Neurobiology of Stress最新文献

{"title":"Isolation of the differential effects of chronic and acute stress in a manner that is not confounded by stress severity","authors":"Michael A. Conoscenti ,&nbsp;Daniel B. Weatherill ,&nbsp;Yuqing Huang ,&nbsp;Raphael Tordjman ,&nbsp;Michael S. Fanselow","doi":"10.1016/j.ynstr.2024.100616","DOIUrl":"https://doi.org/10.1016/j.ynstr.2024.100616","url":null,"abstract":"<div><p>Firm conclusions regarding the differential effects of the maladaptive consequences of acute versus chronic stress on the etiology and symptomatology of stress disorders await a model that isolates chronicity as a variable for studying the differential effects of acute versus chronic stress. This is because most previous studies have confounded chronicity with the total amount of stress. Here, we have modified the stress-enhanced fear learning (SEFL) protocol, which models some aspects of posttraumatic stress disorder (PTSD) following an acute stressor, to create a chronic variant that does not have this confound. Comparing results from this new protocol to the acute protocol, we found that chronic stress further potentiates enhanced fear-learning beyond the nonassociative enhancement induced by acute stress. This additional component is not observed when the unconditional stimulus (US) used during subsequent fear learning is distinct from the US used as the stressor, and is enhanced when glucose is administered following stressor exposure, suggesting that it is associative in nature. Furthermore, extinction of stressor-context fear blocks this additional associative component of SEFL as well as reinstatement of generalized fear, suggesting reinstatement of generalized fear may underlie this additional SEFL component.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"30 ","pages":"Article 100616"},"PeriodicalIF":5.0,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000122/pdfft?md5=bfdd912f53a37b524afc51a614eff203&pid=1-s2.0-S2352289524000122-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139744207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating and fragmenting memories under stress and alcohol","authors":"Krystian B. Loetscher ,&nbsp;Elizabeth V. Goldfarb","doi":"10.1016/j.ynstr.2024.100615","DOIUrl":"https://doi.org/10.1016/j.ynstr.2024.100615","url":null,"abstract":"<div><p>Stress can powerfully influence the way we form memories, particularly the extent to which they are integrated or situated within an underlying spatiotemporal and broader knowledge architecture. These different representations in turn have significant consequences for the way we use these memories to guide later behavior. Puzzlingly, although stress has historically been argued to promote fragmentation, leading to disjoint memory representations, more recent work suggests that stress can also facilitate memory binding and integration. Understanding the circumstances under which stress fosters integration will be key to resolving this discrepancy and unpacking the mechanisms by which stress can shape later behavior. Here, we examine memory integration at multiple levels: linking together the content of an individual experience, threading associations between related but distinct events, and binding an experience into a pre-existing schema or sense of causal structure. We discuss neural and cognitive mechanisms underlying each form of integration as well as findings regarding how stress, aversive learning, and negative affect can modulate each. In this analysis, we uncover that stress can indeed promote each level of integration. We also show how memory integration may apply to understanding effects of alcohol, highlighting extant clinical and preclinical findings and opportunities for further investigation. Finally, we consider the implications of integration and fragmentation for later memory-guided behavior, and the importance of understanding which type of memory representation is potentiated in order to design appropriate interventions.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"30 ","pages":"Article 100615"},"PeriodicalIF":5.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000110/pdfft?md5=9e42d24cee79dcb3f01b797c025c5c18&pid=1-s2.0-S2352289524000110-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139718726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does sleep promote adaptation to acute stress: An experimental study","authors":"Emil Hein ,&nbsp;Risto Halonen ,&nbsp;Thomas Wolbers ,&nbsp;Tommi Makkonen ,&nbsp;Markus Kyllönen ,&nbsp;Liisa Kuula ,&nbsp;Ilmari Kurki ,&nbsp;Philipp Stepnicka ,&nbsp;Anu-Katriina Pesonen","doi":"10.1016/j.ynstr.2024.100613","DOIUrl":"10.1016/j.ynstr.2024.100613","url":null,"abstract":"<div><h3>Objectives</h3><p>Evidence of the impact of chronic stress on sleep is abundant, yet experimental sleep studies with a focus on acute stress are scarce and the results are mixed. Our study aimed to fill this gap by experimentally investigating the effects of pre-sleep social stress on sleep dynamics during the subsequent night, as measured with polysomnography (PSG).</p></div><div><h3>Methods</h3><p>Thirty-four healthy individuals (65% females, M_age = 25.76 years SD = 3.35) underwent a stress-inducing (SC) or neutral control condition (CC) in virtual reality (VR). We used overnight EEG measurements to analyze the basic sleep parameters and power spectral density (PSD) across the sleep cycles, and measured heart rate and its variability (HRV), skin electrodermal activity (EDA), and salivary cortisol to capture physiological arousal during the VR task and the pre-sleep period.</p></div><div><h3>Results</h3><p>Following acute stress (SC), the amount of slow-wave sleep (SWS) was higher and N2 sleep lower relative to CC, specifically in the first sleep cycle. In SC, PSD was elevated in the beta-low (16–24 Hz) and beta-high (25–35 Hz) frequency ranges during both stages N2 and SWS over the entire night.</p></div><div><h3>Conclusions</h3><p>Sleep promoted adaptation to acute social stress by a longer duration of SWS in the subsequent sleep period, especially in early sleep. A similar homeostatic effect towards restorative sleep is well-evidenced in animal model stress studies but has not been previously reported in experimental human studies. Whether the high-frequency PSD activity during stages N2 and SWS also serves in the resolution of transient stress, remains open.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100613"},"PeriodicalIF":5.0,"publicationDate":"2024-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000092/pdfft?md5=75e8e488b45b3696b26a52389004630c&pid=1-s2.0-S2352289524000092-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal and postnatal influences on behavioral development in a mouse model of preconceptional stress","authors":"Joseph Scarborough ,&nbsp;Monica Iachizzi ,&nbsp;Sina M. Schalbetter ,&nbsp;Flavia S. Müller ,&nbsp;Ulrike Weber-Stadlbauer ,&nbsp;Juliet Richetto","doi":"10.1016/j.ynstr.2024.100614","DOIUrl":"10.1016/j.ynstr.2024.100614","url":null,"abstract":"<div><p>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 <em>in utero</em> 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.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100614"},"PeriodicalIF":5.0,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000109/pdfft?md5=b97bf3fea3070183621d3222eeb88a1a&pid=1-s2.0-S2352289524000109-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139667489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice","authors":"Joyce Liu ,&nbsp;Daniel J. Lustberg ,&nbsp;Abigail Galvez,&nbsp;L. Cameron Liles,&nbsp;Katharine E. McCann,&nbsp;David Weinshenker","doi":"10.1016/j.ynstr.2024.100612","DOIUrl":"10.1016/j.ynstr.2024.100612","url":null,"abstract":"<div><p>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 (<em>Dbh −/−)</em>, 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 <em>Dbh</em> 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 <em>Dbh −/−</em> mice showed high levels of grooming. Defensive burying was potently suppressed in controls by drugs that reduce NE transmission, while excessive grooming in <em>Dbh −/−</em> 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. <em>Dbh −/−</em> 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 <em>Dbh −/−</em> mice were asleep by the 90-min time point, often in shredded bobcat urine-soaked nesting material. Compared with controls exposed to predator odor, <em>Dbh −/−</em> 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.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100612"},"PeriodicalIF":5.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000080/pdfft?md5=fa3fb26776e68b02a3ca666fa926db0c&pid=1-s2.0-S2352289524000080-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139667483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frontal cortical volume deficits as enduring evidence of childhood abuse in community adults with AUD and HIV infection comorbidity","authors":"Stephanie A. Sassoon ,&nbsp;Rosemary Fama ,&nbsp;Kilian M. Pohl ,&nbsp;Adolf Pfefferbaum ,&nbsp;Edith V. Sullivan","doi":"10.1016/j.ynstr.2024.100608","DOIUrl":"10.1016/j.ynstr.2024.100608","url":null,"abstract":"<div><h3>Background</h3><p>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).</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusions</h3><p>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.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100608"},"PeriodicalIF":5.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000043/pdfft?md5=7ff3b4d56cbe3ab090853e523d58eebc&pid=1-s2.0-S2352289524000043-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139523287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging a putative marker of brain cortisol regulation in alcohol use disorder","authors":"Terril L. Verplaetse ,&nbsp;Ansel T. Hillmer ,&nbsp;Shivani Bhatt ,&nbsp;Aleksandra Rusowicz ,&nbsp;Songye Li ,&nbsp;Nabeel Nabulsi ,&nbsp;David Matuskey ,&nbsp;Yiyun Huang ,&nbsp;Sherry A. McKee ,&nbsp;Kelly P. Cosgrove","doi":"10.1016/j.ynstr.2024.100609","DOIUrl":"10.1016/j.ynstr.2024.100609","url":null,"abstract":"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>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 (<em>V</em>_T; mL/cm³). <em>A priori</em> regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate.</p></div><div><h3>Results</h3><p>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 <em>V</em>_T was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (<em>p</em> &lt; 0.05). In AUD, vmPFC [¹⁸F]AS2471907 <em>V</em>_T was associated with drinks per week (r = 0.81, <em>p</em> = 0.01) and quantity per drinking episode (r = 0.75, <em>p</em> = 0.02).</p></div><div><h3>Conclusions</h3><p>This is the first <em>in vivo</em> 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.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100609"},"PeriodicalIF":5.0,"publicationDate":"2024-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000055/pdfft?md5=2ad0ca0c2b05a36a7d0a86365f2daa6f&pid=1-s2.0-S2352289524000055-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139539676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early resource scarcity causes cortical astrocyte enlargement and sex-specific changes in the orbitofrontal cortex transcriptome in adult rats","authors":"Claire Deckers ,&nbsp;Reza Karbalaei ,&nbsp;Nylah A. Miles ,&nbsp;Eden V. Harder ,&nbsp;Emily Witt ,&nbsp;Erin P. Harris ,&nbsp;Kathryn Reissner ,&nbsp;Mathieu E. Wimmer ,&nbsp;Debra A. Bangasser","doi":"10.1016/j.ynstr.2024.100607","DOIUrl":"10.1016/j.ynstr.2024.100607","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100607"},"PeriodicalIF":5.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000031/pdfft?md5=e66276def98c8a6053aa3e3c05353b8f&pid=1-s2.0-S2352289524000031-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139469195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fear conditioning and extinction distinctively alter bidirectional synaptic plasticity within the amygdala of an animal model of post-traumatic stress disorder","authors":"Kwanghoon Park,&nbsp;Hoyong Park,&nbsp;ChiHye Chung","doi":"10.1016/j.ynstr.2024.100606","DOIUrl":"10.1016/j.ynstr.2024.100606","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100606"},"PeriodicalIF":5.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S235228952400002X/pdfft?md5=efc33c66b1b819d4579e8e5cb8495837&pid=1-s2.0-S235228952400002X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139437866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A reverse translational study of PPAR-α agonist efficacy in human and rodent models relevant to alcohol use disorder","authors":"Barbara J. Mason ,&nbsp;David Estey ,&nbsp;Amanda Roberts ,&nbsp;Giordano de Guglielmo ,&nbsp;Olivier George ,&nbsp;John Light ,&nbsp;Mike Stoolmiller ,&nbsp;Susan Quello ,&nbsp;Michael Skinner ,&nbsp;Farhad Shadan ,&nbsp;Adnan Begovic ,&nbsp;Mark C. Kyle ,&nbsp;R. Adron Harris","doi":"10.1016/j.ynstr.2023.100604","DOIUrl":"10.1016/j.ynstr.2023.100604","url":null,"abstract":"<div><p>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 <em>in vivo</em> 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.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100604"},"PeriodicalIF":5.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289523000929/pdfft?md5=93cc59a2d8f4ecbc4279f315ca745ee6&pid=1-s2.0-S2352289523000929-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139105554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}