Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization

Abstract Lesioning or inactivating the infralimbic (IL) subregion of the medial prefrontal cortex before acquisition produces more generalized and extinction-resistant fear memories. However, whether and how it modulates memory specificity and extinction susceptibility while consolidation takes place is still unknown. The present study aims to investigate these questions using muscimol-induced temporary inactivation and anisomycin-induced protein synthesis inhibition in the rat IL following contextual fear conditioning. Results indicate that the IL activity immediately after acquisition, but not six hours later, controls memory generalization over a week, regardless of its strength. Such IL function depends on the context-shock pairing since muscimol induced no changes in animals exposed to immediate shocks or the conditioning context only. Animals in which the IL was inactivated during consolidation extinguished similarly to controls within the session but were unable to recall the extinction memory the following day. Noteworthy, these post-acquisition IL inactivation-induced effects were not associated with changes in anxiety, as assessed in the elevated plus-maze test. Anisomycin results indicate that the IL protein synthesis during consolidation contributes more to producing extinction-sensitive fear memories than memory specificity. Collectively, present results provide evidence for the IL's role in controlling generalization and susceptibility to extinction during fear memory consolidation.

Download Full-text

The Oscillatory Profile Induced by the Anxiogenic Drug FG-7142 in the Amygdala–Hippocampal Network Is Reversed by Infralimbic Deep Brain Stimulation: Relevance for Mood Disorders

Biomedicines ◽

10.3390/biomedicines9070783 ◽

2021 ◽

Vol 9 (7) ◽

pp. 783

Author(s):

Hanna Vila-Merkle ◽

Alicia González-Martínez ◽

Rut Campos-Jiménez ◽

Joana Martínez-Ricós ◽

Vicent Teruel-Martí ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Mood Disorders ◽

Brain Stimulation ◽

Antidepressant Treatment ◽

Fg 7142 ◽

Infralimbic Cortex ◽

Anaesthetized Rats ◽

Hippocampal Network ◽

Deep Brain ◽

Stimulation Of

Anxiety and depression exhibit high comorbidity and share the alteration of the amygdala–hippocampal–prefrontal network, playing different roles in the ventral and dorsal hippocampi. Deep brain stimulation of the infralimbic cortex in rodents or the human equivalent—the subgenual cingulate cortex—constitutes a fast antidepressant treatment. The aim of this work was: (1) to describe the oscillatory profile in a rodent model of anxiety, and (2) to deepen the therapeutic basis of infralimbic deep brain stimulation in mood disorders. First, the anxiogenic drug FG-7142 was administered to anaesthetized rats to characterize neural oscillations within the amygdala and the dorsoventral axis of the hippocampus. Next, deep brain stimulation was applied. FG-7142 administration drastically reduced the slow waves, increasing delta, low theta, and beta oscillations in the network. Moreover, FG-7142 altered communication in these bands in selective subnetworks. Deep brain stimulation of the infralimbic cortex reversed most of these FG-7142 effects. Cross-frequency coupling was also inversely modified by FG-7142 and by deep brain stimulation. Our study demonstrates that the hyperactivated amygdala–hippocampal network associated with the anxiogenic drug exhibits an oscillatory fingerprint. The study contributes to comprehending the neurobiological basis of anxiety and the effects of infralimbic deep brain stimulation.

Download Full-text

Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

10.1101/2021.09.16.460695 ◽

2021 ◽

Author(s):

Stephanie L Grella ◽

Amanda H Fortin ◽

John H Bladon ◽

Leanna F Reynolds ◽

Evan Ruesch ◽

...

Keyword(s):

Dentate Gyrus ◽

Conditioned Fear ◽

Large Population ◽

Fear Memory ◽

Memory Recall ◽

Negative Experiences ◽

Operant Responding ◽

Small Set ◽

The Brain ◽

Stimulation Of

Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system, we labeled dorsal dentate gyrus (dDG) neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells were artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory was sufficient to disrupt reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrated operant responding for reactivation of a positive memory, confirming its reward-like properties. These results show that interference from a rewarding experience can counteract negative states. While interference induced by memory reactivation involved a relatively small set of neurons, we also found that activating a large population of randomly labeled dDG neurons was effective at disrupting fear reconsolidation. Importantly, reconsolidation-interference was specific to the fear memory. These findings implicate the dDG as a potential therapeutic node for modulating memories to suppress fear.

Download Full-text

Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

10.21203/rs.3.rs-916568/v1 ◽

2021 ◽

Author(s):

Stephanie Grella ◽

Amanda Fortin ◽

John Bladon ◽

Leanna Reynolds ◽

Evan Ruesch ◽

...

Keyword(s):

Conditioned Fear ◽

Large Population ◽

Fear Memory ◽

Affective States ◽

Negative Experiences ◽

Operant Responding ◽

Small Set ◽

Negative Affective States ◽

The Brain ◽

Stimulation Of

Abstract Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system, we labeled dorsal dentate gyrus (dDG) neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells were artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory was sufficient to disrupt reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrated operant responding for reactivation of a positive memory, confirming its rewarding properties. These results show that interference from a rewarding experience can counteract negative affective states. While interference induced by memory reactivation involved a relatively small set of neurons, we also found that activating a large population of randomly labeled dDG neurons was effective at disrupting reconsolidation. Importantly, reconsolidation-interference was specific to the fear memory. These findings implicate the dDG as a potential therapeutic node for modulating memories to suppress fear.

Download Full-text

Synapse-specific representation of the identity of overlapping memory engrams

Science ◽

10.1126/science.aat3810 ◽

2018 ◽

Vol 360 (6394) ◽

pp. 1227-1231 ◽

Cited By ~ 43

Author(s):

Kareem Abdou ◽

Mohammad Shehata ◽

Kiriko Choko ◽

Hirofumi Nishizono ◽

Mina Matsuo ◽

...

Keyword(s):

Retrograde Amnesia ◽

Fear Memory ◽

Memory Recall ◽

Optogenetic Stimulation ◽

Specific Memory ◽

Memory Engram ◽

And Storage ◽

The Brain ◽

Cell Ensemble ◽

Stimulation Of

Memories are integrated into interconnected networks; nevertheless, each memory has its own identity. How the brain defines specific memory identity out of intermingled memories stored in a shared cell ensemble has remained elusive. We found that after complete retrograde amnesia of auditory fear conditioning in mice, optogenetic stimulation of the auditory inputs to the lateral amygdala failed to induce memory recall, implying that the memory engram no longer existed in that circuit. Complete amnesia of a given fear memory did not affect another linked fear memory encoded in the shared ensemble. Optogenetic potentiation or depotentiation of the plasticity at synapses specific to one memory affected the recall of only that memory. Thus, the sharing of engram cells underlies the linkage between memories, whereas synapse-specific plasticity guarantees the identity and storage of individual memories.

Download Full-text