Systemic Cellular Activation Mapping of an Extinction-Impaired Animal Model

Park, Kwanghoon; Chung, ChiHye

doi:10.3389/fncel.2019.00099

Cited by 12 publications

(11 citation statements)

References 55 publications

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“…The remote recall of contextual fear downregulates c-Fos in the hippocampus of WT (Gräff et al 2014; Wheeler et al 2013), but not in αCaMKII +/- mice (Frankland et al 2004). Contrary to our observation, recent extinction of contextual fear enhances c-Fos expression in the hippocampus of WT as compared to the Naive group of mice (Park and Chung 2019). This is possibly due to the difference in the basal levels of c-Fos in Naive groups or, again fear conditioning protocol (3 vs. 5 US).…”

Section: Discussioncontrasting

confidence: 99%

“…We have shown for the first time that the T286A +/- mice exhibit impaired extinction of remote contextual fear memory, with spared extinction of recent contextual fear. Our results demonstrate that remote fear memory extinction failure was associated with upregulated c-Fos levels in the ENT, RE, CM, MD, AD, and MS. c-Fos immunomapping have been previously used to analyze neuronal substrates of many aspects of contextual fear memory processing, including fear memory encoding (Park and Chung 2019; Lin et al 2018; Frankland et al 2004), recall (Wheeler et al 2013; Hall et al 2001; Conejo et al 2007), recent extinction (Park and Chung 2019; Knox et al 2016), remote extinction (Silva et al 2018) and even extinction deficits (Park and Chung 2019; Hefner et al 2008; Talukdar et al 2018). Nevertheless, none of these studies investigated the role of autophosphorylation of IZCaMKII in remote fear memory extinction.…”

Section: Discussionmentioning

confidence: 99%

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Identification of neuronal ensembles involved in remote fear memory extinction impairments

Tomaszewski,

Łukasiewicz,

Robacha

et al. 2023

Preprint

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Remote memory consolidation, extinction, and its impairments have been of interest to researchers for years, especially due to its clinical relevance in patients with emotional disorders, like PTSD (Post Traumatic Stress Disorder), anxiety, and phobias. Its neuronal substrates are key elements to understand the persistent nature of remote memory and open a new perspective to novel therapeutic approaches for human fear-related disorders. While the majority of reports investigate the mechanisms and ensembles of recent fear memory extinction (hours to days following conditioning), only a few refer to the remote time point (i.e. weeks after conditioning), usually describing successful memory extinction. The neuronal correlates of impaired remote fear memory extinction were yet beyond the scope. Here we present selective impairment of contextual remote fear memory extinction in alpha calcium/calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation-limited mice (T286A +/- ). To map brain regions involved in this phenomenon, we applied screening of c-Fos expression, a neuroplasticity marker, across 23 brain areas following contextual fear conditioning and extinction of recent (1-day old) and remote (30-days old) fear memory in WT and T286A +/- mice. Following impaired remote fear memory extinction in T286A +/- mice, we found upregulated c-Fos expression in the entorhinal cortex (ENT), nucleus reuniens (RE), centromedial (CM), mediodorsal (MD), anterodorsal (AD) thalamic nuclei, and medial septum (MS), compared to WT animals performing normal remote fear memory extinction. Thus our data suggest that alphaCaMKII-autophosphorylation-dependent c-Fos expression in these areas controls distant contextual fear extinction and may shed light on these brain regions as potential targets for therapeutic strategies against emotional disorders such as PTSD.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of neuronal ensembles involved in remote fear memory extinction impairments

Tomaszewski,

Łukasiewicz,

Robacha

et al. 2023

Preprint

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“…Changes in c-Fos have been reported as early as 1–3 h after blast exposure in the hippocampus and amygdala ( Säljö et al, 2002 ; Du et al, 2013 ; Rex et al, 2013 ; Ou et al, 2022 ), and elevated levels can persist ( Säljö et al, 2002 ; Russell et al, 2018b ). As described earlier, the PVT and central amygdala are involved in fear conditioning, and increased c-Fos activation in these regions was reported in a single prolonged stress mouse model of PTSD ( Penzo et al, 2015 ; Park and Chung, 2019 ; Azevedo et al, 2020 ). Only one study has examined IEG response 7 days after a restraint stressor and bTBI, and found sex differences in c-Fos response in the paraventricular nucleus of the hypothalamus ( Russell et al, 2018b ).…”

Section: Introductionsupporting

confidence: 61%

Limbic Responses Following Shock Wave Exposure in Male and Female Mice

McNamara

Tucker²,

Liu³

et al. 2022

Front. Behav. Neurosci.

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Blast traumatic brain injury (bTBI) presents a serious threat to military personnel and often results in psychiatric conditions related to limbic system dysfunction. In this study, the functional outcomes for anxiety- and depressive-like behaviors and neuronal activation were evaluated in male and female mice after exposure to an Advanced Blast Simulator (ABS) shock wave. Mice were placed in a ventrally exposed orientation inside of the ABS test section and received primary and tertiary shock wave insults of approximately 15 psi peak pressure. Evans blue staining indicated cases of blood-brain barrier breach in the superficial cerebral cortex four, but not 24 h after blast, but the severity was variable. Behavioral testing with the elevated plus maze (EPM) or elevated zero maze (EZM), sucrose preference test (SPT), and tail suspension test (TST) or forced swim test (FST) were conducted 8 days–3.5 weeks after shock wave exposure. There was a sex difference, but no injury effect, for distance travelled in the EZM where female mice travelled significantly farther than males. The SPT and FST did not indicate group differences; however, injured mice were less immobile than sham mice during the TST; possibly indicating more agitated behavior. In a separate cohort of animals, the expression of the immediate early gene, c-Fos, was detected 4 h after undergoing bTBI or sham procedures. No differences in c-Fos expression were found in the cerebral cortex, but female mice in general displayed enhanced c-Fos activation in the paraventricular nucleus of the thalamus (PVT) compared to male mice. In the amygdala, more c-Fos-positive cells were observed in injured animals compared to sham mice. The observed sex differences in the PVT and c-Fos activation in the amygdala may correlate with the reported hyperactivity of females post-injury. This study demonstrates, albeit with mild effects, behavioral and neuronal activation correlates in female rodents after blast injury that could be relevant to the incidence of increased post-traumatic stress disorder in women.

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“…It is important to note that we cannot preclude the possibility that CNO-mediated hM3Dq DREADD stimulation may evoke a differential degree of activation across specific forebrain circuits (Alexander et al, 2009), which should be taken into account in the interpretation of our behavioural results. Nevertheless, such broad activation of multiple forebrain regions is common in diverse ethological contexts (Duncan et al, 1996; Ons et al, 2004; Park and Chung, 2019), as well as in response to therapeutic modalities (Linden et al, 2004; Wise et al, 2007; Bechtholt et al, 2008) used to target mood-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Acute Chemogenetic Activation of CamKIIα-Positive Forebrain Excitatory Neurons Regulates Anxiety-Like Behaviour in Mice

Salvi

Pati

Chaudhari

et al. 2019

Front. Behav. Neurosci.

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Anxiety disorders are amongst the most prevalent mental health disorders. Several lines of evidence have implicated cortical regions such as the medial prefrontal cortex, orbitofrontal cortex, and insular cortex along with the hippocampus in the top–down modulation of anxiety-like behaviour in animal models. Both rodent models of anxiety, as well as treatment with anxiolytic drugs, result in the concomitant activation of multiple forebrain regions. Here, we sought to examine the effects of chemogenetic activation or inhibition of forebrain principal neurons on anxiety and despair-like behaviour. We acutely activated or inhibited Ca2+/calmodulin-dependent protein kinase II α (CamKIIα)-positive forebrain excitatory neurons using the hM3Dq or the hM4Di Designer Receptor Exclusively Activated by Designer Drug (DREADD) respectively. Circuit activation was confirmed via an increase in expression of the immediate early gene, c-Fos, within both the hippocampus and the neocortex. We then examined the influence of DREADD-mediated activation of forebrain excitatory neurons on behavioural tests for anxiety and despair-like behaviour. Our results indicate that acute hM3Dq DREADD activation of forebrain excitatory neurons resulted in a significant decline in anxiety-like behaviour on the open field, light–dark avoidance, and the elevated plus maze test. In contrast, hM3Dq DREADD activation of forebrain excitatory neurons did not alter despair-like behaviour on either the tail suspension or forced swim tests. Acute hM4Di DREADD inhibition of CamKIIα-positive forebrain excitatory neurons did not modify either anxiety or despair-like behaviour. Taken together, our results demonstrate that chemogenetic activation of excitatory neurons in the forebrain decreases anxiety-like behaviour in mice.

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Systemic Cellular Activation Mapping of an Extinction-Impaired Animal Model

Cited by 12 publications

References 55 publications

Identification of neuronal ensembles involved in remote fear memory extinction impairments

Identification of neuronal ensembles involved in remote fear memory extinction impairments

Limbic Responses Following Shock Wave Exposure in Male and Female Mice

Acute Chemogenetic Activation of CamKIIα-Positive Forebrain Excitatory Neurons Regulates Anxiety-Like Behaviour in Mice

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