Adjunct treatment with ketamine enhances the therapeutic effects of extinction learning after chronic unpredictable stress

Paredes, Denisse; Knippenberg, Anna R.; Bulin, Sarah E.; Keppler, Lydia J.; Morilak, David A.

doi:10.1016/j.ynstr.2022.100468

Cited by 5 publications

(4 citation statements)

References 66 publications

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“…This induces the same deficit observed in males after 14 days CUS ( Bulin et al, 2020 ). Further, when these procedures produced similar stress-compromised starting points in males and females, we have shown comparable effects of extinction ( Paredes et al, 2021 , 2022 ).…”

Section: Methodssupporting

confidence: 58%

Ventral Hippocampal Input to Infralimbic Cortex Is Necessary for the Therapeutic-Like Effects of Extinction in Stressed Rats

Paredes

Morilak

2023

International Journal of Neuropsychopharmacology

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Background Post-traumatic stress disorder is characterized by deficits in cognitive flexibility related to dysfunction of the medial prefrontal cortex (mPFC). Exposure therapy can effectively reverse these deficits. Fear extinction in rodents bears similarity to exposure therapy. Extinction reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST), a mPFC-mediated process. This therapeutic effect requires activity of pyramidal neurons and BDNF signaling in infralimbic cortex (IL). However, the circuit mechanisms governing BDNF-mediated plasticity initiated by extinction in IL are unknown. The ventral hippocampus (vHipp) plays a role in regulating IL activity during extinction, and plasticity in vHipp is necessary for extinction memory consolidation. Therefore, we investigated the role of vHipp input to IL in the effects of extinction in reversing stress-induced cognitive deficits. Methods vHipp input to IL was silenced using a Gi-DREADD via local infusion of CNO into IL before extinction. A day later, rats were tested on AST. In a separate experiment, we tested whether vHipp input to the IL induces BDNF signaling to exert therapeutic effects. We activated the vHipp using a Gq-DREADD, and injected an anti-BDNF neutralizing antibody into IL. Rats were tested on the AST 24 hours later. Results Silencing the vHipp input to IL prevented the beneficial effects of extinction in reversing stress-induced cognitive deficits. Activating vHipp input to IL in the absence of extinction was sufficient to reverse stress-induced deficits in set-shifting. The beneficial effects of were blocked by local infusion of a neutralizing anti-BDNF antibody into IL. Conclusions vHipp-driven BDNF signaling in IL is critical for extinction to counteract the deleterious cognitive effects of chronic stress.

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Section: Methodssupporting

confidence: 58%

Ventral Hippocampal Input to Infralimbic Cortex Is Necessary for the Therapeutic-Like Effects of Extinction in Stressed Rats

Paredes

Morilak

2023

International Journal of Neuropsychopharmacology

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“…Ketamine has recently garnered much attention due to its rapid antidepressant effects [ 37 , 50 ], while numerous studies have demonstrated its effectiveness in reducing the symptom severity in anxiety disorders and PTSD [ 27 , 28 , 30 , 31 , 32 ]. Concurrently, several studies have shown that ketamine can positively impact fear-related learning processes [ 51 , 52 ], most notably FE [ 25 , 45 , 46 , 47 ], resulting in the suppression of learned fear responses.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies in rodents have shown that ketamine facilitates FE in adults [ 25 , 45 , 46 , 47 ]. Ketamine’s effects on adult extinction learning are mediated by the mTOR signaling pathway in the mPFC [ 25 ] and can be associated with alterations in mPFC glutamatergic transmission [ 46 ]. On the other hand, only one study to date has reported on the behavioral effects of ketamine in a FE paradigm in adolescents [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

Ketamine’s Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway

Glavonic,

Dragic,

Mitic

et al. 2024

Pharmaceuticals

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Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine’s effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine’s mechanisms in adolescent FE, our study suggests that ketamine’s effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates.

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“…Ketamine has been shown to facilitate fear extinction in rats that were subjected to stress ( Paredes et al, 2022 ; Sala et al, 2022 ) or exhibiting high anxiety-like behavior ( Fortress et al, 2018 ), but there have been positive and negative effects reported in ‘normal’ rats ( Clifton et al, 2018 ; Girgenti et al, 2017 ). These behavioral effects of ketamine are associated with neural changes including increased synaptic plasticity and mTORC1 levels in the PFC, and reversal of PFC glutamatergic neuronal hyperexcitability and dendritic atrophy ( Fortress et al, 2018 ; Girgenti et al, 2017 ; Paredes et al, 2022 ; Sala et al, 2022 ). In an interesting parallel from human functional imaging work, ketamine increased vmPFC-amygdala connectivity and reduced amygdala responses to threat ( Krystal et al, 2021 ).…”

Section: Glutamate: Counting On Ketamine?mentioning

confidence: 99%

Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

Singewald¹,

Sartori²,

Reif

et al. 2023

Neuropharmacology

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Adjunct treatment with ketamine enhances the therapeutic effects of extinction learning after chronic unpredictable stress

Cited by 5 publications

References 66 publications

Ventral Hippocampal Input to Infralimbic Cortex Is Necessary for the Therapeutic-Like Effects of Extinction in Stressed Rats

Ventral Hippocampal Input to Infralimbic Cortex Is Necessary for the Therapeutic-Like Effects of Extinction in Stressed Rats

Ketamine’s Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway

Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

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