Role of the prefrontal cortical protease TACE/ADAM17 in neurobehavioral responses to chronic stress during adolescence.

INTRODUCTION: Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses. METHODS: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma. RESULTS: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle). CONCLUSION: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress.

Prefrontal cortical protease TACE/ADAM17 is involved in neuroinflammation and stress-related eating alterations.

Childhood traumatic stress profoundly affects prefrontal cortical networks regulating top-down control of eating and body weight. However, the neurobiological mechanisms contributing to trauma-induced aberrant eating behaviors remain largely unknown. Traumatic stress influences brain immune responses, which may, in turn, disrupt prefrontal cortical networks and behaviors. The tumor necrosis factor alpha-converting enzyme / a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and neuroinflammation. This study aimed to determine the role of TACE/ADAM17 on traumatic stress-induced disruption of eating patterns. We demonstrate a novel mechanistic connection between prefrontal cortical TACE/ADAM17 and trauma-induced eating behaviors. Fifty-two (52) adolescent Lewis rats (postnatal day, PND, 15) were injected intracerebrally either with a novel Accell™ SMARTpool ADAM17 siRNA or a corresponding siRNA vehicle. The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Observation cages were used to monitor ethological behaviors in a more naturalistic environment over long periods. We found that traumatic stress blunts startle reactivity and alter eating behaviors (increased intake and disrupted eating patterns). We also found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited decreased eating and increased grooming behaviors compared to controls. These changes were associated with decreased AIF-1 expression (a typical marker of microglia and neuroinflammation). This study demonstrates that prefrontal cortical TACE/ADAM17 is involved in neuroinflammation and may play essential roles in regulating feeding patterns under stress conditions. TACE/ADAM17 represents a promising target to ameliorate inflammation-induced brain and behavior alterations.

Short-term exposure to an obesogenic diet during adolescence elicits anxiety-related behavior and neuroinflammation: modulatory effects of exogenous neuregulin-1.

Childhood obesity leads to hippocampal atrophy and altered cognition. However, the molecular mechanisms underlying these impairments are poorly understood. The neurotrophic factor neuregulin-1 (NRG1) and its cognate ErbB4 receptor play critical roles in hippocampal maturation and function. This study aimed to determine whether exogenous NRG1 administration reduces hippocampal abnormalities and neuroinflammation in rats exposed to an obesogenic Western-like diet (WD). Lewis rats were randomly divided into four groups (12 rats/group): (1) control diet+vehicle (CDV); (2) CD + NRG1 (CDN) (daily intraperitoneal injections: 5 µg/kg/day; between postnatal day, PND 21-PND 41); (3) WD + VEH (WDV); (4) WD + NRG1 (WDN). Neurobehavioral assessments were performed at PND 43-49. Brains were harvested for MRI and molecular analyses at PND 49. We found that NRG1 administration reduced hippocampal volume (7%) and attenuated hippocampal-dependent cued fear conditioning in CD rats (56%). NRG1 administration reduced PSD-95 protein expression (30%) and selectively reduced hippocampal cytokine levels (IL-33, GM-CSF, CCL-2, IFN-γ) while significantly impacting microglia morphology (increased span ratio and reduced circularity). WD rats exhibited reduced right hippocampal volume (7%), altered microglia morphology (reduced density and increased lacunarity), and increased levels of cytokines implicated in neuroinflammation (IL-1α, TNF-α, IL-6). Notably, NRG1 synergized with the WD to increase hippocampal ErbB4 phosphorylation and the tumor necrosis alpha converting enzyme (TACE/ADAM17) protein levels. Although the results did not provide sufficient evidence to conclude that exogenous NRG1 administration is beneficial to alleviate obesity-related outcomes in adolescent rats, we identified a potential novel interaction between obesogenic diet exposure and TACE/ADAM17-NRG1-ErbB4 signaling during hippocampal maturation. Our results indicate that supraoptimal ErbB4 activities may contribute to the abnormal hippocampal structure and cognitive vulnerabilities observed in obese individuals.

Oxidative stress and neuroinflammation in a rat model of co-morbid obesity and psychogenic stress.

BACKGROUND: There is growing recognition for a reciprocal, bidirectional link between anxiety disorders and obesity. Although the mechanisms linking obesity and anxiety remain speculative, this bidirectionality suggests shared pathophysiological processes. Neuroinflammation and oxidative damage are implicated in both pathological anxiety and obesity. This study investigates the relative contribution of comorbid diet-induced obesity and stress-induced anxiety to neuroinflammation and oxidative stress. METHODS: Thirty-six (36) male Lewis rats were divided into four groups based on diet type and stress exposure: 1) control diet unexposed (CDU) and 2) exposed (CDE), 3) Western-like high-saturated fat diet unexposed (WDU) and 4) exposed (WDE). Neurobehavioral tests were performed to assess anxiety-like behaviors. The catalytic concentrations of glutathione peroxidase and reductase were measured from plasma samples, and neuroinflammatory/oxidative stress biomarkers were measured from brain samples using Western blot. Correlations between behavioral phenotypes and biomarkers were assessed with Pearson's correlation procedures. RESULTS: We found that WDE rats exhibited markedly increased levels of glial fibrillary acidic protein (185 %), catalase protein (215 %), and glutathione reductase (GSHR) enzymatic activity (418 %) relative to CDU rats. Interestingly, the brain protein levels of glutathione peroxidase (GPx) and catalase were positively associated with body weight and behavioral indices of anxiety. CONCLUSIONS: Together, our results support a role for neuroinflammation and oxidative stress in heightened emotional reactivity to obesogenic environments and psychogenic stress. Uncovering adaptive responses to obesogenic environments characterized by high access to high-saturated fat/high-sugar diets and toxic stress has the potential to strongly impact how we treat psychiatric disorders in at-risk populations.

Adolescent Vulnerability to Heightened Emotional Reactivity and Anxiety After Brief Exposure to an Obesogenic Diet.

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 1 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 1-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 messenger RNA (mRNA) levels in the rats that consumed the WD. CONCLUSION: 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 foundation of psychological treatments for posttraumatic stress disorder (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.