Prevalence of Substance use Among Depressed Female Patients

Depressive disorder is a common mental disorder and one of the leading causes of disability around the globe. It is characterized by depressed mood, lack of enjoyment, decreased activity, negative thoughts and reduced concentration for at least two weeks. Globally 350 million people are suffering from depression and 18.34 million people from Southeast Asia alone. Major depressive disorder is growing in overall disease burden around the world. It is predicted to be the leading cause of disease burden by 2030, and it is already the leading cause in women worldwide. Depression affects the prefrontal cortex, cingulate gyrus, amygdala, hippocampus, thalamus and hypothalamus. These brain regions are involved in the regulation of motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed people.

Aversive stimuli bias corticothalamic responses to motivationally significant cues

Making predictions about future rewards or punishments is fundamental to adaptive behavior. These processes are influenced by prior experience. For example, prior exposure to aversive stimuli or stressors changes behavioral responses to negative- and positive-value predictive cues. Here, we demonstrate a role for medial prefrontal cortex (mPFC) neurons projecting to the paraventricular nucleus of the thalamus (PVT; mPFC→PVT) in this process. We found that a history of aversive stimuli negatively biased behavioral responses to motivationally relevant cues in mice and that this negative bias was associated with hyperactivity in mPFC→PVT neurons during exposure to those cues. Furthermore, artificially mimicking this hyperactive response with selective optogenetic excitation of the same pathway recapitulated the negative behavioral bias induced by aversive stimuli, whereas optogenetic inactivation of mPFC→PVT neurons prevented the development of the negative bias. Together, our results highlight how information flow within the mPFC→PVT circuit is critical for making predictions about motivationally-relevant outcomes as a function of prior experience.

Aggressive behavior: from theory to practice

The problem of aggressive behaviour predicting remains important after decades of studying aggression. A large quantity of aggression theories and models do not allow to fully explain the aggressive behaviour emergence. Unified theory of aggressive behaviour proposes to regard aggression as a balance of provoking and limiting factors, which are based on adaptive problems: retention of a sexual partner, co-opting the resources of others, defending against attack, inflicting costs on same-sex rivals, negotiating status and power hierarchies, deterring rivals from future aggression, deterring mates from sexual infidelity. Factors of aggressive behaviour include the level of physiological arousal, negative or positive reinforcement of aggressive behaviour in the past, a state of frustration, aversive stimuli and the dominant emotion. Based on the proposed theory, a aggressive behaviour predicting scale is proposed, which allows to calculate the probability of aggressive behaviour, as well as its dynamics. The aggressive behaviour predicting scale is easy to use, does not take much time and allows to quantify and assess the probability of aggression.

Pain is so close to pleasure: the same dopamine neurons can mediate approach and avoidance in Drosophila

In mammals, dopamine is considered a central neuromodulator involved in all kinds of rewarding experiences ('common currency' hypothesis). In insects, the role of dopaminergic neurons in aversive stimuli was discovered before dopaminergic neurons were found to also be involved in processing appetitive stimuli. Here, we screened about 50 transgenic Drosophila lines, representing different subpopulations of dopaminergic neurons for their ability to sustain approach or avoidance behavior, when activated optogenetically in four different operant self-stimulation paradigms. None of the lines sustain consistent behavioral valence in all experiments. Individual lines sustain approach in one experiment and avoidance in another. One line mediated strong avoidance early in the experiment and weak approach in later stages. The evidence presented here appears to contradict a 'common currency' dopamine function in flies. Instead, different dopaminergic neurons convey valence in a context-dependent and flexible manner, reflecting the genetic heterogeneity of the dopaminergic neuronal population.

GABAB receptor/HCN channel complexes in VTA dopamine neurons limit synaptic inhibition and prevent anxiety-like behavior

Aversive stimuli inhibiting dopamine neurons in the ventral tegmental area (DAVTA neurons) induce anxiety-like behaviors. The inhibition of DAVTA neurons is prolonged by GABAB receptor (GBR)-activated K+-currents, which exhibit a rapid desensitization of unknown physiological relevance. We now report that GBRs associate via auxiliary KCTD16 subunits with HCN channels, which facilitates activation of hyperpolarization activated currents (Ih) by GBR-activated K+ currents. Activation of Ih underlies rapid K+ current desensitization in DAVTA neurons and limits GBR-mediated inhibition. Disruption of the GBR/HCN complex in KCTD16-/- mice or blockade of Ih prolongs optogenetically driven inhibition of DAVTA neuron firing. KCTD16-/- mice exhibit an increased anxiety-like behavior in response to stressful stimuli, which is reproduced by in vivo CRISPR/Cas9-mediated KCTD16 ablation in DAVTA neurons or intra-VTA infusion of HCN antagonist to wild-type mice. Our data reveal that GBR-induced Ih protect DAVTA neurons from prolonged GBR mediated inhibition in response to stressors, which moderates anxiety-like behaviors.

Floor vibrations for motivation and feedback in the rat vibration actuating search task

Motivating rodents to perform cognitive tasks often relies on the application of aversive stimuli. The Vibration Actuating Search Task (VAST) is a novel open-field task in which gradient floor vibration provides motivation for the rodent to navigate in the direction of diminishing vibration to an unmarked target destination. Using floor vibration as a motivational stimulus may overcome several of the potential confounds associated with stimuli used in other tasks. In a series of three experiments, we determined whether (1) rats exhibit place preference for floor vibration over other aversive stimuli (i.e., water, foot shock, and bright light), (2) exposure to floor vibration is associated with a lower corticosterone response than exposure to these other stimuli, (3) rats successfully acquire the VAST, and (4) VAST performance is sensitive to 6 h of sleep deprivation (SD). Our results showed that rats exhibited place preference for vibration over water, foot shock, and bright light environments, and that corticosterone levels were lower in rats exposed to vibration than those exposed to water. VAST performance also significantly improved over two days of testing for some metrics, and SD impaired VAST performance. Overall, we conclude that (1) rats exhibit place preference for vibration over other stimuli commonly used to motivate task performance, (2) the vibrations employed by the VAST produce lower concentrations of circulating corticosterone than forced swimming, (3) rats can learn to use gradient floor vibration as a mode of performance feedback within two days of testing, and (4) VAST performance is substantially impaired by SD. Thus, the VAST is an effective and practical testbed for studying the mechanisms by which SD causes deficits in feedback-dependent decision making.

Running away or running to? Do prey make decisions solely based on the landscape of fear or do they also include stimuli from a landscape of safety?

Predator prey interactions are a key part of ecosystem function, and non-consumptive effects fall under the landscape of fear theory. Under the landscape of fear, the antipredator responses of prey are based on the spatial and temporal distribution of predatory cues in the environment. However, the aversive stimuli (fear) are not the only stimuli prey can utilize when making behavioral decisions. Prey might also be using attractive stimuli that represent safety to guide decision making. Using a novel, orthogonal design, we were able to spatially separate aversive and attractive stimuli to determine if prey are utilizing safety cues to navigate their environment. Crayfish Faxonius rusticus were placed in the center of a behavioral arena. Aversive stimuli of either predatory bass Micropterus salmoides cues or conspecific alarm cues increased along the x-axis of the behavioral arena. Safety cues (shelters) increased along the y-axis by decreasing the number of shelter openings in this direction. Crayfish were allowed two phases to explore the arena: one without the fearful stimuli and one with the stimuli. Linear mixed models were conducted to determine if movement behaviors and habitat utilization were affected by the phase of the trial and the type of aversive stimuli. Crayfish responded more strongly to alarm cues than fear cues, with only alarm cues significantly impacting habitat utilization. When responding to alarm cues, crayfish used safety cues as well as fear cues to relocate themselves within the arena. Based on these results, we argue that crayfish are utilizing a landscape of safety in conjunction with a landscape of fear when navigating their environment.

Dense cortical input to the rostromedial tegmental nucleus mediates aversive signaling

The rostromedial tegmental nucleus (RMTg) encodes negative reward prediction error (RPE) and plays an important role in guiding behavioral responding to aversive stimuli. While initial studies describing the RMTg revealed the presence of cortical afferents, the density and distribution of this input has not been explored in detail. In addition, the functional consequences of cortical modulation of RMTg signaling are only just beginning to be investigated. The current study anatomically and functionally characterizes cortical input to the RMTg in rats. Findings from this work reveal dense input spanning the entire medial prefrontal cortex (PFC) as well as the orbitofrontal cortex and anterior insular cortex. Afferents were most dense in the dorsomedial subregion of the PFC (dmPFC), an area which has also been implicated in both RPE signaling and aversive responding. RMTg-projecting dmPFC neurons originate in layer V and collateralize extensively throughout the brain. In-situ mRNA hybridization further revealed that neurons in this circuit are predominantly D1 receptor-expressing with a high degree of D2 receptor colocalization. Optogenetic stimulation of dmPFC terminals in the RMTg drives avoidance, and cFos expression is enhanced in this neural circuit during exposure to aversive stimuli. Exposure to such aversive stimuli results in significant physiological and structural plasticity suggestive of a loss of top-down modulation of RMTg-mediated signaling. Altogether, these data reveal the presence of a prominent cortico-subcortical projection involved in adaptive behavioral responding and provide a foundation for future work aimed at exploring alterations in circuit function in diseases characterized by deficits in cognitive control over the balance between reward and aversion.

The collective praise intervention: A brief intervention highlighting prosocial behavior reduces hostility towards Muslims

Muslims are consistently the target of dehumanization and hostile policies. Previous research shows that interventions that highlight the hypocrisy wherein people collectively blame entire groups for the heinous acts of individual members of outgroups but not ingroups are effective in reducing animosity towards Muslims. However, these interventions rely on aversive materials (e.g., terrorist acts), which can hinder the scalability of interventions due to individuals’ tendency to resist/avoid challenging and aversive stimuli. In three preregistered studies (combined N = 2,635), we developed and tested a nonaversive, hypocrisy-based intervention that highlights the hypocrisy involved in attributing ingroup members’ prosocial acts to the entire ingroup (i.e., Christians) but not doing the same for outgroup members (i.e., Muslims). Results indicated that this collective praise intervention reliably reduces dehumanization of Muslims, anti-Muslim policy support, and collective blame of Muslims. We argue that the intervention’s use of nonaversive stimuli allows for both practical and scalable applications.