Neurobiology of Stress最新文献

Depression during pregnancy is detrimental for the wellbeing of the expectant mother and can exert long-term consequences on the offspring's development and mental health. In this context, both the gestational environment and the postpartum milieu may be negatively affected by the depressive pathology. It is, however, challenging to assess whether the contributions of prenatal and postnatal depression exposure are distinct, interactive, or cumulative, as it is unclear whether antenatal effects are due to direct effects on fetal development or because antenatal symptoms continue postnatally. Preclinical models have sought to answer this question by implementing stressors that induce a depressive-like state in the dams during pregnancy and studying the effects on the offspring. The aim of our present study was to disentangle the contribution of direct stress in utero from possible changes in maternal behavior in a novel model of preconceptional stress based on social isolation rearing (SIR). Using a cross-fostering paradigm in this model, we show that while SIR leads to subtle changes in maternal behavior, the behavioral changes observed in the offspring are driven by a complex interaction between sex, and prenatal and postnatal maternal factors. Indeed, male offspring are more sensitive to the prenatal environment, as demonstrated by behavioral and transcriptional changes driven by their birth mother, while females are likely affected by more complex interactions between the pre and the postpartum milieu, as suggested by the important impact of their surrogate foster mother. Taken together, our findings suggest that male and female offspring have different time-windows and behavioral domains of susceptibility to maternal preconceptional stress, and thus underscore the importance of including both sexes when investigating the mechanisms that mediate the negative consequences of exposure to such stressor.

In rodents, exposure to predator odors such as cat urine acts as a severe stressor that engages innate defensive behaviors critical for survival in the wild. The neurotransmitters norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and we have shown previously that dopamine β-hydroxylase knockout (Dbh −/−), which reduces NE and increases DA in mouse noradrenergic neurons, disrupts innate behaviors in response to mild stressors such as novelty. We examined the consequences of Dbh knockout on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls. Over the first 10 min of predator odor exposure, controls exhibited robust defensive burying behavior, whereas Dbh −/− mice showed high levels of grooming. Defensive burying was potently suppressed in controls by drugs that reduce NE transmission, while excessive grooming in Dbh −/− mice was blocked by DA receptor antagonism. In response to a cotton square scented with a novel “neutral” odor (lavender), most control mice shredded the material, built a nest, and fell asleep within 90 min. Dbh −/− mice failed to shred the lavender-scented nestlet, but still fell asleep. In contrast, controls sustained high levels of arousal throughout the predator odor test and did not build nests, while Dbh −/− mice were asleep by the 90-min time point, often in shredded bobcat urine-soaked nesting material. Compared with controls exposed to predator odor, Dbh −/− mice demonstrated decreased c-fos induction in the anterior cingulate cortex, lateral septum, periaqueductal gray, and bed nucleus of the stria terminalis, but increased c-fos in the locus coeruleus and medial amygdala. These data indicate that relative ratios of central NE and DA signaling coordinate the type and valence of responses to predator odor.

Background

Childhood abuse is an underappreciated source of stress, associated with adverse mental and physical health consequences. Childhood abuse has been directly associated with risky behavior thereby increasing the likelihood of alcohol misuse and risk of HIV infection, conditions associated with brain structural and functional deficits. Here, we examined the neural and behavioral correlates of childhood trauma history in alcohol use disorder (AUD), HIV infection (HIV), and their comorbidity (AUD+HIV).

Methods

Occurrence of childhood trauma was evaluated by retrospective interview. Cortical (frontal, temporal, parietal, and occipital), subcortical (hippocampus, amygdala), and regional frontal volumes were derived from structural MRI, adjusted for intracranial volume and age. Test scores of executive functioning, attention/working memory, verbal/visual learning, verbal/visual memory, and motor speed functional domains were standardized on age and education of a laboratory control group.

Results

History of childhood abuse was associated with smaller frontal lobe volumes regardless of diagnosis. For frontal subregional volumes, history of childhood abuse was selectively associated with smaller orbitofrontal and supplementary motor volumes. In participants with a child abuse history, poorer verbal/visual memory performance was associated with smaller orbitofrontal and frontal middle volumes, whereas in those without childhood abuse, poorer verbal/visual memory performance was associated with smaller orbitofrontal, frontal superior, and supplemental motor volumes.

Conclusions

Taken together, these results comport with and extend the findings that childhood abuse is associated with brain and behavioral sequelae in AUD, HIV, and AUD+HIV comorbidity. Further, these findings suggest that sequelae of abuse in childhood may be best conceptualized as a spectrum disorder as significant deficits may be present in those who may not meet criteria for a formal trauma-related diagnosis yet may be suffering enduring stress effects on brain structural and functional health.

Background

Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [¹⁸F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls.

Methods

We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [¹⁸F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [¹⁸F]AS2471907 volume of distribution (V_T; mL/cm³). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate.

Results

Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [¹⁸F]AS2471907 V_T was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [¹⁸F]AS2471907 V_T was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02).

Conclusions

This is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN augments maternal behaviors and promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.

Synaptic plasticity in the amygdala plays an essential role in the formation and inhibition of fear memory; however, this plasticity has mainly been studied in the lateral amygdala, making it largely uninvestigated in other subnuclei. Here, we investigated long-term potentiation (LTP) and long-term depression (LTD) in the basolateral amygdala (BLA) to the medial division of the central amygdala (CEm) synapses of juvenile C57BL/6N (B6) and 129S1/SvImJ (S1) mice. We found that in naïve B6 and S1 mice, LTP was not induced at the BLA to CEm synapses, whereas fear conditioning lowered the threshold for LTP induction in these synapses of both B6 and S1 mice. Interestingly, fear extinction disrupted the induction of LTP at the BLA to CEm synapses of B6 mice, whereas LTP was left intact in S1 mice. Both low-frequency stimulation (LFS) and modest LFS (mLFS) induced LTD in naïve B6 and S1 mice, suggesting that the BLA to CEm synapses express bidirectional plasticity. Fear conditioning disrupted both types of LTD induction selectively in S1 mice and LFS-LTD, presumably NMDAR-dependent LTD was partially recovered by fear extinction. However, mLFS-LTD which has been known to be endocannabinoid receptor 1 (CB1R)-dependent was not induced after fear extinction in both mouse strains. Our observations suggest that fear conditioning enhances LTP while fear extinction diminishes LTP at the BLA to the CEm synapses of B6 mice with successful extinction. Considering that S1 mice showed strong fear conditioning and impaired extinction, strong fear conditioning in the S1 strain may be related to disrupted LTD, and impaired extinction may be due to constant LTP and weak LFS-LTD at the BLA to CEm synapses. Our study contributes to the further understanding of the dynamics of synaptic potentiation and depression between the subnuclei of the amygdala in juvenile mice after fear conditioning and extinction.

Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Alzheimer's Disease and related dementias (ADRD) are an increasing threat to global health initiatives. Efforts to prevent the development of ADRD require understanding behaviors that increase and decrease risk of neurodegeneration and cognitive decline, in addition to uncovering the underlying biological mechanisms behind these effects. Stress exposure and alcohol consumption have both been associated with increased risk for ADRD in human populations. However, our ability to understand causal mechanisms of ADRD requires substantial preclinical research. In this review, we summarize existing human and animal research investigating the connections between lifetime stress and alcohol exposures and ADRD.

Chronic stress and alcohol (ethanol) use are highly interrelated and can change an individual’s behavior through molecular adaptations that do not change the DNA sequence, but instead change gene expression. A recent wealth of research has found that these nongenomic changes can be transmitted across generations, which could partially account for the “missing heritability” observed in genome-wide association studies of alcohol use disorder and other stress-related neuropsychiatric disorders. In this review, we summarize the molecular and behavioral outcomes of nongenomic inheritance of chronic stress and ethanol exposure and the germline mechanisms that could give rise to this heritability. In doing so, we outline the need for further research to: (1) Investigate individual germline mechanisms of paternal, maternal, and biparental nongenomic chronic stress- and ethanol-related inheritance; (2) Synthesize and dissect cross-generational chronic stress and ethanol exposure; (3) Determine cross-generational molecular outcomes of preconception ethanol exposure that contribute to alcohol-related disease risk, using cancer as an example. A detailed understanding of the cross-generational nongenomic effects of stress and/or ethanol will yield novel insight into the impact of ancestral perturbations on disease risk across generations and uncover actionable targets to improve human health.

Social isolation during adolescence can increase the risk of mental disorders. Epigenetic changes induced by chronic social isolation may serve as a mechanism underlying emotional disturbances. To test this, we exposed female mice to a post-weaning 6-week social isolation (SI) stress. We found the significantly increased methylation of histone H3 at lysine 9 (H3K9), a histone mark linked to gene repression, as well as the increased H3K9 methyltransferases SUV39H1 and SETDB1, in prefrontal cortex (PFC) of SI females. To find out potential downstream genes affected by this epigenetic alteration, we examined genes linked to neuronal and synaptic functions. Activity-dependent genes, including Arc, c-Fos and Npas4, were significantly reduced in PFC of SI females, correlated with the increased H3K9me2 occupancy around Arc enhancer. Treatment of SI females with UNC0642, a selective inhibitor of H3K9 methylation, significantly attenuated the anxiety-like behavior and elevated Arc expression. These results have revealed an epigenetic mechanism and intervention avenue for anxiety induced by chronic social isolation.