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Variation in the serotonin transporter genotype is associated with maternal restraint and rejection of infants: A nonhuman primate (Macaca mulatta) model
Full text linkStudies show that maternal behaviors are mediated by the bivariate serotonin transporter (5-HTT) genotype, although the findings are mixed, with some studies showing that mothers with the s allele exhibit increased maternal sensitivity, while other studies show that mothers with the s allele show decreased maternal sensitivity. Nonhuman primate studies offer increased control over extraneous variables and may contribute to a better understanding of the effects of the 5-HTT genotype on maternal sensitivity. This study assesses the influence of 5-HTT genotype variation on maternal sensitivity in parenting in 125 rhesus macaque mothers (Macaca mulatta) during the first three-months of their infants' lives, an age well before typical infants undergo weaning. Mothers were genotyped for the 5-HTT genotype and maternal behaviors were collected, including neglectfulness, sensitivity, and premature rejections during undisturbed social interactions. Results showed that mothers homozygous for the s allele rejected their infants the most and restrained their infants the least, an indication that mothers with the s allele are more likely to neglect their infants' psychological and physical needs. These findings suggest that, at an age when an infant's needs are based on warmth, security, and protection, mothers with an s allele exhibit less sensitive maternal behaviors. High rates of rejections and low rates of restraints are behaviors that typically characterize premature weaning and are inappropriate for their infant's young age. This study is an important step in understanding the etiology of variability in maternal warmth and care, and further suggests that maternal 5-HTT genotype should be examined in studies assessing genetic influences on variation in maternal sensitivity, and ultimately, mother-infant attachment quality
Long‐term outcomes in <scp>ALG13‐Congenital Disorder of Glycosylation</scp>
No full textNational Center for Advancing Translational Sciences https://doi.org/10.13039/100006108National Institute of Child Health and Human Development https://doi.org/10.13039/10000007
Network analysis reveals abnormal functional brain circuitry in anxious dogs
No full textAnxiety is a common disease within human psychiatric disorders and has also been described as a frequently neuropsychiatric problem in dogs. Human neuroimaging studies showed abnormal functional brain networks might be involved in anxiety. In this study, we expected similar changes in network topology are also present in dogs. We performed resting-state functional MRI on 25 healthy dogs and 13 patients. The generic Canine Behavioral Assessment & Research Questionnaire was used to evaluate anxiety symptoms. We constructed functional brain networks and used graph theory to compare the differences between two groups. No significant differences in global network topology were found. However, focusing on the anxiety circuit, global efficiency and local efficiency were significantly higher, and characteristic path length was significantly lower in the amygdala in patients. We detected higher connectivity between amygdala-hippocampus, amygdala-mesencephalon, amygdala-thalamus, frontal lobe-hippocampus, frontal lobe-thalamus, and hippocampus-thalamus, all part of the anxiety circuit. Moreover, correlations between network metrics and anxiety symptoms were significant. Altered network measures in the amygdala were correlated with stranger-directed fear and excitability; altered degree in the hippocampus was related to attachment/attention seeking, trainability, and touch sensitivity; abnormal frontal lobe function was related to chasing and familiar dog aggression; attachment/attention seeking was correlated with functional connectivity between amygdala-hippocampus and amygdala-thalamus; familiar dog aggression was related to global network topology change. These findings may shed light on the aberrant topological organization of functional brain networks underlying anxiety in dogs
The role of suboptimal mitochondrial function in stress adaptation and depression pathogenesis
No full textThe brain requires massive amounts of energy to operate optimally. These demands are almost exclusively covered by the powerhouses of neurons, the mitochondria. Recently, a considerable body of evidence implicates impaired mitochondrial bioenergetics in psychopathology, although the mechanism behind this link remains elusive. Here we test the hypothesis that interaction of suboptimal mitochondrial function with chronic stress confers vulnerability to depression, using the novel Ndufs4 deficient transgenic mouse model. To this end, we subjected wild type and transgenic adult male mice to the well-established chronic variable stress (CVS) paradigm and assessed its effects on physiological parameters and affective behavior. We found that chronically stressed Ndufs4 deficient mice showed reduced exploration behavior and a markedly higher preference for the outer zone in the open field arena that is not decreased with time, a greater propensity to passive coping and earlier signs of behavioral despair in the forced swim test, but no significant loss of interest in self-care in the splash test and no weight change alterations. Moreover, cFos imaging analysis revealed that impaired mitochondrial function was linked with higher activity in the dorsomedial hypothalamic nucleus (DMH) in response to acute stress and aberrant spontaneous activity in significant stress-related areas, i.e DMH and the ventral portions of hippocampal CA1 and dentate gyrus, under conditions of chronic stress. Taken together, these results provide evidence that compromised mitochondrial function mediates effects of chronic stress on mood and may be a vulnerability factor to maladaptive stress-coping. Our research could be the basis for the development of novel antidepressant pharmaceuticals that target brain metabolic processes and could benefit at least a portion of currently treatment-resistant patients
Aberrant hippocampal morphology and function in Post-Traumatic Stress Disorder
No full textPost-Traumatic Stress Disorder (PTSD) is a debilitating disorder that affects approximately 8% of the population. It can be caused by experiencing a traumatic event and is characterized by symptoms like insomnia, hypervigilance and hyperarousal, and intrusive memories (i.e., flashbacks and nightmares) of the event. Over-generalization of the trauma memory has been suggested to underlie these intrusive memories triggered by indiscriminate environmental factors, and has been related to deficits in hippocampal function. Particularly pattern separation, the process by which memories are stored as unique representations resistant to confusion, mediated by the dentate gyrus (DG), may be compromised. However, since most evidence originates from patient studies that are done retrospectively, it is unknown whether this abnormal hippocampal functioning is in fact part of pathology or constitutes a predisposition to PTSD. Here, we used a validated mouse model for PTSD-induction to induce a PTSD-like phenotype in part of the mice, whereas others are resilient and do not display any PTSD-related symptoms. This model perfectly mimics the human situation, in which only 20 - 25% of the individuals experiencing a trauma will ultimately develop the disorder, whereas the majority stays healthy. We assessed fear generalization, and monitored hippocampal activity (using arterial spin labeling) and the PTSD-associated neuroendocrine changes (i.e., corticosterone levels) over the course of PTSD-development in PTSD-like compared to resilient mice. Moreover, Golgi staining enabled us to assess spine density in the ventral DG as the neurobiological template for pattern separation. In line with literature, PTSD-like animals displayed no fear generalization, but did display suppressed corticosterone response to stress. Moreover, we observed reduced hippocampal activity in PTSD-like mice, but only after trauma induction, indicating the reflection of pathology rather than a predisposition. Lastly, spine density in the ventral DG was significantly reduced in PTSD-like mice. These results indicate that the hippocampal dysfunction associated with PTSD is a consequence of PTSD development, and that high stress-induced corticosterone levels might be protective for the development of PTSD
Social Bonding: A Matter of Serotonin Transporter Gene Variation and Oxytocin Neurotransmission?
No full textOne genetic factor influencing social coping style is the short (''s") variant of the human Serotonin-transporter-linked polymorphic region (5-HTILPR) that has been associated with higher sensitivity to social stress in a Gene-Environment interaction fashion (GxE). Besides the GxE concept, 5-HTTLPR might be related to the Gene-Environment correlation (rGE) concept, according to which, since our social environment is shaped by our geneticallydetermined and inheritable behaviors, it is inheritable as well.
In our approach, the social behavior of male Wistar 5-HTT +/+ and 5-HTT -/- rats (with the latter modeling the s- carriers of the 5-HTILPR) is assessed during social interaction between 2 animals that are similar (homogenotype interaction) or different (hetorogenotype interaction) with reference to the 5-HTI genotype. Juvenile, adolescent and adult groups are separately tested considering that the nature of social interactions changes during development.
In line with previous studies in which 5-HTT-/- mice negatively altered their behavior when switched trom homogenotype to heterogenotype interaction, we hypothesized that, tor 5-HTI/- rats the formation or lack of social bands (bonding is expressed as social play and prosocial behavior) is influenced by the type of social interaction (homo- vs heterogenotype) reflecting a GxE effect and this effect is altered across ages.
Furthermore, taking into account previous reports showing 5-HTI-/- reduction of social play compared to 5-HTT +/+ rats during homogenotype interactions, we examined the hypothesis that the 5-HTT-/- genotype has a significant rGE effect, which can be reflected as increased influence of the 5-HTI-/- rats' behavior on their partners' social behavior and thus, their social environment.
Regarding the neural underpinnings of this behavioral profile it has been reported that 5-HTI/- animals display abnormally elevated corticotropine releasing factor (CRF) levels under stressful conditions. We are also interested in Oxytocin (OXT), an hormone known to enhance (pro)social behavior and reduce anxiety, since findings supporting a significant 5-HT-OXT interaction might suggest altered OXT neurotransmission in our animal model. Taken together, we hypothesize that in 5-HTT-/- rats the formation of social bands is characterized by increased OXT neurotransmission and lower CRF levels.
As expected, we observed a 5-HTT-/- GxE effect during adolescence, with the heterogenotype interaction decreasing prosocial behavior (reflecting a lack of bonding) and increasing self-grooming (indicative for anxiety). In adulthood, we observed 5-HTT-/- GxE effect on the duration of no- contact, which was increased in heterogenotype vs homogenotype condition, suggesting lack of bonding. lnterestingly, in juveniles, the 5-HTT-/GxE effect is expressed in an opposite direction, increasing social play (that can be considered as a bonding behavior) during heterogenotype compared to homogenotype interaction. Unfortunately, we were not able to understand the role of OXT-related activation in occurrence or lack of bonding due to anti- OXTR antibody inefficiency, but the correlation between the (lack of) bonding and anxiety and the CRF levels during social interaction is currently under statistica! investigation
Neuronal activity patterns associated with a traumatic experience in PTSD-vulnerable and -resilient mice
No full textPosttraumatic stress disorder (PTSD) is a clinical condition that can develop when an individual is exposed to a traumatic event, leading to significant social, occupational and interpersonal impairment. Although many individuals experience at least one traumatic event in their lifetime, only a subset of around 10 to 20% of these develop PTSD. This suggests the existence of inter-individual differences in vulnerability to developing psychopathology after trauma exposure. Discovering the exact neurobiological nature of these differences may be key to understanding the factors that constitute PTSD resilience, ultimately enabling the development of new treatment options. In this study we use an established mouse model for PTSD induction that employs a battery of behavioral tests to differentiate between subgroups of mice that show varying degrees of PTSD symptomatology after trauma exposure. Since re-experiencing of traumatic memories forms a core feature of PTSD, it is interesting to study the neuronal activity patterns that are induced by a specific traumatic experience and that are likely to be involved in the formation of a trauma memory trace. By coupling a fluorescent molecular label to the promoter of the immediate-early gene Arc, neurons that are active in these mice during trauma exposure can be labeled. In our study, we try to investigate 1) if neuronal activation patterns during trauma exposure differ between the PTSD-like and resilient mice, 2) if the neurons that are activated during trauma exposure are re-activated during subsequent re-exposure to the trauma environment and 3) whether both subgroups of mice differed from each other in neuronal type and distribution in the hippocampus. Neuronal activation during trauma exposure did not differ between PTSD-like and resilient mice, but during re-exposure to the trauma environment PTSD-like mice showed significantly less neuronal activation in both the dorsal and ventral hippocampus. A small percentage of neurons that were activated during trauma exposure were re-activated during re-exposure to the trauma environment, although this only significantly differed between both subgroups of mice in the ventral inferior dentate gyrus. This suggests that PTSD-like and resilient mice did not differ in fear memory encoding, but did so in memory recall. To investigate whether PTSD-like and resilient mice differed from each other in the type of interneurons that were present, brain slices of these mice were stained for the GABAergic cell markers parvalbumin and somatostatin. PTSD-like mice showed significantly more parvalbumin positive cells in the ventral CA1, while the number of somatostatin positive cells in the dorsal dentate gyrus and dorsal CA1 was significantly reduced when compared to resilient mice, suggesting an altered inhibitory network between these subgroups of mice
Imipramine reduces chronic stress induced c-Fos expression in the non-preganglionic Edinger-Westphal nucleus
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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