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NASA: Over the last five years, with the advent of flights of U.S. Shuttle/Spacelab missions dedicated entirely to life sciences research, the opportunities for conducting serious studies that use a fully outfitted space laboratory to better understand basic biological processes have increased. The last of this series of Shuttle/Spacelab missions, currently scheduled for 1998, is dedicated entirely to neuroscience and behavioral research. The mission, named Neurolab, includes a broad range of experiments that build on previous research efforts, as well as studies related to less mature areas of space neuroscience. The Neurolab mission provides the global scientific community with the opportunity to use the space environment for investigations that exploit microgravity to increase our understanding of basic processes in neuroscience. The results from this premier mission should lead to a significant advancement in the field as a whole and to the opening of new lines of investigation for future research. Experiments under development for this mission will utilize human subjects as well as a variety of other species. The capacity to carry out detailed experiments on both human and animal subjects in space allows a diverse complement of studies that investigate functional changes and their underlying molecular, cellular, and physiological mechanisms. In order to conduct these experiments, a wide array of biomedical instrumentation will be used, including some instruments and devices being developed especially for the mission.^ieng

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The first three parts of the transduction mechanism for m1 muscarinic receptors (m1 receptors, receptor-G protein coupling, and the activation of phospholipase C) were studied in the rat hippocampus following unilateral or bilateral surgical lesions of the fimbria/fornix. One nM 3H-pirenzepine was used to label m1 receptors selectively. No changes in m1 receptor numbers were found between age 1.7 and 29 months old during normal aging or one year after cholinergic denervation. The interaction between m1 receptors and their associated G protein was examined by competition between 1 nM 3H-pirenzepine and oxotremorine-M in the presence and absence of a guanine nucleotide. The percentage of guanine nucleotide-sensitive high affinity binding sites for the agonist was similar in rats 1.7-29 months old and in rats 1 year after denervation. The ability of oxotremorine-M to activate phospholipase C, via m1, m3, and m5 receptors was also unchanged more than a year after cholinergic denervation of the hippocampus. We concluded that the initial steps in the m1 receptor transduction mechanism remain remarkably stable after denervation.

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The present study mapped neuroanatomical sites in the hypothalamus and periaqueductal gray (PAG) of the rabbit which, when stimulated electrically, evoked the cardiorespiratory components of the defense reaction (CRDR). This included increases in heart rate, blood pressure, hindlimb blood flow and respiration rate. All of the components of the CRDR were elicited by electrical stimulation of the posterior hypothalamus, at sites dorsal and medial to the fornix. Although there were regions throughout the PAG in which electrical stimulation elicited concomitant increases in blood pressure, hindlimb blood flow and respiration rate, only stimulation of the dorsal PAG evoked tachycardia. Injection of horseradish peroxidase into the rostral ventrolateral medulla (RVLM) led to heavy retrograde and anterograde labeling in the region of the hypothalamus that yielded the CRDR when stimulated electrically. Heavy labeling was also observed in the dorsal and ventral PAG. The results of this study provide evidence that the posterior hypothalamus and the dorsal PAG are nodal structures in the mediation of the CRDR and that cells in posterior hypothalamus, dorsal PAG and ventral PAG make monosynaptic connections with the RVLM.

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The present study examined the role of the auditory cortex in the extinction of differentially conditioned heart rate (HR) responses in rabbits. Lesions were placed bilaterally in either the auditory cortex or the visual cortex. Three days after recovery from surgery, the auditory cortex lesion group and the visual cortex lesion control group were habituated to the tonal conditioned stimuli (CSs), and then given 2 days of Pavlovian differential conditioning (60 trials per day) in which one tone (CS+) was always paired with the unconditioned stimulus and another tone (CS-) was never paired with the unconditioned stimulus. Animals that had demonstrated reliable differential conditioning (CS+ response at least 5 beats greater than the CS- response) were placed on an extinction schedule for 7 days. The extinction schedule was identical to the differential conditioning schedule with the exception that shock never followed the CS+. The results of the study indicate that auditory cortex lesions prevent the extinction of differential bradycardia conditioned responses (CRs) to tonal CSs. Whereas the bradycardia responses to the CS+ quickly extinguished in the group that had control lesions in the visual cortex, the auditory cortex lesion group continued to exhibit significantly larger bradycardiac HR CRs to the CS+ relative to the CS- during all 7 days of extinction. These results suggest that the animals in the auditory cortex lesioned group did not inhibit responses to a previously reinforced stimulus (i.e., CS+) as well as animals with control lesions in the visual cortex.

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Electrical stimulation of the rostral medullary raphe (RMR) of the rabbit elicited pressor responses that were accompanied by tachycardia or bradycardia. Stimulation of dorsal sites (the dorsal raphe obscurus) evoked a pressor/tachycardia response and stimulation of ventral sites (the ventral raphe obscurus, raphe magnus and raphe pallidus) produced a pressor/bradycardia response. Electrical stimulation of the RMR after sinoaortic denervation led to an increase in the magnitude of the pressor response elicited from all stimulation sites, a decrease in the magnitude of the bradycardia produced by stimulation at the ventral sites, but had no effect upon the magnitude of the tachycardia observed from stimulation of the dorsal sites. These findings suggest that electrical stimulation of the dorsal sites leads to inhibition of the cardiomotor component of the baroreceptor reflex. The results of vagal blockade experiments demonstrated that baroreceptor attenuation of the pressor responses at ventral sites was mediated primarily by parasympathetic input to the heart. Chemical stimulation of the RMR with L-glutamate also led to a pressor/tachycardia response at the dorsal sites and a pressor/brachycardia response at the ventral sites. This finding provides evidence that neuronal cell bodies, not axon of passage, mediated the responses elicited by electrical stimulation.

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Single cell recordings were made from neurons in the rostral medullary raphe (RMR) of the rabbit. The recording sites were ones that had been shown to yield pressor responses from electrical stimulation and by pressure injections of glutamate. Electrical stimulation of the intermediolateral (IML) region of the spinal cord led to antidromic activation of 12 of the 100 cells studied. Eleven of these cells were located in raphe pallidus or raphe magnus, and one cell was located in raphe obscurus. These findings were consistent with the results of horseradish peroxidase (HRP) histochemistry experiments. Injections of HRP into the IML led to heavy cell body labeling in raphe pallidus and raphe magnus, but sparse labeling in raphe obscurus. Cells in the RMR could be orthodromically activated by electrical stimulation of the putative defense area of the periaqueductal (PAG) but not by stimulation of putative defense areas in the hypothalamus. Most of these cells were located in raphe pallidus or raphe magnus. Similarly, HRP injections into raphe pallidus and raphe magnus led to heavy cell body labeling in the PAG but not the hypothalamus; no cell body labeling was found in the PAG when injections were made into raphe obscurus.

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Previous findings from our laboratory indicate that lesions of the auditory cortex disrupt the retention of differentially conditioned bradycardiac responses to tonal stimuli in rabbits. In the present experiment, the effect of lesions of the auditory cortex on the acquisition of differential bradycardiac conditioning was examined. The effect of lesions in the auditory cortex were compared to the effect produced by control lesions in the visual cortex. After 7 days of recovery, animals received 7 days of differential Pavlovian bradycardiac conditioning in which one tone (CS+) was paired with the unconditioned stimulus, and another tone (CS-) was never paired with the unconditioned stimulus. All animals demonstrated differential conditioning during the first 3 days of conditioning. On days 4-7, however, auditory cortex lesioned animals did not exhibit significant differential heart rate (HR) conditioning, whereas control animals with lesions in the visual cortex showed no loss of conditioning during this period. The loss of differential conditioning in animals with lesions in the auditory cortex appears to be due to an increase in the magnitude of the response to the CS-. These data support the hypothesis that the auditory cortex serves to inhibit the response to the CS- in differential conditioning of bradycardia to acoustic stimuli, and that the inhibition may be mediated by a descending corticothalamic or corticolimbic pathway.

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The effects of chronic treatment with a neuroleptic on D2 dopamine receptors in the striatum and frontal cortex were studied. Exposure to haloperidol for 21 days caused an upregulation in the striatum but not in the cortex of D2 receptors. These results indicate that dopamine-regulating mechanisms in the cortex may differ from those in the striatum and suggest that the anti-psychotic action of neuroleptics may be due in part to blockade of receptors in the cortex.

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Exposure of primary astrocyte cultures to ammonia caused a dose- and time-dependent reduction of isoproterenol-stimulated cyclic AMP (cAMP) production. This treatment did not affect basal cAMP levels. This defect in receptor-linked cAMP production may contribute to the pathogenesis of hepatic and ammonia encephalopathies.

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The effects of lesions to the mesocortical dopaminergic system on D2 dopamine receptors and muscarine receptors in the frontal cortex of the rat was examined. Four weeks following 6-hydroxydopamine lesioning of the ventral tegmental area, there was a 26% increase in the number of [3H]spiroperidol sites, and a 13% decrease in the number of [3H]oxotremorine-M sites in the frontal cortex, indicating a development of D2 receptor supersensitivity, as a result of deafferentation, and a loss of acetylcholine sites, as result of terminal degeneration. This demonstrates that in the frontal cortex, as in the striatum and nucleus accumbens, the activity of dopaminergic terminals may be partially modulated by cholinergic inputs.

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D-2 dopamine receptors and serotonin receptors in the frontal cortex of rat and human were labelled with 3H-spiroperidol. The D-2 receptors were then distinguished in 4 ways. Dissociation of spiroperidol was biphasic, indicating two populations of sites. Cinanserin in competition with 3H-spiroperidol exhibited high (75%) and low (25%) affinity sites. Dopamine and LY 141865 in competition with 1.25 nM 3H-spiroperidol exhibited high (20-25%) and low (80-75%) affinity sites in the absence of cinanserin, while in the presence of 300 nM cinanserin only the high affinity sites remained. Lesioning of the dopaminergic meso-cortical pathway increased the number of cinanserin-resistant sites by 26%. Thus 3H-spiroperidol binding in the presence of cinanserin can be used to selectively label D-2 receptors in the frontal cortex.

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The distribution of L-3,4-dihydroxy-[3H]phenylalanine (L-[3H]DOPA) was examined in rats following i.v. injection, to ascertain the possible usefulness of using this ligand to image dopaminergic systems using positron emission tomography. It was found that L-DOPA and its metabolites were preferentially localized in the basal ganglia as compared to other brain regions, and that this preferential localization could be abolished by lesioning of the nigro-striatal tract. The parameters of the L-DOPA uptake and the sensitivity of this uptake to alterations in dopaminergic pathways indicate that this ligand may be useful in visualizing aberrations in dopaminergic pathways in various pathological conditions.

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Vagal preganglionic motoneurons originating in nucleus ambiguus (NA) and dorsal vagal nucleus (DVN) were identified via retrograde labeling with horseradish peroxidase (HRP). DVN and NA were then explored for cardiovascular responsive sites using microstimulation. Stimulation within DVN from slightly caudal to obex to 3.00 mm rostral to obex produced a primary bradycardia (n = 15, X = -123 bpm). Stimulation within NA from slightly rostral to obex to 1.5 mm caudal to obex produced a similar primary bradycardia (n = 15, X = -127 bpm). Extracellular recordings were made from 7 cells in DVN and 10 cells in NA in regions producing maximal bradycardia to electrical stimulation. These cells were antidromically activated by cervical vagus nerve (VN) stimulation, increased their firing rates to systemic injection of phenylephrine (PE), revealed an expiratory rhythm, showed an increase in firing rate coinciding with spontaneous and elicited decreases in heart rate, had conduction velocities in the A-delta and B-fiber range, and produced bradycardia upon stimulation through the recording electrode with thresholds as low as 4 microA. The data indicate that in rabbits, chronotropic cardioinhibitory vagal motoneurons are discretely localized on the lateral, caudal portions of DVN and NA between 0.5 mm caudal and 1.5 mm rostral to obex.

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