Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks The article “Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks”, written by Dhana Wolf, Martin Klasen, Patrick Eisner, Florian D. Zepf, Mikhail Zvyagintsev, Nicola Palomero‑Gallagher, René Weber, Albrecht Eisert, Klaus Mathiak was originally published electronically on the publisher’s internet portal (currently SpringerLink) on June, 08, 2018 without open access.

Altered motor, anxiety-related and attentional task performance at baseline associate with multiple gene copies of the vesicular acetylcholine transporter and related protein overexpression in ChAT::Cre+ rats Abstract Transgenic rodents expressing Cre recombinase cell specifically are used for exploring mechanisms regulating behavior, including those mediated by cholinergic signaling. However, it was recently reported that transgenic mice overexpressing a bacterial artificial chromosome containing choline acetyltransferase (ChAT) gene, for synthesizing the neurotransmitter acetylcholine, present with multiple vesicular acetylcholine transporter (VAChT) gene copies, resulting in altered cholinergic tone and accompanying behavioral abnormalities. Since ChAT::Cre+ rats, used increasingly for understanding the biological basis of CNS disorders, utilize the mouse ChAT promotor to control Cre recombinase expression, we assessed for similar genotypical and phenotypical differences in such rats compared to wild-type siblings. The rats were assessed for mouse VAChT copy number, VAChT protein expression levels and for sustained attention, response control and anxiety. Rats were also subjected to a contextual fear conditioning paradigm using an unconditional fear-inducing stimulus (electrical foot shocks), with blood samples taken at baseline, the fear acquisition phase and retention testing, for measuring blood plasma markers of hypothalamic–pituitary–adrenal gland (HPA)-axis activity. ChAT::Cre+ rats expressed multiple mouse VAChT gene copies, resulting in significantly higher VAChT protein expression, revealed anxiolytic behavior, hyperlocomotion and deficits in tasks requiring sustained attention. The HPA-axis was intact, with unaltered circulatory levels of acute stress-induced corticosterone, leptin and glucose. Our findings, therefore, reveal that in ChAT::Cre+ rats, VAChT overexpression associates with significant alterations of certain cognitive, motor and affective functions. Although highly useful as an experimental tool, it is essential to consider the potential effects of altered cholinergic transmission on baseline behavior in ChAT::Cre rats.

TMS reveals inhibitory extrastriate cortico-cortical feedback modulation of V1 activity in humans Abstract The interaction between the primary visual cortex (V1) and extrastriate visual areas provides the first building blocks in our perception of the world. V2, in particular, seems to play a crucial role in shaping contextual modulation information through feedback projections to V1. However, whether this feedback is inhibitory or excitatory is still unclear. In order to test the nature of V2 feedback to V1, we used neuronavigation-guided offline inhibitory transcranial magnetic stimulation (TMS) on V2 before testing participants on collinear facilitation, a contrast detection task with lateral masking. This contextual modulation task is thought to rely on horizontal connections in V1 and possibly extrastriate feedback. Results showed that when inhibitory TMS was delivered over V2, contrast thresholds decreased for targets presented in the contralateral hemifield, consistent with the retinotopic mapping of this area, while having no effect for targets presented in the ipsilateral hemifield or after control (CZ) stimulation. These results suggest that feedback from V2 to V1 during contextual modulation is mostly inhibitory, corroborating recent observations in monkey electrophysiology and extending this mechanism to human visual system. Moreover, we provide for the first time direct evidence of the involvement of extrastriate visual areas in collinear facilitation.

Individual differences in neonatal white matter are associated with executive function at 3 years of age Abstract The development of executive function (EF) in early childhood contributes to social and academic aspects of school readiness and facilitates emerging self-regulatory competence. Numerous efforts are underway to identify aspects of early brain development that contribute to emerging EF. Existing research supports the importance of multiple white matter tracts for EF in older children and adults. However, this research has not been extended to young children. In this study, we consider neonatal white matter microstructure in relation to children’s performance on a battery of EF tasks three years later. We obtained diffusion tensor imaging data from a sample of neonates (N = 27) shortly after birth. At 3 years of age, children completed a computerized battery of EF tasks. The primary data analyses involved regression models estimated for each white matter tract. Multiple demographic and measure-related covariates were included in each model. A follow-up analysis of tracts determined to be associated with EF examined individual data points along those fibers. Among the white matter tracts analyzed, the cingulum was significantly associated with EF at 3 years of age. Specifically, lower axial diffusivity values along the cingulum were associated with increased performance on the EF battery. Results are discussed as providing initial evidence that individual differences in neonatal brain structure may facilitate the acquisition of EF abilities in early childhood. These findings are consistent with previous research that supports the value of the cingulum for higher-order cognitive abilities. Cautions and implications of these results are considered.

Source-based morphometry: a decade of covarying structural brain patterns Abstract In this paper, we review and discuss brain imaging studies which have used the source-based morphometry (SBM) approach over the past decade. SBM is a data-driven linear multivariate approach for decomposing structural brain imaging data into commonly covarying imaging components and subject-specific loading parameters. It is a well-established technique which has predominantly been used to study neuroanatomic differences between healthy controls and patients with neuropsychiatric diseases. We start by discussing the advantages of this technique over univariate analysis for imaging studies, followed by a discussion of results from recent studies which have successfully applied this methodology. We also present recent extensions of this framework including nonlinear SBM, biclustered independent component analysis (B-ICA) and conclude with the possible directions of work for future.

Thalamic degeneration in MPTP-treated Parkinsonian monkeys: impact upon glutamatergic innervation of striatal cholinergic interneurons Abstract In both Parkinson’s disease (PD) patients and MPTP-treated non-human primates, there is a profound neuronal degeneration of the intralaminar centromedian/parafascicular (CM/Pf) thalamic complex. Although this thalamic pathology has long been established in PD (and other neurodegenerative disorders), the impact of CM/Pf cell loss on the integrity of the thalamo-striatal glutamatergic system and its regulatory functions upon striatal neurons remain unknown. In the striatum, cholinergic interneurons (ChIs) are important constituents of the striatal microcircuitry and represent one of the main targets of CM/Pf-striatal projections. Using light and electron microscopy approaches, we have analyzed the potential impact of CM/Pf neuronal loss on the anatomy of the synaptic connections between thalamic terminals (vGluT2-positive) and ChIs neurons in the striatum of parkinsonian monkeys treated chronically with MPTP. The following conclusions can be drawn from our observations: (1) as reported in PD patients, and in our previous monkey study, CM/Pf neurons undergo profound degeneration in monkeys chronically treated with low doses of MPTP. (2) In the caudate (head and body) nucleus of parkinsonian monkeys, there is an increased density of ChIs. (3) Despite the robust loss of CM/Pf neurons, no significant change was found in the density of thalamostriatal (vGluT2-positive) terminals, and in the prevalence of vGluT2-positive terminals in contact with ChIs in parkinsonian monkeys. These findings provide new information about the state of thalamic innervation of the striatum in parkinsonian monkeys with CM/Pf degeneration, and bring up an additional level of intricacy to the consequences of thalamic pathology upon the functional microcircuitry of the thalamostriatal system in parkinsonism. Future studies are needed to assess the importance of CM/Pf neuronal loss, and its potential consequences on the neuroplastic changes induced in the synaptic organization of the thalamostriatal system, in the development of early cognitive impairments in PD.

Developing brain as a source of circulating norepinephrine in rats during the critical period of morphogenesis Abstract The development of individual organs and the whole organism is under the control by morphogenetic factors over the critical period of morphogenesis. This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ during morphogenesis, in rats during the perinatal period (Ugrumov in Neuro Chem 35:837–850, 2010). Norepinephrine, which is a morphogenetic factor, was used as a marker of the endocrine activity of the developing brain, although it is also secreted by peripheral organs. In this study, it was first shown that the concentration of norepinephrine in the peripheral blood of neonatal rats is sufficient to ensure the morphogenetic effect on the peripheral organs and the brain itself. Using pharmacological suppression of norepinephrine production in the brain, but not in peripheral organs, it was shown that norepinephrine is delivered from the brain to the general circulation in neonatal rats, that is, during morphogenesis. In fact, even partial suppression of norepinephrine production in the brain of neonatal rats led to a significant decrease of norepinephrine concentration in plasma, suggesting that at this time the brain is an important source of circulating norepinephrine. Conversely, the suppression of the production of norepinephrine in the brain of prepubertal rats did not cause a change in its concentration in plasma, showing no secretion of brain-derived norepinephrine to the bloodstream after morphogenesis. The above data support our hypothesis that morphogenetic factors, including norepinephrine, are delivered from the developing brain to the bloodstream, which occurs only during the critical period of morphogenesis.

Structure related to function: prefrontal surface area has an indirect effect on the relationship between amygdala volume and trait neuroticism Abstract Trait neuroticism refers to individual differences in negative emotional response to threat, frustration, or loss, operationally defined by elevated levels of irritability, anger, sadness, anxiety, worry, hostility, self-consciousness, and vulnerability to mental and physical difficulties. While functional studies have been fairly consistent when identifying regions associated with neuroticism during emotional stimuli, structural imagining studies do not tend to find a relationship between amygdala volume and trait neuroticism. There is a great deal of functional evidence that frontoparietal areas are related to the amygdala, and to emotional reactivity more generally, as a function of their involvement in emotion regulation. Specifically, top–down emotion appraisal and expression appear to involve parts of the dorsolateral and dorsomedial prefrontal cortices, which operate at least in part via the indirect modulation of the amygdala. It was hypothesized that cortical surface area and cortical thickness in regions associated with emotion appraisal/expression and emotional attention (i.e., superior frontal and rostral middle frontal gyri, respectively) would have an indirect effect on the relationship between amygdala volume and self-reported neuroticism (respectively), potentially explaining the inconsistency in the structural literature. In sample of 1106 adults, superior frontal and rostral middle frontal gyri, as parcellated by Freesurfer, were examined as potentially restricting variance in a model of indirect effects, which may elucidate the overall relationship between cortical and subcortical gray matter volume and trait neuroticism. Results indicated that, despite no association between bilateral amygdala volume and trait neuroticism, when right superior frontal surface area was entered into the model of indirect effects, a significant relationship between amygdala volume and trait neuroticism emerged. Two of the three remaining models indicated that cortical surface area had an indirect effect on the relationship between amygdala volume and trait neuroticism. These findings highlight the relationship between structural and functional neuroimaging studies. Specifically, the results indicate that when volume is related to behavior, individual differences in higher-order cortical regions, particularly surface area, may help to better understand the relationship between emotion and subcortical gray matter volume.

Shaping of discrete auditory inputs to extramodular zones of the lateral cortex of the inferior colliculus Abstract The multimodal lateral cortex of the inferior colliculus (LCIC) exhibits a modular-extramodular micro-organization that is evident early in development. In addition to a set of neurochemical markers that reliably highlight its modular-extramodular organization (e.g. modules: GAD67-positive, extramodular zones: calretinin-positive, CR), mature projection patterns suggest that major LCIC afferents recognize and adhere to such a framework. In adult mice, distinct afferent projections appear segregated, with somatosensory inputs targeting LCIC modules and auditory inputs surrounding extramodular fields. Currently lacking is an understanding regarding the development and shaping of multimodal LCIC afferents with respect to its emerging modular-extramodular microarchitecture. Combining living slice tract-tracing and immunocytochemical approaches in GAD67-GFP knock-in mice, the present study characterizes the critical period of projection shaping for LCIC auditory afferents arising from its neighboring central nucleus (CNIC). Both crossed and uncrossed projection patterns exhibit LCIC extramodular mapping characteristics that emerge from initially diffuse distributions. Projection mismatch with GAD-defined modules and alignment with encompassing extramodular zones becomes increasingly clear over the early postnatal period (birth to postnatal day 12). CNIC inputs terminate almost exclusively in extramodular zones that express CR. These findings suggest multimodal LCIC inputs may initially be sparse and intermingle, prior to segregation into distinct processing streams. Future experiments are needed to determine the likely complex interactions and mechanisms (e.g. activity-dependent and independent) responsible for shaping early modality-specific LCIC circuits.

Segregated precuneus network and default mode network in naturalistic imaging Abstract A resting-state network centered at the precuneus has been recently proposed as a precuneus network (PCUN) or “parietal memory network”. Due to its spatial adjacency and overlapping with the default mode network (DMN), it is still not consensus to consider PCUN and DMN separately. Whether considering PCUN and DMN as different networks is a critical question that influences our understanding of brain functions and impairments. Previous resting-state studies using multiple methodologies have demonstrated a robust separation of the two networks. However, since there is no gold standard in justifying the functional difference between the networks in resting-state, we still lack of biological evidence to directly support the separation of the two networks. This study compared the responses and functional couplings of PCUN and DMN when participants were watching a movie and examined how the continuity of the movie context modulated the response of the networks. We identified PCUN and DMN in resting-state fMRI of 48 healthy subjects. The networks’ response to a context-rich video and its context-shuffled version was characterized using the variance of temporal fluctuations and functional connectivity metrics. The results showed that (1) scrambling the contextual information altered the fluctuation level of DMN and PCUN in reversed ways; (2) compared to DMN, the FC within PCUN showed significantly higher sensitivity to the contextual continuity; (3) PCUN exhibited a significantly stronger functional network connectivity with the primary visual regions than DMN. These findings provide evidence for the distinct functional roles of PCUN and DMN in processing context-rich information and call for separately considering the functions and impairments of these networks in resting-state studies.