A thalamic reticular networking model of consciousness

<p>Abstract</p> <p>[Background]</p> <p>It is reasonable to consider the thalamus a primary candidate for the location of consciousness, given that the thalamus has been referred to as the gateway of nearly all sensory inputs to the corresponding cortical areas. Interestingly, in an early stage of brain development, communicative innervations between the dorsal thalamus and telencephalon must pass through the ventral thalamus, the major derivative of which is the thalamic reticular nucleus (TRN). The TRN occupies a striking control position in the brain, sending inhibitory axons back to the thalamus, roughly to the same region where they receive afferents.</p> <p>[Hypotheses]</p> <p>The present study hypothesizes that the TRN plays a pivotal role in dynamic attention by controlling thalamocortical synchronization. The TRN is thus viewed as a functional networking filter to regulate conscious perception, which is possibly embedded in thalamocortical networks. Based on the anatomical structures and connections, modality-specific sectors of the TRN and the thalamus appear to be responsible for modality-specific perceptual representation. Furthermore, the coarsely overlapped topographic maps of the TRN appear to be associated with cross-modal or unitary conscious awareness. Throughout the latticework structure of the TRN, conscious perception could be accomplished and elaborated through accumulating intercommunicative processing across the first-order input signal and the higher-order signals from its functionally associated cortices. As the higher-order relay signals run cumulatively through the relevant thalamocortical loops, conscious awareness becomes more refined and sophisticated.</p> <p>[Conclusions]</p> <p>I propose that the thalamocortical integrative communication across first- and higher-order information circuits and repeated feedback looping may account for our conscious awareness. This TRN-modulation hypothesis for conscious awareness provides a comprehensive rationale regarding previously reported psychological phenomena and neurological symptoms such as blindsight, neglect, the priming effect, the threshold/duration problem, and TRN-impairment resembling coma. This hypothesis can be tested by neurosurgical investigations of thalamocortical loops via the TRN, while simultaneously evaluating the degree to which conscious perception depends on the severity of impairment in a TRN-modulated network.</p

Pharmacokinetics of radiotracers in human plasma during positron emission tomography

Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [18F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [11C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [11C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [11C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [11C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [11C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [11C]-(S)-nicotine. [11C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [11C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration. Synapse 34:124-134, 1999. © 1999 Wiley-Liss, Inc

Notch1 Signaling Influences V2 Interneuron and Motor Neuron Development in the Spinal Cord

The Notch signaling pathway plays a variety of roles in cell fate decisions during development. Previous studies have shown that reduced Notch signaling results in premature differentiation of neural progenitor cells, while increased Notch activities promote apoptotic death of neural progenitor cells in the developing brain. Whether Notch signaling is involved in the specification of neuronal subtypes is unclear. Here we examine the role of Notch1 in the development of neuronal subtypes in the spinal cord using conditional knockout (cKO) mice lacking Notch1 specifically in neural progenitor cells. Notch1 inactivation results in accelerated neuronal differentiation in the ventral spinal cord and gradual disappearance of the ventral central canal. These changes are accompanied by reduced expression of Hes1 and Hes5 and increased expression of Mash1 and Neurogenin 1 and 2. Using markers (Nkx2.2, Nkx6.1, Olig2, Pax6 and Dbx1) for one or multiple progenitor cell types, we found reductions of all subtypes of progenitor cells in the ventral spinal cord of Notch1 cKO mice. Similarly, using markers (Islet1/2, Lim3, Sim1, Chox10, En1 and Evx1/2) specific for motor neurons and distinct classes of interneurons, we found increases in the number of V0-2 interneurons in the ventral spinal cord of Notch1 cKO mice. Specifically, the number of Lim3+/Chox10+ V2 interneurons is markedly increased while the number of Lim3+/Islet+motor neurons is decreased in the Notch1 cKO spinal cord, suggesting that V2 interneurons are generated at the expense of motor neurons in the absence of Notch1. These results provide support for a role of Notch1 in neuronal subtype specification in the ventral spinal cord