Mismatch novelty exploration training shifts VPAC1 receptor-mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats.

Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.

Synaptic Information Storage Capacity Measured With Information Theory.

Variation in the strength of synapses can be quantified by measuring the anatomical properties of synapses. Quantifying precision of synaptic plasticity is fundamental to understanding information storage and retrieval in neural circuits. Synapses from the same axon onto the same dendrite have a common history of coactivation, making them ideal candidates for determining the precision of synaptic plasticity based on the similarity of their physical dimensions. Here, the precision and amount of information stored in synapse dimensions were quantified with Shannon information theory, expanding prior analysis that used signal detection theory (Bartol et al., 2015). The two methods were compared using dendritic spine head volumes in the middle of the stratum radiatum of hippocampal area CA1 as well-defined measures of synaptic strength. Information theory delineated the number of distinguishable synaptic strengths based on nonoverlapping bins of dendritic spine head volumes. Shannon entropy was applied to measure synaptic information storage capacity (SISC) and resulted in a lower bound of 4.1 bits and upper bound of 4.59 bits of information based on 24 distinguishable sizes. We further compared the distribution of distinguishable sizes and a uniform distribution using Kullback-Leibler divergence and discovered that there was a nearly uniform distribution of spine head volumes across the sizes, suggesting optimal use of the distinguishable values. Thus, SISC provides a new analytical measure that can be generalized to probe synaptic strengths and capacity for plasticity in different brain regions of different species and among animals raised in different conditions or during learning. How brain diseases and disorders affect the precision of synaptic plasticity can also be probed.

Silencing CA1 pyramidal cells output reveals the role of feedback inhibition in hippocampal oscillations.

The precise temporal coordination of neural activity is crucial for brain function. In the hippocampus, this precision is reflected in the oscillatory rhythms observed in CA1. While it is known that a balance between excitatory and inhibitory activity is necessary to generate and maintain these oscillations, the differential contribution of feedforward and feedback inhibition remains ambiguous. Here we use conditional genetics to chronically silence CA1 pyramidal cell transmission, ablating the ability of these neurons to recruit feedback inhibition in the local circuit, while recording physiological activity in mice. We find that this intervention leads to local pathophysiological events, with ripple amplitude and intrinsic frequency becoming significantly larger and spatially triggered local population spikes locked to the trough of the theta oscillation appearing during movement. These phenotypes demonstrate that feedback inhibition is crucial in maintaining local sparsity of activation and reveal the key role of lateral inhibition in CA1 in shaping circuit function.

Dynamics of neuronal firing modulated by high-frequency electrical pulse stimulations at axons in rat hippocampus.

Objective. The development of electrical pulse stimulations in brain, including deep brain stimulation, is promising for treating various brain diseases. However, the mechanisms of brain stimulations are not yet fully understood. Previous studies have shown that the commonly used high-frequency stimulation (HFS) can increase the firing of neurons and modulate the pattern of neuronal firing. Because the generation of neuronal firing in brain is a nonlinear process, investigating the characteristics of nonlinear dynamics induced by HFS could be helpful to reveal more mechanisms of brain stimulations. The aim of present study is to investigate the fractal properties in the neuronal firing generated by HFS.Approach. HFS pulse sequences with a constant frequency 100 Hz were applied in the afferent fiber tracts of rat hippocampal CA1 region. Unit spikes of both the pyramidal cells and the interneurons in the downstream area of stimulations were recorded. Two fractal indexes-the Fano factor and Hurst exponent were calculated to evaluate the changes of long-range temporal correlations (LRTCs), a typical characteristic of fractal process, in spike sequences of neuronal firing.Mainresults. Neuronal firing at both baseline and during HFS exhibited LRTCs over multiple time scales. In addition, the LRTCs significantly increased during HFS, which was confirmed by simulation data of both randomly shuffled sequences and surrogate sequences.Conclusion. The purely periodic stimulation of HFS pulses, a non-fractal process without LRTCs, can increase rather than decrease the LRTCs in neuronal firing.Significance. The finding provides new nonlinear mechanisms of brain stimulation and suggests that LRTCs could be a new biomarker to evaluate the nonlinear effects of HFS.

Selection of experience for memory by hippocampal sharp wave ripples.

Experiences need to be tagged during learning for further consolidation. However, neurophysiological mechanisms that select experiences for lasting memory are not known. By combining large-scale neural recordings in mice with dimensionality reduction techniques, we observed that successive maze traversals were tracked by continuously drifting populations of neurons, providing neuronal signatures of both places visited and events encountered. When the brain state changed during reward consumption, sharp wave ripples (SPW-Rs) occurred on some trials, and their specific spike content decoded the trial blocks that surrounded them. During postexperience sleep, SPW-Rs continued to replay those trial blocks that were reactivated most frequently during waking SPW-Rs. Replay content of awake SPW-Rs may thus provide a neurophysiological tagging mechanism to select aspects of experience that are preserved and consolidated for future use.

A voltage-based Event-Timing-Dependent Plasticity rule accounts for LTP subthreshold and suprathreshold for dendritic spikes in CA1 pyramidal neurons.

Long-term potentiation (LTP) is a synaptic mechanism involved in learning and memory. Experiments have shown that dendritic sodium spikes (Na-dSpikes) are required for LTP in the distal apical dendrites of CA1 pyramidal cells. On the other hand, LTP in perisomatic dendrites can be induced by synaptic input patterns that can be both subthreshold and suprathreshold for Na-dSpikes. It is unclear whether these results can be explained by one unifying plasticity mechanism. Here, we show in biophysically and morphologically realistic compartmental models of the CA1 pyramidal cell that these forms of LTP can be fully accounted for by a simple plasticity rule. We call it the voltage-based Event-Timing-Dependent Plasticity (ETDP) rule. The presynaptic event is the presynaptic spike or release of glutamate. The postsynaptic event is the local depolarization that exceeds a certain plasticity threshold. Our model reproduced the experimentally observed LTP in a variety of protocols, including local pharmacological inhibition of dendritic spikes by tetrodotoxin (TTX). In summary, we have provided a validation of the voltage-based ETDP, suggesting that this simple plasticity rule can be used to model even complex spatiotemporal patterns of long-term synaptic plasticity in neuronal dendrites.

Formation of memory assemblies through the DNA-sensing TLR9 pathway.

As hippocampal neurons respond to diverse types of information1, a subset assembles into microcircuits representing a memory2. Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage3-5. Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of TLR9 signalling and accumulation of centrosomal DNA damage repair complexes6. Neuron-specific knockdown of Tlr9 impaired memory while blunting contextual fear conditioning-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Notably, TLR9 had an essential role in centrosome function, including DNA damage repair, ciliogenesis and build-up of perineuronal nets. We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and TLR9-mediated repair, resulting in their recruitment to memory circuits. With compromised TLR9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments implicated in accelerated senescence, psychiatric disorders and neurodegenerative disorders. Maintaining the integrity of TLR9 inflammatory signalling thus emerges as a promising preventive strategy for neurocognitive deficits.

Retrograde endocannabinoid signaling at inhibitory synapses in vivo.

Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory synapses on a timescale of seconds during behavior.

Sequential activity of CA1 hippocampal cells constitutes a temporal memory map for associative learning in mice.

Sequential neural dynamics encoded by time cells play a crucial role in hippocampal function. However, the role of hippocampal sequential neural dynamics in associative learning is an open question. We used two-photon Ca2+ imaging of dorsal CA1 (dCA1) neurons in the stratum pyramidale (SP) in head-fixed mice performing a go-no go associative learning task to investigate how odor valence is temporally encoded in this area of the brain. We found that SP cells responded differentially to the rewarded or unrewarded odor. The stimuli were decoded accurately from the activity of the neuronal ensemble, and accuracy increased substantially as the animal learned to differentiate the stimuli. Decoding the stimulus from individual SP cells responding differentially revealed that decision-making took place at discrete times after stimulus presentation. Lick prediction decoded from the ensemble activity of cells in dCA1 correlated linearly with lick behavior. Our findings indicate that sequential activity of SP cells in dCA1 constitutes a temporal memory map used for decision-making in associative learning. VIDEO ABSTRACT.

Local activation of CA1 pyramidal cells induces theta-phase precession.

Hippocampal theta-phase precession is involved in spatiotemporal coding and in generating multineural spike sequences, but how precession originates remains unresolved. To determine whether precession can be generated directly in hippocampal area CA1 and disambiguate multiple competing mechanisms, we used closed-loop optogenetics to impose artificial place fields in pyramidal cells of mice running on a linear track. More than one-third of the CA1 artificial fields exhibited synthetic precession that persisted for a full theta cycle. By contrast, artificial fields in the parietal cortex did not exhibit synthetic precession. These findings are incompatible with precession models based on inheritance, dual-input, spreading activation, inhibition-excitation summation, or somato-dendritic competition. Thus, a precession generator resides locally within CA1.

Gamma oscillatory complexity conveys behavioral information in hippocampal networks.

The hippocampus and entorhinal cortex exhibit rich oscillatory patterns critical for cognitive functions. In the hippocampal region CA1, specific gamma-frequency oscillations, timed at different phases of the ongoing theta rhythm, are hypothesized to facilitate the integration of information from varied sources and contribute to distinct cognitive processes. Here, we show that gamma elements -a multidimensional characterization of transient gamma oscillatory episodes- occur at any frequency or phase relative to the ongoing theta rhythm across all CA1 layers in male mice. Despite their low power and stochastic-like nature, individual gamma elements still carry behavior-related information and computational modeling suggests that they reflect neuronal firing. Our findings challenge the idea of rigid gamma sub-bands, showing that behavior shapes ensembles of irregular gamma elements that evolve with learning and depend on hippocampal layers. Widespread gamma diversity, beyond randomness, may thus reflect complexity, likely functional but invisible to classic average-based analyses.

Ventral Hippocampal CA1 Pyramidal Neurons Encode Nociceptive Information.

As a main structure of the limbic system, the hippocampus plays a critical role in pain perception and chronicity. The ventral hippocampal CA1 (vCA1) is closely associated with negative emotions such as anxiety, stress, and fear, yet how vCA1 neurons encode nociceptive information remains unclear. Using in vivo electrophysiological recording, we characterized vCA1 pyramidal neuron subpopulations that exhibited inhibitory or excitatory responses to plantar stimuli and were implicated in encoding stimuli modalities in naïve rats. Functional heterogeneity of the vCA1 pyramidal neurons was further identified in neuropathic pain conditions: the proportion and magnitude of the inhibitory response neurons paralleled mechanical allodynia and contributed to the confounded encoding of innocuous and noxious stimuli, whereas the excitatory response neurons were still instrumental in the discrimination of stimulus properties. Increased theta power and theta-spike coupling in vCA1 correlated with nociceptive behaviors. Optogenetic inhibition of vCA1 pyramidal neurons induced mechanical allodynia in naïve rats, whereas chemogenetic reversal of the overall suppressed vCA1 activity had analgesic effects in rats with neuropathic pain. These results provide direct evidence for the representations of nociceptive information in vCA1.

Increased Interhemispheric Connectivity of a Distinct Type of Hippocampal Pyramidal Cells.

Neurons typically generate action potentials at their axon initial segment based on the integration of synaptic inputs. In many neurons, the axon extends from the soma, equally weighting dendritic inputs. A notable exception is found in a subset of hippocampal pyramidal cells where the axon emerges from a basal dendrite. This structure allows these axon-carrying dendrites (AcDs) a privileged input route. We found that in male mice, such cells in the CA1 region receive stronger excitatory input from the contralateral CA3, compared with those with somatic axon origins. This is supported by a higher count of putative synapses from contralateral CA3 on the AcD. These findings, combined with prior observations of their distinct role in sharp-wave ripple firing, suggest a key role of this neuron subset in coordinating bi-hemispheric hippocampal activity during memory-centric oscillations.

A Dual Effect of Dopamine on Hippocampal LTP and Cognitive Functions in Control and Kindled Mice.

The impact of dopamine on synaptic plasticity and cognitive function following seizure is not well understood. Here, using optogenetics in the freely behaving animal, we examined exploratory behavior and short-term memory in control and kindled male mice during tonic stimulation of dopaminergic neurons within the ventral tegmental area (VTA). Furthermore, using field potential recording, we compared the effect of dopamine on synaptic plasticity in stratum radiatum and stratum oriens layers of both ventral and dorsal hippocampal CA1 regions, and again in both control and kindled male mice. Our results demonstrate that tonic stimulation of VTA dopaminergic neurons enhances novelty-driven exploration and short-term spatial memory in kindled mice, essentially rescuing the seizure-induced cognitive impairment. In addition, we found that dopamine has a dual effect on LTP in control versus kindled mice, such that application of dopamine prevented LTP induction in slices from control mice, but rescued LTP in slices taken from the kindled animal. Taken together, our results highlight the potential for dopaminergic modulation in improving synaptic plasticity and cognitive function following seizure.

A realistic computational model for the formation of a Place Cell.

Hippocampal Place Cells (PCs) are pyramidal neurons showing spatially localized firing when an animal gets into a specific area within an environment. Because of their obvious and clear relation with specific cognitive functions, Place Cells operations and modulations are intensely studied experimentally. However, although a lot of data have been gathered since their discovery, the cellular processes that interplay to turn a hippocampal pyramidal neuron into a Place Cell are still not completely understood. Here, we used a morphologically and biophysically detailed computational model of a CA1 pyramidal neuron to show how, and under which conditions, it can turn into a neuron coding for a specific cue location, through the self-organization of its synaptic inputs in response to external signals targeting different dendritic layers. Our results show that the model is consistent with experimental findings demonstrating PCs stability within the same spatial context over different trajectories, environment rotations, and place field remapping to adapt to changes in the environment. To date, this is the only biophysically and morphologically accurate cellular model of PCs formation, which can be directly used in physiologically accurate microcircuits and large-scale model networks to study cognitive functions and dysfunctions at cellular level.

CA3 hippocampal synaptic plasticity supports ripple physiology during memory consolidation.

The consolidation of recent memories depends on memory replays, also called ripples, generated within the hippocampus during slow-wave sleep, and whose inactivation leads to memory impairment. For now, the mobilisation, localisation and importance of synaptic plasticity events associated to ripples are largely unknown. To tackle this question, we used cell surface AMPAR immobilisation to block post-synaptic LTP within the hippocampal region of male mice during a spatial memory task, and show that: 1- hippocampal synaptic plasticity is engaged during consolidation, but is dispensable during encoding or retrieval. 2- Plasticity blockade during sleep results in apparent forgetting of the encoded rule. 3- In vivo ripple recordings show a strong effect of AMPAR immobilisation when a rule has been recently encoded. 4- In situ investigation suggests that plasticity at CA3-CA3 recurrent synapses supports ripple generation. We thus propose that post-synaptic AMPAR mobility at CA3 recurrent synapses is necessary for ripple-dependent rule consolidation.

Engram cell connectivity as a mechanism for information encoding and memory function.

Information derived from experiences is incorporated into the brain as changes to ensembles of cells, termed engram cells, which allow memory storage and recall. The mechanism by which those changes hold specific information is unclear. Here, we test the hypothesis that the specific synaptic wiring between engram cells is the substrate of information storage. First, we monitor how learning modifies the connectivity pattern between engram cells at a monosynaptic connection involving the hippocampal ventral CA1 (vCA1) region and the amygdala. Then, we assess the functional significance of these connectivity changes by artificially activating or inhibiting its presynaptic and postsynaptic components, respectively. Finally, we identify a synaptic plasticity mechanism mediated by postsynaptic density protein 95 (PSD-95), which impacts the connectivity pattern among engram cells and contributes to the long-term stability of the memory. These findings impact our theory of learning and memory by helping us explain the translation of specific information into engram cells and how these connections shape brain function.

Aversive stimulus-tuned responses in the CA1 of the dorsal hippocampus.

Throughout life animals inevitably encounter unforeseen threatening events. Activity of principal cells in the hippocampus is tuned for locations and for salient stimuli in the animals' environment thus forming a map known to be pivotal for guiding behavior. Here, we explored if a code of threatening stimuli exists in the CA1 region of the dorsal hippocampus of mice by recording neuronal response to aversive stimuli delivered at changing locations. We have discovered a rapidly emerging, location independent response to innoxious aversive stimuli composed of the coordinated activation of subgroups of pyramidal cells and connected interneurons. Activated pyramidal cells had higher basal firing rate, more probably participated in ripples, targeted more interneurons than place cells and many of them lacked place fields. We also detected aversive stimulus-coupled assemblies dominated by the activated neurons. Notably, these assemblies could be observed even before the delivery of the first aversive event. Finally, we uncovered the systematic shift of the spatial code from the aversive to, surprisingly, the reward location during the fearful stimulus. Our results uncovered components of the dorsal CA1 circuit possibly key for re-sculpting the spatial map in response to abrupt aversive events.

The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling.

Glyphosate, a herbicide marketed as Roundup, is widely used but there are concerns this exposure could impair cognitive function. In the CA1 region of rat hippocampal slices, we investigated whether glyphosate alters synaptic transmission and long-term potentiation (LTP), a cellular model of learning and memory. Our hypothesis is that glyphosate alters neuronal function and impairs LTP induction via activation of pro-inflammatory processes. Roundup depressed excitatory synaptic potentials(EPSPs) in a dose-dependent manner with complete suppression at 2000 mg/L. At concentrations ≤ 20 mg/L Roundup did not affect basal transmission, but 4 mg/L Roundup administered for 30 min inhibited LTP induction. Acute administration of 10-100 µM glyphosate also inhibited LTP induction. Minocycline, an inhibitor of microglial activation, and TAK-242, an inhibitor of toll-like receptor 4 (TLR4), both overcame the inhibitory effects of 100 µM glyphosate. Similarly, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), a different TLR4 antagonist, overcame the inhibitory effects. In addition, ISRIB (integrated stress response inhibitor) and quercetin, an inhibitor of endoplasmic reticulum stress, overcame the inhibitory effects. We also observed that in vivo glyphosate injection (16.9 mg/kg i.p.) impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by TAK-242. These observations indicate that glyphosate can impair cognitive function through pro-inflammatory signaling in microglia.

The medial septum controls hippocampal supra-theta oscillations.

Hippocampal theta oscillations orchestrate faster beta-to-gamma oscillations facilitating the segmentation of neural representations during navigation and episodic memory. Supra-theta rhythms of hippocampal CA1 are coordinated by local interactions as well as inputs from the entorhinal cortex (EC) and CA3 inputs. However, theta-nested gamma-band activity in the medial septum (MS) suggests that the MS may control supra-theta CA1 oscillations. To address this, we performed multi-electrode recordings of MS and CA1 activity in rodents and found that MS neuron firing showed strong phase-coupling to theta-nested supra-theta episodes and predicted changes in CA1 beta-to-gamma oscillations on a cycle-by-cycle basis. Unique coupling patterns of anatomically defined MS cell types suggested that indirect MS-to-CA1 pathways via the EC and CA3 mediate distinct CA1 gamma-band oscillations. Optogenetic activation of MS parvalbumin-expressing neurons elicited theta-nested beta-to-gamma oscillations in CA1. Thus, the MS orchestrates hippocampal network activity at multiple temporal scales to mediate memory encoding and retrieval.