Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth, Máté; Flandreau, Elizabeth I.; Deslauriers, Jessica; Geyer, Mark A.; Mansuy, Isabelle M; Pich, Emilio Merlo; Risbrough, Victoria B.

doi:10.1038/npp.2015.338

Cited by 34 publications

(35 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To study susceptibility empirically, research focuses on using preclinical rodent models to assess a PTSD-like phenotype (Milad et al, 2006;Yehuda and LeDoux, 2007;Goswami et al, 2012). Many animal models of PTSD with face and construct validity have been developed (Hartmann et al, 2012;Toth et al, 2016;Deslauriers et al, 2019). The purpose of this review is not to review these, but to identify those models that are suitable for investigating individual differences in susceptibility.…”

Section: Modeling a Ptsd-like Phenotype In Animalsmentioning

confidence: 99%

See 1 more Smart Citation

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

Alexander

Nalloor

Bunting

et al. 2020

Front. Syst. Neurosci.

View full text Add to dashboard Cite

• Susceptibility to developing a PTSD-like phenotype exists in animals. It can be identified behaviorally and therefore can be studied. • Susceptibility can be studied by identifying susceptibility factors (pre-trauma) and sequalae factors (peri-and posttrauma) to a PTSD-like phenotype. • Some susceptible individuals have impaired functioning in the hippocampus BEFORE emotional trauma. • Understanding susceptibility can inform ways to successfully build resilience. • Investigations into susceptibility also highlight the important idea that susceptibility is a dynamic feature of PTSD. Susceptibility is not strictly determined by genetics but requires an interaction with environmental factors, making it modifiable over time.

show abstract

Section: Modeling a Ptsd-like Phenotype In Animalsmentioning

confidence: 99%

“…(3) Models with construct validity (e.g., knockout of FKBP5, COMT, or CRH overexpression in early life) do not produce a complex PTSD-like phenotype (Hartmann et al, 2012;Toth et al, 2016;Deslauriers et al, 2019). (4) Animal models can inform about some, but not all, aspects of the PTSD phenomenon.…”

Section: Modeling a Ptsd-like Phenotype In Animalsmentioning

confidence: 99%

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

Alexander

Nalloor

Bunting

et al. 2020

Front. Syst. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The CRHR1 is abundantly expressed in fear-modulating corticolimbic circuits, including the mPFC (Steckler and Holsboer, 1999). Studies in humans and rodents indicate that CRH-CRHR1 hyper-signaling represents a candidate mechanism for PTSD risk (Bremner et al, 1997;Jovanovic et al, 2020;Rajbhandari et al, 2015;Toth et al, 2016). CRHR1 hyper-signaling alters brain structural integrity (Chen et al, 2004;Kolber et al, 2010;Toth et al, 2014) and has long-lasting consequences in stress susceptibility (Uribe-Mariño et al, 2016), mainly when it is triggered early in life (Toth et al, 2016).…”

Section: Age and Diet Modulate The Expression Of The Corticotropin-rementioning

confidence: 99%

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

Vega-Torres

Azadian

Rios-Orsini

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Emerging evidence demonstrates that diet-induced obesity disrupts corticolimbic circuits underlying emotional regulation. Studies directed at understanding how obesity alters brain and behavior are easily confounded by a myriad of complications related to obesity. This study investigated the early neurobiological stress response triggered by an obesogenic diet. Furthermore, this study directly determined the combined impact of a short-term obesogenic diet and adolescence on critical behavioral and molecular substrates implicated in emotion regulation and stress.Methods: Adolescent (postnatal day 31) or adult (postnatal day 81) Lewis rats were fed for one week with an experimental Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). We used the acoustic fear-potentiated startle (FPS) paradigm to determine the effects of the WD on cued fear conditioning and fear extinction. We used c-Fos mapping to determine the functional influence of the diet and stress on corticolimbic circuits. Results:We report that one-week WD consumption was sufficient to induce fear extinction deficits in adolescent rats, but not in adult rats. We identify fear-induced alterations in corticolimbic neuronal activation and demonstrate increased prefrontal cortex CRHR1 mRNA levels in the rats that consumed the WD. Conclusions:Our findings demonstrate that short-term consumption of an obesogenic diet during adolescence heightens behavioral and molecular vulnerabilities associated with risk for anxiety and stress-related disorders. Given that fear extinction promotes resilience, and that fear extinction principles are the Vega-Torres et. al., 3 foundation of psychological treatments for PTSD, understanding how obesogenic environments interact with the adolescent period to affect the acquisition and expression of fear extinction memories is of tremendous clinical relevance. KEYWORDS PTSD, diet-induced obesity, adolescence, anxiety, fear-potentiated startle, CRHR1 HIGHLIGHTS • Short-term WD consumption during adolescence impairs cued fear extinction memory retention in a fear-potentiated startle paradigm.• Short-term WD consumption during adolescence attenuates neuronal activation to electric footshock stress in the basomedial nuclei of the amygdala.• Short-term WD consumption increases CRHR1 mRNA levels in the medial prefrontal cortex.• Adult LEW rats exhibit increased basal HPA axis tone and heightened emotional reactivity to footshock stress relative to adolescent rats.

show abstract

“…Collectively, these studies suggest widespread sex differences in CRF receptors at the cellular level. However, systems level sex differences in CRF-mediated behaviors and activated circuitry have been largely underexplored because the majority of previous studies assessed systems level effects of CRF only in male rodents (but see, Toth et al, 2015; Toth et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Sex differences in corticotropin releasing factor-evoked behavior and activated networks

Wiersielis

Wicks

Simko

et al. 2016

Psychoneuroendocrinology

View full text Add to dashboard Cite

Hypersecretion of corticotropin releasing factor (CRF) is linked to the pathophysiology of major depression and post-traumatic stress disorder, disorders that are more common in women than men. Notably, preclinical studies have identified sex differences in CRF receptors that can increase neuronal sensitivity to CRF in female compared to male rodents. These cellular sex differences suggest that CRF may regulate brain circuits and behavior differently in males and females. To test this idea, we first evaluated whether there were sex differences in anxiety-related behaviors induced by the central infusion of CRF. High doses of CRF increased self-grooming more in female than in male rats, and the magnitude of this effect in females was greater when they were in the proestrous phase of their estrous cycle (higher ovarian hormones) compared to the diestrous phase (lower ovarian hormones), which suggests that ovarian hormones potentiate this anxiogenic effect of CRF. Brain regions associated with CRF-evoked self-grooming were identified by correlating a marker of neuronal activation, cFOS, with time spent grooming. In the infralimbic region, which is implicated in regulating anxiety, the correlation for CRF-induced neuronal activation and grooming was positive in proestrous females, but negative for males and diestrous females, indicating that ovarian hormones altered this relationship between neuronal activation and behavior. Because CRF regulates a number of regions that work together to coordinate different aspects of responding to stress, we then examined more broadly whether CRF-activated functional connectivity networks differed between males and cycling females. Interestingly, hormonal status altered correlations for CRF-induced neuronal activation between a variety of brain regions, but the most striking differences were found when comparing proestrous females to males, particularly when comparing neuronal activation between prefrontal cortical and other forebrain regions. These results suggest that ovarian hormones alter the way brain regions work together in response to CRF, which could drive different strategies for coping with stress in males versus females. These sex differences in stress responses could also help explain female vulnerability to psychiatric disorders characterized by CRF hypersecretion.

show abstract

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Cited by 34 publications

References 57 publications

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

Sex differences in corticotropin releasing factor-evoked behavior and activated networks

Contact Info

Product

Resources

About