microRNA regulation of persistent stress-enhanced memory

Abstract

Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. Using a stress-enhanced fear learning protocol that results in differential susceptibility in inbred mice, we integrated small-RNA sequencing with quantitative proteomics on basolateral amygdala tissue collected one month after training. We identified persistently changed microRNAs, including mir-135b-5p, and predicted target proteins associated with PTSD-like heightened fear expression. Functional manipulations of mir-135b-5p bidirectionally modulated stress-associated memory. mir-135b-5p is expressed in human amygdala and its passenger strand was elevated in serum from a well-characterized military PTSD cohort. miR-135b-5p is a therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.One Sentence Summary: mir-135 can be manipulated to weaken persistent, stress-associated memory and serve as a biomarker of PTSD.Main Text: Unlike memory acquisition and consolidation, mechanisms supporting long-lasting, remote memory are largely unknown, yet highly relevant to neuropsychiatric disorders of memory, such as posttraumatic stress disorder (PTSD). PTSD is a chronic, debilitating disorder in which patients exhibit memories of trauma that are heightened, perseverant and extinctionresistant (1). Nearly everyone experiences at least one traumatic event in their lifetime, but only 10-20% will later display enduring symptoms of PTSD (2). Exposure therapy, a form of cognitive behavioral therapy (CBT) that utilizes extinction of fearful memories, is considered the gold standard PTSD treatment. However, some patients are resistant or experience exacerbated symptoms and, of those who do respond, most retain their PTSD diagnosis (3). Development of adjunctive pharmacotherapies to enhance success of CBT is needed, but deeper insight into the neurobiology of PTSD-like behaviors to identify potential targets is first required. To identify mechanisms governing differential stress susceptibility, we developed a stress-enhanced fear learning (SEFL) paradigm in inbred C57BL/6 mice that results in PTSD-like characteristics,

Unilateral brain injury to pregnant rats induces asymmetric neurological deficits in the offspring

“…Strikingly, the effects were dependent on the side of the brain injury, and developed on the contralesional side after the left UBI. Thus, in addition to the previously described intergenerational inheritance of stress‐induced responses, drug‐induced changes in memory, and stroke‐induced cognitive deficits (Benito et al., 2018; Goodman & Gotlib, 1999; Khashan et al., 2008; Klengel et al., 2016; Malanga et al., 2007; van Os & Selten, 1998; Sillivan et al., 2020; Skinner, 2016; Todrank et al., 2011; Wang et al., 2013; Xue et al., 2020), the effects of a unilateral brain injury are also intergenerationally transmitted leading to neurological deficits in the offspring.…”

“…The developing nervous system is vulnerable to environmental perturbations affecting pregnant females. Effects of environmental factors may be transmitted to the next generation and cause neuropsychiatric disorders including depression, anxiety, and posttraumatic stress disorder in the offspring (Benito et al., 2018; Klengel et al., 2016; Sillivan et al., 2020; Skinner, 2016). Intergenerational transmission has been demonstrated for aversive stimuli including chronic and early life stress, increased anxiety, and depressive‐like behavior.…”