Discrimination reversal conditioning of an eyeblink response is impaired by NMDA receptor blockade.

In the present study we examined the effects of the specific NMDA receptor antagonist CPP on discrimination reversal learning in rabbits. We report two primary findings. First, the institution of NMDA receptor blockade had no effect on a learned discrimination. Second, after stimulus reversal, CPP treatment impaired acquisition of the discrimination reversal. This impairment manifested itself early in training as a retardation in acquisition of a CR to the new CS+ and late in training as an inability to suppress responsiveness to the new CS-. Given the comparability of the present results with previously published results for phenytoin-treated rabbits, we suggest that the effects of phenytoin on learning in this paradigm is at least in part mediated by its effects on NMDA receptors. We further suggest that these findings emphasize the need to better define the role of NMDA receptor activation and hippocampally-mediated circuits in a variety of associative learning paradigms.

Somatotopic reorganization in the brainstem and thalamus following peripheral nerve injury in adult primates.

Injury-induced reorganization of central somatotopic maps is a phenomenon that has proven to be useful for elucidating the mechanisms and time course of neural plasticity. To date, the overwhelming majority of this line of research has focused on such plastic events in cortical areas, at the expense of subcortical structures. In this study, we used multi-unit electrophysiological recording techniques to assess the somatotopic organization of brainstem and thalamic areas following chronic survival from paired median and ulnar nerve section in adult squirrel monkeys. We report that the extent of cutaneously-driven reorganization in both the cuneate nucleus of the brainstem and the ventroposterior lateral nucleus of the thalamus is comparable to that previously documented for area 3b of cortex. These observations are consistent with those previously reported in thalamus, and are unique for brainstem.

Role of NMDA receptors in adult primate cortical somatosensory plasticity.

We have previously shown that most of the reorganization that typically follows median nerve transection in adult squirrel monkeys is dependent on normally functioning N-methyl-D-aspartate (NMDA) receptors. Here, we have evaluated two additional hypotheses: (1) is the immediate "unmasking" found after median nerve transection NMDA receptor-dependent? and (2) are NMDA receptors necessary for both the initiation and maintenance of the second phase of reorganizational changes, or only the former? To address these issues, we implanted osmotic minipumps subcutaneously to deliver an NMDA receptor antagonist (3-((+/-)-2- carboxypiperazin-4-yl)propyl-1-phosphonic acid, CPP) systemically either before examining the immediate effects of median nerve transection, or after reorganization had presumably occurred. For the first set of experiments, NMDA receptor blockade was initiated either 1 or 4 weeks prior to multi-unit mapping in area 3b followed by transection of the median nerve and remapping of the cortex. In the second set of experiments, median nerve transection was followed 4 weeks later by either 1 or 4 weeks of NMDA receptor blockade prior to terminal mapping. We report that the immediate unmasking of new receptive fields after acute nerve injury is not prevented by NMDA receptor blockade; nor are completely reorganized cortical maps dependent upon NMDA receptors for their maintenance. We conclude that the immediate changes in cortical topography are not due to an NMDA receptor-dependent mechanism, but more likely due to release from tonic inhibition. Furthermore, the later phase of reorganization, as for some forms of hippocampal long-term potentiation (LTP), is dependent on normally functioning NMDA receptors for its initiation, but not for its maintenance.

Phenytoin blocks the reversal of a classically conditioned discriminative eyeblink response in rabbits.

PURPOSE: Cognitive deficits associated with chronic treatment with phenytoin (PHT) have been reported. PHT blocks transfer from a signaled appetitive bar press to an active avoidance response in rats. We investigated the effects of PHT and the prodrug fosphenytoin in rabbits required to learn a discrimination and reversal of a classical eyeblink conditioning paradigm. METHODS: Before drug treatment was started, rabbits were trained to produce a discriminated eyeblink response. PHT (n = 7) was administered centrally or the prodrug fosphenytoin (n = 2) was given systemically. Control animals were similarly treated centrally with either saline (n = 3) or no drug treatment (n = 13). Rabbits were then challenged with a stimulus reversal while being maintained on the respective drug. RESULTS: On the first day of reversal training, control animals typically displayed high response rates to both tones, followed by a reduction in responsiveness to the new conditioned stimulus (CS-) in the ensuing days. In contrast, PHT-treated animals failed to suppress responsiveness to the new CS-. CONCLUSIONS: The response patterns observed are similar to those observed in rabbits with hippocampal ablations, leading us to suggest that the adverse effects of phenytoin may be due to actions in the hippocampus.

Somatotopic consolidation: a third phase of reorganization after peripheral nerve injury in adult squirrel monkeys.

It has previously been demonstrated that the central somatosensory topographic reorganization within deprived cortex that follows peripheral nerve injury in adult monkeys occurs in at least two stages: an immediate unmasking period; and a more prolonged period where deprived areas of cortex come to express new receptive fields in a topographically arranged manner. In the present experiments, we have compared cortical topography many months after combined median and ulnar nerve transection with "complete" reorganization evident at relatively short (i.e., 2-5 months) survival times. We find further reorganizational changes in cortical topography with longer survival times. That is, the roughly somatotopic, generally multiple-digit receptive fields frequently observed at the shorter survival times are generally sharpened to more distinct, single-digit receptive fields at longer survival times. We hypothesize that the early crudely topographic maps reflect all available inputs while the refined map is the outcome of an extraction process where only the most useful subset of available inputs is expressed. It is further suggested that this distillation process is a use-dependent phenomenon.

Denervation-induced sprouting of intact peripheral afferents into the cuneate nucleus of adult rats.

In adult monkeys with dorsal rhizotomies extending from the second cervical (C2) to the fifth thoracic (T5) vertebrae, cortex deprived of its normal inputs regained responsiveness to inputs conveyed by intact peripheral afferents from the face [T.P. Pons, P.E. Garraghty, A.K. Ommaya, J.H. Kaas, E. Taub, M. Mishkin, Massive reorganization of the primary somatosensory cortex after peripheral sensory deafferentation, Science 252 (1991) 1857-1860]. It has been suggested that the extent of this massive topographic reorganization may be due to the establishment of novel connections between intact afferents and neurons denervated after dorsal rhizotomy [P.E. Garraghty, D.P. Hanes, S.L. Florence, J.H. Kaas, Pattern of peripheral deafferentation predicts reorganizational limits in adult primate somatosensory cortex, Somatosens. Motor Res. 11 (1994) 109-117]. Using adult rats with comparably extensive dorsal rhizotomies, we employed anatomical tracing techniques to address this possibility. Subcutaneous hindpaw injections of horseradish peroxidase conjugated to either wheat germ agglutinin or cholera toxin subunit B revealed aberrant expansions of gracile projections into the cuneate and, in one case, external cuneate nucleus within three months of the deafferentation. It seems plausible that such modest sprouting of ascending projections at the level of the brainstem may form functional connections which, through divergence, ultimately drive a larger population of neurons in cortex. This new growth may well account for both the substantial cortical reorganization observed in the 'Silver Spring monkeys' [T.P. Pons, P.E. Garraghty, A.K. Ommaya, J.H. Kaas, E. Taub, M. Mishkin, Massive reorganization of the primary somatosensory cortex after peripheral sensory deafferentation, Science 252 (1991) 1857-1860] and the 'referred sensation' phenomena (see J.P. Donoghue, Plasticity of adult sensorimotor representations, Curr. Opin. Neurobiol., 5 (1995) 749-754 for review) reported to follow proximal limb amputations in humans.

Lysophosphatidic acid and EGF stimulate mitogenesis in human airway smooth muscle cells.

Enhanced proliferation of airway smooth muscle is thought to contribute to the pathogenesis of asthma and other obstructive airway diseases. Lysophosphatidic acid (LPA) is a simple bioactive lipid mediator that stimulates mitogenesis in fibroblasts and some other cell types. The effects of LPA on mitogenesis of cultured human airway smooth muscle cells were determined by measuring [3H]thymidine incorporation into cellular DNA. LPA induced a concentration-dependent stimulation of [3H]thymidine incorporation of a similar magnitude to that induced by serum, with the effects of 50 microM LPA being similar to those of 5% serum. Stimulation by LPA and by serum was almost completely eliminated in cells exposed to pertussis toxin, indicating involvement of a pertussis toxin-sensitive G protein in mitogenic signaling by these agents. Epidermal growth factor (EGF) induced stimulation of a similar magnitude as that with LPA, but the stimulation by EGF was insensitive to pertussis toxin. LPA and EGF, when added together, exhibited a markedly synergistic stimulation of [3H]thymidine incorporation that was typically 10-fold greater than the stimulation with either agent alone. LPA and EGF also stimulated mitogenesis assessed by cell growth, and again LPA and EGF together exhibited synergism. These results suggest the possibility that stimulation of airway smooth muscle cell proliferation by LPA, either alone or by enhancing effects of other growth factors, could play a role in normal airway remodeling or in the pathological proliferation of smooth muscle in various airway diseases.