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Abstract Background Migraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors. Methods We used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol. Results We found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions’ interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity. Conclusions Altogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol’s prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing.

Measuring autonomic parameters like heart rate in behaving mice is not only a standard procedure in cardiovascular research but is applied in many other interdisciplinary research fields. With an electrocardiogram (ECG), the heart rate can be measured by deriving the electrical potential between subcutaneously implanted wires across the chest. This is an inexpensive and easy-to-implement technique and particularly suited for repeated recordings of up to eight weeks. This protocol describes a step-by-step guide for manufacturing the needed equipment, performing the surgical procedure of electrode implantation, and processing of acquired data, yielding accurate and reliable detection of heartbeats and calculation of heart rate (HR). We provide MATLAB graphical user interface (GUI)–based tools to extract and start processing the acquired data without a lot of coding knowledge. Finally, based on an example of a data set acquired in the context of defensive reactions, we discuss the potential and pitfalls in analyzing HR data.Key features• Next to surgical steps, the protocol provides a detailed description of manufacturing custom-made ECG connectors and a shielded, light-weight patch cable.• Suitable for recordings in which signal quality is challenged by ambient noise or noise from other recording devices.• Described for 2-channel differential recording but easily expandable to record from more channels.• Includes a summary of potential analysis methods and a discussion on the interpretation of HR dynamics in the case study of fear states.

The signal-to-noise ratio in bioimages is often low, which is problematic for segmentation. Here the authors report a deep learning method, deepflash2, to facilitate the segmentation of ambiguous bioimages through multi-expert annotations and integrated quality assurance.

Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states.

The central amygdala inhibitory microcircuits mediate fear extinction by reversible, stimulus- and context-specific changes in neuronal responses. These alterations are absent when extinction is deficient and selective silencing of PKCδ neurons impairs fear extinction.

Brain-wide neural circuits enable bi- and quadrupeds to express adaptive locomotor behaviors in a context- and state-dependent manner, e.g., in response to threats or rewards. These behaviors include dynamic transitions between initiation, maintenance and termination of locomotion. Advances within the last decade have revealed an intricate coordination of these individual locomotion phases by complex interaction of multiple brain circuits. This review provides an overview of the neural basis of state-dependent modulation of locomotion initiation, maintenance and termination, with a focus on insights from circuit-centered studies in rodents. The reviewed evidence indicates that a brain-wide network involving excitatory circuit elements connecting cortex, midbrain and medullary areas appears to be the common substrate for the initiation of locomotion across different higher-order states. Specific network elements within motor cortex and the mesencephalic locomotor region drive the initial postural adjustment and the initiation of locomotion. Microcircuits of the basal ganglia, by implementing action-selection computations, trigger goal-directed locomotion. The initiation of locomotion is regulated by neuromodulatory circuits residing in the basal forebrain, the hypothalamus, and medullary regions such as locus coeruleus. The maintenance of locomotion requires the interaction of an even larger neuronal network involving motor, sensory and associative cortical elements, as well as defined circuits within the superior colliculus, the cerebellum, the periaqueductal gray, the mesencephalic locomotor region and the medullary reticular formation. Finally, locomotor arrest as an important component of defensive emotional states, such as acute anxiety, is mediated via a network of survival circuits involving hypothalamus, amygdala, periaqueductal gray and medullary premotor centers. By moving beyond the organizational principle of functional brain regions, this review promotes a circuit-centered perspective of locomotor regulation by higher-order states, and emphasizes the importance of individual network elements such as cell types and projection pathways. The realization that dysfunction within smaller, identifiable circuit elements can affect the larger network function supports more mechanistic and targeted therapeutic intervention in the treatment of motor network disorders.

TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.

A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.

AimsThe objective of this study is to investigate whether type of depressive symptoms (i.e. cognitive-affective or somatic) is related to a patient-perceived need for professional psychological care in individuals with diabetes.MethodsIn total 2266 participants were recruited as part of the screening procedure for a multi-center randomized controlled trial on the treatment of depressive symptoms among individuals with diabetes. Individuals were invited to complete Beck Depression Inventory-II (BDI-II). Patients with elevated depressive symptoms (BDI-II ≥14) were interviewed about their psychological care need. Based on their care needs patients were categorized into: unmet need, no need, met need and unclear need. These groups were compared on type of depressive symptoms, as categorized into cognitive-affective symptoms and somatic symptoms.Results568 eligible individuals had elevated depressive symptoms, of whom 519 were reached. Among these depressed individuals, 19.7% (102 of 519) had an unmet need for psychological care. Participants with an unmet need were younger (pConclusionsCognitive-affective symptoms of depression-but not somatic symptoms-were associated with an unmet need for psychological care among depressed individuals with diabetes. Future research is needed to reveal better predictors explaining the discrepancy between distress and low care needs in order to optimize screening procedures.

Präventive Massnahmen zur frühen Förderung des Zweitspracherwerbs werden u.a. in Spielgruppen implementiert. In der diesbezüglichen Qualifizierung der Spielgruppenleitenden im Kanton Basel-Stadt spielt der Ansatz der alltagsintegrierten Förderung eine tragende Rolle. Jegliche Dialoge, Erwachsenen- wie kind-initiierte, sind hier Fördergelegenheiten. In einer Teilstudie des SNF-geförderten Forschungsprojekts «MeKi – Frühe sprachliche Förderung mehrsprachiger Kinder ab 3 Jahren» werden die Interaktionen zwischen Spielgruppenleitenden und einzelnen Zielkindern videographiert und gesprächsanalytisch untersucht. Der folgende Beitrag konzentriert sich auf die empirisch ermittelten Interaktionsarten und die Interpretation ihres Sprachfördergehalts.

Cognitive Behavior Therapy (CBT) and Mindfulness-Based Cognitive Therapy (MBCT) have shown to be effective interventions for treating depressive symptoms in patients with diabetes. However, little is known about which intervention works best for whom (i.e., moderators of efficacy). The aim of this study was to identify variables that differentially predicted response to either CBT or MBCT (i.e., prescriptive predictors).The sample consisted of 91 adult outpatients with type 1 or type 2 diabetes and comorbid depressive symptoms (i.e., BDI-II ≥ 14) who were randomized to either individual 8-week CBT (n = 45) or individual 8-week MBCT (n = 46). Patients were followed for a year and depressive symptoms were measured at pre-treatment, post-treatment, and at 9-months follow-up. The predictive effect of demographics, depression related characteristics, and disease specific characteristics on change in depressive symptoms was assessed by means of hierarchical regression analyses.Analyses showed that education was the only factor that differentially predicted a decrease in depressive symptoms directly after the interventions. At post-treatment, individuals with higher educational attainment responded better to MBCT, as compared to CBT. Yet, this effect was not apparent at 9-months follow-up.This study did not identify variables that robustly differentially predicted treatment effectiveness of CBT and MBCT, indicating that both CBT and MBCT are accessible interventions that are effective for treating depressive symptoms in broad populations with diabetes. More research is needed to guide patient-treatment matching in clinical practice.

Abstract: The role of corticotropin-releasing factor in autonomic regulation of heart rate, heart rate variability and behavior responses was investigated in two genetic mouse models: corticotropin-releasing factor receptor 1-deficient mice, and corticotropin-releasing factor-transgenic mice overexpressing corticotropin-releasing factor. Heart rate was recorded by radio-telemetry during novelty exposure and auditory fear conditioning. Locomotor activity and freezing served as behavioral indices. Locomotor activity and heart rate were invariably increased in response to novelty exposure in both corticotropin-releasing factor receptor 1-deficient mice and littermate wild-type controls. The heart rate responses during retention of conditioned auditory fear and the exponential relationship between heart rate and heart rate variability were unaffected by genotype. Moreover, conditioned fear responses inferred from multiple behavioral measures including freezing did not differ between corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor receptor 1 wild-type control mice. Corticotropin-releasing factor-transgenic mice exhibited markedly reduced locomotor activity during novelty exposure when compared with littermate wild-type controls. Baseline and novelty-driven heart rate was slightly elevated in corticotropin-releasing factor-transgenic mice, whereas the novelty-induced increase of heart rate was not different between genotypes. In contrast, corticotropin-releasing factor-transgenic mice did not display a heart rate response indicative of conditioned auditory fear. It is concluded that corticotropin-releasing factor receptor 1-deficiency does not affect heart rate adjustment and behavioral responses to acute fearful stimuli. The resiliency of behavioral and cardiovascular patterns elevation argues against the involvement of corticotropin-releasing factor receptor 1 in acute emotional regulation on these two functional levels despite an absent corticosterone elevation in corticotropin-releasing factor receptor 1-deficient mice. It is hypothesized that the lack of a conditioned heart rate response in corticotropin-releasing factor-transgenic mice is attributable to an impairment of cognitive function. The results are compared with those of corticotropin-releasing factor receptor 2-deficient mice, and the role of the corticotropin-releasing factor system in cardiovascular regulation is discussed. [Copyright &y& Elsevier]