Chronic fluoxetine dissociates contextual from auditory fear memory

Sanders, J.E.; Mayford, Mark

doi:10.1016/j.neulet.2016.08.057

Cited by 9 publications

(21 citation statements)

References 54 publications

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“…In support of our results, the pharmacological inhibition of ASM activity via chronic administration of the FIASMA fluoxetine impaired the expression of contextual fear but not of cued fear in male mice [ 61 ], further supporting a specific involvement of ASM in contextual fear memory. Similarly, the chronic administration of FIASMAs, such as fluoxetine, paroxetine, imipramine and sertraline, improved symptoms of PTSD in patients and was effective in preventing symptom relapses in PTSD patients [ 62 , 63 , 64 , 65 ].…”

Section: Discussionsupporting

confidence: 83%

Acid Sphingomyelinase Is a Modulator of Contextual Fear

Zoicas¹,

Kornhuber²

2022

IJMS

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Acid sphingomyelinase (ASM) regulates a variety of physiological processes and plays an important role in emotional behavior. The role of ASM in fear-related behavior has not been investigated so far. Using transgenic mice overexpressing ASM (ASMtg) and ASM deficient mice, we studied whether ASM regulates fear learning and expression of cued and contextual fear in a classical fear conditioning paradigm, a model used to investigate specific attributes of post-traumatic stress disorder (PTSD). We show that ASM does not affect fear learning as both ASMtg and ASM deficient mice display unaltered fear conditioning when compared to wild-type littermates. However, ASM regulates the expression of contextual fear in a sex-specific manner. While ASM overexpression enhances the expression of contextual fear in both male and female mice, ASM deficiency reduces the expression of contextual fear specifically in male mice. The expression of cued fear, however, is not regulated by ASM as ASMtg and ASM deficient mice display similar tone-elicited freezing levels. This study shows that ASM modulates the expression of contextual fear but not of cued fear in a sex-specific manner and adds a novel piece of information regarding the involvement of ASM in hippocampal-dependent aversive memory.

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Section: Discussionsupporting

confidence: 83%

Acid Sphingomyelinase Is a Modulator of Contextual Fear

Zoicas¹,

Kornhuber²

2022

IJMS

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“…Zfpm1 CKO animals are strongly responsive to fluoxetine Previously, chronic fluoxetine administration has been shown to decrease the freezing behavior in the CFC and in the fear renewal (Karpova et al, 2011;Sanders and Mayford, 2016). Similarly, chronic fluoxetine treatment significantly lowered the freezing of female Zfpm1 CKO animals to levels comparable to those of control animals in the CFC.…”

Section: Discussionmentioning

confidence: 92%

“…Chronic fluoxetine treatment reverses the increased contextual fear memory in the Zfpm1 CKO mice Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are used as antidepressants that increase the serotonin level in the synapses by inhibiting its reuptake into presynaptic serotonergic neurons via serotonin transporter SLC6A4 (Vaswani et al, 2003). Previous experiments in mice demonstrated fluoxetine treatment (3 weeks) facilitates fear erasure (Karpova et al, 2011;Sanders and Mayford, 2016;Yohn et al, 2018). Thus, control and Zfpm1 CKO female animals (only females were used as they were conditioned normally in the CFC experiment; see above) received fluoxetine (15 mg/kg/d in drinking water) for 3 weeks.…”

Section: Zfpm1 Cko Animals Have Increased Contextual Fear Memorymentioning

confidence: 99%

Inactivation of the GATA Cofactor ZFPM1 Results in Abnormal Development of Dorsal Raphe Serotonergic Neuron Subtypes and Increased Anxiety-Like Behavior

et al. 2020

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Serotonergic neurons in the dorsal raphe (DR) nucleus are associated with several psychiatric disorders including depression and anxiety disorders, which often have a neurodevelopmental component. During embryonic development, GATA transcription factors GATA2 and GATA3 operate as serotonergic neuron fate selectors and regulate the differentiation of serotonergic neuron subtypes of DR. Here, we analyzed the requirement of GATA cofactor ZFPM1 in the development of serotonergic neurons using Zfpm1 conditional mouse mutants. Our results demonstrated that, unlike the GATA factors, ZFPM1 is not essential for the early differentiation of serotonergic precursors in the embryonic rhombomere 1. In contrast, in perinatal and adult male and female Zfpm1 mutants, a lateral subpopulation of DR neurons (ventrolateral part of the DR) was lost, whereas the number of serotonergic neurons in a medial subpopulation (dorsal region of the medial DR) had increased. Additionally, adult male and female Zfpm1 mutants had reduced serotonin concentration in rostral brain areas and displayed increased anxiety-like behavior. Interestingly, female Zfpm1 mutant mice showed elevated contextual fear memory that was abolished with chronic fluoxetine treatment. Altogether, these results demonstrate the importance of ZFPM1 for the development of DR serotonergic neuron subtypes involved in mood regulation. It also suggests that the neuronal fate selector function of GATAs is modulated by their cofactors to refine the differentiation of neuronal subtypes.

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“…As later tests could not detect any alteration in memory of control mice treated with VOR and FLX, it could be assumed that the impact was reversible. FLX treatment (∼19 (mg/kg)/day) of adult C57BL/6J mice has been previously reported to impair contextual fear memory but spare auditory fear memory . In addition, the functional aspect of ER stress is complex as UPR can have distinct outcomes in different diseases and when different signaling components are manipulated .…”

Section: Resultsmentioning

confidence: 99%

Cognitive Improvement by Vorinostat through Modulation of Endoplasmic Reticulum Stress in a Corticosterone-Induced Chronic Stress Model in Mice

Athira

Madhana

Bais

et al. 2020

ACS Chem. Neurosci.

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Chronic stress is the leading cause of memory impairment today. Various stress-based models are being developed for studying cognitive impairment. Repurposing of existing drugs in a new pharmacology class is the safest and cheapest option for treatment instead of new drug discovery. Vorinostat (VOR) is the first histone deacetylase (HDAC) inhibitor approved for the treatment of cutaneous T-cell lymphoma by the U.S. FDA. VOR follows the rule of five and is reported to cross the blood−brain barrier. Therefore, we aimed to evaluate the procognitive potential of VOR (25 mg/kg) administered by intraperitoneal (ip) route in a stress-based model of chronic corticosterone (CORT) injections (20 mg/kg, subcutaneously (sc)). The study comprised six groups. Normal mice were administered vehicle (VEH) (days 1−21, sc) in the first group, VOR (days 8−21, 25 mg/kg, ip) in the second group, and fluoxetine (FLX) (days 8−21, 15 mg/kg, oral) in the third group. Mice in the remaining three groups were given 20 mg/kg (sc) CORT for 21 days, and VOR (days 8−21, 25 mg/kg, ip) or FLX (days 8−21, 15 mg/kg, oral) was additionally administered to the treatment groups. Behavioral tests such as Morris water maze test, novel object recognition test, and object in place test were performed at the end of the dosing schedule to assess cognition. After behavior tests, mice were sacrificed, and hippocampus was separated from brain tissue for reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry studies. VOR treatment attenuated endoplasmic reticulum (ER) stress in CORT mice as evident from the reduction in DNA damage-inducible transcript 3 (Ddit3) (gene encoding CHOP), caspase 12 (Casp12), and calpain-2 (Capn2) mRNA levels, and cleaved caspase 3 (CASP3) protein expression. Bax inhibitor-1 (BI-1) was significantly increased in VOR-treated CORT mice. VOR also reversed CORT induced increase in HDAC2 level in the CA3 region. The protective effects of VOR were comparable to that of FLX in CORT mice. Thus, VOR has the potential to reverse cognitive dysfunction via modulation of ER stress markers and HDAC2.

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Chronic fluoxetine dissociates contextual from auditory fear memory

Cited by 9 publications

References 54 publications

Acid Sphingomyelinase Is a Modulator of Contextual Fear

Acid Sphingomyelinase Is a Modulator of Contextual Fear

Inactivation of the GATA Cofactor ZFPM1 Results in Abnormal Development of Dorsal Raphe Serotonergic Neuron Subtypes and Increased Anxiety-Like Behavior

Cognitive Improvement by Vorinostat through Modulation of Endoplasmic Reticulum Stress in a Corticosterone-Induced Chronic Stress Model in Mice

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