Neuroscience
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Absence epilepsy is characterised by a paroxysmal loss of consciousness, of abrupt onset and termination, and is associated with a bilateral synchronous spike and wave discharge (SWD) on the electroencephalogram. Absence seizures involve an interplay between thalamic and cortical structures, although most research has so far focussed on sensory thalamic nuclei and the reticular thalamic nucleus (RTN). Thus, microinfusion of ethosuximide (ETX), a first choice anti-absence drug, into either the ventrobasal thalamus or RTN of the genetic absence epilepsy rat from Strasbourg (GAERS), a validated rat model of absence epilepsy, does not produce immediate cessation of seizure activity, as is seen following systemic administration. ⋯ No reduction of SWD was seen when ETX was infused into M1. Microinfusion of CGP 36742 (5 nmol/side), a GABA(B) antagonist, produced immediate cessation of seizure activity in both S1po and M1 and a delayed effect in S1FL. These data suggest that the ability of ETX to abolish genetically determined absence seizures is cortical-area specific and support the involvement of S1po in the initiation of SWDs.
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We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague-Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. ⋯ Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.
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Comparative Study
The contribution of autophosphorylated alpha-calcium-calmodulin kinase II to injury-induced persistent pain.
Increases in neuronal activity in response to tissue or nerve injury can lead to prolonged functional changes in the spinal cord resulting in an enhancement/sensitization of nociceptive processing. To assess the contribution of alpha-calcium-calmodulin kinase II (alpha-CaMKII) to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a point mutation in the alpha-CaMKII gene at position 286 (threonine to alanine). The mutated protein is unable to autophosphorylate and thus cannot function independently of calcium and calmodulin. ⋯ In contrast, the decreased mechanical and thermal thresholds associated with nerve injury, Complete Freund's Adjuvant-induced inflammation or formalin-evoked tissue injury were manifest equally in wild-type and mutant mice. Double-labeling immunofluorescence studies revealed that in the mouse alpha-CaMKII is expressed in the superficial dorsal horn as well as in a population of small diameter primary afferent neurons. In summary, our results suggest that alpha-CaMKII, perhaps secondary to an N-methyl-D-aspartate-mediated calcium increase in postsynaptic dorsal horn nociresponsive neurons, is a critical contributor to the spontaneous/ongoing component of tissue-injury evoked persistent pain.
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The median raphe nucleus is involved in controlling and maintaining hippocampal activity through its projection to inhibitory neurons in medial septum and hippocampus. It has been shown that anterogradely axonal-traced fibers originating in the median raphe nucleus project onto calbindin-containing neurons in hippocampus and parvalbumin-containing neurons in medial septum. Parallel immunohistochemistry studies showing serotonin fibers contacting calbindin- and parvalbumin-positive neurons have led to the assumption that raphe fibers projecting on these types of neurons are mainly serotonergic. ⋯ By use of triple immunofluorescence-labeling we analyzed the serotonergic content of the biotin dextran amine-labeled fibers contacting parvalbumin- and calbindin-positive neurons. Surprisingly, we found a significant non-serotonergic projection from both dorsal and median raphe nuclei onto calbindin- and parvalbumin-containing interneurons in septum and hippocampus, with a preference in hippocampus for projecting onto calbindin-positive neurons. These results indicate that the raphe nuclei may exert their control on hippocampal and septal activity not only through a serotonergic projection, but also through a significant non-serotonergic pathway.
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The amygdala and hippocampus are key limbic structures of the temporal lobe, and are implicated in the pathology of mood disorders. Bcl-2, an intracellular protein, has recently been identified in the primate amygdala and hippocampus, and is now recognized as an intracellular target of mood stabilizing drugs. However, there are few data on the cellular phenotypes of bcl-2-expressing cells, or their distribution in specific subregions of the amygdala and hippocampus. ⋯ Bcl-2 is thus important in intrinsic circuitry of the hippocampus, and in amygdaloid subregions modulated by the hippocampus. In addition, the extended amygdala, a key amygdaloid output, is richly endowed with bcl-2 positive cells. This distribution suggests a role for bcl-2 in circuits mediating emotional learning and memory which may be targets of mood stabilizing drugs.