R. F. Jansen

Gene expression in major depressive disorder

The search for genetic variants underlying major depressive disorder (MDD) has not yet provided firm leads to its underlying molecular biology. A complementary approach is to study gene expression in relation to MDD. We measured gene expression in peripheral blood from 1848 subjects from The Netherlands Study of Depression and Anxiety. Subjects were divided into current MDD (N=882), remitted MDD (N=635) and control (N=331) groups. MDD status and gene expression were measured again 2 years later in 414 subjects. The strongest gene expression differences were between the current MDD and control groups (129 genes at false-discovery rate, FDR<0.1). Gene expression differences across MDD status were largely unrelated to antidepressant use, inflammatory status and blood cell counts. Genes associated with MDD were enriched for interleukin-6 (IL-6)-signaling and natural killer (NK) cell pathways. We identified 13 gene expression clusters with specific clusters enriched for genes involved in NK cell activation (downregulated in current MDD, FDR=5.8 × 10−5) and IL-6 pathways (upregulated in current MDD, FDR=3.2 × 10−3). Longitudinal analyses largely confirmed results observed in the cross-sectional data. Comparisons of gene expression results to the Psychiatric Genomics Consortium (PGC) MDD genome-wide association study results revealed overlap with DVL3. In conclusion, multiple gene expression associations with MDD were identified and suggest a measurable impact of current MDD state on gene expression. Identified genes and gene clusters are enriched with immune pathways previously associated with the etiology of MDD, in line with the immune suppression and immune activation hypothesis of MDD.

Melatonin affects the temporal organization of the song of the zebra finch.

In birds and mammals, including humans, melatonin‐binding sites are abundant in brain areas that have no known clock function. Although the role of such binding sites is still unclear, it is assumed that these sites link neural functions to circadian or circannual demands of neuroendocrine homeostasis and reproduction. To investigate a possible direct role of melatonin in motor control, we studied the song and neural song system of the zebra finch. Neurons of two sensory‐motor areas of the descending song control circuit that are crucial for the organization of the song pattern, the HVC and RA, express the melatonin‐1B receptor (Mel1B), while the hypoglossal motor neurons of the song circuit express melatonin‐1C receptors (Mel1C). Application of melatonin to brain slices decreases the firing‐rate of RA‐neurons. Systemic administration of a Mel1B antagonist at the beginning of the night shortens the song and motif length and affects the song syllable lengths produced the next day. The temporal pattern of the song, however, does not undergo daily changes. Thus, melatonin is likely to affect a non‐circadian motor pattern by local modulation of song control neurons and in consequence alters a sexual signal, the song of the zebra finch.

Brain-derived neurotrophic factor signaling in the HVC is required for testosterone-induced song of female canaries.

Testosterone-induced singing in songbirds is thought to involve testosterone-dependent morphological changes that include angiogenesis and neuronal recruitment into the HVC, a central part of the song control circuit. Previous work showed that testosterone induces the production of vascular endothelial growth factor (VEGF) and its receptor (VEGFR2 tyrosine kinase), which in turn leads to an upregulation of brain-derived neurotrophic factor (BDNF) production in HVC endothelial cells. Here we report for the first time that systemic inhibition of the VEGFR2 tyrosine kinase is sufficient to block testosterone-induced song in adult female canaries, despite sustained androgen exposure and the persistence of the effects of testosterone on HVC morphology. Expression of exogenous BDNF in HVC, induced locally by in situ transfection, reversed the VEGFR2 inhibition-mediated blockade of song development, thereby restoring the behavioral phenotype associated with androgen-induced song. The VEGFR2-inhibited, BDNF-treated females developed elaborate male-like song that included large syllable repertoires and high syllable repetition rates, features known to attract females. Importantly, although functionally competent new neurons were recruited to HVC after testosterone treatment, the time course of neuronal addition appeared to follow BDNF-induced song development. These findings indicate that testosterone-associated VEGFR2 activity is required for androgen-induced song in adult songbirds and that the behavioral effects of VEGFR2 inhibition can be rescued by BDNF within the adult HVC.

Copulation in the hermaphroditic snail Lymnaea stagnalis: a review

Summary Male copulatory behavior of the hermaphroditic snail Lymnaea stagnalis is a complex one: the appetitive behavior consists of a number of elements which do not always appear in the same sequence and have variable durations. Backfills of the penis nerve revealed the neurons that send projections to the male copulatory apparatus. Immunocytochemical experiments have demonstrated that these neurons contain at least ten different messenger molecules. Based on in situ hybridization and chemical purification data, it is suspected that this number will probably be doubled. How the different neurons and the molecules they contain might be involved in generation of the different elements of male copulatory behavior is discussed.

Assessing aversive emotional states through the heart in mice: implications for cardiovascular dysregulation in affective disorders

Beat-to-beat fluctuations of heart rate (HR) convey information of the brain state with the cardiac time series reflecting the flow of efferent nerve traffic of the autonomic nervous system. Instantaneous HR was studied in mice during exposure to novelty and the expression of fear conditioned to an auditory cue as affective challenge to characterize baseline dynamics and conditioned adjustments to learned fear. These studies included pharmacological and genetic interventions of brain systems implicated in aversive emotional states, the corticotropin-releasing factor (CRF) system and the serotonin (5-HT)1A receptor. Non-linear analyses of neuroautonomic cardiac control provide for functionally adequate measures of dynamical properties. Both CRF1 and 5-HT1A receptor agonists elicited profound sympatho-vagal antagonism with pathological HR dynamics indicative of central autonomic dysregulation via mechanisms resulting in impaired fear adjustment. Non-linear measures provide for a qualitative assessment of dynamical features with regard to physiological or pathological state, are crucial for the translation of results from mouse to man, and may improve our understanding of brain-heart interactions for autonomic dysregulation in affective disorders.

The reconstruction of individual spike trains from extracellular multineuron recordings using a neural network emulation program

A method for the reconstruction of the individual spike trains from extracellular multineuron recordings is described. A neural network emulation program is trained to recognize a sample set of digitized spikes. The digitized spikes are fed into the neural network, and the network output is used to classify spikes in terms of the training set. The system runs on any PC and its speed makes is especially well suited for the analysis of large amounts of data.

Atrophy and degeneration of peptidergic neurons and cessation of egg laying in the aging pond snail Lymnaea stagnalis.

The morphology of the neuroendocrine caudodorsal cells (CDCs), which are involved in the regulation of female reproduction in the pond snail Lymnaea stagnalis, was studied in young (200 to 234 days of age) and old (400 to 500 days) animals. Lucifer Yellow fills of ventral CDCs showed that in young animals ventral CDCs branch ipsilaterally as well as contralaterally in the cerebral commissure. In old animals these branches were reduced at different degrees and in some cases even lacking completely, leaving only an axon crossing the commissure. Immunocytochemical stainings with antibodies against CDC peptides (CDCH-I and alpha CDCP) corroborated the finding that ventral CDCs degenerate. Among the other types of CDCs (dorsal, lateral), degeneration was found as well. The immunocytochemical findings showed that in old animals the axon terminals of the CDCs were strongly stained, indicating that they are packed with secretory vesicles containing peptides. It was also found that these darkly stained, peptide-containing axon terminals protruded into the perineurium. These findings suggest that accumulation of peptides in the terminals of the CDCs of old animals may be due to the impaired release. The relationship between atrophy and degeneration of CDCs and cessation of egg-laying activity in Lymnaea is discussed.

Gene expression in major depressive disorder: ERRATUM

Correction to: Molecular Psychiatry advance online publication, 26 May 2015; doi:10.1038/mp.2015.57 Following publication of the above article, the authors noticed that the Supplementary Figure legends were not published with the paper. The legends accompany this erratum. In addition, the Supplementary Tables were originally presented as PDF files.

Sociality and learning in social software

Lately, Web2.0 or social software receives a lot of attention, both by practitioners and academics, because of its ability to support social learning processes. We explore two criticisms that assess the learning impediments within current manifestations of social software. Firstly, we hold that social software is biased towards market-organising and secondly, it lacks a social theory of learning. By using both the social learning cycle of Boisot and the learning architecture of Wenger we theorise about structures that could guide the design of learning within social software. The objective of this paper is to support the design for object-centred sociality in social software to enable a more social approach to learning.

Display of individuality in avoidance behavior and risk assessment of inbred mice

Factors determining individuality are still poorly understood. Rodents are excellent model organisms to study individuality, due to a rich behavioral repertoire and the availability of well-characterized isogenic populations. However, most current behavioral assays for rodents have short test duration in novel test environments and require human interference, which introduce coercion, thereby limiting the assessment of naturally occurring individuality. Thus, we developed an automated behavior system to longitudinally monitor conditioned fear for assessing PTSD-like behavior in individual mice. The system consists of a safe home compartment connected to a risk-prone test compartment (TC). Entry and exploration of the TC is solely based on deliberate choice determined by individual fear responsiveness and fear extinction. In this novel ethological assay, C57BL/6J mice show homogeneous responses after shock exposure (innate fear), but striking variation in long-lasting fear responses based on avoidance and risk assessment (learned fear), including automated stretch-attend posture quantification. TC entry (retention) latencies after foot shock differed >24 h and the re-explored TC area differed >50% among inbred mice. Next, we compared two closely related C57BL/6 substrains. Despite substantial individual differences, previously observed higher fear of C57BL/6N vs. C57BL/6J mice was reconfirmed, whereas fear extinction was fast and did not differ. The observed variation in fear expression in isogenic mice suggests individual differences in coping style with PTSD-like avoidance. Investigating the assumed epigenetic mechanisms, with reduced interpretational ambiguity and enhanced translational value in this assay, may help improve understanding of personality type-dependent susceptibility and resilience to neuropsychiatric disorders such as PTSD.