ABSTRACT
BACKGROUND: Demyelination is the end product of numerous pathological processes, and also is one of the main causes of neurological disability in Multiple sclerosis (MS). Research into the pathogenesis of MS is hampered by the conventional rodent models' inability to produce stable demyelination. NEW METHOD: Focal demyelinating lesions were stereotactically targeted to the corpus callosum with a two-point injection of lysophosphatidylcholine (LPC-2) in mice. Three groups were analyzed (nâ¯=â¯8, each) and water maze, sensorimotor test, and compound action potential were included in functional tests. Electron microscopy was used for morphological analyses while western blot and immunohistochemistry were included for molecular detection. RESULTS: Ten days after the LPC-2 injection, the expression of myelin basic protein (MBP) was reduced, while non-phosphorylated neurofilament (SMI-32) was increased. The amplitude of the N1 segment decreased and less well-defined myelin sheaths was found. Behavioral tests showed increased latency to escape and reduced time spent in target quadrant. Four weeks later, MBP expression still reduced, SMI-32 expression was increased, both spatial learning (D24-D27) and spatial memory (D28) were still significantly impaired in LPC-2 injection mice. COMPARISON WITH EXISTING METHOD(S): Compared with the classic single-point LPC-injection model, our studies showed that the two-point LPC-injection not only could induce demyelination in a short-term manner, but also could cause demyelination in a long-term manner with little remyelination in the mouse corpus callosum. CONCLUSIONS: We established a simple, reliable, and inexpensive model of demyelination in the corpus callosum in mice, with functional and morphological reproducibility, and good validity.
Subject(s)
Demyelinating Autoimmune Diseases, CNS/physiopathology , Disease Models, Animal , Leukoencephalopathies/physiopathology , Action Potentials/physiology , Animals , Corpus Callosum/drug effects , Corpus Callosum/physiopathology , Corpus Callosum/ultrastructure , Demyelinating Autoimmune Diseases, CNS/chemically induced , Demyelinating Autoimmune Diseases, CNS/pathology , Exploratory Behavior/drug effects , External Capsule/drug effects , External Capsule/physiopathology , External Capsule/ultrastructure , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Leukoencephalopathies/chemically induced , Leukoencephalopathies/pathology , Lysophosphatidylcholines/toxicity , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Myelin Basic Protein/metabolism , Neurofilament Proteins/metabolism , Rotarod Performance Test , Transduction, GeneticABSTRACT
The basolateral amygdala (BLA) controls numerous behaviors, like anxiety and reward seeking, via the activity of glutamatergic principal neurons. These BLA neurons receive excitatory inputs primarily via two major anatomical pathways - the external capsule (EC), which contains afferents from lateral cortical structures, and the stria terminalis (ST), containing synapses from more midline brain structures. Chronic intermittent ethanol (CIE) exposure/withdrawal produces distinct alterations in these pathways. Specifically, 10â¯days of CIE (via vapor inhalation) increases presynaptic function at ST synapses and postsynaptic function at EC synapses. Given that 10-day CIE/withdrawal also increases anxiety-like behavior, we sought to examine the development of these alterations at these inputs using an exposure time-course in both male and female rats. Specifically, using 3, 7, and 10â¯days CIE exposure, we found that all three durations increase anxiety-like behavior in the elevated plus maze. At BLA synapses, increased presynaptic function at ST inputs required shorter exposure durations relative to post-synaptic alterations at EC inputs in both sexes. But, synaptic alterations in females required longer ethanol exposures compared to males. These data suggest that presynaptic alteration at ST-BLA afferents is an early neuroadaptation during repeated ethanol exposures. And, the similar patterns of presynaptic-then-postsynaptic facilitation across the sexes suggest the former may be required for the latter. These cooperative interactions may contribute to the increased anxiety-like behavior that is observed following CIE-induced withdrawal and may provide novel therapeutic targets to reverse withdrawal-induced anxiety.
Subject(s)
Basolateral Nuclear Complex/drug effects , Central Nervous System Depressants/administration & dosage , Ethanol/administration & dosage , Sex Characteristics , Administration, Inhalation , Animals , Anxiety/chemically induced , Anxiety/physiopathology , Basolateral Nuclear Complex/physiopathology , Estrous Cycle/drug effects , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , External Capsule/drug effects , External Capsule/physiopathology , Female , Glutamic Acid/metabolism , Internal Capsule/drug effects , Internal Capsule/physiopathology , Male , Maze Learning/drug effects , Maze Learning/physiology , Rats, Sprague-Dawley , Substance Withdrawal Syndrome/physiopathology , Synapses/drug effects , Synapses/physiology , Time Factors , Tissue Culture TechniquesABSTRACT
The objective of this study was to examine whether white-matter (WM) connectivity of patients with schizophrenia at early stage of treatment is related to treatment response after paliperidone extended-release (ER) treatment. Forty-one patients with schizophrenia and 17 age- and sex-matched healthy control subjects were included in this study. Brain magnetic resonance scans at 3 Tesla were conducted at early stage of treatment. Voxel-wise statistical analysis of the fractional anisotropy (FA) data was performed using Tract-Based Spatial Statistics. At baseline and eight weeks after paliperidone treatment, patients were assessed using the Positive and Negative Syndrome Scale, the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Among the patients with schizophrenia, the FA values of the corpus callosum, corona radiata, internal capsule, external capsule, superior longitudinal fasciculus and fronto-temporal WM regions showed significant negative correlations with scores of the treatment response. The current study suggests that the treatment response after paliperidone ER treatment may be associated with the fronto-temporo-limbic WM connectivity at early stage of treatment in patients with schizophrenia, and it could be used as a predictor of treatment response to paliperidone ER treatment after studies with large samples verify these results.