ABSTRACT
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.
Subject(s)
Action Potentials/genetics , Affect/physiology , CLOCK Proteins/genetics , Circadian Rhythm/genetics , Dopaminergic Neurons/physiology , Mutation/genetics , Action Potentials/drug effects , Adaptation, Ocular/drug effects , Adaptation, Ocular/genetics , Animals , Cell Line, Transformed , Dopamine Agents/pharmacology , Dopaminergic Neurons/drug effects , Food Preferences/drug effects , Food Preferences/physiology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Motor Activity/drug effects , Motor Activity/genetics , Rats , Swimming , Time Factors , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolism , Ventral Tegmental Area/cytologyABSTRACT
The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.
Subject(s)
Antidepressive Agents/pharmacology , Dendritic Spines/drug effects , Depressive Disorder/physiopathology , Ketamine/pharmacology , Prefrontal Cortex/drug effects , Stress, Psychological/physiopathology , Synapses/drug effects , Animals , Antidepressive Agents/therapeutic use , Corticosterone/pharmacology , Dendritic Spines/pathology , Dendritic Spines/physiology , Depressive Disorder/chemically induced , Depressive Disorder/drug therapy , Disease Models, Animal , Escape Reaction/drug effects , Ketamine/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuronal Plasticity/drug effects , Prefrontal Cortex/pathology , Prefrontal Cortex/physiopathology , Stress, Psychological/chemically induced , Synapses/physiologySubject(s)
Clubfoot/epidemiology , Casts, Surgical , Child, Preschool , Clubfoot/surgery , Clubfoot/therapy , Female , Humans , Infant , Male , Manipulation, Orthopedic , Prospective Studies , ZambiaABSTRACT
Contractures of the knee after poliomyelitis are common in children in developing countries and treatment, particularly that of severe contractures, presents a surgical challenge. This paper describes a new method for correcting contractures of the knee. Mild contractures need manipulation only and a plaster cast. Moderate contractures are treated by a partial soft-tissue release of the hamstrings and fascia lata followed by gradual stretching of the remaining soft-tissues by manipulation and plaster. Where the contracture is severe, skeletal traction is used through Steinmans pins inserted into the tibia and os calcis. One hundred and thirty-six knees with varying degrees of contracture were treated by these methods. Full correction was achieved and then maintained by plaster immobilisation, physiotherapy and calipers. This prevented recurrence during an average follow-up period of two and a half years. The severity of the contracture of the knee was in direct proportion to the severity of associated flexion-abduction contractures at the hip and equinus deformity at the ankle, the degree of muscle imbalance. All of the contractures of the hip and some of the ankle (46.8%) needed simultaneous operative correction. The basic method is technically simple, requires no special equipment and the results recommend its use particularly in developing countries.
Subject(s)
Contracture/therapy , Knee , Poliomyelitis/complications , Traction , Adolescent , Child , Contracture/etiology , Hip Contracture/etiology , Hip Contracture/surgery , Hip Contracture/therapy , Humans , Manipulation, Orthopedic , ZambiaABSTRACT
Homologous nerve transplantation is a logical method of bridging major nerve defects but its usefulness is negated by immune rejection. The discovery of an effective method of immunosuppression would allow utilisation of this technique. The present study compared the effects of irradiation, dexamethasone, and chloramphenicol in homologous nerve transplantation. Segments of homologous sciatic nerve were implanted into the dorsal subcutaneous (s.c.) tissues of 83 rabbits. In one group the graft was irradiated in vitro before implantation and in other groups the recipient rabbits received either dexamethasone or chloramphenicol systemically for up to 3 weeks after implantation. The transplanted nerve segments were removed at different time intervals and examined for signs of rejection. In conclusion, rejection commenced during the 1st week and peaked during the 3rd week. In the control group without immunosuppressant, all animals exhibited severe rejection. Both pre-implantation irradiation of the grafts at 450 rad dose-level and systemic chloramphenicol at 100 mg/kg/day were found to completely suppress rejection. These methods were considerably more effective than conventional steroids. Thus, the idea of a "nerve bank" is postulated.
Subject(s)
Graft Rejection/drug effects , Graft Rejection/radiation effects , Immunosuppressive Agents/pharmacology , Peripheral Nerves/transplantation , Animals , Chloramphenicol/pharmacology , Cobalt Radioisotopes , Dexamethasone/pharmacology , Female , Gamma Rays , Male , RabbitsABSTRACT
An unusual case of giant-cell tumours of the tendon sheath (syn. Pigmented villonodular tenosynovitis or fibrous xanthoma) of a long thumb flexor is presented. The unusual features are: two distinctly different tumours of almost similar size and shape arising from the tendon sheath at its either ends but with a segment of normal tendon sheath in between and presence of early malignant changes in the distal tumour with a benign proximal one, confirmed microscopically. Lastly, radiograph showed definite bony involvement in the proximal phalanx of the thumb. On extensive review of the literature, I found reports of rare presentation of malignant changes and bony erosion, but none had these various features.
Subject(s)
Giant Cell Tumors/pathology , Hand , Soft Tissue Neoplasms/pathology , Tendons/pathology , Adult , Humans , Male , Tenosynovitis/pathologyABSTRACT
An unusual case of old unreduced bilateral temporomandibular joint (TM joint) dislocation is presented. Extensive reviews of English and Japanese literature described managing such cases by various methods including closed or open joint reduction. However, successful bilateral condylectomies carried out in seven months old dislocation, provided free range of painless movements and good stability. As there is no possibility of redislocation or painful degenerative arthritis following this procedure, it's role in African environment is described.