Brain-wide interactions during hippocampal sharp wave ripples.

During periods of disengagement from the environment, transient population bursts, known as sharp wave ripples (SPW-Rs), occur sporadically. While numerous experiments have characterized the bidirectional relationship between SPW-Rs and activity in chosen brain areas, the topographic relationship between different segments of the hippocampus and brain-wide target areas has not been studied at high temporal and spatial resolution. Yet, such knowledge is necessary to infer the direction of communication. We analyzed two publicly available datasets with simultaneous high-density silicon probe recordings from across the mouse forebrain. We found that SPW-Rs coincide with a transient brain-wide increase in functional connectivity. In addition, we show that the diversity in SPW-R features, such as their incidence, magnitude, and intrahippocampal topography in the septotemporal axis, are correlated with slower excitability fluctuations in cortical and subcortical areas. Further, variations in SPW-R features correlated with the timing, sign, and magnitude of downstream responses with large-amplitude SPW-Rs followed by transient silence in extrahippocampal structures. Our findings expand on previous results and demonstrate that the activity patterns in extrahippocampal structures depend both on the intrahippocampal topographic origin and magnitude of hippocampal SPW-Rs.

Physiological characteristics of neurons in the mammillary bodies align with topographical organization of subicular inputs.

The mammillary bodies (MBOs), a group of hypothalamic nuclei, play a pivotal role in memory formation and spatial navigation. They receive extensive inputs from the hippocampus through the fornix, but the physiological significance of these connections remains poorly understood. Damage to the MBOs is associated with various forms of anterograde amnesia. However, information about the physiological characteristics of the MBO is limited, primarily due to the limited number of studies that have directly monitored MBO activity along with population patterns of its upstream partners. Employing large-scale silicon probe recording in mice, we characterize MBO activity and its interaction with the subiculum across various brain states. We find that MBO cells are highly diverse in their relationship to theta, ripple, and slow oscillations. Several of the physiological features are inherited by the topographically organized inputs to MBO cells. Our study provides insights into the functional organization of the MBOs.

Mixing novel and familiar cues modifies representations of familiar visual images and affects behavior.

While visual responses to familiar and novel stimuli have been extensively studied, it is unknown how neuronal representations of familiar stimuli are affected when they are interleaved with novel images. We examined a large-scale dataset from mice performing a visual go/no-go change detection task. After training with eight images, six novel images were interleaved with two familiar ones. Unexpectedly, we found that the behavioral performance in response to familiar images was impaired when they were mixed with novel images. When familiar images were interleaved with novel ones, the dimensionality of their representation increased, indicating a perturbation of their neuronal responses. Furthermore, responses to familiar images in the primary visual cortex were less predictive of responses in higher-order areas, indicating less efficient communication. Spontaneous correlations between neurons were predictive of responses to novel images, but less so to familiar ones. Our study demonstrates the modification of representations of familiar images by novelty.

Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice.

There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-ß in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-ß 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.

Subiculum as a generator of sharp wave-ripples in the rodent hippocampus.

Sharp wave-ripples (SWRs) represent synchronous discharges of hippocampal neurons and are believed to play a major role in memory consolidation. A large body of evidence suggests that SWRs are exclusively generated in the CA3-CA2 network. In contrast, here, we provide several lines of evidence showing that the subiculum can function as a secondary SWRs generator. SWRs with subicular origin propagate forward into the entorhinal cortex as well as backward into the hippocampus proper. Our findings suggest that the output structures of the hippocampus are not only passively facilitating the transfer of SWRs to the cortex, but they also can actively contribute to the genesis of SWRs. We hypothesize that SWRs with a subicular origin may be important for the consolidation of information conveyed to the hippocampus via the temporoammonic pathway.

Mechanisms of neural organization and rhythmogenesis during hippocampal and cortical ripples.

Neural activity during ripples has attracted great theoretical and experimental attention over the last three decades. Perhaps one reason for such interest is that ripples occur during quiet waking moments and during sleep, times when we reflect and dream about what has just occurred and what we expect to happen next. The hope is that understanding such 'offline' activity may yield insights into reflection, planning, and the purposes of sleep. This review focuses on the mechanisms by which neurons organize during these high-frequency events. In studying ripples, broader principles have emerged that relate intrinsic neural properties, network topology and synaptic plasticity in controlling neural activity. Ripples, therefore, serve as an excellent model for studying how properties of a neural network relate to neural dynamics. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Propagation of hippocampal ripples to the neocortex by way of a subiculum-retrosplenial pathway.

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.

Publisher Correction: Propagation of hippocampal ripples to the neocortex by way of a subiculum-retrosplenial pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Species-specific differences in synaptic transmission and plasticity.

Synaptic transmission and plasticity in the hippocampus are integral factors in learning and memory. While there has been intense investigation of these critical mechanisms in the brain of rodents, we lack a broader understanding of the generality of these processes across species. We investigated one of the smallest animals with conserved hippocampal macroanatomy-the Etruscan shrew, and found that while synaptic properties and plasticity in CA1 Schaffer collateral synapses were similar to mice, CA3 mossy fiber synapses showed striking differences in synaptic plasticity between shrews and mice. Shrew mossy fibers have lower long term plasticity compared to mice. Short term plasticity and the expression of a key protein involved in it, synaptotagmin 7 were also markedly lower at the mossy fibers in shrews than in mice. We also observed similar lower expression of synaptotagmin 7 in the mossy fibers of bats that are evolutionarily closer to shrews than mice. Species specific differences in synaptic plasticity and the key molecules regulating it, highlight the evolutionary divergence of neuronal circuit functions.

Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting.

Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.

VGLUT2 Functions as a Differential Marker for Hippocampal Output Neurons.

The subiculum is the gatekeeper between the hippocampus and cortical areas. Yet, the lack of a pyramidal cell-specific marker gene has made the analysis of the subicular area very difficult. Here we report that the vesicular-glutamate transporter 2 (VGLUT2) functions as a specific marker gene for subicular burst-firing neurons, and demonstrate that VGLUT2-Cre mice allow for Channelrhodopsin-2 (ChR2)-assisted connectivity analysis.

Molecular determinants of proton selectivity and gating in the red-light activated channelrhodopsin Chrimson.

Channelrhodopsins are light-gated ion channels of green algae used for the precise temporal and spatial control of transmembrane ion fluxes. The channelrhodopsin Chrimson from Chlamydomonas noctigama allows unprecedented deep tissue penetration due to peak absorption at 590 nm. We demonstrate by electrophysiological recordings and imaging techniques that Chrimson is highly proton selective causing intracellular acidification in HEK cells that is responsible for slow photocurrent decline during prolonged illumination. We localized molecular determinants of both high proton selectivity and red light activation to the extracellular pore. Whereas exchange of Glu143 only drops proton conductance and generates an operational Na-channel with 590 nm activation, exchange of Glu139 in addition increased the open state lifetime and shifted the absorption hypsochromic by 70 nm. In conjunction with Glu300 in the center and Glu124 and Glu125 at the intracellular end of the pore, Glu139 contributes to a delocalized activation gate and stabilizes by long-range interaction counterion configuration involving protonation of Glu165 that we identified as a key determinant of the large opsin shift in Chrimson.