Individual differences in threat and reward neural circuitry activation: Testing dimensional models of early adversity, anxiety and depression.
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ABSTRACT:
SUBMITTER: Young KS
PROVIDER: S-EPMC9149108 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDepressive disorders are linked to dysfunction in reward-related behaviors and corticostriatal reward circuitry. Low-grade dysregulation of the immune system, e.g., elevations in plasma interleukin 6 (IL-6) and tumor necrosis factor α, have been thought to affect corticostriatal reward circuitry. Little is presently known about the degree to which these relationships generalize to patients with treatment-resistant depression (TRD) and/or childhood trauma history.MethodsResting-state functional connectivity between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) regions and plasma inflammatory marker levels (IL-6, tumor necrosis factor α) were measured in 74 adults with TRD. Regression analyses examined associations of inflammatory markers with VS-vmPFC connectivity and the moderating effects of self-reported childhood trauma on these associations, with exploratory analyses examining trauma subtypes.ResultsIL-6 was negatively associated with VS-vmPFC connectivity (specifically for the left VS). Childhood trauma moderated the relationships between tumor necrosis factor α and VS-vmPFC connectivity (specifically for the right VS) such that greater childhood trauma severity (particularly emotional neglect) was associated with stronger cytokine-connectivity associations.ConclusionsThis study independently extends previously reported associations between IL-6 and reductions in corticostriatal connectivity to a high-priority clinical population of treatment-seeking patients with TRD and further suggests that childhood trauma moderates specific associations between cytokines and corticostriatal connectivity. These findings suggest that associations between elevated plasma cytokine levels and reduced corticostriatal connectivity are a potential pathophysiological mechanism generalizable to patients with TRD and that such associations may be affected by trauma severity.
| S-EPMC8889578 | biostudies-literature
Project description:Disrupted circadian rhythms are a core feature of mood and anxiety disorders. Circadian rhythms are coordinated by a light-entrainable master clock located in the suprachiasmatic nucleus. Animal models of mood and anxiety disorders often exhibit blunted rhythms in locomotor activity and clock gene expression. Interestingly, the changes in circadian rhythms correlate with mood-related behaviours. Although animal models of depression and anxiety exhibit aberrant circadian rhythms in physiology and behavior, it is possible that the methodology being used to induce the behavioral phenotype (e.g., brain lesions, chronic stress, global gene deletion) affect behavior independently of circadian system. This study investigates the relationship between individual differences in circadian locomotor parameters and mood-related behaviors in healthy rats. The circadian phenotype of male Lewis rats was characterized by analyzing wheel running behavior under standard 12h:12h LD conditions, constant dark, constant light, and rate of re-entrainment to a phase advance. Rats were then tested on a battery of behavioral tests: activity box, restricted feeding, elevated plus maze, forced swim test, and fear conditioning. Under 12h:12h LD conditions, percent of daily activity in the light phase and variability in activity onset were associated with longer latency to immobility in the forced swim test. Variability in onset also correlated positively with anxiety-like behavior in the elevated plus maze. Rate of re-entrainment correlated positively with measures of anxiety in the activity box and elevated plus maze. Lastly, we found that free running period under constant dark was associated with anxiety-like behaviors in the activity box and elevated plus maze. Our results provide a previously uncharacterized relationship between circadian locomotor parameters and mood-related behaviors in healthy rats and provide a basis for future examination into circadian clock functioning and mood.
| S-EPMC5538649 | biostudies-other
Project description:Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.
| S-EPMC4843434 | biostudies-literature
Project description:Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genes SLC43A2 and TNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within the SLC17A3 promoter region and the SIAH3 gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions within C2CD2L and MRPL28 showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.
2021-01-31 | GSE164056 | GEO
Project description:Behavioural inhibition is a key anxiety-like behaviour in rodents and humans, distinct from avoidance of danger, and reduced by anxiolytic drugs. In some situations, it is not clear how behavioural inhibition minimises harm or maximises benefit for the agent, and can even appear counterproductive. Extant explanations of this phenomenon make use of descriptive models but do not provide a formal assessment of its adaptive value. This hampers a better understanding of the neural computations underlying anxiety behaviour. Here, we analyse a standard rodent anxiety model, the operant conflict test. We harvest Bayesian Decision Theory to show that behavioural inhibition normatively arises as cost-minimising strategy in temporally correlated environments. Importantly, only if behavioural inhibition is aimed at minimising cost, it depends on probability and magnitude of threat. Harnessing a virtual computer game, we test model predictions in four experiments with human participants. Humans exhibit behavioural inhibition with a strong linear dependence on threat probability and magnitude. Strikingly, inhibition occurs before motor execution and depends on the virtual environment, thus likely resulting from a neural optimisation process rather than a pre-programmed mechanism. Individual trait anxiety scores predict behavioural inhibition, underlining the validity of this anxiety model. These findings put anxiety behaviour into the context of cost-minimisation and optimal inference, and may ultimately pave the way towards a mechanistic understanding of the neural computations gone awry in human anxiety disorder.
| S-EPMC4674090 | biostudies-literature
Project description:Humans and animals show increased attention towards threatening stimuli when they are in increased states of anxiety. The few animal studies that have examined this phenomenon, known as attention bias, have applied environmental manipulations to induce anxiety but the effects of drug-induced anxiety levels on attention bias have not been demonstrated. Here, we present an attention bias test to identify high and low anxiety states in sheep using pharmacological manipulation. Increased anxiety was induced using 1-methyl-chlorophenylpiperazine (m-CPP) and decreased anxiety with diazepam, and then we examined the behaviour of sheep in response to the presence of a dog as a threat. Increased attention towards the threat and increased vigilance were shown in sheep that received the m-CPP and reduced in sheep receiving the diazepam. The modulated attention towards a threat displayed by the m-CPP and diazepam animals suggests that attention bias can assess different levels of anxiety in sheep. Measuring attention bias has the potential to improve animal welfare assessment protocols.
| S-EPMC4938034 | biostudies-literature
Project description:Social anxiety disorder (SAD) involves abnormalities in social motivation, which may be independent of well-documented differences in fear and arousal systems. Yet, the neurobiology underlying motivational difficulties in SAD is not well understood. The aim of the current study was to spatiotemporally dissociate reward circuitry dysfunction from alterations in fear and arousal-related neural activity during anticipation and notification of social and non-social reward and punishment. During fMRI acquisition, non-depressed adults with social anxiety disorder (SAD; N = 21) and age-, sex- and IQ-matched control subjects (N = 22) completed eight runs of an incentive delay task, alternating between social and monetary outcomes and interleaved in alternating order between gain and loss outcomes. Adults with SAD demonstrated significantly reduced neural activity in ventral striatum during the anticipation of positive but not negative social outcomes. No differences between the SAD and control groups were observed during anticipation of monetary gain or loss outcomes or during anticipation of negative social images. However, consistent with previous work, the SAD group demonstrated amygdala hyper-activity upon notification of negative social outcomes. Degraded anticipatory processing in bilateral ventral striatum in SAD was constrained exclusively to anticipation of positive social information and dissociable from the effects of negative social outcomes previously observed in the amygdala. Alterations in anticipation-related neural signals may represent a promising target for treatment that is not addressed by available evidence-based interventions, which focus primarily on fear extinction and habituation processes.
| S-EPMC5390704 | biostudies-literature
Project description:Depression is associated with alterations in corticostriatal reward circuitry. One pathophysiological pathway that may drive these changes is inflammation. Biomarkers of inflammation (for example, cytokines and C-reactive protein (CRP)) are reliably elevated in depressed patients. Moreover, administration of inflammatory stimuli reduces neural activity and dopamine release in reward-related brain regions in association with reduced motivation and anhedonia. Accordingly, we examined whether increased inflammation in depression affects corticostriatal reward circuitry to lead to deficits in motivation and goal-directed motor behavior. Resting-state functional magnetic resonance imaging was conducted on 48 medically stable, unmedicated outpatients with major depression. Whole-brain, voxel-wise functional connectivity was examined as a function of CRP using seeds for subdivisions of the ventral and dorsal striatum associated with motivation and motor control. Increased CRP was associated with decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) (corrected P<0.05), which in turn correlated with increased anhedonia (R=-0.47, P=0.001). Increased CRP similarly predicted decreased dorsal striatal to vmPFC and presupplementary motor area connectivity, which correlated with decreased motor speed (R=0.31 to 0.45, P<0.05) and increased psychomotor slowing (R=-0.35, P=0.015). Of note, mediation analyses revealed that these effects of CRP on connectivity mediated significant relationships between CRP and anhedonia and motor slowing. Finally, connectivity between striatum and vmPFC was associated with increased plasma interleukin (IL)-6, IL-1beta and IL-1 receptor antagonist (R=-0.33 to -0.36, P<0.05). These findings suggest that decreased corticostriatal connectivity may serve as a target for anti-inflammatory or pro-dopaminergic treatment strategies to improve motivational and motor deficits in patients with increased inflammation, including depression.
| S-EPMC4862934 | biostudies-literature
Project description:Understanding the brain circuitry that underlies reward is critical to improve treatment for many common health issues, including obesity, depression, and addiction. Here we focus on insights into the organization and function of reward circuitry and its synaptic and structural adaptations in response to cocaine exposure. While the importance of certain circuits, such as the mesocorticolimbic dopamine pathway, are well established in drug reward, recent studies using genetics-based tools have revealed functional changes throughout the reward circuitry that contribute to different facets of addiction, such as relapse and craving. The ability to observe and manipulate neuronal activity within specific cell types and circuits has led to new insight into not only the basic connections between brain regions, but also the molecular changes within these specific microcircuits, such as neurotrophic factor and GTPase signaling or ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function, that underlie synaptic and structural plasticity evoked by drugs of abuse. Excitingly, these insights from preclinical rodent work are now being translated into the clinic, where transcranial magnetic simulation and deep brain stimulation therapies are being piloted in human cocaine dependence. Thus, this review seeks to summarize current understanding of the major brain regions implicated in drug-related behaviors and the molecular mechanisms that contribute to altered connectivity between these regions, with the postulation that increased knowledge of the plasticity within the drug reward circuit will lead to new and improved treatments for addiction.
| S-EPMC5509624 | biostudies-literature
Project description:BackgroundThe sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of reward-dependent agency perception in an in-person and online cohort.MethodsThe in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort implementation for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency.ResultsAll subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive feedback-dependent agency compared to healthy controls. Finally, in our online sample, we found that higher self-agency following negative-loss feedback was associated with worse anhedonia symptoms.ConclusionTogether this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety.
| S-EPMC10016695 | biostudies-literature