Altered fear learning across development in both mouse and human

Abstract

The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective. F ear learning is a highly adaptive, evolutionarily conserved process that allows one to respond appropriately to cues associated with danger. In the case of psychiatric disorders, however, fear may persist long after an environmental threat has passed. This unremitting and often debilitating form of fear is a core component of many anxiety disorders, including posttraumatic stress disorder (PTSD), and involves exaggerated and inappropriate fear responses. Existing treatments, such as exposure therapy, are based on principles of fear extinction, during which cues previously associated with threat are presented in the absence of the initial aversive event until cues are considered safe and fear responses are reduced. Extinction-based exposure therapies have the strongest empirical evidence for benefitting adult patients suffering from PTSD (1), yet a comparative lack of knowledge about the development of fear neural circuitry prohibits similarly successful treatment outcomes in children and adolescents (2). Adolescence, in particular, is a developmental stage when the incidence of anxiety disorders peaks in humans (3-6), and it is estimated that over 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents (7, 8). Because of insufficient or inaccurate diagnoses and a dearth of pediatric and adolescent specialized treatments, fewer than one in five children or adolescents are expected to receive treatment for their anxiety disorders (9), leaving a vast number with inadequate or no treatment (2, 10). The increased frequency of anxiety disorders in pediatric and adolescent populations highlights the importance of understanding neural mechanisms of fear regulation from a developmental perspective, as existing therapies directly rely upon principles of fear-extinction learning. Converging evidence from human and rodent studies suggests that insufficient top-down regulation of subcortical structures (11-14), such as the amygdala, may coincide with diminished prototypical extinction learning (15...

Regulation of the Mouse Medial Prefrontal Cortical Synapses by Endogenous Estradiol

“…It has been suggested that an enhanced glutamatergic input from the IL-mPFC activates amygdala neurons particularly the GABAergic neurons in the intercalated cell masses and suppresses the centromedial amygdala output and fear response (Ninan, 2014;Pare et al, 2004). Consistently, the IL-mPFC glutamatergic synapses undergo potentiation during fear extinction (Pattwell et al, 2012b;Sepulveda-Orengo et al, 2013). To understand whether endogenous estradiol modulates the IL-mPFC synapses, we studied glutamatergic synaptic transmission and plasticity in the IL-mPFC layer 5 pyramidal neurons, the major projection neurons (Gabbott et al, 2005), from proestrus (high estradiol) and diestrus (low estradiol) mice (Spencer et al, 2010).…”

“…The IL-mPFC-mediated top-down regulation of the amygdala, a mechanism believed to control fear extinction, involves synaptic potentiation in the IL-mPFC (Pare et al, 2004;Pattwell et al, 2012b;Sepulveda-Orengo et al, 2013). Therefore, the estradiol-dependent facilitation of synaptic potentiation in the IL-mPFC might contribute significantly to the enhancement of fear extinction (Chang et al, 2009;Zeidan et al, 2011).…”

“…mPFC slices (300 mm) were prepared and allowed to recover for at least 1 h at room temperature before transferring to a recording chamber perfused with aforementioned ACSF (32 1C) containing 2 mM CaCl 2 . Spontaneous excitatory post-synaptic currents (sEPSCs), excitatory post-synaptic currents (EPSCs), and NMDA EPSCs were evoked in the IL-mPFC layer 5 pyramidal neurons using an electrode solution consisted of CsCl (145 mM), HEPES (10 mM), EGTA (0.5 mM), QX-314 (5 mM), GTP (0.2 mM), and MgATP (5 mM) (osmolarity 290 mOsm, pH 7.4) (Pattwell et al, 2012a;Pattwell et al, 2012b). NMDA EPSC decay time constant and amplitude were assessed before and after the perfusion of ifenprodil (10 mM) for 15 min.…”

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

“…Paralleling the influence of stress on the maturation of fear learning, separation from the mother advances the onset of adult-like extinction learning, from which fears reemerge (Callaghan and Richardson, 2011). In contrast to the ease with which fears are diminished in these younger animals, both fear extinction learning and retention are attenuated during adolescence (Kim et al, 2011;McCallum et al, 2010;Pattwell et al, 2012). Relative to pre-and post-adolescent animals, adolescents exhibit diminished fear extinction learning that is paralleled by an absence of fear-learning-induced synaptic plasticity within the PL and extinction-learning-induced plasticity within the IL .…”

Associations between neurocognitive functioning and social and occupational resilience among South African women exposed to childhood trauma

“…This is important, because different types of traumatic exposure have differential effects on outcome (Brewin, Andrews, & Valentine, 2000). Trauma occurring in early life may have particularly strong effects on neurocognitive function given the multiple developmental changes in the brain that are occurring and the subsequent effects on extinction learning (Caspi et al, 2003; Gould et al, 2012; Pattwell et al, 2012; Slopen, Koenen, & Kubzansky, 2014). Animal studies have shown that early life stress permanently affects extinction learning and fear-related memory (Chocyk et al, 2014).…”