Neuroscience
-
The weaver mouse, is a phenocopy of Parkinson's disease (PD) in which dopaminergic neurons degenerate gradually during development, reaching at P21 a neurodegeneration of 55%. Thus, the weaver mouse constitutes an appropriate in vivo PD model for investigating the effect of neuroprotective agents. In the present study, long-term treatment (from P1 to P21) with 17β-estradiol (17β-estradiol) significantly protected the dopaminergic neurons in the substantia nigra (SN) of weaver mouse by 54%, as was detected by immunohistochemical experiments, using the specific antibody against tyrosine hydroxylase (TH). ⋯ Our results show the in vivo neuroprotective effect of 17β-estradiol, which is strongly enhanced by co administration of NAC, indicating a strong synergistic effect of the two drugs. Furthermore, the main mechanism underlying this neuroprotective action seems to be the reversal of the oxidative stress shown by the high peroxidation levels. These results could be of clinical relevance since both drugs are already used separately in the clinic, 17β-estradiol for treatment of PD and NAC as a mucolytic agent and for the treatment of several disorders.
-
Cognitive flexibility is the ability to switch between different rules or concepts and behavioral flexibility is the overt physical manifestation of these shifts. Behavioral flexibility is essential for adaptive responses and commonly measured by reversal learning and set-shifting performance in rodents. Both tasks have demonstrated vulnerability to stress with effects dependent upon stressor type and number of repetitions. ⋯ Enhancing post-synaptic norepinephrine function, serotonin availability, and dopamine receptor activation rescues and/or prevents behavioral flexibility performance following stress. While this review highlights a lack of a standardization of stress paradigms, some consistent effects are apparent. Future studies are necessary to specify the mechanisms underlying the stress-induced impairments of behavioral flexibility, which will aid in alleviating these symptoms in patients with some psychiatric disorders.
-
To thrive in a changing environment, organisms evolved strategies for rapidly modifying their behavioral responses to sensory stimuli. In this review, we investigate the role of sensory cortical circuits in these flexible behaviors. ⋯ Last, we discuss inactivation studies which indicate that sensory cortex facilitates behavioral flexibility, but is not always required for adapting to changes in environmental conditions. This analysis provides insights into the contributions of cortical and subcortical sensory circuits to flexibility in behavior.
-
Tissue-type Plasminogen Activator Induces Synaptic Vesicle Endocytosis in Cerebral Cortical Neurons.
The release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons plays a central role in the development of synaptic plasticity, adaptation to metabolic stress and neuronal survival. Our earlier studies indicate that by inducing the recruitment of the cytoskeletal protein βII-spectrin and voltage-gated calcium channels to the active zone, tPA promotes Ca(2+)-dependent translocation of synaptic vesicles (SVs) to the synaptic release site where they release their load of neurotransmitters into the synaptic cleft. Here we used a combination of in vivo and in vitro experiments to investigate whether this effect leads to depletion of SVs in the presynaptic terminal. ⋯ We report that this tPA-induced sequence of events leads to the association of newly formed SVs with F-actin clusters in the endocytic zone. In summary, the data presented here indicate that following the exocytotic release of neurotransmitters tPA activates the mechanism whereby SVs are retrieved from the presynaptic membrane and endocytosed to replenish the pool of vesicles available for a new cycle of exocytosis. Together, these results indicate that in murine cerebral cortical neurons tPA plays a central role coupling SVs exocytosis and endocytosis.
-
Injury to the sciatic nerve induces loss of sensory neurons in the affected dorsal root ganglia (DRGs). Previous studies have suggested the involvement of the neurotrophin receptors p75 neurotrophin receptor (p75(NTR)) and sortilin, proposing that sensory neuron subpopulations undergo proneurotrophin-induced apoptosis in a similar manner to what can be observed in the CNS following injury. ⋯ Using an unbiased stereological approach we found that loss of sortilin did not prevent the injury-induced loss of DRG neurons. This result demonstrates that previous findings linking p75(NTR) and proneurotrophins to loss of sensory neurons need to involve sortilin-independent pathways and suggests that proneurotrophins may elicit different functions in the CNS and PNS.