Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(7), P. 1929 - 1940

Published: Feb. 13, 2024

Long-term memories are believed to be encoded by unique transcriptional signatures in the brain. The expression of immediate early genes (IEG) promotes structural and molecular changes required for memory consolidation. Recent evidence has shown that brain is equipped with mechanisms not only promote, but actively constrict formation. However, it remains unknown whether IEG may play a role suppression. Here we uncovered novel function neuronal PAS domain protein 4 (Npas4), as an inducible suppressor gene highly salient aversive experiences. Using contextual fear conditioning paradigm, found low stimulus salience leads monophasic Npas4 expression, while learning induces biphasic hippocampus. later phase requires N-methyl-D-aspartate (NMDA) receptor activity independent dopaminergic neurotransmission. Our vivo pharmacological genetic manipulation experiments suggested restricts consolidation promote behavioral flexibility, facilitating extinction specificity responses. Moreover, immunofluorescence electrophysiological analysis revealed concomitant increase synaptic input from cholecystokinin (CCK)-expressing interneurons. results demonstrate how experiences evoke temporal patterns fine-tune our study provides associated suppression possible mechanism balance memories, thereby evade formation maladaptive behavior.

Language: Английский

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Cortico-subcortical networks that determine behavioral memory renewal are redefined by noradrenergic neuromodulation

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 20, 2025

Abstract During spatial appetitive extinction learning (EL), rodents learn that previously rewarded behavior is no longer rewarded. Renewal of the extinguished enabled by re-exposure to context in which occurred. When renewal response (RR) unrewarded, it rapidly followed (RE). Although hippocampus known be engaged, whether this dynamic supported different brain networks unclear. To clarify this, male rats engaged context-dependent memory acquisition, EL and RR testing a T-Maze. Fluorescence situ hybridization disambiguated somatic immediate early gene expression neuronal somata or RE. Graph analysis revealed pronounced hippocampal connectivity with retrosplenial prefrontal cortex (PFC) during initial RR. By contrast, RE was accompanied shift towards elevated coordinated activity within all subfields. Given β-adrenergic receptors (β-AR) regulate memory, we activated β-AR further scrutinize these network effects. This enhanced prevented Effects were associated initially increased thalamic-hippocampus activity, decrease intraconnectivity predominance PFC. Our findings highlight critical hippocampal-cortical-thalamic underpins behavior, noradrenergic neuromodulation playing pivotal role governing circuit’s dynamics.

Language: Английский

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Why are threatening experiences remembered so well? Insights into memory strengthening from protocols of gradual aversive learning

Neuroscience & Biobehavioral Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 106145 - 106145

Published: April 1, 2025

Language: Английский

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Hierarchical Bayesian modeling of multi-region brain cell count data

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 21, 2024

We can now collect cell-count data across whole animal brains quantifying recent neuronal activity, gene expression, or anatomical connectivity. This is a powerful approach since it multi-region measurement, but because the imaging done post-mortem, each only provides one set of counts. Experiments are expensive and cells counted by aligning large number brain sections, they time-intensive. The resulting datasets tend to be under-sampled with fewer animals than regions. As consequence, these challenge for traditional statistical approaches. demonstrate that hierarchical Bayesian methods well suited presenting ‘standard’ partially-pooled model applying two example datasets. For both outperformed standard parallel t-tests. Overall, approach’s ability capture nested its rigorous handling uncertainty in substantially improve inference data. Significance Statement Cell-count important studying activation expression relating complex processes brain. However, difficulty expense collection means such often have small sample sizes. Many routine analyses not well-suited, especially if there high variability among surprising outliers Here we describe multilevel, mixed effects show improves inferences compared usual different characteristics.

Language: Английский

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Male rats emit aversive 44-kHz ultrasonic vocalizations during prolonged Pavlovian fear conditioning

Published: Oct. 4, 2024

Rats are believed to communicate their emotional state by emitting two distinct types of ultrasonic vocalizations. The first is long “22-kHz” vocalizations (>300 ms, <32 kHz) with constant frequency, signaling aversive states and the second, short “50-kHz” calls (<150 >32 kHz), often frequency-modulated, in appetitive situations. Here we describe emitted at a higher pitch male Wistar spontaneously hypertensive rats (SHR) an intensified – prolonged fear conditioning. These calls, which named “44-kHz” vocalizations, (>150 ms), generally frequency (usually within 35-50 kHz range) have overall spectrographic image similar 22-kHz calls. Some 44-kHz comprised both 22-kHz-like 44-kHz-like elements. Furthermore, separate clustering methods confirmed that these can be separated from other We observed associated freezing behavior during conditioning training, they constituted up 19.4% all most them appeared next each forming uniform groups (bouts). also show some rats’ responses playback were more akin e.g., heart rate changes, whereas intermediate level between Our results suggest wider vocal repertoire than previously believed, current definitions major call may require reevaluation. hope future investigations rat models human diseases will contribute expanding our understanding therapeutic strategies related psychiatric conditions.

Language: Английский

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Hierarchical Bayesian modeling of multi-region brain cell count data

Published: Nov. 25, 2024

We can now collect cell-count data across whole animal brains quantifying recent neuronal activity, gene expression, or anatomical connectivity. This is a powerful approach since it multi-region measurement, but because the imaging done post-mortem, each only provides one set of counts. Experiments are expensive and cells counted by aligning large number brain sections, they time-intensive. The resulting datasets tend to be under-sampled with fewer animals than regions. As consequence, these challenge for traditional statistical approaches. demonstrate that hierarchical Bayesian methods well suited presenting ‘standard’ partially-pooled model applying two example datasets. For both outperformed standard parallel t-tests. Overall, approach’s ability capture nested its rigorous handling uncertainty in substantially improve inference data.

Language: Английский

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Hierarchical Bayesian modeling of multi-region brain cell count data

Published: Nov. 25, 2024

We can now collect cell-count data across whole animal brains quantifying recent neuronal activity, gene expression, or anatomical connectivity. This is a powerful approach since it multi-region measurement, but because the imaging done post-mortem, each only provides one set of counts. Experiments are expensive and cells counted by aligning large number brain sections, they time-intensive. The resulting datasets tend to be under-sampled with fewer animals than regions. As consequence, these challenge for traditional statistical approaches. demonstrate that hierarchical Bayesian methods well suited presenting ‘standard’ partially-pooled model applying two example datasets. For both outperformed standard parallel t-tests. Overall, approach’s ability capture nested its rigorous handling uncertainty in substantially improve inference data.

Language: Английский

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Male rats emit aversive 44-kHz ultrasonic vocalizations during prolonged Pavlovian fear conditioning

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 8, 2023

Abstract Rats are believed to communicate their emotional state by emitting two distinct types of ultrasonic vocalizations. The first is long “22-kHz” vocalizations (>300 ms, <32 kHz) with constant frequency, signaling aversive states and the second, short “50-kHz” calls (<150 >32 kHz), often frequency-modulated, in appetitive situations. Here we describe emitted at a higher pitch male Wistar spontaneously hypertensive rats (SHR) an intensified – prolonged fear conditioning. These calls, which named “44-kHz” vocalizations, (>150 ms), generally frequency (usually within 35-50 kHz range) have overall spectrographic image similar 22-kHz calls. Some 44-kHz comprised both 22-kHz-like 44-kHz-like elements. Furthermore, separate clustering methods confirmed that these can be separated from other We observed associated freezing behavior during conditioning training, they constituted up 19.4% all most them appeared next each forming uniform groups (bouts). also show some rats’ responses playback were more akin e.g., heart rate changes, whereas intermediate level between Our results suggest wider vocal repertoire than previously believed, current definitions major call may require reevaluation. hope future investigations rat models human diseases will contribute expanding our understanding therapeutic strategies related psychiatric conditions.

Language: Английский

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