Sex differences in hippocampal response to endocannabinoids after exposure to severe stress

Zer-Aviv, Tomer Mizrachi; Akirav, Irit

doi:10.1002/hipo.22577

Cited by 50 publications

(21 citation statements)

References 51 publications

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“…Similarly, both cannabinoid drugs prevented the effects of shock and reminders on hippocampal and amygdala dependent processes. These findings are consistent with previous findings showing an increase in CB1r protein levels in the BLA and CA1 one week after exposure to the single prolonged stress model of PTSD (Zer‐Aviv & Akirav, ). Neumeister et al, () showed that PTSD was associated with CB1r upregulation in an amygdala‐hippocampal‐cortico‐striatal neural circuit in response to low anandamide levels.…”

Section: Discussionsupporting

confidence: 93%

“…WIN and URB also prevented the shock and reminders induced increase in startle response. This corroborates with previous studies from our lab demonstrating that systemic administration of cannabinoids after exposure to a traumatic event prevented the development of stress-induced impairment in Ext as well as the increase in startle and anxiety levels (Ganon-Elazar and Akirav, , 2012Akirav, , 2013Korem and Akirav, 2014;Zer-Aviv and Akirav, 2016).…”

Section: Effects On Inhibitory Avoidance and Acoustic Startle Responsesupporting

confidence: 92%

“…; Abush and Akirav, ; Ganon‐Elazar and Akirav, ; Korem and Akirav, ), the FAAH inhibitor URB597 (URB; 0.4 or 0.3 mg/kg, i.p. ; Zer‐Aviv and Akirav, ), and the CB1 receptor antagonist AM251 (AM; 0.5 mg/kg, i.p. ; Braida et al, ) were dissolved in 10% dimethylsulfoxide, 5% Tween‐80, 1% absolute ethanol and saline (0.9% NaCl).…”

Section: Methodsmentioning

confidence: 99%

“…Facilitation of eCB signaling can decrease the effects of both acute and chronic stress on almost every variable examined, including alterations in anxiety, depression, reward sensitivity, hyperalgesia, morphologic changes in the amygdala, and plasticity in the hippocampus and nucleus accumbens (NAcs) (Abush & Akirav, ; Akirav, ; Alteba, Korem, & Akirav, ; Bortolato et al, ; Ganon‐Elazar & Akirav, ; Hill & Gorzalka, ; Korem & Akirav, ; Marsicano et al, ; Moreira & Wotjak, ; Segev & Akirav, ; Zer‐Aviv & Akirav, ).…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoids prevent the differential long‐term effects of exposure to severe stress on hippocampal‐ and amygdala‐dependent memory and plasticity

et al. 2017

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Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including posttraumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal-dependent memory is compromised while amygdala-dependent memory is strengthened. Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response. In this study we aimed to examine cannabinoids modulation of the long-term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala. Following exposure to the shock and reminders model of PTSD in an inhibitory avoidance light-dark apparatus rats demonstrated: (i) enhanced fear retrieval and impaired inhibitory extinction (Ext), (ii) no long-term potentiation (LTP) in the CA1, (iii) impaired hippocampal-dependent short-term memory in the object location task, (iv) enhanced LTP in the amygdala, and (v) enhanced amygdala-dependent conditioned taste aversion memory. The cannabinoid CB1/2 receptor agonist WIN55-212,2 (0.5mg/kg, i.p.) and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3mg/kg, i.p.), administered 2 hr after shock exposure prevented these opposing effects on hippocampal- and amygdala-dependent processes. Moreover, the effects of WIN55-212,2 and URB597 on Ext and acoustic startle were prevented by co-administration of a low dose of the CB1 receptor antagonist AM251 (0.5mg/kg, i.p.), suggesting that the preventing effects of both drugs are mediated by CB1 receptors. Exposure to shock and reminders increased CB1 receptor levels in the CA1 and basolateral amygdala 1 month after shock exposure and this increase was also prevented by administering WIN55-212,2 or URB597. Taken together, these findings suggest the involvement of the eCB system, and specifically CB1 receptors, in the opposite effects of severe stress on memory and plasticity in the hippocampus and amygdala.

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Section: Discussionsupporting

confidence: 93%

Section: Effects On Inhibitory Avoidance and Acoustic Startle Responsesupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cannabinoids prevent the differential long‐term effects of exposure to severe stress on hippocampal‐ and amygdala‐dependent memory and plasticity

et al. 2017

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“…Controls were given the vehicle (Veh) only. Drug doses were based on previous reports [6,21,22]. Shock, situational reminders (SRs), and extinction Rats were placed in an inhibitory avoidance apparatus (for details see [7]).…”

Section: Methods and Materials Subjectsmentioning

confidence: 99%

Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity

Segev

Korem

Zer-Aviv

et al. 2018

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.

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Lifespan changes in cannabinoid 1 receptor mRNA expression in the female C57BL/6J mouse brain

Zhao

Huang

et al. 2022

J of Comparative Neurology

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Many brain functions that underlie behavior, cognition, and emotions vary with age, as does susceptibility to neuropsychological disorders. The expression of specific genes that are involved in these functions, such as the genes encoding for oxytocin, its receptors, and apolipoprotein D, varies with age across different brain regions. The cannabinoid 1 receptor (CB1R) is one of the most widely spread G‐protein coupled receptors in the central nervous system and is increasingly recognized for its important contribution to various brain functions. Although changes in CB1R expression with age have been reported in the male mouse brain, they have not been well investigated in the female brain. Here, we used fluorescence in situ hybridization to target CB1R mRNA in the whole brains of female C57BL/6J mice aged 4, 6, 12, 52 (12 months) and 86 weeks (20 months), and quantified CB1R‐positive cells in 36 brain regions across the whole brain. The results showed that CB1R‐positive cells number changed with age. Specifically, CB1R expression increased with age in some subregions of the cortex, decreased with age in the lateral septal area, and reached its lowest level at 52 weeks in the thalamus, hypothalamus, and hindbrain subregions. Cluster analysis revealed that some brain regions shared similar temporal characteristics in CB1R‐positive cell number across the lifespan. Our results provide evidence that investigation of the neural basis of age‐related characteristics of female brain functions is not only warranted but required.

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Sex differences in hippocampal response to endocannabinoids after exposure to severe stress

Cited by 50 publications

References 51 publications

Cannabinoids prevent the differential long‐term effects of exposure to severe stress on hippocampal‐ and amygdala‐dependent memory and plasticity

Cannabinoids prevent the differential long‐term effects of exposure to severe stress on hippocampal‐ and amygdala‐dependent memory and plasticity

Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity

Lifespan changes in cannabinoid 1 receptor mRNA expression in the female C57BL/6J mouse brain

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