Neuroscience
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The cellular prion protein (PrP(C)) is a neuronal-anchored glycoprotein that has been associated with various functions in the CNS such as synaptic plasticity, cognitive processes and neuroprotection. Here we investigated age-related behavioral and neurochemical alterations in wild-type (Prnp(+/+)), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice. Three- or 11 month-old animals were submitted to a battery of behavioral tasks including open field, activity cages, elevated plus-maze, social recognition and inhibitory avoidance tasks. ⋯ The i.c.v. infusion of STI1 peptide 230-245, which includes the PrP(C) binding site, improved the age-related social recognition deficits in Prnp(+/+). In comparison with the two other age-matched genotypes, the 11 month-old Tg-20 mice also exhibited reduced activity of seric acetylcholinesterase, increased expression of the protein synaptophysin and decreased caspase-3 positive-cells in the hippocampus. The present findings obtained with genetic and pharmacological approaches provide convincing evidence that PrP(C) exerts a critical role in the age-related behavioral deficits in mice probably through adaptive mechanisms including apoptotic pathways and synaptic plasticity.
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Drug therapies for attentional disorders alter the signal-to-noise ratio in the superior colliculus.
Despite high levels of use, the mechanism of action of effective pharmacotherapies in attention deficit hyperactivity disorder (ADHD) is unknown. It has recently been hypothesized that one site of therapeutic action is the midbrain superior colliculus, a structure traditionally associated with visual processing, but also strongly implicated in distractibility, a core symptom of ADHD. ⋯ The effects on the signal-to-noise ratio were mediated by serotonin (5-HT) via a pre-synaptic mechanism. This modulatory action would bias the system towards salient events and lead to an overall decrease in distractibility.
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Neurons in the dorsomedial hypothalamus (DMH) play a key role in mediating tachycardia elicited by emotional stress. DMH activation by microinjections of the GABA(A) antagonist evokes tachycardia and physiological changes typically seen in experimental stress. DMH inhibition abolishes the tachycardia evoked by stress. ⋯ Activation of the right DMH caused greater tachycardia compared to the left DMH activation (average DeltaHR: R=+92 bpm; L=+48 bpm; P<0.05). Tachycardia evoked by air jet stress was smallest after right DMH inhibition (average DeltaHR: R=+57 bpm and L=+134 bpm; P<0.05). These results indicate that the descending cardiovascular pathways from DMH are predominantly lateralized and the right DMH might exert a prominent control on heart rate changes during emotional stress.
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Impaired cognitive functions are well-described in the aging process. GABA(B) antagonists can facilitate learning and memory in young subjects, but these agents have not been well-characterized in aging. ⋯ There was no evidence that this improved learning was due to enhanced olfactory detection abilities produced by the drug. These results highlight the potential of targeting GABA(B) receptors to ameliorate age-related cognitive deficits and demonstrate the utility of olfactory discrimination learning as a preclinical model for testing novel therapies to improve cognitive functions in aging.
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There is evidence of structural and functional deterioration in the brain, including the prefrontal cortex (PFC) and hippocampus, during the normal aging process in animals and humans. Extracellular matrix-associated glycoproteins, such as chondroitin sulfate proteoglycans (CSPGs), are involved in not only maintaining the structures and functions of adult neurons, but also regulating the proliferation, migration, and neurite outgrowth of neural stem cells in the brain. On the other hand, a herbal medicine, yokukansan (YKS), is used in a variety of clinical situations for treating symptoms associated with age-related neurodegenerative disorders such as Alzheimer's disease, but its pharmacological properties have not been fully understood. ⋯ Aged rats also showed a decreased number of BrdU-labeled cells in the PFC and hippocampus, and these decreases were improved by YKS treatment, which also increased the numbers in young rats. These results suggest that aging influences the microenvironment for adult and immature neurons in the brain, which may affect the proliferation and migration of neural stem/progenitor cells, and YKS has pharmacological potency for these age-related events. These findings help to understand the physiology and pathology of the aged brain and provide an anti-aging strategy for the brain.