Second messenger-mediated actions of norepinephrine on target neurons in central circuits: a new perspective on intracellular mechanisms and functional consequences.

Ever since the initial demonstration of a widespread distribution of noradrenergic fibers to functionally diverse regions of the mammalian forebrain, there has been considerable interest in determining the electrophysiological effects of norepinephrine (NE) on individual neurons within these target areas. While early studies showed that NE could directly inhibit cell firing via increased intracellular levels of cyclic AMP, more recent work has revealed a spectrum of noradrenergic actions, which are more accurately characterized as neuromodulatory. More specifically, numerous experimental conditions have been described where NE at levels subthreshold for producing direct depressant effects on spontaneous firing can facilitate neuronal responses to both excitatory and inhibitory synaptic stimuli. The goal of this report is to review recent evidence which suggests that the various modulatory actions of NE on central neurons result from the activation of different adrenoceptor-linked second messenger systems. In particular, we have focused on the candidate signal transduction mechanisms that may underlie NE's ability to augment cerebellar and cortical neuronal responsiveness to GABAergic synaptic inputs. The consequences of such NE-induced changes in synaptic efficacy are considered not only with respect to their influences on feature extraction properties of individual sensory cortical neurons but also with regard to the potential impact such actions would have on the signal processing capabilities of a network of noradrenergically innervated cortical cells.

Selective neocortical and thalamic cell death in the gerbil after transient ischemia.

In animal models of transients ischemia, selective vulnerability and delayed neuronal death in the hippocampus have been extensively described. However, little is known about selective damage in the neocortex and the thalamus, even though deficits in sensorimotor function are common in humans surviving hypoxic/ischemic episodes. This study investigated the neurodegenerative effects of transient ischemia in the gerbil neocortex and thalamus with use of Cresyl Violet and silver impregnation staining methods. In addition, immunohistochemistry of an astrocyte-associated protein, glial fibrillary acidic protein, was used to assess the astrocytic response to ischemia. Pyramidal cells in layers 3 and 6 of somatosensory and auditory cortex were exceptionally sensitive to ischemia, whereas the neurons in layers 2, 4 and 5 were more resistant to ischemia. More pyramidal cells were killed in layer 3 than in layer 6. This bilaminar pattern of neuronal death developed after periods of ischemia ranging from 3 to 10 min and was identifiable at post-ischemic survival times of 6 h to one month. Somatodendritic argyrophilia in the neocortex was identified as early as 6-12 h after 5 min of ischemia. The greatest number of degenerating cortical neurons were stained two to four days after ischemia. With 10 min of ischemia, argyrophilic neurites and neurons were also found as early as 8 h after the occlusion. The most extensive damage was noted in the ventroposterior nucleus, the medial geniculate nucleus, and the intralaminar nuclei two to four days after ischemia. Thus, selective vulnerability and delayed neuronal death are evident in both the neocortex and the thalamus after transient ischemia. These regions need to be examined when considering the efficacy of potential neuroprotective drugs.