Robert M. Beckstead

Striatal preprotachykinin and preproenkephalin mRNA levels and the levels of nigral substance P and pallidal Met5-enkephalin depend on corticostriatal axons that use the excitatory amino acid neurotransmitters aspartate and glutamate: quantitative radioimmunocytochemical and in situ hybridization evidence

Because excitatory amino acid (EAA) neurotransmission has been implicated in long-term postsynaptic events, we conducted an initial study to determine whether or not the EAA-utilizing corticostriatal projection might influence peptide biosynthesis in neurons of the rats basal ganglia. The content of EAAs in the caudatoputamen was reduced by frontal cortical ablation or by chronic intracerebroventricular infusion of methionine sulfoximine (MS). At 7 days following cortical ablation striatal Asp and Glu were reduced by 15% and 24%, respectively, while MS infusion (24 micrograms/day) for 7 days reduced synaptosomal levels of Asp by 61% and Glu by 48%. With either treatment, quantitative radioimmunocytochemistry revealed that substance P (SP) in the substantia nigra was increased by approximately 38%, while Met5-enkephalin (ME) in the globus pallidus was not changed. In situ hybridization with oligonucleotide probes revealed changes in the rostral striatum of preprotachykinin (PPT) and preproenkephalin (PPE) mRNA levels: cortical ablation reduced PPT mRNA by 17% and PPE mRNA by 20% dorsally, while it increased PPE mRNA (but not PPT mRNA) by 23% ventrally. Likewise, the infusion of MS decreased PPT (32%) and PPE mRNA (28%) dorsally, and increased PPE mRNA (50%) ventrally. In addition to the 7 day time point, the same measurements of EAAs, peptides and mRNAs were made at 14, 21 and 28 days after cortical excisions. At 14 days, the level of striatal Asp had returned to control value, but Glu remained depressed by 21%; nigral SP remained increased by 24%, and pallidal ME decreased by 15%. PPT and PPE mRNA remained depressed dorsally by 15% and 25%, respectively, while the increase in PPE mRNA noted ventrally at 7 days had returned to control values by 14 days. With the exception of Glu, which remained depressed by 18% at 21 and 28 days, all other values had returned to control levels by 21 days. The results indicate that a large reduction in EAA neurotransmission can influence differentially the steady-state levels of neuropeptides in striatal neurons and this change is brought about, at least in part, by an alteration in gene transcription.

Chronic methionine sulfoximine administration reduces synaptosomal aspartate and glutamate in rat striatum

Methionine sulfoxime (MS) is an inhibitor of glutamine synthetase, an astroglial enzyme believed to be involved in the maintenance of glutamine, a major precursor for neurotransmitter pools of the excitatory amino acids aspartate and glutamate in striatal afferent axon terminals. MS was infused for 7 days (24 micrograms/day) into the lateral cerebral ventricle of rats. On the side of MS infusion, there was a decrease of striatal synaptosomal aspartate (61%), glutamine (63%), and glutamate (48%), while taurine and gamma-aminobutyrate were unaltered when compared to vehicle-treated rats. The results indicate that chronic MS infusion is an effective means by which neurotransmitter aspartate and glutamate levels can be selectively reduced in the striatum.

Autoradiographic localization of [125I-Tyr0]bradykinin binding sites in brains of Wistar-Kyoto and spontaneously hypertensive rats.

Abstract1. The present study was undertaken to localize and characterize bradykinin (BK) binding sites in brains from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR).2. Serial sections of brains were cut from adult WKY and SHR and specific [125I-Tyr0]bradykinin ([125I-Tyr0]BK) binding was determined using in vitro quantitative receptor autoradiographic techniques.3. Specific binding of [125I Tyr0]BK was localized in the medulla oblongata to the regions of the nucleus of the solitary tract (NTS), area postrema (AP), dorsal motor nucleus of the vagus (X), and caudal subnucleus of the spinal trigeminal nucleus in both strains of rat. The specific binding (85–90% of total binding) was of high affinity and saturable with KD values in the range of 100 pM and a Bmax of 0.75 fmol per mg tissue equivalent in the NTS–X–AP complex of both the WKY and SHR. In competition studies, the rank order of potencies was similar in both strains with BK = Lys-BK > icatibant >>> DesArg9-BK. The B2 receptor antagonist icatibant inhibited [125I-Tyr0]BK binding with a Ki value of 0.63 ± 0.19 nM in WKY and 0.91 ± 0.73 nM in SHR, while Ki values for the B> 1 receptor agonist DesArg9-BK were 1475 ± 1055 and 806 ± 362 nM in WKY and SHR, respectively.4. Our finding of specific high-affinity [125I-Tyr0]BK B2 binding sites in the NTS, AP, and the X of WKY and SHR is important because these brain areas are associated with central cardiovascular regulation. However, alterations in BK B2 receptors in the medulla that could contribute to the hypertensive state in the SHR were not detected.

Perception, Cognition, and Language

It is well established by now that certain areas of the cerebral cortex serve as the primary recipients of sensory information, and that another area, the primary motor cortex, is synaptically close to the lower motor circuits. In other words, these areas differ from other parts of the cortex in that they are specialized for particular and rather immediate sensory or motor functions. You will also recall that within the primary sensory and motor areas there are subregions that are dedicated to a particular part of the receptive surface or a particular muscle. This areal specialization in the cerebral cortex is an example of a principle of cortical organization that is commonly referred to as the localization of function. It means simply that not all of the cortex participates equally in every brain function; certain areas appear to be specialized to contribute more than other areas to particular brain computations. It is also the case that the cortices of the two hemispheres are functionally asymmetrical; each side has its limitations and particular capabilities, and a number of cerebral functions are lateralized to a greater or lesser degree.

Distribution of corticotectal axons from the caudal part of the anterior ectosylvian sulcus in the cat

Axonal projections from cells in cortex surrounding the caudal part of the anterior ectosylvian sulcus (AES) to the superior colliculus (SC) were examined using anterograde tracers. The projection terminates in the medial two-thirds of the deep layers of SC bilaterally, and appears to be topographically organized, perhaps according to the sensory modality (auditory and visual) represented in the caudal part of AES.

The Life Cycle of Neurotransmitters

Because neurotransmitters are the very currency of brain commerce, disturbances of their metabolism can devastate normal synaptic signaling. Since it is possible to intervene at one or more stages in the life cycle of neurotransmitters for therapeutic purposes—a fact that fuels the activity of the global pharmaceutical industry—understanding neurotransmitter biochemistry is of paramount importance in medical neuroscience.

Memory and Learning

We can all agree by this advanced stage in our survey of neuroscience that the primary biological function of a nervous system, whether it is the simple nerve net of a jellyfish or the exquisitely complex human brain, is to monitor the conditions in and around its owner and to orchestrate its owner’s behavior to optimize its chances for survival and reproductive success. Much of this information processing and response selection capability of nervous systems appears to be built in to the basic plan through genetic evolution (e.g., respiratory reflexes). But nervous systems are endowed also with the ability to undergo some degree of physical alteration to provide flexibility in coping with the variability that might arise in their environment. The degree to which such alteration is possible is determined by the complexity of the nervous system, which in turn is determined by the ecological niche that its owner has come to occupy through the evolutionary process. The nerve net of the jellyfish will support only a handful of sensorimotor responses, which are stub- bornly resistant to change. By contrast, a broad ecological domain such as our own guarantees a variable environment, which favors a more complex and adaptive nervous system.

Primary Somatosensory Processing

Upon entering the CNS, sensory signals are distributed over several parallel pathways in each of which information is serially processed through multiple synaptic stations. Several chapters in this book are devoted to the processing of information in specific sensory modalities. In the present chapter, we will identify the locations of the nuclei in the spinal cord and brain stem that receive the first synapses of peripheral sensory axons, and analyze in greater detail the intrinsic structural and functional organization of those nuclei that receive sensory information from the skin and musculoskeletal (together, the somatosensory) systems. This information should be correlated with details given in the next chapter on the output of these secondary sensory nuclei and further somatosensory processing.

Smell, Taste, and Viscerosensation

The neural pathways that process the sensations of smell, taste, and viscerosensation are, at least initially, anatomically separate from one another. Nevertheless, each of these three senses ultimately provides essential data to the skeletomotor and visceromotor systems that main- tain the internal environment (survival of the individual) and control reproduction (perpetuation of the species). In fact, the three usually work in concert to guide the acquisition of metabolic fuels as well as successful mating behavior.

The Ontogeny of the Forebrain

The emergence of the telencephalic vesicles allows us to distinguish the final two major forebrain regions, the telencephalon and the diencephalon, from one another (have a look back at Figs. 8.1 and 8.2). The telencephalic vesicles give rise to the two cerebral hemispheres while the diencephalon remains as the rostral end of the neural tube. In the diencephalon, the lumen of the neural tube forms the tall narrow slit of the third ventricle (see Fig. 9.3). The roof of the third ventricle remains as a thin choroid membrane, which eventually invaginates to form a modest choroid plexus. The sulcus limitans persists in both walls of the third ventricle, where it is called the hypothalamic sulcus and delimits the thalamus above from the hypothalamus below. The hypothalamus grows more modestly than the thalamus during development, and each differentiates into several nuclear groups. Neither, however, expands as exuberantly as the cerebral hemispheres. In fact, the hemispheres are by far the most productive parts of the developing CNS in terms of ultimate volume and morphological differentiation.