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Anxiety disorders have been linked to a disbalance of excitation and inhibition in a network of brain structures comprising frontal cortical regions, the amygdala and the hippocampus, among others. Recent imaging studies suggest sex differences in the activation of this anxiety network during the processing of emotional information. Rodent models with genetically altered ϒ-amino butyric acid (GABA) neurotransmission allow studying the neuronal basis of such activation shifts and their relation to anxiety endophenotypes, but to date sex effects have rarely been addressed. Using mice with a null mutation of the GABA synthetizing enzyme glutamate decarboxylase 65 (GAD65-/-), we started to compare anxiety-like behavior and avoidance in male vs. female GAD65-/- mice and their wildtype littermates. In an open field, female GAD65-/- mice displayed increased activity, while male GAD65-/- mice showed an increased adaptation of anxiety-like behavior over time. GAD65-/- mice of both sexes had a higher preference for social interaction partners, which was further heightened in male mice. In male mice higher escape responses were observed during an active avoidance task. Together, female mice showed more stable emotional responses despite GAD65 deficiency. To gain insights into interneuron function in network structures controlling anxiety and threat perception, fast oscillations (10-45 Hz) were measured in ex vivo slice preparations of the anterior cingulate cortex (ACC). GAD65-/- mice of both sexes displayed increased gamma power in the ACC and a higher density of PV-positive interneurons, which are crucial for generating such rhythmic activity. In addition, GAD65-/- mice had lower numbers of somatostatin-positive interneurons in the basolateral amygdala and in the dorsal dentate gyrus especially in male mice, two key regions important for anxiety and active avoidance responses. Our data suggest sex differences in the configuration of GABAergic interneurons in a cortico-amygdala-hippocampal network controlling network activity patterns, anxiety and threat avoidance behavior.

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The "abdominal brain" does not only consist of a separate enteric nervous system but also of bidirectional connections to the autonomous nerve system with parasympathicus und sympathicus as well as brain and spinal cord. Novel studies have shown that these connections can quickly transfer information on the ingested nutrients to the brain to conduct the feeling of hunger and more complex behaviour, such as "reward-related learning". However, even emotional experience, in particular, stress, has a strong impact onto the gastrointestinal system. The immune system, motility and barrier function of the gastrointestinal tract are modulated by the intestinal microbiota. Local bacteria may directly influence neuronal communication by released metabolic products and neuropeptides as well as may control inflammatory factors. Intensive research over the last 10 years was able to provide evidence that intestinal microbiota may affect emotional and cognitive aspects of our behaviour and, thus, it might be in the focus of numerous neuropsychiatric diseases, such as depressions and anxiety disorders.The presented review is to provide a short summary of the I): anatomic basics of the so-called gut-brain axis and II): modi of the bidirectional regulation. Through indirect connections to the limbic system, gut-brain axis can substantially influence stress and anxiety but also the pain processing. In addition, the role of microbiota is outlined and future paths are shown, e.g., how the (microbiota-)gut-brain axis may alter emotional experience, pain processing and intestinal function. Such associations are relevant for further development of visceral medicine, and, thus, also for the abdominal surgeon to derive future treatment concepts with interdisciplinary orientation.

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Remembering the location of food is essential for survival. Rodents and humans employ mainly hippocampus-dependent spatial strategies, but when being stressed they shift to striatum-mediated stimulus-based strategies. To investigate underlying brain circuits, we tested mice with a heightened stress susceptibility due to a lack of the GABA-synthetizing enzyme GAD65 (GAD65-/- mice) in a dual solution task. Here, GAD65-/- mice preferred to locate a food reward in an open field via a proximal cue, while their wildtype littermates preferred a spatial strategy. The analysis of cFos co-activation across brain regions and of stress-induced mRNA expression changes of GAD65 pointed towards the hippocampal dorsal dentate gyrus (dDG) as a central structure for mediating stress effects on strategy choices via GAD65. Reducing the GAD65 expression locally in the dDG by a shRNA mediated knock down was sufficient to replicate the phenotype of the global GAD65 knock out and to increase dDG excitability. Using DREADD vectors to specifically interfere with dDG circuit activity during dual solution retrieval but not learning confirmed that the dDG modulates strategy choices and that a balanced excitability of this structure is necessary to establish spatial strategy preference. These data highlight the dDG as a critical hub for choosing between spatial and non-spatial foraging strategies.

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Inflammatory diseases of the skin, including atopic dermatitis and psoriasis, have gained increasing attention with rising incidences in developed countries over the past decades. While bodily properties, such as immunological responses of the skin, have been described in some detail, interactions with the brain via different routes are less well studied. The suggested routes of the skin-brain axis comprise the immune system, HPA axis, and the peripheral and central nervous system, including microglia responses and structural changes. They provide starting points to investigate the molecular mechanisms of neuropsychiatric comorbidities in AD and psoriasis. To this end, mouse models exist for AD and psoriasis that could be tested for relevant behavioral entities. In this review, we provide an overview of the current mouse models and assays. By combining an extensive behavioral characterization and state-of-the-art genetic interventions with the investigation of underlying molecular pathways, insights into the mechanisms of the skin-brain axis in inflammatory cutaneous diseases are examined, which will spark further research in humans and drive the development of novel therapeutic strategies.

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Early life stress is an important vulnerability factor for the development of anxiety disorders, depression and late-onset cognitive decline. Recently, we demonstrated that juvenile stress (JS) lastingly enhanced long-term potentiation via reduction of steady-state glutamine synthetase mRNA expression and the associated dysregulation of the astrocytic glutamate-glutamine cycle in the rat ventral CA1. We now investigated the regulation of steady-state mRNA expression of neuronal gene products that determine GABAergic and glutamatergic neurotransmission in layers of the ventral and dorsal CA1 after JS. We further studied their interaction with stress in young adult age (AS) to address their putative role in psychopathology development. Strikingly, mRNA levels of the glutamic acid decarboxylase (GAD) isoforms GAD65 and of the GABA-A receptor α2 (Gabra2) were increased after single JS or AS, but not after combined JS/AS stress experience. In fact, JS/AS resulted in layer-specific reduction of Gabra2 and also of Gabra1 mRNA levels in the ventral CA1. Furthermore, GAD65 and Gabra2 mRNAs were correlated with glutamatergic AMPA and NMDA receptor subunit mRNAs after single JS and AS, but not after combined JS/AS. Together, these data indicate a loss of allostatic regulation of steady-state mRNA levels of key GABAergic components that may result in a dysregulation of excitation/ inhibition balance in the ventral CA1 upon dual stress exposure. Finally, individual differences in local glucocorticoid receptor mRNA expression may contribute to this regulation.

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We recently introduced behavioral profiling as a translational approach to increase the validity of animal models of posttraumatic stress disorder (PTSD). Behavioral profiling utilizes the response of a 'normal population' of control animals and compares the performance of animals with a history of traumatic stress in different behavioral tests that can capture PTSD-like symptoms. Thus, affected, PTSD-like individuals can be subdivided from resilient trauma-exposed animals. While in our recent study we focused mainly on tests for activity and anxiety, we now expand the behavioral tests battery and include also fear memory and extinction tasks as well as a spatial object recognition test in our behavioral profiling approach. Utilizing underwater trauma as the traumatic event, we found that only a small subset of animals exposed to underwater trauma showed lasting increases in anxiety-like behavior and heightened emotional memory formation. Adding juvenile stress as a model for childhood adversity increased the prevalence of such affected animals and furthermore and induced additional cognitive deficits in a subgroup of such emotionally affected individuals. In addition, multiple affected individual rats displayed increased local circuit activity in the dorsal dentate gyrus, as measured in vivo with paired pulse protocols in anesthetized animals. Together, our findings highlight behavioral profiling, refined by including multiple behavioral tests, as a valid tool to identify PTSD-like vs. resilient individual animals and further suggest that enhanced local inhibition in specific circuits of the dorsal dentate gyrus may be associated with the observed symptoms.

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Studies in humans and rodents suggest a critical role for the hippocampal formation in cognition and emotion, but also in the adaptation to stressful events. Successful stress adaptation promotes resilience, while its failure may lead to stress-induced psychopathologies such as depression and anxiety disorders. Hippocampal architecture and physiology is shaped by its strong control of activity via diverse classes of inhibitory interneurons that express typical calcium binding proteins and neuropeptides. Celltype-specific opto- and chemogenetic intervention strategies that take advantage of these biochemical markers have bolstered our understanding of the distinct role of different interneurons in anxiety, fear and stress adaptation. Moreover, some of the signature proteins of GABAergic interneurons have a potent impact on emotion and cognition on their own, making them attractive targets for interventions. In particular, neuropeptide Y is a promising endogenous agent for mediating resilience against severe stress. In this review, we evaluate the role of the major types of interneurons across hippocampal subregions in the adaptation to chronic and acute stress and to emotional memory formation.

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Adverse experiences during childhood are among the most prominent risk factors for developing mood and anxiety disorders later in life. Early-life stress interventions have been established as suitable models to study the neurobiological basis of childhood adversity in rodents. Different models such as maternal separation, impaired maternal care and juvenile stress during the postweaning/prepubertal life phase are utilized. Especially within the limbic system, they induce lasting alterations in neuronal circuits, neurotransmitter systems, neuronal architecture and plasticity that are further associated with emotional and cognitive information processing. Recent studies found that astrocytes, a special group of glial cells, have altered functions following early-life stress as well. As part of the tripartite synapse, astrocytes interact with neurons in multiple ways by affecting neurotransmitter uptake and metabolism, by providing gliotransmitters and by providing energy to neurons within local circuits. Thus, astrocytes comprise powerful modulators of neuronal plasticity and are well suited to mediate the long-term effects of early-life stress on neuronal circuits. In this review, we will summarize current findings on altered astrocyte function and hippocampal plasticity following early-life stress. Highlighting studies for astrocyte-related plasticity modulation as well as open questions, we will elucidate the potential of astrocytes as new targets for interventions against stress-induced neuropsychiatric disorders.

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Only a minority of trauma-exposed individuals develops Posttraumatic stress disorder (PTSD) and active processes may support trauma resilience. Individual behavioral profiling allows investigating neurobiological alterations related to resilience or pathology in animal models of PTSD and is utilized here to examine the activation of different interneuron subpopulations of the dentate gyrus-amygdala system associated with trauma resilience or pathology. To model PTSD, rats were exposed to juvenile stress combined with underwater trauma (UWT) in adulthood. Four weeks later, individual anxiety levels were assessed in the elevated plus maze test for classifying rats as highly anxious 'affected' vs. 'non-affected', i.e. behaving as control animals. Analyzing the activation of specific interneuron subpopulations in the dorsal and ventral dentate gyrus (DG), the basolateral (BLA) and central amygdala by immunohistochemical double-labeling for cFos and different interneuron markers, revealed an increased activation of cholecystokinin (CCK)-positive interneurons in the ventral DG, together with increased activation of parvalbumin- and CCK-positive interneurons in the BLA of affected trauma-exposed rats. By contrast, increased activation of neuropeptide Y (NPY)-positive interneurons was observed in the dorsal DG of trauma-exposed, but non-affected rats. To test for a direct contribution of NPY in the dorsal DG to trauma resilience, a local shRNA-mediated knock down was performed after UWT. Such a treatment significantly reduced the prevalence of resilient animals. Our results suggest that distinct interneuron populations are associated with resilience or pathology in PTSD with high regional specificity. NPY within the dorsal DG was found to significantly contribute to trauma resilience.

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A traumatic childhood is among the most important risk factors for developing stress-related psychopathologies such as posttraumatic stress disorder or depression later in life. However, despite the proven role of astrocytes in regulating transmitter release and synaptic plasticity, the contribution of astrocytic transmitter metabolism to such stress-induced psychopathologies is currently not understood. In rodents, childhood adversity can be modeled by juvenile stress exposure, resulting in increased anxiety, and impaired coping with stress in adulthood. We describe that such juvenile stress in rats, regardless of additional stress in adulthood, leads to reduced synaptic efficacy in the ventral CA1 (vCA1) Schaffer collaterals, but increased long-term potentiation (LTP) of synaptic transmission after high-frequency stimulation. We tested whether the glutamate-glutamine-cycle guides the lasting changes on plasticity observed after juvenile stress by blocking the astrocytic glutamate-degrading enzyme, glutamine synthetase (GS). Indeed, the pharmacological inhibition of GS by methionine sulfoximine in slices from naïve rats mimics the effect of juvenile stress on vCA1-LTP, while supplying glutamine is sufficient to normalize the LTP. Assessing steady-state mRNA levels in the vCA1 stratum radiatum reveals distinct shifts in the expression of GS, astrocytic glutamate, and glutamine transporters after stress in juvenility, adulthood, or combined juvenile/adult stress. While GS mRNA expression levels are lastingly reduced after juvenile stress, GS protein levels are maintained stable. Together our results suggest a critical role for astrocytes and the glutamate-glutamine cycle in mediating long-term effects of juvenile stress on plasticity in the vCA1, a region associated with anxiety and emotional memory processing.

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Activation of the amygdala is one of the hallmarks of acute stress reactions and a central element of the negative impact of stress on hippocampus-dependent memory and cognition. Stress-induced psychopathologies, such as posttraumatic stress disorder, exhibit a sustained hyperactivity of the amygdala, triggered at least in part by deficits in GABAergic inhibition that lead to shifts in amygdalo-hippocampal interaction. Here, we have utilized lentiviral knock down of neurofascin to reduce GABAergic inhibition specifically at the axon initial segment (AIS) of principal neurons within the basolateral amygdala (BLA) of rats. Metaplastic effects of such a BLA modulation on hippocampal synaptic function were assessed using BLA priming prior to the induction of long-term potentiation (LTP) on dentate gyrus synapses in anesthetized rats in vivo. The knock down of neurofascin in the BLA prevented a priming-induced impairment on LTP maintenance in the dentate gyrus. At the behavioral level, a similar effect was observable, with neurofascin knock down preventing the detrimental impact of acute traumatic stress on hippocampus-dependent spatial memory retrieval in a water maze task. These findings suggest that reducing GABAergic inhibition specifically at the AIS synapses of the BLA alters amygdalo-hippocampal interactions such that it attenuates the adverse impact of acute stress exposure on cognition-related hippocampal functions.

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Cholinergic neuromodulation in the hippocampus controls the salience of background context memory acquired in the presence of elemental stimuli predicting an aversive reinforcement. With pharmacogenetic inhibition we here demonstrate that hilar perforant path-associated (HIPP) cells of the dentate gyrus mediate the devaluation of background context memory during Pavlovian fear conditioning. The salience adjustment is sensitive to reduction of hilar neuropeptide Y (NPY) expression via dominant negative CREB expression in HIPP cells and to acute blockage of NPY-Y1 receptors in the dentate gyrus during conditioning. We show that NPY transmission and HIPP cell activity contribute to inhibitory effects of acetylcholine in the dentate gyrus and that M1 muscarinic receptors mediate the cholinergic activation of HIPP cells as well as their control of background context salience. Our data provide evidence for a peptidergic local circuit in the dentate gyrus that mediates the cholinergic encoding of background context salience during fear memory acquisition.Intra-hippocampal circuits are essential for associating a background context with behaviorally salient stimuli and involve cholinergic modulation at SST+ interneurons. Here the authors show that the salience of the background context memory is modulated through muscarinic activation of NPY+ hilar perforant path associated interneurons and NPY signaling in the dentate gyrus.

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The formation of fear memories is a powerful and highly evolutionary conserved mechanism that serves the behavioral adaptation to environmental threats. Accordingly, classical fear conditioning paradigms have been employed to investigate fundamental molecular processes of memory formation. Evidence suggests that a circadian regulation mechanism allows for a timestamping of such fear memories and controlling memory salience during both their acquisition and their modification after retrieval. These mechanisms include an expression of molecular clocks in neurons of the amygdala, hippocampus, and medial prefrontal cortex and their tight interaction with the intracellular signaling pathways that mediate neural plasticity and information storage. The cellular activities are coordinated across different brain regions and neural circuits through the release of glucocorticoids and neuromodulators such as acetylcholine, which integrate circadian and memory-related activation. Disturbance of this interplay by circadian phase shifts or traumatic experience appears to be an important factor in the development of stress-related psychopathology, considering these circadian components are of critical importance for optimizing therapeutic approaches to these disorders.

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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.

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Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

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Novel RNA-guided cellular functions are paralleled by an increasing number of RNA-binding proteins (RBPs). Here we present 'serial RNA interactome capture' (serIC), a multiple purification procedure of ultraviolet-crosslinked poly(A)-RNA-protein complexes that enables global RBP detection with high specificity. We apply serIC to the nuclei of proliferating K562 cells to obtain the first human nuclear RNA interactome. The domain composition of the 382 identified nuclear RBPs markedly differs from previous IC experiments, including few factors without known RNA-binding domains that are in good agreement with computationally predicted RNA binding. serIC extends the number of DNA-RNA-binding proteins (DRBPs), and reveals a network of RBPs involved in p53 signalling and double-strand break repair. serIC is an effective tool to couple global RBP capture with additional selection or labelling steps for specific detection of highly purified RBPs.

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Childhood trauma is a well-described risk factor for the development of stress-related psychopathology such as posttraumatic stress disorder or depression later in life. Childhood adversity can be modeled in rodents by juvenile stress (JS) protocols, resulting in impaired coping with stressful challenges in adulthood. In the current study, we investigated the long-lasting impact of JS on the expression of molecular factors for glutamate and γ-aminobutyric acid (GABA) uptake and turnover in sublayers of the dentate gyrus (DG) using laser microdissection and quantitative real-time polymerase chain reaction. We observed reduced mRNA expression levels after JS for factors mediating astrocytic glutamate and GABA uptake and degradation. These alterations were prominently observed in the dorsal but not ventral DG granule cell layer, indicating a lasting change in astrocytic GABA and glutamate metabolism that may affect dorsal DG network activity. Indeed, we observed increased inhibition and a lack of facilitation in response to paired-pulse stimulation at short interstimulus intervals in the dorsal DG after JS, while no alterations were evident in basal synaptic transmission or forms of long-term plasticity. The shift in paired-pulse response was mimicked by pharmacologically blocking the astrocytic GABA transporter GAT-3 in naïve animals. Accordingly, reduced expression levels of GAT-3 were confirmed at the protein level in the dorsal granule cell layer of rats stressed in juvenility. Together, these data demonstrate a lasting shift in the excitatory/inhibitory balance of dorsal DG network activity by JS that appears to be mediated by decreased GABA uptake into astrocytes.

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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.

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Bidirectional initiation of transcription by RNA polymerase II occurs prevalently at active promoters during protein-coding gene (PCG) expression. Upstream, antisense noncoding RNAs (ncRNAs) of differing lengths, stabilities and processings are being expressed from these promoters in concert with downstream, processive messenger RNA transcription. Although abundantly detected, the functional role and regulatory capacity of such transcripts have only been determined for individual cases. Long ncRNAs in general are reportedly able to regulate all steps of the gene expression process. Therefore, to get insight into the functionality of long ncRNAs transcribed bidirectionally from cancer-associated PCGs is of interest, as expression changes of tumor suppressor genes and oncogenes are prevalent in cancer.Here, we review the sources and characteristics of antisense transcription occurring at PCG loci in the human genome, and focus on the functional impact of bidirectional long ncRNA expression at cancer-associated PCGs.

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The CA3 associative network plays a critical role in the generation of network activity patterns related to emotional state and fear memory. We investigated long-term changes in the corticosterone (CORT)-sensitive function of this network following fear conditioning and fear memory reactivation. In acute slice preparations from mice trained in either condition, the ratio of orthodromic population spike (PS) to antidromic PS was reduced compared to unconditioned animals, indicating a decrease in efficacy of neuronal coupling within the associative CA3 network. However, spontaneous sharp wave-ripples (SW-R), which are thought to arise from this network, remained unaltered. Following CORT application, we observed an increase in orthodromic PS and a normalization to control levels of their ratio to antidromic PS, while SW-R increased in slices of fear conditioned and fear reactivated mice, but not in slices of unconditioned controls. Together with our previous observations of altered hippocampal gamma activity under these learning paradigms, these data suggest that fear conditioning and fear reactivation lastingly alters the CORT-sensitive configuration of different network activity patterns generated by the CA3 associational network. Observed changes in the mRNA expression of receptors for glutamate, GABA and cannabinoids in the stratum pyramidale of area CA3 may provide a molecular mechanism for these adaptive changes.

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