Bidirectional synaptic changes in deep and superficial hippocampal neurons following in vivo activity.

Neuronal activity during experience is thought to induce plastic changes within the hippocampal network that underlie memory formation, although the extent and details of such changes in vivo remain unclear. Here, we employed a temporally precise marker of neuronal activity, CaMPARI2, to label active CA1 hippocampal neurons in vivo, followed by immediate acute slice preparation and electrophysiological quantification of synaptic properties. Recently active neurons in the superficial sublayer of stratum pyramidale displayed larger post-synaptic responses at excitatory synapses from area CA3, with no change in pre-synaptic release probability.

Experience alters hippocampal and cortical network communication via a KIBRA-dependent mechanism.

Synaptic plasticity is hypothesized to underlie "replay" of salient experience during hippocampal sharp-wave/ripple (SWR)-based ensemble activity and to facilitate systems-level memory consolidation coordinated by SWRs and cortical sleep spindles. It remains unclear how molecular changes at synapses contribute to experience-induced modification of network function. The synaptic protein KIBRA regulates plasticity and memory.

A Lightweight Drive Implant for Chronic Tetrode Recordings in Juvenile Mice.

In vivo electrophysiology provides unparalleled insight into the sub-second-level circuit dynamics of the intact brain and represents a method of particular importance for studying mouse models of human neuropsychiatric disorders. However, such methods often require large cranial implants, which cannot be used in mice at early developmental time points. As such, virtually no studies of in vivo physiology have been performed in freely behaving infant or juvenile mice, despite the fact that a better understanding of neurological development in this critical window would likely provide unique insights into age-dependent developmental disorders such as autism or schizophrenia.

A novel, lightweight drive implant for chronic tetrode recordings in juvenile mice.

Short Abstract: We describe a novel micro-drive design, surgical implantation procedure, and post-surgery recovery strategy that allows for chronic field and single-unit recordings from up to sixteen brain regions simultaneously in juvenile and adolescent mice across a critical developmental window from p20 to p60 and beyond.

Long Abstract: electrophysiology provides unparalleled insight into sub-second-level circuit dynamics of the intact brain and represents a method of particular importance for studying mouse models of human neuro-psychiatric disorders. However, such methods often require large cranial implants which cannot be used in mice at early developmental timepoints.

Flexibility of functional neuronal assemblies supports human memory.

Episodic memories, or consciously accessible memories of unique events, represent a key aspect of human cognition. Evidence from rodent models suggests that the neural representation of these complex memories requires cooperative firing of groups of neurons on short time scales, organized by gamma oscillations. These co-firing groups, termed "neuronal assemblies," represent a fundamental neurophysiological unit supporting memory.

Spatial Learning Drives Rapid Goal Representation in Hippocampal Ripples without Place Field Accumulation or Goal-Oriented Theta Sequences.

The hippocampus is critical for rapid acquisition of many forms of memory, although the circuit-level mechanisms through which the hippocampus rapidly consolidates novel information are unknown. Here, the activity of large ensembles of hippocampal neurons in adult male Long-Evans rats was monitored across a period of rapid spatial learning to assess how the network changes during the initial phases of memory formation and retrieval. In contrast to several reports, the hippocampal network did not display enhanced representation of the goal location via accumulation of place fields or elevated firing rates at the goal.

Hippocampal replays appear after a single experience and incorporate greater detail with more experience.

The hippocampus is implicated in memory formation, and neurons in the hippocampus take part in replay sequences that have been proposed to reflect memory of explored space. By recording from large ensembles of hippocampal neurons as rats explored various tracks, we show that sustained replay appears after a single experience. Further, we found that with repeated experience in a novel environment, replay slows down, taking more time to traverse the same trajectory.

Time cells in the human hippocampus and entorhinal cortex support episodic memory.

The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, evidence accumulated over the last decade suggests that populations of "time cells" in the hippocampus encode temporal information. We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task.

Alternating sequences of future and past behavior encoded within hippocampal theta oscillations.

Neural networks display the ability to transform forward-ordered activity patterns into reverse-ordered, retrospective sequences. The mechanisms underlying this transformation remain unknown. We discovered that, during active navigation, rat hippocampal CA1 place cell ensembles are inherently organized to produce independent forward- and reverse-ordered sequences within individual theta oscillations.

Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC.

A consensus statement: defining terms for reactivation analysis.

During a two-day Royal Society meeting entitled '' held at Chicheley Hall in May, 2019, we discussed and defined a set of terms for investigating and reporting in memory reactivations to facilitate a common language and thus simplifying comparison of results. Here, we present the results of the discussion and supply a set of terms such as reactivation and replay, for which the authors have reached a common consensus. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Uncovering temporal structure in hippocampal output patterns.

Place cell activity of hippocampal pyramidal cells has been described as the cognitive substrate of spatial memory. Replay is observed during hippocampal sharp-wave-ripple-associated population burst events (PBEs) and is critical for consolidation and recall-guided behaviors. PBE activity has historically been analyzed as a phenomenon subordinate to the place code.

The content of hippocampal "replay".

One of the most striking features of the hippocampal network is its ability to self-generate neuronal sequences representing temporally compressed, spatially coherent paths. These brief events, often termed "replay" in the scientific literature, are largely confined to non-exploratory states such as sleep or quiet rest. Early studies examining the content of replay noted a strong correlation between the encoded spatial information and the animal's prior behavior; thus, replay was initially hypothesized to play a role in memory formation and/or systems-level consolidation via "off-line" reactivation of previous experiences.

Reverse Replay of Hippocampal Place Cells Is Uniquely Modulated by Changing Reward.

Hippocampal replays are episodes of sequential place cell activity during sharp-wave ripple oscillations (SWRs). Conflicting hypotheses implicate awake replay in learning from reward and in memory retrieval for decision making. Further, awake replays can be forward, in the same order as experienced, or reverse, in the opposite order.

PLACE CELLS. Autoassociative dynamics in the generation of sequences of hippocampal place cells.

Neuronal circuits produce self-sustaining sequences of activity patterns, but the precise mechanisms remain unknown. Here we provide evidence for autoassociative dynamics in sequence generation. During sharp-wave ripple (SWR) events, hippocampal neurons express sequenced reactivations, which we show are composed of discrete attractors.

Hippocampal place-cell sequences depict future paths to remembered goals.

Effective navigation requires planning extended routes to remembered goal locations. Hippocampal place cells have been proposed to have a role in navigational planning, but direct evidence has been lacking. Here we show that before goal-directed navigation in an open arena, the rat hippocampus generates brief sequences encoding spatial trajectories strongly biased to progress from the subject's current location to a known goal location.

Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2.

Fragile X syndrome (FXS), the most common genetic form of mental retardation and autism, is caused by loss-of-function mutations in an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). Neurons from patients and the mouse Fmr1 knockout (KO) model are characterized by an excess of dendritic spines, suggesting a deficit in excitatory synapse elimination. In response to neuronal activity, myocyte enhancer factor 2 (MEF2) transcription factors induce robust synapse elimination.

The state of synapses in fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading genetic cause of autism. There is increasing evidence in both FXS and other forms of autism that alterations in synapse number, structure, and function are associated and contribute to these prevalent diseases. FXS is caused by loss of function of the Fmr1 gene, which encodes the RNA binding protein, fragile X mental retardation protein (FMRP).

Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate.

Salient stimuli that modify behavior induce transcription of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and transport Arc mRNA into dendrites, suggesting that local Arc translation mediates synaptic plasticity that encodes such stimuli. Here, we demonstrate that long-term synaptic depression (LTD) in hippocampal neurons induced by group 1 metabotropic glutamate receptors (mGluRs) relies on rapid translation of Arc.

Multiple Gq-coupled receptors converge on a common protein synthesis-dependent long-term depression that is affected in fragile X syndrome mental retardation.

Gq-coupled, M1 muscarinic acetylcholine receptors (mAChRs) facilitate hippocampal learning, memory, and synaptic plasticity. M1 mAChRs induce long-term synaptic depression (LTD), but little is known about the underlying mechanisms of mAChR-dependent LTD and its link to cognitive function. Here, we demonstrate that chemical activation of M1 mAChRs induces LTD in hippocampal area CA1, which relies on rapid protein synthesis, as well as the extracellular signal-regulated kinase and mammalian target of rapamycin translational activation pathways.

Fragile X mental retardation protein induces synapse loss through acute postsynaptic translational regulation.

Fragile X syndrome, as well as other forms of mental retardation and autism, is associated with altered dendritic spine number and structure. Fragile X syndrome is caused by loss-of-function mutations in Fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates protein synthesis in vivo. It is unknown whether FMRP plays a direct, cell-autonomous role in regulation of synapse number, function, or maturation.

Current advances in local protein synthesis and synaptic plasticity.

Local or dendritic protein synthesis is required for long-term functional synaptic change, such as long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD both rely on similar signal transduction cascades, which regulate translation initiation. Current research indicates that the specificity by which new proteins participate in either LTP or LTD may be determined in part by specific RNA-binding proteins as well as activity-dependent capture.

Brain cholesterol turnover required for geranylgeraniol production and learning in mice.

The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway.

Antiviral effect and virus-host interactions in response to alpha interferon, gamma interferon, poly(i)-poly(c), tumor necrosis factor alpha, and ribavirin in hepatitis C virus subgenomic replicons.

The recently developed hepatitis C virus (HCV) subgenomic replicon system was utilized to evaluate the efficacy of several known antiviral agents. Cell lines that persistently maintained a genotype 1b replicon were selected. The replicon resident in each cell line had acquired adaptive mutations in the NS5A region that increased colony-forming efficiency, and some replicons had acquired NS3 mutations that alone did not enhance colony-forming efficiency but were synergistic with NS5A mutations.