The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for ...social memory, how this input acts on the local circuit is unknown. Using mice, we found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). Parvalbumin-expressing basket cells were largely responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulated CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.
Contextual learning involves associating cues with an environment and relating them to past experience. Previous data indicate functional specialization within the hippocampal circuit: the dentate ...gyrus (DG) is crucial for discriminating similar contexts, whereas CA3 is required for associative encoding and recall. Here, we used Arc/H1a catFISH imaging to address the contribution of the largely overlooked CA2 region to contextual learning by comparing ensemble codes across CA3, CA2, and CA1 in mice exposed to familiar, altered, and novel contexts. Further, to manipulate the quality of information arriving in CA2 we used two hippocampal mutant mouse lines, CA3-NR1 KOs and DG-NR1 KOs, that result in hippocampal CA3 neuronal activity that is uncoupled from the animal's sensory environment. Our data reveal largely coherent responses across the CA axis in control mice in purely novel or familiar contexts; however, in the mutant mice subject to these protocols the CA2 response becomes uncoupled from CA1 and CA3. Moreover, we show in wild-type mice that the CA2 ensemble is more sensitive than CA1 and CA3 to small changes in overall context. Our data suggest that CA2 may be tuned to remap in response to any conflict between stored and current experience.
Hippocampal CA2 pyramidal cells project into both the neighboring CA1 and CA3 subfields, leaving them well positioned to influence network physiology and information processing for memory and space. ...While recent work has suggested unique roles for CA2, including encoding position during immobility and generating ripple oscillations, an interventional examination of the integrative functions of these connections has yet to be reported. Here we demonstrate that CA2 recruits feedforward inhibition in CA3 and that chronic genetically engineered shutdown of CA2-pyramidal-cell synaptic transmission consequently results in increased excitability of the recurrent CA3 network. In behaving mice, this led to spatially triggered episodes of network-wide hyperexcitability during exploration accompanied by the emergence of high-frequency discharges during rest. These findings reveal CA2 as a regulator of network processing in hippocampus and suggest that CA2-mediated inhibition in CA3 plays a key role in establishing the dynamic excitatory and inhibitory balance required for proper network function.
•CA2 silencing results in increased excitability of the recurrent CA3 network•A loss of CA2 transmission leads to unexpected network pathophysiology•Spatially triggered network hyperexcitability events mimic single place fields•CA2 driven feedforward inhibition in CA3 is crucial for hippocampal E/I balance
Boehringer et al. show that silencing CA2 pyramidal cells leads to hyperexcitability in CA3 and a novel pathophysiology manifesting as spatially triggered hippocampal network population discharges. This establishes a key role of CA2-recruited inhibition in CA3 in maintaining hippocampal E/I balance.
The long-term storage of episodic memory requires communication between prefrontal cortex and hippocampus. However, how consolidation alters dynamic interactions between these regions during ...subsequent recall remains unexplored. Here we perform simultaneous electrophysiological recordings from anterior cingulate cortex (ACC) and hippocampal CA1 in mice during recall of recent and remote contextual fear memory. We find that, in contrast to recent memory, remote memory recall is accompanied by increased ACC-CA1 synchronization at multiple frequency bands. The augmented ACC-CA1 interaction is associated with strengthened coupling among distally spaced CA1 neurons, suggesting an ACC-driven organization of a sparse code. This robust shift in physiology permits a support vector machine classifier to accurately determine memory age on the basis of the ACC-CA1 synchronization pattern. Our findings reveal that memory consolidation alters the dynamic coupling of the prefrontal-hippocampal circuit and results in a physiological signature of memory age.
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•ACC-CA1 coupling is enhanced during recall of a remote fear memory•ACC entrains long-distance neuronal synchrony in CA1 during remote recall•Sequential ACC-CA1 interactions during exploration predict successful remote recall•The pattern of ACC-CA1 synchronization can accurately decode the age of memory
Makino et al. demonstrate dynamic electrophysiological interactions between ACC and CA1 during recall of remote contextual fear memory, which result in the reactivation of a sparse population of CA1 neurons. These interactions serve as a signature of memory age that can be decoded by a machine learning classifier.
Chronic and acute stress differentially affect behavior as well as the structural integrity of the hippocampus, a key brain region involved in cognition and memory. However, it remains unclear if and ...how the facilitatory effects of acute stress on hippocampal information coding are disrupted as the stress becomes chronic. To examine this, we compared the impact of acute and chronic stress on neural activity in the CA1 subregion of male mice subjected to a chronic immobilization stress (CIS) paradigm. We observed that following first exposure to stress (acute stress), the spatial information encoded in the hippocampus sharpened, and the neurons became increasingly tuned to the underlying theta oscillations in the local field potential (LFP). However, following repeated exposure to the same stress (chronic stress), spatial tuning was poorer and the power of both the slow-gamma (30–50 Hz) and fast-gamma (55–90 Hz) oscillations, which correlate with excitatory inputs into the region, decreased. These results support the idea that acute and chronic stress differentially affect neural computations carried out by hippocampal circuits and suggest that acute stress may improve cognitive processing.
The structured reactivation of hippocampal neuronal ensembles during fast synchronous oscillatory events, termed sharp-wave ripples (SWRs), has been suggested to play a crucial role in the storage ...and use of memory. Activity in both the CA2 and CA3 subregions can precede this population activity in CA1, and chronic inhibition of either region alters SWR oscillations. However, the precise contribution of CA2 to the oscillation, as well as to the reactivation of CA1 neurons within it, remains unclear. Here, we employ chemogenetics to transiently silence CA2 pyramidal cells in mice, and we observe that although SWRs still occur, the reactivation of CA1 pyramidal cell ensembles within the events lose both temporal and informational precision. These observations suggest that CA2 activity contributes to the fidelity of experience-dependent hippocampal replay.
•Silencing of CA2 decreases the temporal precision of SWRs and neuronal spiking•Assemblies from distinct experiences are co-activate following CA2 inhibition•CA1 spiking is more synchronous during replay in the absence of CA2•CA2 influences the informational and temporal precision of neuronal reactivation
He et al. find that DREADD-mediated silencing of CA2 decreases the temporal and informational precision of hippocampal replay. Ripples are less coordinated across CA1 and CA3, and cell assemblies show increased co-activity, both in and out of SWRs. CA2 plays a role in filtering information to be reactivated during replay.
Down syndrome, the leading genetic cause of intellectual disability, results from an extra-copy of chromosome 21. Mice engineered to model this aneuploidy exhibit Down syndrome-like memory deficits ...in spatial and contextual tasks. While abnormal neuronal function has been identified in these models, most studies have relied on
measures. Here, using
recording in
Dp(16)1Yey model, we find alterations in the organization of spiking of hippocampal CA1 pyramidal neurons, including deficits in the generation of complex spikes. These changes lead to poorer spatial coding during exploration and less coordinated activity during sharp-wave ripples, events involved in memory consolidation. Further, the density of CA1 inhibitory neurons expressing neuropeptide Y, a population key for the generation of pyramidal cell bursts, were significantly increased in Dp(16)1Yey mice. Our data refine the 'over-suppression' theory of Down syndrome pathophysiology and suggest specific neuronal subtypes involved in hippocampal dysfunction in these model mice.
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.
Adverse effects of chronic stress include anxiety, depression, and memory deficits. Some of these stress-induced behavioural deficits are mediated by impaired hippocampal function. Much of our ...current understanding about how stress affects the hippocampus has been derived from post-mortem analyses of brain slices at fixed time points. Consequently, neural signatures of an ongoing stressful experiences in the intact brain of awake animals and their links to later hippocampal dysfunction remain poorly understood. Further, no information is available on the impact of stress on sharp-wave ripples (SPW-Rs), high frequency oscillation transients crucial for memory consolidation. Here, we used in vivo tetrode recordings to analyze the dynamic impact of 10 days of immobilization stress on neural activity in area CA1 of mice. While there was a net decrease in pyramidal cell activity in stressed animals, a greater fraction of CA1 spikes occurred specifically during sharp-wave ripples, resulting in an increase in neuronal synchrony. After repeated stress some of these alterations were visible during rest even in the absence of stress. These findings offer new insights into stress-induced changes in ripple-spike interactions and mechanisms through which chronic stress may interfere with subsequent information processing.
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