Trust your gut, lest thou be anxious.

Can gut-residing bacteria influence mood and anxiety? And can targeting bacteria-produced metabolites reduce anxiety? Based on two Nature and Nature Medicine papers, the answers to these questions are likely yes. Needham, Campbell, and colleagues identified bacteria that enhance anxiety-like behaviors in mice and ways to mitigate anxiety in autistic patients.

A Thalamic Circuit Lights up Mood.

The contributions of areas downstream of retinal ganglion cells involved in the processing and regulation of mood remain largely unspecified. In this issue of Cell, Fernandez et al. (2018) identify a thalamic circuit within the perihabenular region (pHb) linking daily changes of light pattern to mood regulation.

An Amygdala-Hippocampus Subnetwork that Encodes Variation in Human Mood.

Human brain networks that encode variation in mood on naturalistic timescales remain largely unexplored. Here we combine multi-site, semi-chronic, intracranial electroencephalography recordings from the human limbic system with machine learning methods to discover a brain subnetwork that correlates with variation in individual subjects' self-reported mood over days. First we defined the subnetworks that influence intrinsic brain dynamics by identifying regions that showed coordinated changes in spectral coherence. The most common subnetwork, found in 13 of 21 subjects, was characterized by ß-frequency coherence (13-30 Hz) between the amygdala and hippocampus. Increased variability of this subnetwork correlated with worsening mood across these 13 subjects. Moreover, these subjects had significantly higher trait anxiety than the 8 of 21 for whom this amygdala-hippocampus subnetwork was absent. These results demonstrate an approach for extracting network-behavior relationships from complex datasets, and they reveal a conserved subnetwork associated with a psychological trait that significantly influences intrinsic brain dynamics and encodes fluctuations in mood.

Light Affects Mood and Learning through Distinct Retina-Brain Pathways.

Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.

The selection landscape and genetic legacy of ancient Eurasians.

The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation.

The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBα, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbα gene or pharmacological inhibition of REV-ERBα activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBα repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBα could be targeting in the treatment of circadian rhythm-related affective disorders.

Targeting thalamic circuits rescues motor and mood deficits in PD mice.

Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Disrupted routines anticipate musical exploration.

Understanding and predicting the emergence and evolution of cultural tastes manifested in consumption patterns is of central interest to social scientists, analysts of culture, and purveyors of content. Prior research suggests that taste preferences relate to personality traits, values, shifts in mood, and immigration destination. Understanding everyday patterns of listening and the function music plays in life has remained elusive, however, despite speculation that musical nostalgia may compensate for local disruption. Using more than one hundred million streams of four million songs by tens of thousands of international listeners from a global music service, we show that breaches in personal routine are systematically associated with personal musical exploration. As people visited new cities and countries, their preferences diversified, converging toward their travel destinations. As people experienced the very different disruptions associated with COVID-19 lockdowns, their preferences diversified further. Personal explorations did not tend to veer toward the global listening average, but away from it, toward distinctive regional musical content. Exposure to novel music explored during periods of routine disruption showed a persistent influence on listeners' future consumption patterns. Across all of these settings, musical preference reflected rather than compensated for life's surprises, leaving a lasting legacy on tastes. We explore the relationship between these findings and global patterns of behavior and cultural consumption.

Live music stimulates the affective brain and emotionally entrains listeners in real time.

Music is powerful in conveying emotions and triggering affective brain mechanisms. Affective brain responses in previous studies were however rather inconsistent, potentially because of the non-adaptive nature of recorded music used so far. Live music instead can be dynamic and adaptive and is often modulated in response to audience feedback to maximize emotional responses in listeners. Here, we introduce a setup for studying emotional responses to live music in a closed-loop neurofeedback setup. This setup linked live performances by musicians to neural processing in listeners, with listeners' amygdala activity was displayed to musicians in real time. Brain activity was measured using functional MRI, and especially amygdala activity was quantified in real time for the neurofeedback signal. Live pleasant and unpleasant piano music performed in response to amygdala neurofeedback from listeners was acoustically very different from comparable recorded music and elicited significantly higher and more consistent amygdala activity. Higher activity was also found in a broader neural network for emotion processing during live compared to recorded music. This finding included observations of the predominance for aversive coding in the ventral striatum while listening to unpleasant music, and involvement of the thalamic pulvinar nucleus, presumably for regulating attentional and cortical flow mechanisms. Live music also stimulated a dense functional neural network with the amygdala as a central node influencing other brain systems. Finally, only live music showed a strong and positive coupling between features of the musical performance and brain activity in listeners pointing to real-time and dynamic entrainment processes.

Psychosocial experiences are associated with human brain mitochondrial biology.

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes.

Brain representations of affective valence and intensity in sustained pleasure and pain.

Pleasure and pain are two fundamental, intertwined aspects of human emotions. Pleasurable sensations can reduce subjective feelings of pain and vice versa, and we often perceive the termination of pain as pleasant and the absence of pleasure as unpleasant. This implies the existence of brain systems that integrate them into modality-general representations of affective experiences. Here, we examined representations of affective valence and intensity in an functional MRI (fMRI) study (n = 58) of sustained pleasure and pain. We found that the distinct subpopulations of voxels within the ventromedial and lateral prefrontal cortices, the orbitofrontal cortex, the anterior insula, and the amygdala were involved in decoding affective valence versus intensity. Affective valence and intensity predictive models showed significant decoding performance in an independent test dataset (n = 62). These models were differentially connected to distinct large-scale brain networks-the intensity model to the ventral attention network and the valence model to the limbic and default mode networks. Overall, this study identified the brain representations of affective valence and intensity across pleasure and pain, promoting a systems-level understanding of human affective experiences.

Rats respond to aversive emotional arousal of human handlers with the activation of the basolateral and central amygdala.

Reading danger signals may save an animal's life, and learning about threats from others allows avoiding first-hand aversive and often fatal experiences. Fear expressed by other individuals, including those belonging to other species, may indicate the presence of a threat in the environment and is an important social cue. Humans and other animals respond to conspecifics' fear with increased activity of the amygdala, the brain structure crucial for detecting threats and mounting an appropriate response to them. It is unclear, however, whether the cross-species transmission of threat information involves similar mechanisms, e.g., whether animals respond to the aversively induced emotional arousal of humans with activation of fear-processing circuits in the brain. Here, we report that when rats interact with a human caregiver who had recently undergone fear conditioning, they show risk assessment behavior and enhanced amygdala activation. The amygdala response involves its two major parts, the basolateral and central, which detect a threat and orchestrate defensive responses. Further, we show that humans who learn about a threat by observing another aversively aroused human, similar to rats, activate the basolateral and centromedial parts of the amygdala. Our results demonstrate that rats detect the emotional arousal of recently aversively stimulated caregivers and suggest that cross-species social transmission of threat information may involve similar neural circuits in the amygdala as the within-species transmission.

Fear circuit-based neurobehavioral signatures mirror resilience to chronic social stress in mouse.

Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat-safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.

The impact of COVID-19 on a college freshman sample reveals genetic and nongenetic forms of susceptibility and resilience to stress.

Using a longitudinal approach, we sought to define the interplay between genetic and nongenetic factors in shaping vulnerability or resilience to COVID-19 pandemic stress, as indexed by the emergence of symptoms of depression and/or anxiety. University of Michigan freshmen were characterized at baseline using multiple psychological instruments. Subjects were genotyped, and a polygenic risk score for depression (MDD-PRS) was calculated. Daily physical activity and sleep were captured. Subjects were sampled at multiple time points throughout the freshman year on clinical rating scales, including GAD-7 and PHQ-9 for anxiety and depression, respectively. Two cohorts (2019 to 2021) were compared to a pre-COVID-19 cohort to assess the impact of the pandemic. Across cohorts, 26 to 40% of freshmen developed symptoms of anxiety or depression (N = 331). Depression symptoms significantly increased in the pandemic years and became more chronic, especially in females. Physical activity was reduced, and sleep was increased by the pandemic, and this correlated with the emergence of mood symptoms. While low MDD-PRS predicted lower risk for depression during a typical freshman year, this genetic advantage vanished during the pandemic. Indeed, females with lower genetic risk accounted for the majority of the pandemic-induced rise in depression. We developed a model that explained approximately half of the variance in follow-up depression scores based on psychological trait and state characteristics at baseline and contributed to resilience in genetically vulnerable subjects. We discuss the concept of multiple types of resilience, and the interplay between genetic, sex, and psychological factors in shaping the affective response to different types of stressors.

Threat Expectation Does Not Improve Perceptual Discrimination despite Causing Heightened Priority Processing in the Frontoparietal Network.

Threat cues have been widely shown to elicit increased sensory and attentional neural processing. However, whether this enhanced recruitment leads to measurable behavioral improvements in perception is still in question. Here, we adjudicate between two opposing theories: that threat cues do or do not enhance perceptual sensitivity. We created threat stimuli by pairing one direction of motion in a random dot kinematogram with an aversive sound. While in the MRI scanner, 46 subjects (both men and women) completed a cued (threat/safe/neutral) perceptual decision-making task where they indicated the perceived motion direction of each moving dot stimulus. We found strong evidence that threat cues did not increase perceptual sensitivity compared with safe and neutral cues. This lack of improvement in perceptual decision-making ability occurred despite the threat cue resulting in widespread increases in frontoparietal BOLD activity, as well as increased connectivity between the right insula and the frontoparietal network. These results call into question the intuitive claim that expectation automatically enhances our perception of threat and highlight the role of the frontoparietal network in prioritizing the processing of threat-related environmental cues.

Mood, the Circadian System, and Melanopsin Retinal Ganglion Cells.

The discovery of a third type of photoreceptors in the mammalian retina, intrinsically photosensitive retinal ganglion cells (ipRGCs), has had a revolutionary impact on chronobiology. We can now properly account for numerous non-vision-related functions of light, including its effect on the circadian system. Here, we give an overview of ipRGCs and their function as it relates specifically to mood and biological rhythms. Although circadian disruptions have been traditionally hypothesized to be the mediators of light's effects on mood, here we present an alternative model that dispenses with assumptions of causality between the two phenomena and explains mood regulation by light via another ipRGC-dependent mechanism.

Auditory aversive generalization learning prompts threat-specific changes in alpha-band activity.

Pairing a neutral stimulus with aversive outcomes prompts neurophysiological and autonomic changes in response to the conditioned stimulus (CS+), compared to cues that signal safety (CS-). One of these changes-selective amplitude reduction of parietal alpha-band oscillations-has been reliably linked to processing of visual CS+. It is, however, unclear to what extent auditory conditioned cues prompt similar changes, how these changes evolve as learning progresses, and how alpha reduction in the auditory domain generalizes to similar stimuli. To address these questions, 55 participants listened to three sine wave tones, with either the highest or lowest pitch (CS+) being associated with a noxious white noise burst. A threat-specific (CS+) reduction in occipital-parietal alpha-band power was observed similar to changes expected for visual stimuli. No evidence for aversive generalization to the tone most similar to the CS+ was observed in terms of alpha-band power changes, aversiveness ratings, or pupil dilation. By-trial analyses found that selective alpha-band changes continued to increase as aversive conditioning continued, beyond when participants reported awareness of the contingencies. The results support a theoretical model in which selective alpha power represents a cross-modal index of continuous aversive learning, accompanied by sustained sensory discrimination of conditioned threat from safety cues.

Neural patterns associated with mixed valence feelings differ in consistency and predictability throughout the brain.

Mixed feelings, the simultaneous presence of feelings with positive and negative valence, remain an understudied topic. They pose a specific set of challenges due to individual variation, and their investigation requires analtyic approaches focusing on individually self-reported states. We used functional magnetic resonance imaging (fMRI) to scan 27 subjects watching an animated short film chosen to induce bittersweet mixed feelings. The same subjects labeled when they had experienced positive, negative, and mixed feelings. Using hidden-Markov models, we found that various brain regions could predict the onsets of new feeling states as determined by self-report. The ability of the models to identify these transitions suggests that these states may exhibit unique and consistent neural signatures. We next used the subjects' self-reports to evaluate the spatiotemporal consistency of neural patterns for positive, negative, and mixed states. The insula had unique and consistent neural signatures for univalent states, but not for mixed valence states. The anterior cingulate and ventral medial prefrontal cortex had consistent neural signatures for both univalent and mixed states. This study is the first to demonstrate that subjectively reported changes in feelings induced by naturalistic stimuli can be predicted from fMRI and the first to show direct evidence for a neurally consistent representation of mixed feelings.

Individualized prediction of anxiety and depressive symptoms using gray matter volume in a non-clinical population.

Machine learning is an emerging tool in clinical psychology and neuroscience for the individualized prediction of psychiatric symptoms. However, its application in non-clinical populations is still in its infancy. Given the widespread morphological changes observed in psychiatric disorders, our study applies five supervised machine learning regression algorithms-ridge regression, support vector regression, partial least squares regression, least absolute shrinkage and selection operator regression, and Elastic-Net regression-to predict anxiety and depressive symptom scores. We base these predictions on the whole-brain gray matter volume in a large non-clinical sample (n = 425). Our results demonstrate that machine learning algorithms can effectively predict individual variability in anxiety and depressive symptoms, as measured by the Mood and Anxiety Symptoms Questionnaire. The most discriminative features contributing to the prediction models were primarily located in the prefrontal-parietal, temporal, visual, and sub-cortical regions (e.g. amygdala, hippocampus, and putamen). These regions showed distinct patterns for anxious arousal and high positive affect in three of the five models (partial least squares regression, support vector regression, and ridge regression). Importantly, these predictions were consistent across genders and robust to demographic variability (e.g. age, parental education, etc.). Our findings offer critical insights into the distinct brain morphological patterns underlying specific components of anxiety and depressive symptoms, supporting the existing tripartite theory from a neuroimaging perspective.

Neurocomputational evidence that conflicting prosocial motives guide distributive justice.

In the history of humanity, most conflicts within and between societies have originated from perceived inequality in resource distribution. How humans achieve and maintain distributive justice has therefore been an intensely studied issue. However, most research on the corresponding psychological processes has focused on inequality aversion and has been largely agnostic of other motives that may either align or oppose this behavioral tendency. Here we provide behavioral, computational, and neuroimaging evidence that distribution decisions are guided by three distinct motives-inequality aversion, harm aversion, and rank reversal aversion-that interact with each other and can also deter individuals from pursuing equality. At the neural level, we show that these three motives are encoded by separate neural systems, compete for representation in various brain areas processing equality and harm signals, and are integrated in the striatum, which functions as a crucial hub for translating the motives to behavior. Our findings provide a comprehensive framework for understanding the cognitive and biological processes by which multiple prosocial motives are coordinated in the brain to guide redistribution behaviors. This framework enhances our understanding of the brain mechanisms underlying equality-related behavior, suggests possible neural origins of individual differences in social preferences, and provides a new pathway to understand the cognitive and neural basis of clinical disorders with impaired social functions.