a-lightweight-drive-implant-for-chronic-tetrode-recordings-juvenile

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 ...

UT Southwestern Medical Center

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. mGluR-LTD induction causes long-term increases in AMPA receptor endocytosis rate and dendritic synthesis of Arc, a component of the AMPAR endocytosis machinery. Knockdown of Arc prevents mGluRs from triggering AMPAR endocytosis or LTD, and acute blockade of new Arc synthesis with antisense oligonucleotides blocks mGluR-LTD and AMPAR trafficking. In contrast, LTD induced by NMDA receptors does not persistently alter AMPAR endocytosis rate, induce Arc synthesis, or require Arc protein. These data demonstrate a role for local Arc synthesis specifically in mGluR-LTD and suggest that mGluR-LTD may be one consequence of Arc mRNA induction during experience.

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

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). Therefore, FXS is a tractable model to understand synaptic dysfunction in cognitive disorders. FMRP is present at synapses where it associates with mRNA and polyribosomes. Accumulating evidence finds roles for FMRP in synapse development, elimination, and plasticity. Here, the authors review the synaptic changes observed in FXS and try to relate these changes to what is known about the molecular function of FMRP. Recent advances in the understanding of the molecular and synaptic function of FMRP, as well as the consequences of its loss, have led to the development of novel therapeutic strategies for FXS.

The state of synapses in fragile X syndrome.

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. Here, we demonstrate that MEF2 activation fails to eliminate functional or structural excitatory synapses in hippocampal neurons from Fmr1 KO mice. Similarly, inhibition of endogenous MEF2 increases synapse number in wild-type but not Fmr1 KO neurons. MEF2-dependent synapse elimination is rescued in Fmr1 KO neurons by acute postsynaptic expression of wild-type but not RNA-binding mutants of FMRP. Our results reveal that active MEF2 and FMRP function together in an acute, cell-autonomous mechanism to eliminate excitatory synapses.

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

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. However, recent findings indicate that replay may also serve as a memory retrieval mechanism to guide future behavior or may be an incidental reflection of pre-existing network assemblies. Here, I will review what is known regarding the content of replay events and their correlation with past and future actions, and I will discuss how this knowledge might inform or constrain models which seek to explain the circuit-level mechanisms underlying these events and their role in mnemonic processes.

The content of hippocampal "replay".

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. This finding may provide a circuit-level basis for retrospective evaluation and storage during ongoing behavior. Theta phase procession arose in a minority of place cells, many of which displayed two preferred firing phases in theta oscillations and preferentially participated in reverse replay during subsequent rest. These findings reveal an unexpected aspect of theta-based hippocampal encoding and provide a biological mechanism to support the expression of reverse-ordered sequences.

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

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. This effect was dependent on experience, not passage of time, and was environment specific. By investigating the slow-gamma (25-50 Hz) hover-and-jump dynamics within replays, we show that replay slows by adding more hover locations, increasing the resolution of the behavioral trajectory. We provide evidence that inhibition and cortical engagement both increase as replay slows. Thus, replays can reflect single experiences and evolve with re-exposure, in a manner consistent with the encoding of greater detail into replay memories with experience.

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

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. Rather, population activity rates increased globally as a function of experience. These alterations in activity were mirrored in the power of the theta oscillation and in the quality of theta sequences, without preferential encoding of paths to the learned goal location. In contrast, during brief "offline" pauses in movement, representation of a novel goal location emerged rapidly in ripples, preceding other changes in network activity. These data demonstrate that the hippocampal network can facilitate active navigation without enhanced goal representation during periods of active movement, and further indicate that goal representation in hippocampal ripples before movement onset supports subsequent navigation, possibly through activation of downstream cortical networks. Understanding the mechanisms through which the networks of the brain rapidly assimilate information and use previously learned knowledge are fundamental areas of focus in neuroscience. In particular, the hippocampal circuit is a critical region for rapid formation and use of spatial memory. In this study, several circuit-level features of hippocampal function were quantified while rats performed a spatial navigation task requiring rapid memory formation and use. During periods of active navigation, a general increase in overall network activity is observed during memory acquisition, which plateaus during memory retrieval periods, without specific enhanced representation of the goal location. During pauses in navigation, rapid representation of the distant goal well emerges before either behavioral improvement or changes in online activity.

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

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.

Article	Year
Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron\| PubMed ID: 18614031	2008
The state of synapses in fragile X syndrome. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry\| PubMed ID: 19325170	2009
Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron\| PubMed ID: 20434996	2010
The content of hippocampal "replay". Hippocampus\| PubMed ID: 29266510	2020
Alternating sequences of future and past behavior encoded within hippocampal theta oscillations. Science (New York, N.Y.)\| PubMed ID: 33033222	2020
Hippocampal replays appear after a single experience and incorporate greater detail with more experience. Neuron\| PubMed ID: 35381188	2022
Spatial Learning Drives Rapid Goal Representation in Hippocampal Ripples without Place Field Accumulation or Goal-Oriented Theta Sequences. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 35396328	2022
A novel, lightweight drive implant for chronic tetrode recordings in juvenile mice. bioRxiv : the preprint server for biology\| PubMed ID: 36711560	2023

Brad E. Pfeiffer

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