CACNA1C: Association with pychiatric disorders, behavior, and neurogenesis

Large-scale genome-wide association studies have consistently shown that genetic variation in CACNA1C, a gene that encodes calcium voltage-gated channel subunit alpha1C, increases risk for psychiatric disorders. CACNA1C encodes the Cav1.2 subunit of voltage-gated calcium channels, which themselves have been functionally implicated in a broad spectrum of neuropsychiatric syndromes. Research has concentrated on uncovering the underlying biological mechanisms that could be responsible for this increased risk. This review presents an overview of recent findings regarding Cacna1c variation in animal models, particularly focusing on behavioral phenotypes associated with neurodevelopmental disorders such as cognition, anxiety and depressive phenotypes, and fear conditioning. The impact of reduced gene dosage of Cacna1c on adult hippocampal neurogenesis is also assessed, including new data from a novel Cacna1c+/− rat model

Sex specific effects of pre-pubertal stress on hippocampal neurogenesis and behaviour

Experience of traumatic events in childhood is linked to an elevated risk of developing psychiatric disorders in adulthood. The neurobiological mechanisms underlying this phenomenon are not fully understood. The limbic system, particularly the hippocampus, is significantly impacted by childhood trauma. In particular, it has been hypothesised that childhood stress may impact adult hippocampal neurogenesis (AHN) and related behaviours, conferring increased risk for later mental illness. Stress in utero can lead to impaired hippocampal synaptic plasticity, and stress in the first 2–3 weeks of life reduces AHN in animal models. Less is known about the effects of stress in the post-weaning, pre-pubertal phase, a developmental time-point more akin to human childhood. Therefore, we investigated persistent effects of pre-pubertal stress (PPS) on functional and molecular aspects of the hippocampus. AHN was altered following PPS in male rats only. Specifically males showed reduced production of new neurons following PPS, but increased survival in the ventral dentate gyrus. In adult males, but not females, pattern separation and trace fear conditioning, behaviours that rely heavily on AHN, were also impaired after PPS. PPS also increased the expression of parvalbumin-positive GABAergic interneurons in the ventral dentate gyrus and increased glutamic acid decarboxylase 67 expression in the ventral hilus, in males only. Our results demonstrate the lasting effects of PPS on the hippocampus in a sex- and time-dependent manner, provide a potential mechanistic link between PPS and later behavioural impairments, and highlight sex differences in vulnerability to neuropsychiatric conditions after early-life stres

Sonography of Wrist Ganglion Cysts: Which Location Is Most Common?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150565/1/jum14912.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150565/2/jum14912_am.pd

Creatine supplementation in the elderly: is resistance training really needed?

Introduction: Decreases in muscle mass, strength and power are associated with ageing, all of which increase the risk of falls, and cause a loss of independence. Creatine supplementation is often used in younger athletes to improve anaerobic performance, power and strength, however the potential benefits of creatine supplementation in older individuals are less clear. With an ageing population comes age-related losses in skeletal muscle mass, sarcopenia and associated risks of falls, morbidity and mortality. Importantly many older individuals still regularly perform aerobic and resistance training which serves to maintain this muscle mass and reduce these risks however a large proportion do not partake in regular exrecise [1]. There is evidence that creatine supplementation may maintain muscle mass and function in older adults [2], but an important question is whether resistance training and creatine supplementation have an additive effect on muscle structure and function or can older adults receive the same degree of benefit by just partaking in one of these protocols? Creatine Creatine is important for energy metabolism, and is thought to be an effective ergogenic aid in physical performance [3]. Creatine is synthesised within the body and ingested naturally from meat [3] or artificially through supplements. 94% of total body creatine is located in skeletal muscles and is stored as either free (40%) or phosphorylated creatine (PCr; 60%) [4]. Within skeletal muscles, creatine is hypothesised to shuttle high energy phosphogens between the mitochondria and cytosol [5], increasing the efficiency of cross-bridge cycling and thereby enhancing skeletal muscle contraction (Figure 1). Firstly, ATP synthesised in the mitochondrial matrix is transported via creatine kinase (CK) to the mitochondrial intermembrane space where CK catalyses the formation of ADP and PCr; Figure 2 reveals the equation from which ATP is then generated from stores of PCr via creatine kinase during periods of intense exercise. The ADP produced is transported back to the matrix where it is rephosphorylated when required. Liberated PCr migrates to the cytosol to sites of ATP consumption, where local CK enzymes regenerate ATP to allow for increased contraction. The liberated creatine then diffuses back to the mitochondria to allow for subsequent phosphorylation if required. This “transport” process is thought to occur in endurance-type activities [6-8]. Creatine supplementation has been shown to increase PCr regeneration [9], increasing ATP availability, thus facilitating prolonged physical activity [4]. Aim: This review assesses the current literature on whether creatine supplementation in the presence of resistance training enhances physical performance in older adults above and beyond those undertaking resistance training alone or only taking creatine supplements. Results: Whilst reports are conflicting, there is good evidence to suggest that creatine supplementation with resistance training increases muscular endurance, lower body strength and lean body mass; this is above results obtained with creatine supplementation or resistance training alone. The increased muscle mass observed with training has previously been shown to lead to increased bone mineral content and an associated reduced fracture risk; however, the additional benefits of creatine supplementation on this are less clear, and more work is needed to confirm whether exogenously taken creatine will benefit bone mineral density. Conclusion: Creatine supplementation in the elderly may lead to increased muscle mass, endurance and performance, and those who undertake resistance training may show further improvements with creatine supplementation. However, for elderly subjects who do not partake in resistance training, creatine supplementation offers significant improvements in increasing muscular mass and strength, and increasing their quality of life, whilst these benefits are lower on the whole than those who undertake regular resistance training

Cacna1c hemizygosity results in aberrant fear conditioning to neutral stimuli

CACNA1C, a gene that encodes an alpha-1 subunit of L-type voltage-gated calcium channels, has been strongly associated with psychiatric disorders including schizophrenia and bipolar disorder. An important objective is to understand how variation in this gene can lead to an increased risk of psychopathology. Altered associative learning has also been implicated in the pathology of psychiatric disorders, particularly in the manifestation of psychotic symptoms. In this study, we utilize auditory-cued fear memory paradigms in order to investigate whether associative learning is altered in rats hemizygous for the Cacna1c gene. Cacna1c hemizygous (Cacna1c+/−) rats and their wild-type littermates were exposed to either delay, trace, or unpaired auditory fear conditioning. All rats received a Context Recall (24 h post-conditioning) and a Cue Recall (48 h post-conditioning) to test their fear responses. In the delay condition, which results in strong conditioning to the cue in wild-type animals, Cacna1c+/− rats showed increased fear responses to the context. In the trace condition, which results in strong conditioning to the context in wild-type animals, Cacna1c+/− rats showed increased fear responses to the cue. Finally, in the unpaired condition, Cacna1c+/− rats showed increased fear responses to both context and cue. These results indicate that Cacna1c heterozygous rats show aberrantly enhanced fear responses to inappropriate cues, consistent with key models of psychosis

Symmetry breaking perturbations and strange attractors

The asymmetrically forced, damped Duffing oscillator is introduced as a prototype model for analyzing the homoclinic tangle of symmetric dissipative systems with \textit{symmetry breaking} disturbances. Even a slight fixed asymmetry in the perturbation may cause a substantial change in the asymptotic behavior of the system, e.g. transitions from two sided to one sided strange attractors as the other parameters are varied. Moreover, slight asymmetries may cause substantial asymmetries in the relative size of the basins of attraction of the unforced nearly symmetric attracting regions. These changes seems to be associated with homoclinic bifurcations. Numerical evidence indicates that \textit{strange attractors} appear near curves corresponding to specific secondary homoclinic bifurcations. These curves are found using analytical perturbational tools

Social interaction following prepubertal stress alters prefrontal gene expression associated with cell signalling and oligodendrocytes

Early-life adversity is associated with an increased risk of psychopathology, including mood disorders, later in life. Early-life stress affects several physiological systems, however, the exact mechanisms underlying pathological risk are not fully understood. This knowledge is crucial in developing appropriate therapeutic interventions. The prepubertal period is documented as a key developmental period for the maturation of the prefrontal cortex (PFC), a brain region involved in higher cognitive functions, including social function. In this study, we performed RNA sequencing on the PFC of adult rats who had experienced prepubertal stress (PPS) and controls to investigate the genome-wide consequences of this stress. PPS alters social behaviour in adulthood, therefore we also performed RNA sequencing on PPS and control rats following a social interaction test to determine social activity-dependent gene changes. At a baseline state (1 week following a social interaction test), no genes were differentially expressed in the PPS group. However, 1603 genes were differentially expressed in PPS rats compared to controls following a social interaction. These genes were enriched in biological pathways associated with cell signalling and axon myelination dynamics. Cell enrichment analysis showed these genes were associated with oligodendrocytes, and a comparison with an existing early-life stress sequencing dataset showed that pathways linked to oligodendrocyte morphology are impacted in a range of models of early-life stress in rodents. In conclusion, we identify pathways, including those involved in axon myelination, that are differentially activated in the adult in response to social stimulation following PPS. These differential responses may contribute to vulnerability to psychiatric pathology