Negative Feedback Sensitivity Research Articles

Crucial role of sea surface temperature warming patterns in near-term high-impact weather and climate projection

Recent studies indicate that virtually all global climate models (GCMs) have had difficulty simulating sea surface temperature (SST) trend patterns over the past four decades. GCMs produce enhanced warming in the eastern Equatorial Pacific (EPAC) and Southern Ocean (SO) warming, while observations show intensified warming in the Indo-Pacific Warm Pool (IPWP) and slight cooling in the eastern EPAC and SO. Using Geophysical Fluid Dynamics Laboratory’s latest higher resolution atmospheric model and coupled prediction system, we show the model biases in SST trend pattern have profound implications for near-term projections of high-impact storm statistics, including the frequency of atmospheric rivers (AR), tropical storms (TS) and mesoscale convection systems (MCS), as well as for hydrological and climate sensitivity. If the future SST warming pattern continues to resemble the observed pattern from the past few decades rather than the GCM simulated/predicted patterns, our results suggest (1) a drastically different future projection of high-impact storms and their associated hydroclimate changes, especially over the Western Hemisphere, (2) a stronger global hydrological sensitivity, and (3) substantially less global warming due to stronger negative feedback and lower climate sensitivity. The roles of SST trend patterns over the EPAC, IPWP, SO, and the North Atlantic tropical cyclone Main Development Region (AMDR) are isolated, quantified, and used to understand the simulated differences. Specifically, SST trend patterns in the EPAC and AMDR are crucial for modeled differences in AR and MCS frequency, while those in the IPWP and AMDR are essential for differences in TS frequency over the North Atlantic.

289 Postnatal Obesity Amplifies the Effect of Prenatal Testosterone Excess in Reducing the Progesterone Negative Feedback Sensitivity in First-Generation Ewes

Abstract Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women of reproductive age. Women with PCOS exhibit reduced sensitivity of the GnRH neuronal system to the inhibitory effects of both progesterone and estradiol. Additionally, obesity amplifies the severity of the PCOS phenotype. In sheep, testosterone (T) excess during gestational days (GD) 30-90 and 60-90 reduces neuroendocrine sensitivity to the progesterone negative feedback and recapitulates the PCOS phenotype. This study investigated the contribution of postnatal obesity in amplifying or mitigating the effects of mid-gestational T excess in disrupting the responsiveness to progesterone negative feedback in sheep. Suffolk ewes received T propionate (T; 100 mg i.m.) or corn oil (CO; vehicle) twice weekly from GD 60-90 (term = 147 d). At 5 mo of age, F1 T lambs were assigned randomly to either a maintenance (100% of NRC requirements) or overfed diet (130% of NRC requirements) and control lambs were fed the maintenance diet. At 22 mo of age, F1 ewes (n = 8/group) were synchronized with two injections of PGF2α 11 d apart. After the second PGF2α administration, blood samples were collected daily for 14 d and progesterone concentrations were determined via radioimmunoassay. Ewes that were confirmed to be cycling and in the mid-luteal phase based on progesterone concentrations (progesterone ≥ 1 ng/ml on day 10 and ≥ 0.5 ng/ml on days 8-9 and 11-12) were used for LH pulse characterization. On day 10 after PGF2α synchronization (mid-luteal phase), blood samples were collected every 15 min for 6 h to characterize LH pulsatile secretion via radioimmunoassay. Data were analyzed as one-way ANOVA with Tukey's HSD post-hoc analysis. Frequency of LH pulses was greater (P < 0.05) in T maintenance (3.75 ± 0.41 pulses/6h) and T overfed ewes (3.50 ± 0.34 pulses/6h) compared with controls (2.00 ± 0.37 pulses/6 h). Luteinizing hormone pulse amplitude was greater (P < 0.05) in T overfed (2.03 ± 0.15 ng/mL) compared with T maintenance (1.44 ± 0.17 ng/mL), but not to controls (1.74 ± 0.21 ng/mL). Also, average LH concentration was greater (P < 0.05) in T overfed (2.03 ± 0.24 ng/mL), but not T maintenance (1.31 ± 0.35 ng/mL), compared with controls (0.93 ± 0.30 ng/mLl). In conclusion, these findings demonstrate the activational role of postnatal obesity in amplifying prenatal T-induced alterations in tonic LH secretion during progesterone negative feedback. The activational effect of postnatal obesity in increasing LH secretion and consequently thecal androgen production is likely a contributor to the severity of hyperandrogenic status in women with PCOS. Research support: NIH-NICHD (R01HD099096).

Trait sensitivity to negative feedback determines the intensity of compulsive alcohol seeking and taking in male rats.

Background:Alcohol use disorder is one of the most common psychiatric disorders, and it is a leading cause of mortality worldwide. It has been demonstrated previously that people with alcohol use disorder are less sensitive to the negative outcomes of their actions and less able to use negative feedback to guide and adjust their ongoing behaviour. However, far less is known about the aberrant processing of negative feedback before the onset of alcohol use disorder. In this study, we investigated the theoretical claim that sensitivity to negative feedback — as a stable and enduring behavioural trait — can predict vulnerability to the development of compulsive alcohol consumption in rats.Methods:We trained and tested rats in a series of probabilistic reversal learning tests, and based on this “negative feedback sensitivity screening,” we classified each rat as more or less sensitive to negative feedback. Then, in the intermittent-access 2-bottle choice paradigm, we measured alcohol consumption in the animals classified above. In the next step, using the instrumental second-order chained schedule of alcohol reinforcement task, we examined the influence of sensitivity to negative feedback on the development of compulsive alcohol seeking behaviour. Finally, we measured how trait sensitivity to negative feedback affected the extinction and reinstatement of alcohol seeking after a period of abstinence.Results:Trait sensitivity to negative feedback predicted the vulnerability of rats to the development of compulsive alcohol seeking and consumption. We also found significant differences between the more sensitive and less sensitive groups in their propensity to extinguish alcohol seeking behaviours when the alcohol was no longer available.Limitations:The findings from our study did not answer the question of whether individual differences in sensitivity to negative feedback have a genetic basis or develop in response to postnatal experiences.Conclusion:The results of our study suggest that negative feedback sensitivity screening could be used to evaluate individual vulnerability to the development and maintenance of alcohol use disorder.

CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity.

Despite promising initial reports, corticotropin-releasing factor receptor type-1 (CRF-R1) antagonists have mostly failed to display efficacy in clinical trials for anxiety or depression. Rather than broad-spectrum antidepressant/anxiolytic-like drugs, they may represent an ‘antistress’ solution for single stressful situations or for patients with chronic stress conditions. However, the impact of prolonged CRF-R1 antagonist treatments on the hypothalamic–pituitary–adrenal (HPA) axis under chronic stress conditions remained to be characterized. Hence, our study investigated whether a chronic CRF-R1 antagonist (crinecerfont, formerly known as SSR125543, 20 mg·kg−1·day−1 ip, 5 weeks) would alter HPA axis basal circadian activity and negative feedback sensitivity in mice exposed to either control or chronic stress conditions (unpredictable chronic mild stress, UCMS, 7 weeks), through measures of fecal corticosterone metabolites, plasma corticosterone, and dexamethasone suppression test. Despite preserving HPA axis parameters in control non-stressed mice, the 5-week crinercerfont treatment improved the negative feedback sensitivity in chronically stressed mice, but paradoxically exacerbated their basal corticosterone secretion nearly all along the circadian cycle. The capacity of chronic CRF-R1 antagonists to improve the HPA negative feedback in UCMS argues in favor of a potential therapeutic benefit against stress-related conditions. However, the treatment-related overactivation of HPA circadian activity in UCMS raise questions about possible physiological outcomes with long-standing treatments under ongoing chronic stress.

An Advanced Transcriptional Response to Corticosterone After Single Prolonged Stress in Male Rats.

Stress-related neuropsychiatric disorders are often accompanied by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. In patients suffering from post-traumatic stress disorder (PTSD), increased sensitivity of glucocorticoid negative feedback has regularly been observed. The single prolonged stress (SPS) paradigm was developed to model increased negative feedback and other aspects of PTSD in rats. In this study, we used a setup that precluded the evaluation of negative feedback but rather served to test the hypothesis of the enhanced glucocorticoid receptor (GR) signaling in higher brain areas. We injected corticosterone or vehicle 7 days after SPS and evaluated plasma corticosterone, as well as gene expression in the dorsal hippocampus and amygdala. We observed a strikingly rapid change in the expression of established GR target genes (t = 30 min) only in the SPS group on exogenous corticosterone injection. Our results extend the notion of increased GR sensitivity in PTSD to include transcriptional responses in the hippocampus.

Neural signature of error processing in major depression

The clinical presentation of major depression (MD) is heterogenous and comprises various affective and cognitive symptoms including an increased sensitivity to errors. Various electrophysiological but only few functional magnetic resonance imaging (fMRI) studies investigated neural error processing in MD with inconsistent findings. Thus, reliable evidence regarding neural signatures of error processing in patients with current MD is limited despite its potential relevance as viable neurobiological marker of psychopathology. We therefore investigated a sample of 16 young adult female patients with current MD and 17 healthy controls (HC). During fMRI, we used an established Erikson-flanker Go/NoGo-paradigm and focused on neural alterations during errors of commission. In the absence of significant differences in rates of errors of commission in MD compared to HC, we observed significantly (p < 0.05, FWE-corrected on cluster level) enhanced neural activations of the dorsal anterior cingulate cortex (dACC) and the pre-supplementary motor area (pre-SMA) in MD relative to HC and thus, in brain regions consistently associated to neural error processing and corresponding behavioral adjustments. Considering comparable task performance, in particular similar commission error rates in MD and HC, our results support the evidence regarding an enhanced responsivity of neural error detection mechanisms in MD as a potential neural signature of increased negative feedback sensitivity as one of the core psychopathological features of this disorder.

Medial orbitofrontal cortex dopamine D1/D2 receptors differentially modulate distinct forms of probabilistic decision-making.

Efficient decision-making involves weighing the costs and benefits associated with different actions and outcomes to maximize long-term utility. The medial orbitofrontal cortex (mOFC) has been implicated in guiding choice in situations involving reward uncertainty, as inactivation in rats alters choice involving probabilistic rewards. The mOFC receives considerable dopaminergic input, yet how dopamine (DA) modulates mOFC function has been virtually unexplored. Here, we assessed how mOFC D1 and D2 receptors modulate two forms of reward seeking mediated by this region, probabilistic reversal learning and probabilistic discounting. Separate groups of well-trained rats received intra-mOFC microinfusions of selective D1 or D2 antagonists or agonists prior to task performance. mOFC D1 and D2 blockade had opposing effects on performance during probabilistic reversal learning and probabilistic discounting. D1 blockade impaired, while D2 blockade increased the number of reversals completed, both mediated by changes in errors and negative feedback sensitivity apparent during the initial discrimination of the task, which suggests changes in probabilistic reinforcement learning rather than flexibility. Similarly, D1 blockade reduced, while D2 blockade increased preference for larger/risky rewards. Excess D1 stimulation had no effect on either task, while excessive D2 stimulation impaired probabilistic reversal performance, and reduced both profitable risky choice and overall task engagement. These findings highlight a previously uncharacterized role for mOFC DA, showing that D1 and D2 receptors play dissociable and opposing roles in different forms of reward-related action selection. Elucidating how DA biases behavior in these situations will expand our understanding of the mechanisms regulating optimal and aberrant decision-making.

Central CRF and acute stress differentially modulate probabilistic reversal learning in male and female rats

Acute stress can have variable and sometimes sex-dependent effects on different executive functions, including cognitive flexibility, some of which may be mediated by increased corticotropin releasing factor (CRF). Previous studies on the effects of stress and CRF on cognitive flexibility have used procedures entailing deterministic rewards, yet how they may alter behavior when outcomes are probabilistic is unclear. The present study examined how acute stress and increased CRF activity alters probabilistic reversal learning (PRL) in male and female rats. Rats learned to discriminate between a ‘correct’ lever rewarded on 80 % of trials, and an “incorrect” lever delivering reward on 20 % of trials, with reward contingencies reversed after 8 consecutive correct choices. Separate groups received either intracerebroventricular infusions of CRF (3 μg) or restraint stress prior to a PRL session. Experiments examined how these manipulations affected learning when given prior to a one-day acquisition test or during performance in well-trained rats. Exogenous CRF, and to a lesser extent acute stress, impaired motivation across sexes, slowing deliberation times and increasing the number of trials omitted, particularly following a switch in reward contingencies. Neither manipulation significantly altered errors or reversal performance. However, increased CRF activity reduced negative feedback sensitivity. Across manipulations, females showed increased omissions and choice latencies, and were less sensitive to feedback than males. These results reveal the complexity with which stress, CRF, sex, and experience interact to alter aspects of motivation and probabilistic reinforcement learning and provide insight into how CRF activity may contribute to symptoms of stress-related disorders.

Modulation of cognitive flexibility by reward and punishment in BALB/cJ and BALB/cByJ mice

Learning from feedback is one of the key mechanisms within cognitive flexibility, which is needed to react swiftly to constantly changing environments. The motivation to change behavior is highly dependent on the expectancy of positive (reward) or negative (punishment) feedback. Individuals with conduct disorder (CD) with high callous unemotional traits show decreased sensitivity to negative feedback and increased reward seeking. Previous studies have modeled traits associated with CD (i.e. heightened aggression and anti-social behavior) in BALB/cJ mice (compared to the BALB/cByJ mouse as controls). Based on these findings, we hypothesized reduced negative feedback-related cognitive flexibility to be present in BALB/cJ mice.The effect of negative feedback and reward sensitivity on cognitive flexibility in BALB/cJ and BALB/cByJ mice was examined in a reversal learning paradigm. BALB/cJ mice were more flexible in the acquisition of new contingencies under rewarding conditions compared to BALB/cByJ mice, while the presence of an aversive punishing stimulus decreased their learning performance. Additionally, BALB/cJ mice needed more correction trials to reach the reversal learning criterion. This was accompanied by a higher rate of perseverance, which could represent impaired error detection. The addition of a second punishment enhanced punishment sensitivity in BALB/cJ mice. In contrast, the performance of the BALB/cByJ mice was not affected by additional negative feedback.Taken together, the BALB/cJ can be considered to be less sensitive to learn from negative feedback and therefore may be a useful model to further characterize molecular and neural underpinnings of callous unemotional traits in CD.

Dissociable and Paradoxical Roles of Rat Medial and Lateral Orbitofrontal Cortex in Visual Serial Reversal Learning.

ABSTRACTMuch evidence suggests that reversal learning is mediated by cortico-striatal circuitries with the orbitofrontal cortex (OFC) playing a prominent role. The OFC is a functionally heterogeneous region, but potential differential roles of lateral (lOFC) and medial (mOFC) portions in visual reversal learning have yet to be determined. We investigated the effects of pharmacological inactivation of mOFC and lOFC on a deterministic serial visual reversal learning task for rats. For reference, we also targeted other areas previously implicated in reversal learning: prelimbic (PrL) and infralimbic (IL) prefrontal cortex, and basolateral amygdala (BLA). Inactivating mOFC and lOFC produced opposite effects; lOFC impairing, and mOFC improving, performance in the early, perseverative phase specifically. Additionally, mOFC inactivation enhanced negative feedback sensitivity, while lOFC inactivation diminished feedback sensitivity in general. mOFC and lOFC inactivation also affected novel visual discrimination learning differently; lOFC inactivation paradoxically improved learning, and mOFC inactivation had no effect. We also observed dissociable roles of the OFC and the IL/PrL. Whereas the OFC inactivation affected only perseveration, IL/PrL inactivation improved learning overall. BLA inactivation did not affect perseveration, but improved the late phase of reversal learning. These results support opponent roles of the rodent mOFC and lOFC in deterministic visual reversal learning.

Dissociable Effects of Tryptophan Supplementation on Negative Feedback Sensitivity and Reversal Learning.

Serotonin has been shown to modulate probabilistic reversal learning (PRL) and negative feedback sensitivity (NFS) in both animal and human studies. Whilst these two measures are tightly coupled, some studies have suggested that these may be mediated by independent mechanisms; the former, representing perseveration and cognitive flexibility, and the latter measuring the ability to maintain a response set (win-stay) at the expense of lose-shift behavior when occasional misleading feedback has been presented. Here, we tested this hypothesis in 44 healthy participants who were administered tryptophan (22 placebo, 22 tryptophan), a precursor to serotonin. We found a dissociable effect of tryptophan supplementation on PRL/NFS. Specifically, tryptophan administration increased NFS compared to the placebo group but had no effect on PRL. We discuss these findings in relation to dosages and with a particular focus on the acute tryptophan depletion (ATD) procedures.

Corticosterone negative feedback is weaker during spring vs. autumn migration in a songbird (Junco hyemalis)

Birds face many challenges during seasonal migrations and must make important decisions about whether to accelerate, maintain, or delay travel to their final destinations. Spring migration is likely more challenging than autumn migration as spring journeys are completed more quickly and weather conditions are harsher during this time. These differential challenges may be reflected in the endocrine stress response, as the hypothalamic–pituitary-adrenal (HPA) axis is important for both daily energetic needs and coping with stressors. Indeed, most avian studies have found that both baseline and stress-induced corticosterone (CORT) levels tend to be higher in spring migrants than in autumn migrants. We hypothesized that CORT negative feedback efficacy also differs across the season, and is likely weaker during times of year when birds must be most sensitive to stressors. We therefore predicted that CORT negative feedback efficacy would be weaker during spring vs. autumn migration as spring migrants are more likely to encounter situations where they must decide whether to turn back or delay their travel. We examined male dark-eyed juncos (Junco hyemalis) during their spring and autumn stopovers in Fargo, ND, USA. Our prediction was met as we did find that negative feedback efficacy was weaker during spring vs. autumn, although we notably did not find any seasonal differences in baseline and stress-induced CORT. We also found that spring migrants were heavier, had greater subcutaneous fat stores, and had slightly higher hematocrit compared to autumn migrants. These findings suggest that CORT negative feedback sensitivity may help migrating birds effectively cope with the differential challenges of autumn and spring migration.

Control of parturition in ruminants

Parturition is a process which, when set into motion, occurs to completion. This review concerns the control of parturition in ruminants. Parturition is an endocrine event, dependent upon the activation of the fetal hypothalamus-pituitary-adrenal (HPA) axis. In sheep and other ruminants, increases in plasma concentrations of cortisol induce the activity of 17-hydroxylase and 17,20 lyase in the placenta, increasing the biosynthesis of oestrogen relative to progesterone. The increase in the so-called E:P ratio increases myometrial activity and culminates in labour and delivery. Much work has been done to identify the mechanism of the endogenous activation of the fetal HPA axis. Recent work suggests that production of prostanoids within the fetal brain influences fetal ACTH secretion, and that induction of prostanoid biosynthesis at the end of gestation might be important in the process of parturition. Oestrogen and androgens, secreted by the placenta at the end of gestation, augment activity of the fetal HPA axis by increasing fetal ACTH secretion and by decreasing negative feedback sensitivity to cortisol. Although significant progress has been made concerning the neuroendocrinology of parturition, many significant questions remain. Is parturition regulated or simply programmed? Is parturition the ultimate result of neuronal maturation within the fetal hypothalamus, or is there a complex interplay between the placenta and fetal hypothalamus? Answers to these and other important questions await further research, but may provide key information which will prove useful in understanding general principles of parturition in many mammalian species.

Hippocampal Interaction With Area 25, but not Area 32, Regulates Marmoset Approach-Avoidance Behavior.

Affective disorders are associated with increased sensitivity to negative feedback that influences approach–avoidance decision making. Although neuroimaging studies of these disorders reveal dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp), the causal involvement of these structures and their interaction in the primate brain is unknown. We therefore investigated the effects of localized pharmacological manipulations of areas 25 and 32 and/or the aHipp of the marmoset monkey on performance of an anxiolytic-sensitive instrumental decision-making task in which an approach–avoidance conflict is created by pairing a response with reward and punishment. During control infusions animals avoided punishment, but this bias was reduced by increasing glutamate release within the aHipp or area 32, and inactivation or 5-HT1a antagonism within area 25. Conversely, increasing glutamate release in area 25 enhanced punishment avoidance but, in contrast to previous reports, area 32 and aHipp inactivations had no effect. Simultaneous inactivation or 5-HT1a antagonism within area 25, but not area 32, abolished the reduced punishment avoidance seen after increasing aHipp glutamate. Besides providing causal evidence that these primate areas differentially regulate negative feedback sensitivity, this study links the decision-making deficits in affective disorders to aberrant aHipp–area 25 circuit activity.

Hypothalamic-pituitary-adrenal axis feedback sensitivity in different states of back pain

Pain normally signals a threat to bodily integrity and causes emotional distress. Acute pain serves a protective function, yet, when pain turns chronic, the protective function is lost. A chain of psychophysiological alterations including changes in the stress regulation system, apparent in dysfunctional activity and responsivity of the hypothalamic-pituitary-adrenal (HPA) axis, might be an important factor in this context. Moreover, maladaptive responses may be complicated by affective comorbid symptoms such as anxiety and depression, and alter nociceptive processing. However, the relationship among pain chronicity, stress regulation, and contributing components of comorbid symptomatology as well as somatosensory profiles has rarely been examined. In the present study, we obtained diurnal cortisol profiles at baseline and feedback regulation (following a dexamethasone suppression test (DST)) in subacute (SABP) and chronic (CBP) back pain patients and healthy control individuals (HC). We also assessed anxiety, depression and chronic stress levels and used quantitative sensory testing (QST) to detect sensory abnormalities. We found a hyper-suppression of cortisol following DST and thus enhanced negative stress feedback sensitivity in SABP compared to both CBP and HC. In SABP, DST-related cortisol levels were negatively associated with pain intensity, mediated by cold pain thresholds and anxiety. These data support a stress model of pain chronicity and suggest that stress responses might be indicators of individual vulnerability in the transition period of subacute pain.

Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task

RationaleDepression is characterized by an excessive attribution of value to negative feedback. This imbalance in feedback sensitivity can be measured using the probabilistic reversal-learning (PRL) task. This task was initially designed for clinical research, but introduction of its rodent version provides a new and much needed translational paradigm to evaluate potential novel antidepressants.ObjectivesIn the present study, we aimed at evaluating the effects of a compound showing clear antidepressant properties—ketamine (KET)—on the sensitivity of rats to positive and negative feedback in the PRL paradigm.MethodsWe trained healthy rats in an operant version of the PRL task. For successful completion of the task, subjects had to learn to ignore infrequent and misleading feedback, arising from the probabilistic (80:20) nature of the discrimination. Subsequently, we evaluated the effect of KET (5, 10, and 20 mg/kg) on feedback sensitivity 1, 24, and 48 h after administration.ResultsWe report that acute administration of the highest dose of KET (20 mg/kg) rapidly and persistently decreases the proportion of lose–shift responses made by rats after receiving negative feedback.ConclusionPresent results suggest that KET decreases negative feedback sensitivity and that changes in this basic neurocognitive function might be one of the factors responsible for its antidepressant action.

Study of positive and negative feedback sensitivity in psychosis using the Wisconsin Card Sorting Test

BackgroundSchizophrenia involves marked motivational and learning deficits that may reflect abnormalities in reward processing. The purpose of this study was to examine positive and negative feedback sensitivity in schizophrenia using computational modeling derived from the Wisconsin Card Sorting Test (WCST). We also aimed to explore feedback sensitivity in a sample with bipolar disorder. MethodsEighty-three individuals with schizophrenia and 27 with bipolar disorder were included. Demographic, clinical and cognitive outcomes, together with the WCST, were considered in both samples. Computational modeling was performed using the R syntax to calculate 3 parameters based on trial-by-trial execution on the WCST: reward sensitivity (R), punishment sensitivity (P), and choice consistency (D). The associations between outcome variables and the parameters were investigated. ResultsPositive and negative sensitivity showed deficits, but P parameter was clearly diminished in schizophrenia. Cognitive variables, age, and symptoms were associated with R, P, and D parameters in schizophrenia. The sample with bipolar disorder would show cognitive deficits and feedback abnormalities to a lesser extent than individuals with schizophrenia. ConclusionNegative feedback sensitivity demonstrated greater deficit in both samples. Idiosyncratic cognitive requirements in the WCST might introduce confusion when supposing model-free reinforcement learning. Negative symptoms of schizophrenia were related to lower feedback sensitivity and less goal-directed patterns of choice.

Interferon-alpha-induced inflammation is associated with reduced glucocorticoid negative feedback sensitivity and depression in patients with hepatitis C virus

Major medical illnesses are associated with increased risk for depression and alterations in hypothalamic–pituitary–adrenal (HPA) axis function. Pathophysiological processes such as inflammation that occur as a part of medical illnesses and their treatments have been shown to cause depressive symptoms, and may also affect the HPA axis. We previously reported that patients with hepatitis C virus chronically administered interferon (IFN)-alpha develop increased evening plasma cortisol concentrations and a flattened diurnal cortisol slope, which correlated with increased tumor necrosis factor (TNF) and its soluble receptor 2 (sTNFR2). Increased TNF and sTNFR2 were further correlated with depression and fatigue scores. The current study examined whether flattened cortisol slope might be secondary to reduced glucocorticoid receptor (GR) sensitivity, by measuring glucocorticoid negative feedback to dexamethasone (DEX) administration followed by corticotropin releasing hormone (CRH) challenge. In an exploratory analysis, 28 male and female patients with hepatitis C virus were studied at baseline (Visit 1) and after 12weeks (Visit 2) of either IFN-alpha plus ribavirin (n=17) or no treatment (n=11). Patients underwent dexamethasone DEX–CRH challenge, neuropsychiatric assessments, and measurement of plasma TNF and sTNFR2 during each visit. IFN-alpha did not affect neuroendocrine responses following CRH but did increase post-DEX cortisol, which was correlated with flattening of the diurnal cortisol slope (r=0.57, p=0.002) and with increased depression scores (r=0.38, p=0.047). Furthermore, the change in post-DEX cortisol was associated with IFN-alpha-induced increase in sTNFR2 (r=0.51, p=006), which was in turn correlated with depression (r=0.63, p<0.001) and fatigue (r=0.51, p=0.005) scores. Whereas the relationship between sTNFR2 and depression scores were independent of the change in post-DEX cortisol, the correlation between post-DEX cortisol and depression scores was not significant when controlling for sTNFR2. These findings suggest that inflammation induced in patients with hepatitis C virus during IFN-alpha therapy precipitates decreased GR sensitivity to lead to a flattened diurnal cortisol slope. Decreased GR sensitivity may in turn further increase inflammation and its ultimate effects on behavior. Treatments that target inflammation and/or GR sensitivity may reduce depressive symptoms associated with medical illnesses.

Noradrenergic modulation of risk/reward decision making.

Catecholamine transmission modulates numerous cognitive and reward-related processes that can subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to play an integral role in decisions involving reward uncertainty, yet there is a paucity of research investigating the contributions of noradrenaline (NA) transmission to these functions. The present study was designed to elucidate the contribution of NA to risk/reward decision making in rats, assessed with a probabilistic discounting task. We examined the effects of reducing noradrenergic transmission with the α2 agonist clonidine (10-100 μg/kg), and increasing activity at α2A receptor sites with the agonist guanfacine (0.1-1 mg/kg), the α2 antagonist yohimbine (1-3 mg/kg), and the noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting. Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. In well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward probability changed within a session by altering negative feedback sensitivity. In a subset of rats that displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased preference for the large/risky reward when this option had greater long-term utility. These data highlight an important and previously uncharacterized role for noradrenergic transmission in mediating different aspects of risk/reward decision making and mediating reward and negative feedback sensitivity.

Evaluating the stress response as a bioindicator of sub-lethal effects of crude oil exposure in wild house sparrows (Passer domesticus).

Petroleum can disrupt endocrine function in humans and wildlife, and interacts in particularly complex ways with the hypothalamus-pituitary-adrenal (HPA) axis, responsible for the release of the stress hormones corticosterone and cortisol (hereafter CORT). Ingested petroleum can act in an additive fashion with other stressors to cause increased mortality, but it is not clear exactly why—does petroleum disrupt feedback mechanisms, stress hormone production, or both? This laboratory study aimed to quantify the effects of ingested Gulf of Mexico crude oil on the physiological stress response of house sparrows (Passer domesticus). We examined baseline and stress-induced CORT, negative feedback, and adrenal sensitivity in house sparrows given a 1% oil or control diet (n = 12 in each group). We found that four weeks on a 1% oil diet did not alter baseline CORT titers or efficacy of negative feedback, but significantly reduced sparrows' ability to secrete CORT in response to a standardized stressor and adrenocorticotropin hormone injection, suggesting that oil damages the steroid-synthesizing cells of the adrenal. In another group of animals on the same 1% oil (n = 9) or control diets (n = 8), we examined concentrations of eight different blood chemistry parameters, and CORT in feathers grown before and during the feeding experiments as other potential biomarkers of oil exposure. None of the blood chemistry parameters differed between birds on the oil and control diets after two or four weeks of feeding, nor did feather CORT differ between the two groups. Overall, this study suggests that the response of CORT to stressors, but not baseline HPA function, may be a particularly sensitive bioindicator of sub-lethal chronic effects of crude oil exposure.