The storage of information in the mammalian nervous systems is dependent on a delicate balance between change and stability of neuronal networks. The induction and maintenance of processes that lead ...to changes in synaptic strength to a multistep process which can lead to long-lasting changes, which starts and ends with a highly choreographed and perfectly timed dance of molecules in different cell types of the central nervous system. This is accompanied by synchronization of specific networks, resulting in the generation of characteristic "macroscopic" rhythmic electrical fields, whose characteristic frequencies correspond to certain activity and information-processing states of the brain. Molecular events and macroscopic fields influence each other reciprocally. We review here cellular processes of synaptic plasticity, particularly functional and structural changes, and focus on timing events that are important for the initial memory acquisition, as well as mechanisms of short- and long-term memory storage. Then, we cover the importance of epigenetic events on the long-time range. Furthermore, we consider how brain rhythms at the network level participate in processes of information storage and by what means they participating in it. Finally, we examine memory consolidation at the system level during processes of sleep.
The ability to study cellular physiology using photosensitive, genetically encoded molecules has profoundly transformed neuroscience. The modern optogenetic toolbox includes fluorescent sensors to ...visualize signaling events in living cells and optogenetic actuators enabling manipulation of numerous cellular activities. Most optogenetic tools are not targeted to specific subcellular compartments but are localized with limited discrimination throughout the cell. Therefore, optogenetic activation often does not reflect context-dependent effects of highly localized intracellular signaling events. Subcellular targeting is required to achieve more specific optogenetic readouts and photomanipulation. Here we first provide a detailed overview of the available optogenetic tools with a focus on optogenetic actuators. Second, we review established strategies for targeting these tools to specific subcellular compartments. Finally, we discuss useful tools and targeting strategies that are currently missing from the optogenetics repertoire and provide suggestions for novel subcellular optogenetic applications.
The subcellular targeting of optogenetic molecules provides exciting new opportunities to manipulate neuronal cell biology. In this review, Rost et al. summarize currently available optogenetic tools and established subcellular targeting strategies and highlight important optogenetic tools that remain to be developed.
SignificanceBidirectional communication between the hippocampus and other brain areas via sharp wave ripples (SPW-Rs) has been hypothesized to play an important role in cognitive functions. However, ...brain-wide coupling to SPW-Rs has been difficult to study at high temporal and spatial resolution. Here, we show that SPW-Rs coincide with transient brain-wide increase of functional connectivity. The diversity in SPW-R features was related to slower excitability fluctuations in cortical and subcortical areas. In return, SPW-Rs correlated with the timing, sign, and magnitude of partner structure responses. Our findings provide the most extensive survey of spiking activity surrounding hippocampal SPW-Rs to date.
Hippocampal ripples are highly synchronous neural events critical for memory consolidation and retrieval. A minority of strong ripples has been shown to be of particular importance in situations of ...increased memory demands. The propagation dynamics of strong ripples inside the hippocampal formation are, however, still opaque. We analyzed ripple propagation within the hippocampal formation in a large open-access dataset comprising 267 Neuropixel recordings in 49 awake, head-fixed mice. Surprisingly, strong ripples (top 10% in ripple strength) propagate differentially depending on their generation point along the hippocampal longitudinal axis. The septal hippocampal pole is able to generate longer ripples that engage more neurons and elicit spiking activity for an extended time even at considerable distances. Accordingly, a substantial portion of the variance in strong ripple duration (
² = 0.463) is explained by the ripple generation location on the longitudinal axis, in agreement with a possible distinctive role of the hippocampal septal pole in conditions of high-memory demand. Moreover, we observed that the location of the ripple generation has a significant impact on the spiking rate modulation of different hippocampal subfields, even before the onset of the ripple. This finding suggests that ripple generation location plays a crucial role in shaping the neural activity across the hippocampus.
The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of ...virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.
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•Characterization of potent human monoclonal SARS-CoV-2-neutralizing antibodies•Some SARS-CoV-2 antibodies reacted with mammalian self-antigens in different organs•Crystal structures of two antibodies in complex with SARS-CoV-2 RBD at 2.55/2.70 Å•Post-exposure antibody treatment protected from lung damage in infected hamsters
Kreye et al. report isolation and characterization of monoclonal antibodies from COVID-19 patients, some of which were found to display autoreactivity with mammalian self-antigens in different organs. Crystal structures of two antibodies in complex with the SARS-CoV-2 spike RBD reveal antibody engagement with the ACE2 binding site from different approach angles. One antibody was evaluated further for in vivo efficacy and found to be both protective and efficacious post-challenge in a hamster infection model.
Bouts of high frequency activity known as sharp wave ripples (SPW-Rs) facilitate communication between the hippocampus and neocortex. However, the paths and mechanisms by which SPW-Rs broadcast their ...content are not well understood. Due to its anatomical positioning, the granular retrosplenial cortex (gRSC) may be a bridge for this hippocampo-cortical dialogue. Using silicon probe recordings in awake, head-fixed mice, we show the existence of SPW-R analogues in gRSC and demonstrate their coupling to hippocampal SPW-Rs. gRSC neurons reliably distinguished different subclasses of hippocampal SPW-Rs according to ensemble activity patterns in CA1. We demonstrate that this coupling is brain state-dependent, and delineate a topographically-organized anatomical pathway via VGlut2-expressing, bursty neurons in the subiculum. Optogenetic stimulation or inhibition of bursty subicular cells induced or reduced responses in superficial gRSC, respectively. These results identify a specific path and underlying mechanisms by which the hippocampus can convey neuronal content to the neocortex during SPW-Rs.
Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented ...retrograde activation of presynaptic CB1Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.
•CB2Rs are expressed in hippocampal principal neurons•CB2Rs mediate a cell type-specific self-inhibitory plasticity in CA3/CA2 PCs•CB2Rs reduce the spike probability of CA3 PCs and alter gamma oscillations in vivo•CB2Rs act complementary to presynaptic CB1Rs
The neuronal expression of CB2Rs has been a matter of long-standing debate. Stempel et al. demonstrate that CB2Rs are expressed in hippocampal principal cells and modulate neuronal function both in vitro and in vivo.
Abstract
Almost seventy years after the discovery of the mechanisms of action potential generation, some aspects of their computational consequences are still not fully understood. Based on ...mathematical modeling, we here explore a type of action potential dynamics – arising from a saddle-node homoclinic orbit bifurcation - that so far has received little attention. We show that this type of dynamics is to be expected by specific changes in common physiological parameters, like an elevation of temperature. Moreover, we demonstrate that it favours synchronization patterns in networks – a feature that becomes particularly prominent when system parameters change such that homoclinic spiking is induced. Supported by in-vitro hallmarks for homoclinic spikes in the rodent brain, we hypothesize that the prevalence of homoclinic spikes in the brain may be underestimated and provide a missing link between the impact of biophysical parameters on abrupt transitions between asynchronous and synchronous states of electrical activity in the brain.
Sharp wave-ripple complexes (SWRs) are hippocampal network phenomena involved in memory consolidation. To date, the mechanisms underlying their occurrence remain obscure. Here, we show how the ...interactions between pyramidal cells, parvalbumin-positive (PV
) basket cells, and an unidentified class of anti-SWR interneurons can contribute to the initiation and termination of SWRs. Using a biophysically constrained model of a network of spiking neurons and a rate-model approximation, we demonstrate that SWRs emerge as a result of the competition between two interneuron populations and the resulting disinhibition of pyramidal cells. Our models explain how the activation of pyramidal cells or PV
cells can trigger SWRs, as shown
, and suggests that PV
cell-mediated short-term synaptic depression influences the experimentally reported dynamics of SWR events. Furthermore, we predict that the silencing of anti-SWR interneurons can trigger SWRs. These results broaden our understanding of the microcircuits supporting the generation of memory-related network dynamics.
The hippocampus is a part of the mammalian brain that is crucial for episodic memories. During periods of sleep and inactive waking, the extracellular activity of the hippocampus is dominated by sharp wave-ripple events (SWRs), which have been shown to be important for memory consolidation. The mechanisms regulating the emergence of these events are still unclear. We developed a computational model to study the emergence of SWRs and to explain the roles of different cell types in regulating them. The model accounts for several previously unexplained features of SWRs and thus advances the understanding of memory-related dynamics.
Hippocampal ripples are involved in memory consolidation, but the mechanisms underlying their generation remain unclear. Models relying on interneuron networks in the CA1 region disagree on the ...predominant source of excitation to interneurons: either "direct," via the Schaffer collaterals that provide feedforward input from CA3 to CA1, or "indirect," via the local pyramidal cells in CA1, which are embedded in a recurrent excitatory-inhibitory network. Here, we used physiologically constrained computational models of basket-cell networks to investigate how they respond to different conditions of transient, noisy excitation. We found that direct excitation of interneurons could evoke ripples (140-220 Hz) that exhibited intraripple frequency accommodation and were frequency-insensitive to GABA modulators, as previously shown in
experiments. In addition, the indirect excitation of the basket-cell network enabled the expression of intraripple frequency accommodation in the fast-gamma range (90-140 Hz), as
In our model, intraripple frequency accommodation results from a hysteresis phenomenon in which the frequency responds differentially to the rising and descending phases of the transient excitation. Such a phenomenon predicts a maximum oscillation frequency occurring several milliseconds before the peak of excitation. We confirmed this prediction for ripples in brain slices from male mice. These results suggest that ripple and fast-gamma episodes are produced by the same interneuron network that is recruited via different excitatory input pathways, which could be supported by the previously reported intralaminar connectivity bias between basket cells and functionally distinct subpopulations of pyramidal cells in CA1. Together, our findings unify competing inhibition-first models of rhythm generation in the hippocampus.
The hippocampus is a part of the brain of humans and other mammals that is critical for the acquisition and consolidation of memories. During deep sleep and resting periods, the hippocampus generates high-frequency (∼200 Hz) oscillations called ripples, which are important for memory consolidation. The mechanisms underlying ripple generation are not well understood. A prominent hypothesis holds that the ripples are generated by local recurrent networks of inhibitory neurons. Using computational models and experiments in brain slices from rodents, we show that the dynamics of interneuron networks clarify several previously unexplained characteristics of ripple oscillations, which advances our understanding of hippocampus-dependent memory consolidation.
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