The neurological mechanism of linking stress-induced anxiety to motivation for reward

Stressful situations activate complex biological mechanisms and neural circuits that detect and respond to threats to homeostasis, resulting in behavioral responses that minimize disruption and increase survival. The cognitive processing of stress involves subjective appraisal to guide appropriate behavioral responses. Maladaptive responses to stress can contribute to the development of anxiety-related disorders and depression. The prefrontal cortex, amygdala, bed nucleus of the stria terminalis, and ventral hippocampus are all brain areas involved in anxiety-like behavior induced by stress. Stress can also modulate the activity of dopaminergic neurons in the ventral tegmental area and nucleus accumbens, affecting motivation to seek out or avoid stressors. However, the specific brain areas and mechanisms responsible for controlling motivated coping behaviors in anxiety-provoking situations are not well understood.

The interpeduncular nucleus (IPN), located in the ventral midbrain, is an understudied brain area involved in emotional and social behavior. It is primarily composed of GABAergic neurons and forms part of the medial habenula-to-IPN axis. The IPN receives input from several brain regions and projects to other regions, allowing it to integrate emotional and motivational stimuli. Previous research has shown that the MHb-IPN pathway is involved in controlling motivated nicotine consumption and aversion. GABAergic neurons within the IPN are activated during nicotine withdrawal, leading to increased withdrawal behaviors and anxiety. The release of corticotropin-releasing hormone into the IPN also contributes to anxiety during nicotine withdrawal. Increased IPN activity has been linked to avoidance and motivational drive for novel stimuli. Manipulation of IPN GABAergic activity can influence behavioral reactivity. However, a detailed understanding of IPN neuronal activity dynamics and its response to acute stressors other than nicotine withdrawal is lacking. Further research is needed to explore the role of IPN neuronal activity in stress-induced anxiety and its impact on motivated behavior.

Paul M. Klenowski, Rubing Zhao-Shea, Timothy G. Freels, Susanna Molas, Max Zinter, Peter M’Angale, Cong Xiao, Leonora Martinez-Núñez, Travis Thomson, and Andrew R. Tapper, from the University of Massachusetts Chan Medical School, reported a neuronal coping mechanism linking stress-induced anxiety to motivation for reward.

Stress increases IPN GABAergic neuron activity

The researchers investigated the in vivo responses of GABAergic neurons in the Interpeduncular Nucleus (IPN) during acute stress. They introduced a genetically encoded calcium sensor called GCaMP6m into the IPN of mice using adeno-associated virus (AAV) gene delivery. Fiber photometry was used to record calcium transients in response to restraint stress, which led to a significant increase in corticosterone levels. Analysis of the recordings demonstrated increased GCaMP signal in IPN GAD2+ neurons during and after stress compared to baseline activity. Additionally, immunolabeling for c-fos showed increased neuronal activation in the IPN following restraint stress. Furthermore, foot shock also increased GCaMP activity in IPN GAD2+ neurons. These findings indicate that the IPN is a stress-responsive brain area where stress enhances the activity of GABAergic neurons.

Optical inhibition of GABAergic IPN neurons alleviates stress-induced anxiety

To investigate the role of stress activation of IPN GABAergic neurons in anxiety-like behavior, researchers used AAV2-mediated gene delivery to express either NpHR or eYFP as a control in the IPN of GAD2-Cre mice. Anxiety-like behavior was assessed using the elevated plus maze (EPM) and open-field test, with mice either unstressed or subjected to 5 minutes of restraint while light was delivered to the IPN. In the EPM, restraint stress reduced open-arm exploration in eYFP mice compared to unstressed eYFP and NpHR mice. Optical inhibition of IPN GAD2+ neurons increased open-arm exploration in stressed NpHR mice compared to stressed eYFP mice. In the open-field test, stressed eYFP mice spent less time in the center and more time in the periphery of the arena compared to unstressed eYFP and NpHR mice. However, under light delivery, stressed NpHR mice spent more time in the center and less time in the periphery compared to stressed eYFP mice, with no difference in distance traveled between the groups. These findings indicate that optogenetic inhibition of IPN GABAergic neurons has anxiolytic effects and can block stress-induced anxiety.

Stress-induced grooming decreases IPN GABAergic neuron activity

Researchers explored the connection between stress-induced anxiety and the motivation for rewards in mice, with a specific focus on the interpeduncular nucleus (IPN) in the brain. The research shows that acute stressors activate GABAergic neurons in the IPN, and stress-coping and reward-seeking behaviors can reduce their activity. The study also revealed that optical inhibition of GABAergic IPN neurons alleviates stress-induced anxiety. Additionally, the research demonstrated that stress induces innate behaviors and motivated reward-seeking as mechanisms to oppose IPN neuronal activation. Overall, the findings suggest that the IPN is a stress-responsive brain area where stress enhances GABAergic neuronal activity.

Self-grooming behavior is modulated by optogenetic manipulation of IPN GABAergic neuron activity

Self-grooming behavior, believed to be a form of self-soothing, can be modulated by manipulating the activity of IPN GABAergic neurons in mice through optogenetic techniques. Inhibition of these neurons using NpHR optogenetic manipulation resulted in less grooming behavior, while activation of the neurons using ChR2 optogenetic manipulation increased grooming behavior. Additionally, the consumption of sucrose, a natural reward, was found to decrease the activity of IPN GABAergic neurons, particularly during periods of stress such as food restriction and after restraint stress. These findings suggest that IPN GABAergic activity plays a role in self-grooming behavior and can be influenced by both stress and reward consumption.

Optical silencing of IPN GABAergic neurons inhibits stress-induced increases in motivated sucrose seeking

The study investigated whether stress activation of IPN GABAergic neurons motivates reward-seeking behavior to reduce IPN activity as a coping mechanism for anxiety relief. Researchers used optogenetics to silence stress-induced activity of IPN GABAergic neurons in mice during an operant sucrose self-administration paradigm. They found that mice exposed to stress exhibited an increased motivation for sucrose compared to non-stressed mice, but this increase was not observed in mice whose IPN activity was inhibited by optogenetics. Additionally, activating IPN GAD2+ neurons increased motivation for sucrose, while stimulating MHb-IPN terminals also increased IPN activity and self-grooming behavior. These findings suggest that heightened IPN activity drives reward-seeking behavior, and inhibiting IPN activity can prevent stress-induced increases in motivation for sucrose.