Biology subjects

Madar, A. D.

Publications and source records attributed to Madar, A. D..

4 recordsLinked to original sources

bioRxiv2023

BTSP, not STDP, Drives Shifts in Hippocampal Representations During Familiarization

Synaptic plasticity is widely thought to support memory storage in the brain, but the rules determining impactful synaptic changes in-vivo are not known. We considered the trial-by-trial shifting dynamics of hippocampal place fields (PFs) as an indicator of ongoing plasticity during memory formation. By implementing different plasticity rules in computational models of spiking place cells and comparing to experimentally measured PFs from mice navigating familiar and novel environments, we found that Behavioral-Timescale-Synaptic-Plasticity (BTSP), rather than Hebbian Spike-Timing-Dependent-Plasticity, is the principal mechanism governing PF shifting dynamics. BTSP-triggering events are rare, but more frequent during novel experiences. During exploration, their probability is dynamic: it decays after PF onset, but continually drives a population-level representational drift. Finally, our results show that BTSP occurs in CA3 but is less frequent and phenomenologically different than in CA1. Overall, our study provides a new framework to understand how synaptic plasticity shapes neuronal representations during learning.

neuroscience↗

bioRxiv2020

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is due to a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy. Significance StatementPeople with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathological bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE and supports a long-standing hypothesis of episodic memory theories.

neuroscience↗

bioRxiv2018

Temporal pattern separation in hippocampal neurons through multiplexed neural codes

Pattern separation is a central concept in current theories of episodic memory: this computation is thought to support our ability to avoid confusion between similar memories by transforming similar cortical input patterns of neural activity into dissimilar output patterns before their long-term storage in the hippocampus. Because there are many ways one can define patterns of neuronal activity and the similarity between them, pattern separation could in theory be achieved through multiple coding strategies. Using our recently developed assay that evaluates pattern separation in isolated tissue by controlling and recording the input and output spike trains of single hippocampal neurons, we explored neural codes through which pattern separation is performed by systematic testing of different similarity metrics and various time resolutions. We discovered that granule cells, the projection neurons of the dentate gyrus, can exhibit both pattern separation and its opposite computation, pattern convergence, depending on the neural code considered and the statistical structure of the input patterns. Pattern separation is favored when inputs are highly similar, and is achieved through spike time reorganization at short time scales (< 100 ms) as well as through variations in firing rate and burstiness at longer time scales. These multiplexed forms of pattern separation are network phenomena, notably controlled by GABAergic inhibition, that involve many celltypes with input-output transformations that participate in pattern separation to different extent and with complementary neural codes: a rate code for dentate fast-spiking interneurons, a burstiness code for hilar mossy cells and a synchrony code at long time scales for CA3 pyramidal cells. Therefore, the isolated hippocampal circuit itself is capable of performing temporal pattern separation using multiplexed coding strategies that might be essential to optimally disambiguate multimodal mnemonic representations.\n\nAuthor SummaryPattern separation (the process of disambiguating incoming patterns of neuronal activity) is a central concept in all current theories of episodic memory, as it is hypothesized to support our ability to avoid confusion between similar memories. For the last thirty years, pattern separation has been attributed to the dentate gyrus of the hippocampus, but this has been hard to test experimentally. Moreover, because it is unclear how to define activity patterns in the brain, such a computation could be achieved in many different ways. Here, we demonstrate that pattern separation is performed by hippocampal networks (dentate gyrus and CA3) through a variety of neural codes. By systematically testing different definitions of what it means for spike trains to be similar (using a range of time scales and various standard and innovative metrics that assume different views of the neural code), we assessed how the input-output transformation of multiple hippocampal celltypes relate to pattern separation and found that different celltypes favor complementary coding strategies. This might help storing rich but concise and unambiguous representations of complex events. Finally, we provide the first experimental evidence of the importance of inhibitory signals in mediating pattern separation, and identify through which coding strategies.

neuroscience↗

bioRxiv2017

Pattern separation of spiketrains by individual granule cells of the dentate gyrus

Pattern separation is a process that minimizes overlap between patterns of neuronal activity representing similar experiences. Theoretical work suggests that the dentate gyrus (DG) performs this role for memory processing but a direct demonstration is lacking. One limitation is the difficulty to measure DG inputs and outputs simultaneously. To rigorously assess pattern separation by DG circuitry, we used mouse brain slices to stimulate DG afferents and simultaneously record DG granule cells (GCs) and interneurons. Output spiketrains of GCs are more dissimilar than their input spiketrains, demonstrating for the first time temporal pattern separation at the level of single neurons in the DG. Pattern separation is larger in GCs than in fast-spiking interneurons and hilar mossy cells, and is amplified in CA3 pyramidal cells. Analysis of the neural noise and computational modelling suggest that this form of pattern separation is not explained by simple randomness and arises from specific presynaptic dynamics. Overall, by reframing the concept of pattern separation in dynamic terms and by connecting it to the physiology of different types of neurons, our study offers a new window of understanding in how hippocampal networks might support episodic memory.

neuroscience↗