The Effects of Mindfulness-Based Stress Reduction on the Association Between Autonomic Interoceptive Signals and Emotion Regulation Selection.

OBJECTIVE: The ability to select the most adaptive regulatory strategy as a function of the emotional context plays a pivotal role in psychological health. Recently, we showed that mindfulness-based interventions (MBIs) can improve the sensitivity of regulatory strategy selection to emotional intensity. However, the mechanisms underlying this improvement are unclear. In this study, we tested the hypothesis that MBIs support adaptive regulatory selection by increasing sensitivity to interoceptive signals associated with the emotional stimuli. METHODS: Participants (n = 84, mean [standard deviation {SD}] age = 30.9 [8.3] years; 54% women) were randomized to either a mindfulness-based stress reduction (MBSR) program or a wait-list control condition. Before and after the MBSR program, physiological measures for autonomic nervous system activity were obtained, and participants performed a task examining emotion regulation selections (reappraisal versus distraction) when confronted with low or high negative intensity images. They also completed a battery of mindfulness, interoception, and well-being self-report measures. A cross-classified model was used for the main analyses. RESULTS: The participants assigned to the MBSR were overall more likely to choose reappraisal than distraction (b = 0.26, posterior SD = 0.13, 95confidence interval = 0.02-0.52) after the program. Interoceptive signals in response to negative images were associated with subsequent regulatory selections (b = 0.02, posterior SD = 0.01, 95% confidence interval = 0.01-0.03) in the MBSR group. Specifically, lower cardiac reactivity was associated with the choice to reappraise, whereas higher cardiac reactivity was related to the choice to distract. Greater differences in cardiac reactivity between states that prompt reappraisal and states that prompt distraction were associated with higher well-being (Satisfaction With Life Scale, Pearson r (29) = 0.527, p = .003). CONCLUSIONS: Mindfulness seems to increase the sensitivity of regulatory selections to interoceptive signals, and this is associated with subjective well-being. This may be a central pathway through which MBIs exert their positive effects on mental health and resilience.

Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of "Juvenile" and "Adult Stress" in Rats.

Early life stress is suggested to alter behavioral responses during stressful challenges in adulthood and to exacerbate pathological symptoms that reminisce posttraumatic stress disorder (PTSD). These effects are often associated with changes in γ-Aminobutyric acid type A (GABAA) and κ opioid receptor expression and neuromodulation of the limbic system. Anxiety-like and stress coping behaviors were assessed in rats exposed to stress in adulthood on the background of previous exposure to stress in juvenility. Two weeks following behavioral assessment in adulthood, GABAAR α1 and α2 subunits and κ opioid receptor expression levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and periaqueductal gray (PAG). To illustrate changes at the network level, an integrated expression profile was constructed. We found that exposure to juvenile stress affected rats' behavior during adult stress. The combination of juvenile and adult stress significantly affected rats' long term anxious-like behavior. Probabilities predicting model integrating the expression of GABAA α1-α2 and κ opioid receptors in different brain regions yielded highly successful classification rates. This study emphasizes the ability of exposure to stress in juvenility to exacerbate the impact of coping with stress in adulthood. Moreover, the use of integrated receptor expression network profiling was found to effectively characterize the discussed affective styles and their behavioral manifestations.

Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience.

ALBRECHT, A., MÜLLER, I., ARDI, Z., ÇALISKAN, G., GRUBER, D., IVENS, S., SEGAL, M., BEHR, J., HEINEMANN, U., STORK, O., and RICHTER-LEVIN, G. Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience. NEUROSCI BIOBEHAV REV XXX-XXX, 2016.- Childhood adversity is among the most potent risk factors for developing mood and anxiety disorders later in life. Therefore, understanding how stress during childhood shapes and rewires the brain may optimize preventive and therapeutic strategies for these disorders. To this end, animal models of stress exposure in rodents during their post-weaning and pre-pubertal life phase have been developed. Such 'juvenile stress' has a long-lasting impact on mood and anxiety-like behavior and on stress coping in adulthood, accompanied by alterations of the GABAergic system within core regions for the stress processing such as the amygdala, prefrontal cortex and hippocampus. While many regionally diverse molecular and electrophysiological changes are observed, not all of them correlate with juvenile stress-induced behavioral disturbances. It rather seems that certain juvenile stress-induced alterations reflect the system's attempts to maintain homeostasis and thus promote stress resilience. Analysis tools such as individual behavioral profiling may allow the association of behavioral and neurobiological alterations more clearly and the dissection of alterations related to the pathology from those related to resilience.

Receptor tyrosine kinase EphA7 is required for interneuron connectivity at specific subcellular compartments of granule cells.

Neuronal transmission is regulated by the local circuitry which is composed of principal neurons targeted at different subcellular compartments by a variety of interneurons. However, mechanisms that contribute to the subcellular localisation and maintenance of GABAergic interneuron terminals are poorly understood. Stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin and its interaction with the guanine nucleotide exchange factor collybistin. Lentiviral knockdown experiments in adult rats indicated that the receptor tyrosine kinase EphA7 is required for the stabilisation of basket cell terminals on proximal dendritic and somatic compartments of granular cells of the dentate gyrus. EphA7 deficiency and concomitant destabilisation of GABAergic synapses correlated with impaired long-term potentiation and reduced hippocampal learning. Reduced GABAergic innervation may be explained by an impact of EphA7 on gephyrin clustering. Overexpression or ephrin stimulation of EphA7 induced gephyrin clustering dependent on the mechanistic target of rapamycin (mTOR) which is an interaction partner of gephyrin. Gephyrin interactions with mTOR become released after mTOR activation while enhanced interaction with the guanine nucleotide exchange factor collybistin was observed in parallel. In conclusion, EphA7 regulates gephyrin clustering and the maintenance of inhibitory synaptic connectivity via mTOR signalling.

Behavioral profiling as a translational approach in an animal model of posttraumatic stress disorder.

Diagnosis of psychiatric disorders in humans is based on comparing individuals to the normal population. However, many animal models analyze averaged group effects, thus compromising their translational power. This discrepancy is particularly relevant in posttraumatic stress disorder (PTSD), where only a minority develop the disorder following a traumatic experience. In our PTSD rat model, we utilize a novel behavioral profiling approach that allows the classification of affected and unaffected individuals in a trauma-exposed population. Rats were exposed to underwater trauma (UWT) and four weeks later their individual performances in the open field and elevated plus maze were compared to those of the control group, allowing the identification of affected and resilient UWT-exposed rats. Behavioral profiling revealed that only a subset of the UWT-exposed rats developed long-lasting behavioral symptoms. The proportion of affected rats was further enhanced by pre-exposure to juvenile stress, a well-described risk factor of PTSD. For a biochemical proof of concept we analyzed the expression levels of the GABAA receptor subunits α1 and α2 in the ventral, dorsal hippocampus and basolateral amygdala. Increased expression, mainly of α1, was observed in ventral but not dorsal hippocampus of exposed animals, which would traditionally be interpreted as being associated with the exposure-resultant psychopathology. However, behavioral profiling revealed that this increased expression was confined to exposed-unaffected individuals, suggesting a resilience-associated expression regulation. The results provide evidence for the importance of employing behavioral profiling in animal models of PTSD, in order to better understand the neural basis of stress vulnerability and resilience.

Juvenile stress alters LTP in ventral hippocampal slices: involvement of noradrenergic mechanisms.

Childhood adversity is a prominent risk factor for developing stress-related disorders in adulthood. It can be modeled in rodents, where altered stress responses in adulthood have been observed. The ventral hippocampus is thought to be involved in emotional responses and displays a unique modulation of synaptic plasticity following exposure to stress. Here, we investigated the long-term effect of juvenile stress (at postnatal age of 27-29 days) on synaptic plasticity in the ventral and dorsal hippocampus of adult, 3 month old rats. The rats that had experienced juvenile stress expressed impaired LTP in the dorsal hippocampus (DH), while ventral hippocampus (VH) LTP was facilitated. Furthermore, juvenile stress caused reduced sensitivity to the beta-adrenergic agonist isoproterenol (Iso; 1 µM) in the adult DH, while it enhanced its action in VH slices. Further, juvenile stress resulted in an increase in the expression of beta1-adrenergic receptors in the VH but not in the DH, as revealed by western blot. Taken together, the ventral hippocampus expresses a lasting sensitivity to adrenergic modulation, thus likely to affect the emotional response to challenging situations in adulthood.

Differential activation of amygdala, dorsal and ventral hippocampus following an exposure to a reminder of underwater trauma.

Recollection of emotional memories is attributed in part to the activation of the amygdala and the hippocampus. Recent hypothesis suggests a pivotal role for the ventral hippocampus (VH) in traumatic stress processing and emotional memory retrieval. Persistent re-experiencing and intrusive recollections are core symptoms in acute and posttraumatic stress disorders (ASD; PTSD). Such intrusive recollections are often triggered by reminders associated with the trauma. We examined the impact of exposure to a trauma reminder (under water trauma (UWT)) on the activation of the basolateral amygdala (BLA), dorsal and VH. Rats were exposed to UWT and 24 h later were re-exposed to the context of the trauma. Phosphorylation of the extracellular signal-regulated kinase (ERK) was used as a marker for level of activation of these regions. Significant increase in ERK activation was found in the VH and BLA. Such pattern of activation was not found in animals exposed only to the trauma or in animals exposed only to the trauma reminder. Additionally, the dissociative pattern of activation of the VH sub-regions positively correlated with the activation of the BLA. Our findings suggest a specific pattern of neural activation during recollection of a trauma reminder, with a unique contribution of the VH. Measured 24 h after the exposure to the traumatic experience, the current findings relate to relatively early stages of traumatic memory consolidation. Understanding the neural mechanisms underlying these initial stages may contribute to developing intervention strategies that could reduce the risk of eventually developing PTSD.

The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms in the rat dentate gyrus.

Intrusive re-experiencing is a core symptom in post-traumatic stress disorder (PTSD), often triggered by contextual cues associated with the trauma. It is not yet clear if intrusive re-experiencing is only the result, or whether it may contribute to the establishment of PTSD following acute stress. This study aimed at examining the impact of an underwater trauma (UWT) reminder on anxiety-like behaviour and on neuronal activity and plasticity in the hippocampus and the amygdala. Sprague-Dawley rats were exposed to UWT and 24 h later were re-exposed to the context. The effects on behaviour, activation of the amygdala (BLA) and dentate gyrus (DG), and on long-term potentiation (LTP) and local circuit activity (frequency-dependent inhibition (FDI) and paired-pulse inhibition (PPI)) in the DG were assessed. The exposure to UWT by itself resulted in increased anxiety behaviour in the open field, together with increased PPI. Upon exposure to the UWT reminder, an additional increase in anxiety was also observed in the EPM and in FDI. Moreover, reminder exposure resulted in impaired DG LTP and a significant BLA extracellular-signal-regulated kinases (ERK) 2 activation. In conclusion, these observed effects of exposure to a trauma reminder, following the exposure to the initial trauma, might be associated with the progression of trauma-related pathologies and the development of related disorders.