Current understanding of fear learning and memory in humans and animal models and the value of a linguistic approach for analyzing fear learning and memory in humans

Raber, Jacob; Arzy, Shahar; Boulanger-Bertolus, Julie; Depue, Brendan E.; Haas, Haley E.; Hofmann, Stefan G.; Kangas, Maria; Kensinger, Elizabeth A.; Lowry, Christopher A.; Marusak, Hilary A.; Minnier, Jessica; Mouly, Anne-Marie; Mühlberger, Andreas; Norrholm, Seth D.; Peltonen, Kirsi; Pinna, Graziano; Rabinak, Christine A.; Shiban, Youssef; Soreq, Hermona; Kooij, Michael A. van der; Lowe, Leroy; Weingast, Leah T.; Yamashita, Paula S. M.; Boutros, Sydney Weber

doi:10.1016/j.neubiorev.2019.03.015

Cited by 42 publications

(33 citation statements)

References 651 publications

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“…While novel therapeutic strategies are urgently needed for the management of MDD, PTSD, and other mood disorders, the nuclear receptors PPAR-α and γ are gaining consistent interest as new promising targets for treating behavioral dysfunction (please see Tables 1 and 2 for a summary) [39]. This is further substantiated by the recent discovery that stimulation of PPAR-α can enhance neurosteroid biosynthesis [10], which is implicated in the etiopathology of mood disorders and their treatment [7,[40][41][42][43]. 3.1.1.…”

Section: Mood Disordersmentioning

confidence: 99%

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Hence, the strategy of targeting PPARs for their anti-inflammatory role to improve these disorders is attracting attention. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies. We reviewed running findings in support of a role for PPARs in the treatment of neurological diseases, including Alzheimer’s disease or psychiatric disorders, such as major depression. We discuss the opportunity of targeting PPARs as a future pharmacological approach to decrease neuropsychiatric symptoms at the same time that PPAR ligands resolve neuroinflammatory processes.

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Section: Mood Disordersmentioning

confidence: 99%

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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“…The cost of fear-based learning is closed loop neural activation of entrenched patterns of avoidance ( 43 , 44 ). Repetition of behavior strengthens synaptic connections through long-term potentiation (LTP) from α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-D-aspartate (NMDA) glutamate receptors ( 45 ), which is particularly relevant for the development of habits.…”

Section: General Neuroscience Concepts Underpinning Learning Theorymentioning

confidence: 99%

Neuroscience of Adolescent Anorexia Nervosa: Implications for Family-Based Treatment (FBT)

Mysliwiec¹

2020

Front. Psychiatry

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Over the past 20 years significant progress has been made to elucidate some of the neurobiological underpinnings of the development and maintenance of anorexia nervosa and their possible implications for treatment. There is increasing evidence supporting the notion that anorexia nervosa shares neurobehavioral patterns with anxiety disorders and involves reward processing aberrations and habit formation. There is consensus for the need of early intervention to ameliorate the effects of starvation on the adolescent brain and the effects of illness duration on neurodevelopment. Family-based treatment (FBT) is the first line evidence-based treatment for adolescents with anorexia nervosa achieving sustainable full remission rates of over 40%. FBT has an agnostic treatment approach and its mechanisms of change have until now not been fully understood. To help fill this gap in theoretical understanding, this paper will provide a review of the treatment model of FBT through a neuroscientific lens. It argues that FBT is well designed to address the implications of current key findings of the neuroscience of anorexia nervosa and that it is also well aligned with the current understanding of neuroscience principles underpinning therapeutic change. The paper supports the perspective that FBT utilizes principles of parent facilitated exposure response prevention. It concludes that an integration of a neuroscience perspective to the provision of FBT will assist the clinician in their practice of FBT.

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“…A number of pharmacological agents, including SSRIs administered at low doses that act like selective brain steroidogenic stimulants (SBSSs) and increase corticolimbic allopregnanolone levels (Pinna, 2015), or allopregnanolone analogs, including ganaxolone, by a contextual fear reconsolidation blockade, normalize fear response and facilitate fear extinction (Pibiri et al, 2008; Pinna and Rasmusson, 2014; Rasmusson et al, 2017). Most importantly, these agents prevent the reemergence of fear after the passage of time, during recall (Pinna and Rasmusson, 2014; reviewed in Aspesi and Pinna, 2019; Locci and Pinna, 2019a; Raber et al, 2019). Furthermore, the novel allopregnanolone’s analogs BR297 and BR351 showed strong anti-aggressive effects in isolated mice (Locci et al, 2017).…”

Section: The Socially Isolated Mousementioning

confidence: 99%

“…Although a direct evidence that endocannabinoids stimulate brain neurosteroid biosynthesis has not been provided, recent studies show THC increases allopregnanolone’s precursor, pregnenolone by activating CB1 (Vallée et al, 2014; Vallée, 2016). The detailed description on endocannabinoid and neurosteroidogenic neuronal targets and novel molecules that are currently investigated for the development of new treatments for PTSD has been the focus of recent reviews (Pinna, 2014; Aspesi and Pinna, 2019; Locci and Pinna, 2019a; Raber et al, 2019).…”

Section: The Socially Isolated Mousementioning

confidence: 99%

“…The prefrontal cortex and hippocampus directly project to the amygdaloid nuclei to regulate their hyperactivity following traumatic events (Herry et al, 2008). In susceptible individuals, a stressful experience is associated with impairment of cortical inhibitory activity directed to the amygdala, which results in exaggerated hyperactivity and inappropriate fear responses (Akirav and Maroun, 2007; Raber et al, 2019). In PTSD, amygdala hyperactivity is part of a maladaptive emotional processing resulting from exposure to traumatic events.…”

Section: The Socially Isolated Mousementioning

confidence: 99%

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Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone

Pinna

2019

Front. Behav. Neurosci.

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Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%–13% of the general population and 20%–30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABA A receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABA A receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.

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Current understanding of fear learning and memory in humans and animal models and the value of a linguistic approach for analyzing fear learning and memory in humans

Cited by 42 publications

References 651 publications

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Neuroscience of Adolescent Anorexia Nervosa: Implications for Family-Based Treatment (FBT)

Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone

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