Appropriate animal models of posttraumatic stress disorder (PTSD) are needed because human studies remain limited in their ability to probe the underlying neurobiology of PTSD. Although the single prolonged stress (SPS) model is an established rat model of PTSD, the development of a similarly-validated mouse model emphasizes the benefits and cross-species utility of rodent PTSD models and offers unique methodological advantages to that of the rat. Therefore, the aims of this study were to develop and describe a SPS model for mice and to provide data that support current mechanisms relevant to PTSD. The mouse single prolonged stress (mSPS) paradigm, involves exposing C57Bl/6 mice to a series of severe, multimodal stressors, including 2h restraint, 10 min group forced swim, exposure to soiled rat bedding scent, and exposure to ether until unconsciousness. Following a 7-day undisturbed period, mice were tested for cue-induced fear behavior, effects of paroxetine on cue-induced fear behavior, extinction retention of a previously extinguished fear memory, dexamethasone suppression of corticosterone (CORT) response, dorsal hippocampal glucocorticoid receptor protein and mRNA expression, and prefrontal cortex glutamate levels. Exposure to mSPS enhanced cue-induced fear, which was attenuated by oral paroxetine treatment. mSPS also disrupted extinction retention, enhanced suppression of stress-induced CORT response, increased mRNA expression of dorsal hippocampal glucocorticoid receptors and decreased prefrontal cortex glutamate levels. These data suggest that the mSPS model is a translationally-relevant model for future PTSD research with strong face, construct, and predictive validity. In summary, mSPS models characteristics relevant to PTSD and this severe, multimodal stress modifies fear learning in mice that coincides with changes in the hypothalamo-pituitary-adrenal (HPA) axis, brain glucocorticoid systems, and glutamatergic signaling in the prefrontal cortex.

Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD). Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, we examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using proton magnetic resonance spectroscopy ex vivo, we examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall.

The experienced consequences of the COVID-19 pandemic have diverged across individuals, families, and communities, resulting in inequity within a host of factors. There is a gap of quantitative evidence about the transgenerational impacts of these experiences and factors. OBJECTIVE To identify baseline predictors of COVID-19 experiences, as defined by child and parent report, using a multivariate pattern-learning framework from the Adolescent Brain and Cognitive Development (ABCD) cohort. DESIGN, SETTING, AND PARTICIPANTS ABCD is an ongoing prospective longitudinal study of child and adolescent development in the United States including 11 875 youths, enrolled at age 9 to 10 years. Using nationally collected longitudinal profiling data from 9267 families, a multivariate pattern-learning strategy was developed to identify factor combinations associated with transgenerational costs of the ongoing COVID-19 pandemic. ABCD data (release 3.0) collected from 2016 to 2020 and released between 2019 and 2021 were analyzed in combination with ABCD COVID-19 rapid response data from the first 3 collection points (May-August 2020). EXPOSURES Social distancing and other response measures imposed by COVID-19, including school closures and shutdown of many childhood recreational activities. MAIN OUTCOMES AND MEASURES Mid-COVID-19 experiences as defined by the ABCD's parent and child COVID-19 assessments. RESULTS Deep profiles from 9267 youth (5681 female [47.8%]; mean [SD] age, 119.0 [7.5] months) and their caregivers were quantitatively examined. Enabled by a pattern-learning analysis, social determinants of inequity, including family structure, socioeconomic status, and the experience of racism, were found to be primarily associated with transgenerational impacts of COVID-19, above and beyond other candidate predictors such as preexisting medical or psychiatric conditions. Pooling information across more than 17 000 baseline pre-COVID-19 family indicators and more than 280 measures of day-to-day COVID-19 experiences, non-White (ie, families who reported being Asian, Black, Hispanic, other, or a combination of those choices) and/or Spanish-speaking families were found to have decreased resources (mode 1, canonical vector weight [CVW] = 0.19; rank 5 of 281), escalated likelihoods of financial worry (mode 1, CVW = −0.20; rank 4), and food insecurity (mode 1, CVW = 0.21; rank 2), yet were more likely to have parent-child discussions regarding COVID-19-associated health and prevention issues, such as handwashing (mode 1, CVW = 0.14; rank 9), conserving food or other items (mode 1, CVW = 0.21; rank 1), protecting elderly individuals (mode 1, CVW = 0.11; rank 21), and isolating from others (mode 1, CVW = 0.11; rank 23). In contrast, White families (mode 1, CVW = −0.07; rank 3), those with higher pre-COVID-19 income (mode 1, CVW = −0.07; rank 5), and presence of a parent with a postgraduate degree (mode 1, CVW = −0.06; rank 14) experienced reduced COVID-19-associated impact. In turn, children from families experiencing reduced COVID-19...

A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and search for drug-able targets. Here we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction such as, the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced magnetic resonance imaging (MEMRI). Rats were treated with cocaine for 5-days followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity, in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus, and temporalis muscle that was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared to saline-treatment to control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared to saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. Since neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for treating cocaine abuse and dependence.

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague–Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0,10 or 20mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, asexpected. However, compared to control ratson Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement.