the possibility that degeneracy (i.e. the ability of disparate structural components to yield similar functional outcomes) could act as a broad framework that effectively accomplishes the twin goals of input-feature encoding and homeostasis of intrinsic properties without cross interferences. ABSTRACT: A prominent hypothesis spanning several sensory-perceptual systems implicates spatially clustered synapses in the generation of dendritic spikes that mediate sharply-tuned neuronal responses to input features. In this conductance-based morphologically-precise computational study, we tested this hypothesis by systematically analysing the impact of distinct synaptic and channel localization profiles on sharpness of spatial tuning in hippocampal pyramidal neurons. We found that the generation of dendritic spikes, the emergence of an excitatory ramp in somatic voltage responses, the expression of several intrinsic somatodendritic functional maps and sharp tuning of place-cell responses were all attainable even when iso-feature synapses are randomly dispersed across the dendritic arbor of models with disparate channel combinations. Strikingly, the generation and propagation of dendritic spikes, reliant on dendritic sodium channels and N-methyl-d-asparate receptors, mediated the sharpness of spatial tuning achieved with dispersed synaptic localization. To ensure that our results were not artefacts of narrow parametric choices, we confirmed these conclusions with independent multiparametric stochastic search algorithms spanning thousands of unique models for each synaptic localization scenario. Next, employing virtual knockout models, we demonstrated a vital role for dendritically expressed voltage-gated ion channels, especially the transient potassium channels, in maintaining sharpness of place-cell tuning. Importantly, we established that synaptic potentiation targeted to afferents from one specific place field was sufficient to impart place field selectivity even when intrinsically disparate neurons received randomly dispersed afferents from multiple place field locations. Our results provide quantitative evidence for disparate combinations of channel and synaptic localization profiles to concomitantly yield similar tuning and similar intrinsic properties.