A Novel Insular/Orbital-Prelimbic Circuit That Prevents Persistent Avoidance in a Rodent Model of Compulsive Behavior

Martínez-Rivera, Freddyson J.; Pérez-Torres, José; Velázquez-Díaz, Coraly D.; Sánchez-Navarro, Marcos J.; Huertas-Pérez, Carlos I.; Diehl, María M.; Phillips, Mary L.; Haber, Suzanne N.; Quirk, Gregory J.

doi:10.1016/j.biopsych.2022.02.008

Cited by 9 publications

(4 citation statements)

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“…avoidance) (Boeke et al, 2017; Wanke & Schwabe, 2020). In addition, preclinical studies have identified an important role of mOFC and IL in regulating freezing behaviors in fear conditioning and fear extinction (Diehl et al, 2019; Moscarello & LeDoux, 2013; Rodriguez-Romaguera et al, 2015), although more work is needed to determine the role of these and other structures in flexible avoidance behavior under motivational conflict (Manning, Bradfield, et al, 2021; Martinez-Rivera et al, 2023; Rodriguez-Romaguera et al, 2016). mOFC also plays an important role in risk/reward decision making, with mOFC inactivation biasing risky choices in probabilistic discounting for rewards (Stopper et al, 2014); this may be relevant to our findings of lower suppression of lever pressing in animals with reduced mOFC c-Fos.…”

Section: Discussionmentioning

confidence: 99%

“…Extent of PMA training impacts avoidance extinction in models of exposure with response prevention (ERP) (Martinez-Rivera et al, 2020), a well-established treatment for OCD (Abramowitz, 2006), making this a powerful translational model for understanding the development of and alterations to avoidance behaviors in OCD (Rodriguez-Romaguera et al, 2016). Studies in rodents have identified circuits involved in PMA conditioning and extinction whose homologues are also implicated in neuroimaging studies of avoidance in OCD patients, including medial prefrontal cortex and striatal regions relevant to threat appraisal and motivated behaviors altered in OCD (Diehl et al, 2018; Gillan et al, 2015; Martinez-Rivera et al, 2023; Rodriguez-Romaguera et al, 2016). Despite this progress in using PMA to understand the neurobiology of avoidance relevant to OCD, to date it has only been used in behavioral models relevant to OCD (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Manning,

Crummy,

LaPalombara

et al. 2024

Preprint

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Obsessive compulsive disorder (OCD) typically involves cycling between symptoms of intrusive aversive thoughts (obsessions) and repetitive rituals aimed at avoiding these aversive outcomes (compulsions), which interferes with patients' engagement with other important aspects of their lives. This cycling relationship between obsessions and compulsions highlights a potential role of impaired threat processing and avoidance behavior in OCD symptoms. The most effective behavioral therapy for OCD, exposure with response prevention (ERP), aims to break this cycle. However, it can be difficult for patients to access and engage with, suggesting a need for improved understanding of the neural mechanisms of threat processing and avoidance behavior in OCD to guide development of new and more effective treatments. Platform mediated avoidance (PMA) has proven to be a useful translational paradigm for use in rodents to examine avoidance neurobiology and models relevant to OCD, such as ERP and overtraining-induced persistent avoidance. However, to date this protocol has only been used in rats, and studies in transgenic mouse models relevant to OCD may shed further light on neural mechanisms relevant to disturbances in avoidance and threat processing in the disorder. To address this gap, we tested Sapap3 knockout (KO) mice, a leading preclinical model in OCD research, in the PMA task. Using this paradigm, we examined avoidance acquisition, expression, and extinction, as well as reward seeking under motivational conflict in two separate cohorts conditioned using higher (0.4 mA) or lower (0.24 mA) intensity shock. Surprisingly, the most striking difference observed in Sapap3-KOs vs control mice was heightened suppression of lever pressing for rewards during a tone signaling impending threat, suggesting a shift in action selection under motivational conflict (genotype effect avoidance conditioning: 0.24 mA cohort p=0.011, 0.4 mA cohort p=0.07; avoidance extinction: 0.24 mA p=0.057, 0.4 mA p=0.042). Avoidance responding was also acquired more slowly in Sapap3-KOs trained with a low intensity shock (time x genotype interaction p=0.025) and was extinguished more robustly following ERP (genotype effect p=0.043). In contrast, avoidance was similar between Sapap3 KOs and WT littermate controls trained using higher intensity shock (0.4 mA cohort time effect p<0.0001). Expression of the immediate early gene c-Fos associated with reinstatement of avoidance after ERP showed preliminary evidence for decreased activity of medial orbitofrontal cortex (mOFC) in KOs which may contribute to observed differences in PMA performance (KO vs WT mOFC c-Fos t-test p=0.0456). Together these findings suggest that mOFC dysfunction may contribute to increases in the influence of threats vs rewards over action selection in an animal model with relevance to OCD, and that the Sapap3-KO model presents valuable opportunities for deeper mechanistic investigation of avoidance and threat processing relevant to the human disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Manning,

Crummy,

LaPalombara

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The excitatory actions of 5-HT 2A R occur in PFC pyramidal neurons that connect the 2 hemispheres [ 43 ] and regulate the pons region important for pain processing [ 44 ]. Notably, injections of M100907 into the ventrolateral orbital cortex, which innervates A32V, also reduces PWMT [ 45 , 46 ]. The 5-HT 2A/C R receptor antagonist M100907 exhibits subnanomolar potency and a selectivity of at least 500 times for 5-HT 2A R over other receptors [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting 5-HT2A receptors and Kv7 channels in PFC to attenuate chronic neuropathic pain in rats using a spared nerve injury model

Vizcarra

Barber²,

Franca-Solomon³

et al. 2022

Neuroscience Letters

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“…Behavior was analyzed using custom MATLAB scripts and DeepLabCut (41). This procedure is adapted slightly from previous reports using the task in rats (28,30,(42)(43)(44)(45)(46)(47)(48). Water-restricted mice are trained for 7 sessions on a variable-interval 30s schedule where the center port pokes after the assigned ITI deliver a 10% sucrose reward to the reward port.…”

Section: Methodsmentioning

confidence: 99%

Intercalated amygdala dysfunction drives extinction deficits in theSapap3mouse model of obsessive-compulsive disorder

St. Laurent,

Kusche,

Kreitzer

et al. 2024

Preprint

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Background The avoidance of aversive stimuli due to negative reinforcement learning is critical for survival in real-world environments, which demand dynamic responding to both positive and negative stimuli that often conflict with each other. Individuals with obsessive-compulsive disorder (OCD) commonly exhibit impaired negative reinforcement and extinction, perhaps involving deficits in amygdala functioning. An amygdala subregion of particular interest is the intercalated nuclei of the amygdala (ITC) which has been linked to negative reinforcement and extinction, with distinct clusters mediating separate aspects of behavior. This study focuses on the dorsal ITC cluster (ITCd) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making. Methods We investigated the impact of ITCd function on negative reinforcement and extinction by applying fiber photometry measurement of GCamp6f signals and optogenetic manipulations during a platform-mediated avoidance task in a mouse model of OCD-like behavior: the Sapap3-null mouse. Results We find impaired neural activity in the ITCd of male and female Sapap3-null mice to the encoding of negative stimuli during platform-mediated avoidance. Sapap3-null mice also exhibit deficits in extinction of avoidant behavior, which is modulated by ITCd neural activity. Conclusions Sapap3-null mice fail to extinguish avoidant behavior in platform-mediated avoidance, due to heightened ITCd activity. This deficit can be rescued by optogenetically inhibiting ITCd during extinction. Together, our results provide insight into the neural mechanisms underpinning negative reinforcement deficits in the context of OCD, emphasizing the necessity of ITCd in responding to negative stimuli in complex environments.

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A Novel Insular/Orbital-Prelimbic Circuit That Prevents Persistent Avoidance in a Rodent Model of Compulsive Behavior

Cited by 9 publications

References 81 publications

Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Targeting 5-HT2A receptors and Kv7 channels in PFC to attenuate chronic neuropathic pain in rats using a spared nerve injury model

Intercalated amygdala dysfunction drives extinction deficits in theSapap3mouse model of obsessive-compulsive disorder

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