Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that ...display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.
Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major ...depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression‐like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit‐targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depression‐related behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders.
Here we review recent advances aided by optogenetic tools in understanding mood disorders.
A novel scheme for the focusing of high-energy leptons in future linear colliders was proposed in 2001 P. Raimondi and A. Seryi, Phys. Rev. Lett. 86, 3779 (2001). This scheme has many advantageous ...properties over previously studied focusing schemes, including being significantly shorter for a given energy and having a significantly better energy bandwidth. Experimental results from the ATF2 accelerator at KEK are presented that validate the operating principle of such a scheme by demonstrating the demagnification of a 1.3 GeV electron beam down to below 65 nm in height using an energy-scaled version of the compact focusing optics designed for the ILC collider.
The ability to retain multiple items in short-term memory is fundamental for intelligent behavior, yet little is known about its neural basis. To explore the mechanisms underlying this ability, we ...trained 2 monkeys to remember a sequence of 2 objects across a short delay. We then recorded the activity of neurons from the lateral prefrontal cortex during task performance and found that most neurons had activity that depended on the identity of both objects while a minority reflected just one object. Further, the activity driven by a particular combination of objects was not a simple addition of the activity elicited by individual objects. Instead, the representation of the first object was altered by the addition of the second object to memory, and the form of this change was not systematically predictable. These results indicate that multiple objects are not stored in separate groups of prefrontal neurons. Rather, they are represented by a single population of neurons in a complex fashion. We also found that the strength of the memory trace associated with each object decayed over time, leading to a relatively stronger representation of more recently seen objects. This is a potential mechanism for representing the temporal order of objects.
Working memory (WM) allows us to remember and selectively control a limited set of items. Neural evidence suggests it is achieved by interactions between bursts of beta and gamma oscillations. ...However, it is not clear how oscillations, reflecting coherent activity of millions of neurons, can selectively control individual WM items. Here we propose the novel concept of spatial computing where beta and gamma interactions cause item-specific activity to flow spatially across the network during a task. This way, control-related information such as item order is stored in the spatial activity independent of the detailed recurrent connectivity supporting the item-specific activity itself. The spatial flow is in turn reflected in low-dimensional activity shared by many neurons. We verify these predictions by analyzing local field potentials and neuronal spiking. We hypothesize that spatial computing can facilitate generalization and zero-shot learning by utilizing spatial component as an additional information encoding dimension.
Abstract
Combining anticatabolic agents with parathyroid hormone (PTH) to enhance bone mass has yielded mixed results in osteoporosis patients. Toward the goal of enhancing the efficacy of these ...regimens, we tested their utility in combination with loss of the transcription factor Nmp4 because disabling this gene amplifies PTH-induced increases in trabecular bone in mice by boosting osteoblast secretory activity. We addressed whether combining a sustained anabolic response with an anticatabolic results in superior bone acquisition compared with PTH monotherapy. Additionally, we inquired whether Nmp4 interferes with anticatabolic efficacy. Wild-type and Nmp4
−/−
mice were ovariectomized at 12 weeks of age, followed by therapy regimens, administered from 16 to 24 weeks, and included individually or combined PTH, alendronate (ALN), zoledronate (ZOL), and raloxifene (RAL). Anabolic therapeutic efficacy generally corresponded with PTH + RAL = PTH + ZOL > PTH + ALN = PTH > vehicle control. Loss of Nmp4 enhanced femoral trabecular bone increases under PTH + RAL and PTH + ZOL. RAL and ZOL promoted bone restoration, but unexpectedly, loss of Nmp4 boosted RAL-induced increases in femoral trabecular bone. The combination of PTH, RAL, and loss of Nmp4 significantly increased bone marrow osteoprogenitor number, but did not affect adipogenesis or osteoclastogenesis. RAL, but not ZOL, increased osteoprogenitors in both genotypes. Nmp4 status did not influence bone serum marker responses to treatments, but Nmp4−/−
mice as a group showed elevated levels of the bone formation marker osteocalcin. We conclude that the heightened osteoanabolism of the Nmp4−/−
skeleton enhances the effectiveness of diverse osteoporosis treatments, in part by increasing hyperanabolic osteoprogenitors. Nmp4 provides a promising target pathway for identifying barriers to pharmacologically induced bone formation.
Loss of the transcription factor Nmp4 improves the efficacy of osteoporosis therapies in mice.
Golomb MR, McDonald BC, Warden SJ, Yonkman J, Saykin AJ, Shirley B, Huber M, Rabin B, AbdelBaky M, Nwosu ME, Barkat-Masih M, Burdea GC. In-home virtual reality videogame telerehabilitation in ...adolescents with hemiplegic cerebral palsy.
To investigate whether in-home remotely monitored virtual reality videogame-based telerehabilitation in adolescents with hemiplegic cerebral palsy can improve hand function and forearm bone health, and demonstrate alterations in motor circuitry activation.
A 3-month proof-of-concept pilot study.
Virtual reality videogame-based rehabilitation systems were installed in the homes of 3 participants and networked via secure Internet connections to the collaborating engineering school and children's hospital.
Adolescents (N=3) with severe hemiplegic cerebral palsy.
Participants were asked to exercise the plegic hand 30 minutes a day, 5 days a week using a sensor glove fitted to the plegic hand and attached to a remotely monitored videogame console installed in their home. Games were custom developed, focused on finger movement, and included a screen avatar of the hand.
Standardized occupational therapy assessments, remote assessment of finger range of motion (ROM) based on sensor glove readings, assessment of plegic forearm bone health with dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), and functional magnetic resonance imaging (fMRI) of hand grip task.
All 3 adolescents showed improved function of the plegic hand on occupational therapy testing, including increased ability to lift objects, and improved finger ROM based on remote measurements. The 2 adolescents who were most compliant showed improvements in radial bone mineral content and area in the plegic arm. For all 3 adolescents, fMRI during grip task contrasting the plegic and nonplegic hand showed expanded spatial extent of activation at posttreatment relative to baseline in brain motor circuitry (eg, primary motor cortex and cerebellum).
Use of remotely monitored virtual reality videogame telerehabilitation appears to produce improved hand function and forearm bone health (as measured by DXA and pQCT) in adolescents with chronic disability who practice regularly. Improved hand function appears to be reflected in functional brain changes.
Recent interest in atherosclerosis has focused on the genetic determinants of low-density lipoprotein (LDL) particle size, because of (i) the association of small dense LDL particles with a ...three-fold increased risk for coronary artery disease (CAD) and (ii) the recent report of linkage of the trait to the LDL receptor (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative-pair analysis methods in CAD families, we tested for linkage of a gene or genes controlling LDL particle sizes with the genetic loci for the major apolipoproteins and enzymes participating in lipoprotein metabolism. We confirmed evidence for linkage to the LDL receptor locus (P=.008). For six candidate gene loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE-CI-CII, lipoprotein lipase, and high-density lipoprotein-binding protein, no evidence for linkage was observed by sib-pair linkage analyses (P values ranged from .24 to .81). However, in addition, we did find tentative evidence for linkage with the apoAI-CIII-AIV locus (chromosome 11) (P=.06) and significant evidence for linkage of the cholesteryl ester transfer protein locus (chromosome 16) (P=.01) and the manganese superoxide dismutase locus (chromosome 6) (P=.001), thus indicating multilocus determination of this atherogenic trait.
Growing evidence supports low-intensity pulsed ultrasound (US) as an osteogenic mechanical stimulus. Its effects on isolated bone cells and on fractured bone are established. However, its effects on ...osteoporosis are not clear. This study examined US effects on ovariectomy (OVX) induced bone changes within the rodent hindlimb (distal femur and proximal tibia), and on normal bone in animals following sham-OVX. Animals were exposed to daily unilateral active-US and contralateral inactive-US for 12 weeks. Bone status was assessed using dual energy X-ray absorptiometry and histomorphometry. Ovariectomy resulted in significant bone changes. Low-intensity pulsed US did not influence these changes. These results suggest that the US dose introduced may not be a beneficial treatment for osteoporosis, and that intact bone may be less sensitive to US than fractured bone and isolated bone cells. This may relate to the biophysical mechanisms of action of US, US-bone interactions and tissue level processes taking place. (E-mail: k.bennell@unimelb.edu.au)
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