Structural-functional state of opiate receptors in surviving slices of the olfactory cerebral cortex of rats during long-term potentiation.
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Transport of manganese via the olfactory pathway in rats: dosage dependency of the uptake and subcellular distribution of the metal in the olfactory epithelium and the brain.
The dosage dependency of the uptake of Mn from the olfactory epithelium via olfactory neurons into the brain was studied after intranasal administration of the metal in rats. The results indicate that the Mn transport is saturable both regarding the uptake into the olfactory epithelium and the transfer to the olfactory bulb. Further, our data indicate that Mn moves relatively freely from the olfactory bulb to the olfactory cortex at an amount dependent on the level of influx into the bulb. The transport to the rest of the brain was related to the amounts in the olfactory bulb and the olfactory cortex, but the relative proportion reaching this area increased with increasing doses. Cell fractionations showed that the Mn was present both in the cytosol and in association with various cell constituents. Gel filtrations of the cytosol on a Superdex 30 column showed that about 20% of the Mn in the brain and about 3% in the olfactory epithelium was eluted together with high-molecular-weight materials (MW > 10,000), whereas the rest was eluted in the total volume and may represent unbound metal. It is likely that the metal has been loosely associated with protein(s) or other constituents at the application to the column, but that this association is too loose to be retained during the passage through the column. Our results show that the olfactory neurons provide a pathway with a considerable capacity to transport Mn into the brain. We propose that the neurotoxicity of inhaled Mn is related to an uptake via this route.
Administration, Intranasal↗
Imaging the induction and spread of seizure activity in the isolated brain of the guinea pig: the roles of GABA and glutamate receptors.
1. The induction and spread of seizure activity was studied using imaging and electrophysiological techniques in the isolated whole brain of the guinea pig. We examined the role of GABA and glutamate receptor subtypes in controlling the spread of seizure activity across the olfactory cortex from a focus in the entorhinal cortex. Seizure spread was monitored by video imaging of intrinsic optical signals (reflectance changes) combined with multiple extracellular recordings. Both the unilateral and bilateral spread of seizure activity was monitored in different experiments. 2. Electrical stimulation of the lateral entorhinal cortex (10-15 V, 5 Hz, 5-10 s) evoked seizure activity that originated in the entorhinal cortex/hippocampus and later spread preferentially toward the posteromedial cortical amygdaloid nucleus ipsilaterally and bilaterally. The pattern of seizure spread in a given brain was highly reproducible. 3. The influence of gamma-aminobutyric acid (GABA) receptors on the spread of seizure activity was monitored at higher resolution on one side of the brain. Perfusion of a low concentration of the GABAA antagonist bicuculline methiodide (20 microM) resulted in spontaneous seizures that spread to the posteromedial cortical amygdaloid nucleus more rapidly than electrically evoked seizures [spread times: 5.5 +/- 3.7 s vs. 15.5 +/- 2.7 s, respectively (means +/- SE)]. Seizure spread was also more extensive in the presence of bicuculline involving the posterior perirhinal cortex and larger areas over the medial amygdala. Higher concentrations of bicuculline (100 microM) resulted in even more widespread propagation of spontaneous seizure activity throughout the olfactory cortex as well as to the perirhinal, insular, and occipital cortices. This concentration of bicuculline also further reduced the time required for seizure activity to spread from the entorhinal cortex to the posteromedial cortical amygdaloid nucleus (spread time = 2.3 +/- 1.7 s). The GABAB antagonist, CGP 35348 (200 microM), in contrast, had no significant effect of seizure induction or propagation. 4. The role of glutamate receptor subtypes in seizure propagation was studied by examining the bilateral spread of seizures. Perfusion of the kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (K/A) receptor antagonist (6-cyano-7-nitroquinoxaline-2,3-dione, CNQX, 20 microM) completely and reversibly suppressed stimulus-evoked seizure activity as detected electrophysiologically and optically. CNQX also reduced the magnitudes of field potentials recorded in the isolated brain in a reversible manner by an average of 70.8 +/- 2.21% of control. The N-methyl-D-aspartate (NMDA) receptor antagonist dibenzocyclohepteneimine (MK-801) did not significantly alter the magnitudes or shapes of field potentials recorded in the isolated brain nor did it significantly alter seizure activity measured optically or electrophysiologically. 5. Perfusion of the metabotropic glutamate receptor agonist [trans-1-amino-(IS,3R)-cyclopentanedicarboxylic acid (trans-ACPD), 150 microM] completely and reversibly suppressed stimulus-evoked seizure activity as detected electrophysiologically and optically. The magnitudes of field potentials recorded in the isolated brain also were reduced by trans-ACPD an average of 75.4 +/- 5.39% of control values. 6. These results demonstrate that GABAA-mediated transmission is functionally present and may play an important role in epileptic tissue in limiting the spread of seizure activity from the entorhinal cortex to the posteromedial cortical amygdaloid nucleus and in creating functional pathways or preferential routes of seizure spread. GABAB-mediated postsynaptic inhibition played no significant role in the induction or spread of seizure activity in this study. K/A receptors but not NMDA receptors are necessary for the induction and subsequent spread of seizure activity originating in the entorhinal cortex/hippocampus.
Animals↗
Age-dependent and selective impairment of long-term potentiation in the anterior piriform cortex of mice lacking the fragile X mental retardation protein.
Synaptic function and plasticity were studied in mice lacking the fragile X mental retardation protein (FMRP), a model for the fragile X mental retardation syndrome. Associational connections were studied in slices of anterior piriform (olfactory) cortex, and Schaffer-commissural synapses were studied in slices of hippocampus. Knock-out (KO) mice lacking FMRP were compared with congenic C57BL/6J wild-type (WT) controls. Input-output curves and paired-pulse plasticity were not significantly altered in KO compared with WT mice in either the olfactory cortex or hippocampus. Long-term potentiation (LTP) induced by theta burst stimulation in the anterior piriform cortex was normal in KO mice aged < 6 months but was impaired in KO mice aged > 6 months. The deficit in LTP was significant in mice aged 6-12 months and more pronounced in mice aged 12-18 months. Similar differences between WT and KO mice were seen whether LTP was induced in the presence or absence of a GABAA receptor blocker. Postsynaptic responses to patterned burst stimulation in KO mice showing impaired LTP were not significantly different from those in WT mice, suggesting that the LTP deficit was not caused by alterations in circuit properties. No differences in hippocampal LTP were observed in WT and KO mice at any ages. The results indicate that FMRP deficiency is associated with an age-dependent and region-selective impairment in long-term synaptic plasticity.
Aging↗
Manganese taken up into the CNS via the olfactory pathway in rats affects astrocytes.
Manganese (Mn), administered intranasally in rats, is effectively taken up in the CNS via the olfactory system. In the present study, Mn (as MnCl(2)) dissolved in physiological saline, was instilled intranasally in rats at doses of 0 (control), 10, 250, or 1000 microg. At the start of the experiment each rat received an intranasal instillation. Some rats were killed after one week without further treatment (the 1-w group), whereas the remaining rats received further instillations after one and two weeks and were killed after an additional week (the 3-w group). The brains were removed and either used for ELISA-determination of the astrocytic proteins glial fibrillary acidic protein (GFAP) and S-100b or histochemical staining of GFAP and S-100b, microglia (using an antibody against the iba1-protein) and the neuronal marker Fluoro-Jade. There were no indications that the Mn induced neuronal damage. On the other hand, the ELISA showed that both GFAP and S-100b decreased in the olfactory cortex, the hypothalamus, the thalamus, and the hippocampus of the 3-w group. The only effect observed in the 1-w group was a decrease of S-100b in the olfactory cortex at the highest dose. The immunohistochemistry showed no noticeable reduction in the number of astrocytes. We assume that the decreased levels of GFAP and S-100b are due to an adverse effect of Mn on the astrocytes, although this effect does not result in astrocytic demise. In the 3-w group, exposed to the highest dose of Mn, increased levels of GFAP and S-100b were observed in the olfactory bulbs, but these effects are probably secondary to a Mn-induced damage of the olfactory epithelium. Our results indicate that the astrocytes are the initial targets of Mn toxicity in the CNS.
Administration, Intranasal↗
Negatively calcium-modulated membrane guanylate cyclase signaling system in the rat olfactory bulb.
The mechanism by which the individual odor signals are translated into the perception of smell in the brain is unknown. The signal processing occurs in the olfactory system which has three major components: olfactory neuroepithelium, olfactory bulb, and olfactory cortex. The neuroepithelial layer is composed of ciliated sensory neurons interspersed among supportive cells. The sensory neurons are the sites of odor transduction, a process that converts the odor signal into an electrical signal. The electrical signal is subsequently received by the neurons of the olfactory bulb, which process the signal and then relay it to the olfactory cortex in the brain. Apart from information about certain biochemical steps of odor transduction, there is almost no knowledge about the means by which the olfactory bulb and cortical neurons process this information. Through biochemical, functional, and immunohistochemical approaches, this study shows the presence of a Ca(2+)-modulated membrane guanylate cyclase (mGC) transduction system in the bulb portion of the olfactory system. The mGC is ROS-GC1. This is coexpressed with its specific modulator, guanylate cyclase activating protein type 1 (GCAP1), in the mitral cells. Thus, a new facet of the Ca(2+)-modulated GCAP1--ROS-GC1 signaling system, which, until now, was believed to be unique to phototransduction, has been revealed. The findings suggest a novel role for this system in the polarization and depolarization phenomena of mitral cells and also contradict the existing belief that no mGC besides GC-D exists in the olfactory neurons.
Animals↗
Olfactory projections to the hypothalamus.
Electrophysiological recording, together with anterograde and retrograde axonal tracers, was used to provide a comprehensive description of the origin and distribution of the olfactory input to the lateral hypothalamus. This input was much more substantial to the caudal part of the hypothalamus than to the rostral part and originates from several different areas of the olfactory cortex. Positive responses to electrical stimulation of the olfactory bulb were found consistently in the postero-lateral hypothalamus, but only occasionally at more rostral levels. In agreement with this, injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) in the posterior half of the lateral hypothalamus labeled cells in four cortical areas that receive input from the olfactory bulb: the anterior olfactory nucleus, the piriform cortex (in the deepest layer or ventral endopiriform nucleus), the olfactory tubercle (in the deep polymorphic layer), and the anterior cortical nucleus of the amygdala. Injections of WGA-HRP in the anterolateral hypothalamus labeled cells only in the anterior cortical nucleus of the amygdala. Anterograde axonal tracing confirmed these projections. Injections of 3H-leucine in the anterior olfactory nucleus, the piriform cortex, and the olfactory tubercle produced axonal label that was light and confined to the medial forebrain bundle in the rostral hypothalamus but was more substantial and extended throughout the lateral hypothalamic area caudally. Injections in the anterior cortical amygdaloid nucleus labeled axons in the anterior hypothalamus and in the premammillary nuclei as well as in the posterolateral hypothalamic area. In addition, a projection was demonstrated to the nuclei gemini from the polymorphic zone deep to the olfactory tubercle. Injections of two fluorescent retrograde tracers into the mediodorsal nucleus of the thalamus and the posterolateral hypothalamus showed that cells projecting to both diencephalic sites were intermingled in all of the olfactory cortical areas except the anterior olfactory nucleus, where cells were labeled only from the hypothalamus. In the deep layer of the piriform cortex and in the anterior cortical amygdaloid nucleus cells were also double labeled, indicating that they send collateral axons to both parts of the diencephalon.
Amygdala↗
The olfactory bulb as an independent developmental domain.
The olfactory system is a good model to study the mechanisms underlying guidance of growing axons to their appropriate targets. The formation of the olfactory bulb involves differentiation of several populations of cells and the initiation of the central projections, all under the temporal and spatial patterns of gene expression. Moreover, the nature of interactions between the olfactory epithelium, olfactory bulb and olfactory cortex at early developmental stages is currently of great interest. To explore these questions more fully, the present review aims to correlate recent data from different developmental studies, to gain insight into the mechanisms involved in the specification and development of the olfactory system. From our studies in the pax6 mutant mice (Sey(Neu)/Sey(Neu)), it was concluded that the initial establishment of the olfactory bulb central projections is able to proceed independently of the olfactory sensory axons from the olfactory epithelium. The challenge that now remains is to consider the validity of the olfactory bulb as an independent development domain. In the course of evaluating these ideas, we will review the orchestra of molecular cues involved in the formation of the projection from the OB to the olfactory cortex.
Animals↗
Regional alterations of the NO/NOS system in the aging brain: a biochemical, histochemical and immunochemical study in the rat.
We have used several approaches (immunohistochemistry and enzyme histochemistry, Western blotting, biochemical assay of Ca(2+)-dependent catalytic activity) in order to detect differences in neuronal nitric oxide synthase (nNOS) expression and activity in various brain regions of young-adult (4-month-old) and aged (28-month-old) rats. In most of the brain regions examined (striatum, neocortex, olfactory cortex and hippocampus) some significant decrease in the density per unit area of nNOS neurons, detected either through immunohistochemistry or enzyme histochemistry, was observed in aged rats. However, only in the striatum and olfactory cortex this was accompanied by a significant decrease of the catalytic activity of the constitutive, Ca(2+)-dependent NOS form. In these two regions, the relative level of expression of nNOS protein was also significantly decreased, as assessed by Western blotting of proteic extracts from young-adult and aged rats. Other observed differences were a paler stain of neurons in some brain areas of the aged rats and differences of cellular compartmentalization of the protein in the same rats, as assessed through confocal microscopy. The present observations demonstrate that the expression and activity of nNOS show regionally-specific alterations in the brain of aged healthy rats, with a trend towards decrease, rather than toward increase as suggested by some previous reports. Therefore, hypotheses implicating nitric oxide increase in brain aging should be reconsidered on the basis of a clear-cut distinction between the physiological and the pathological aspects of the aging process.
Aging↗
Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: an immunohistochemical and in situ hybridization study.
The localization of glucocorticoid receptor (GR) immunoreactivity and mRNA in the adult rat brain was examined by light microscopic and electron microscopic immunohistochemistries, and in situ hybridization. For the purpose of detailed investigation of the distribution and comparison of GR immunoreactivities and mRNAs, specific polyclonal antibodies against a part of the transcription modulation (TR) domain of rat GR were used in the immunohistochemistry, whereas fluorescein-labeled RNA probes, complementary to the TR domain in the GR cDNA were used in the in situ hybridization. In the rat brain, GR immunoreactivity was predominantly localized in the cell nucleus, and the expression of GR mRNA was detected in the cytoplasm. GR-immunoreactive and GR mRNA-containing cells were widely distributed from the olfactory bulb of the forebrain to the gracile-cuneate nuclei of the medulla oblongata. The highest densities of GR-immunoreactive and mRNA-containing cells were observed in the subfields of cerebral cortex, olfactory cortex, hippocampal formation, amygdala, septal region, dorsal thalamus, hypothalamus, trapezoid body, cerebellar cortex, locus coeruleus and dorsal nucleus raphe. The distributional pattern of GR immunoreactivity in many regions was well-correlated with that of GR mRNA, but in the CA3 and CA4 pyramidal layers of the hippocampus, different localization was noted. The present study provides the groundwork for elucidating the role of GRs in brain function.
Animals↗
Effects of acute administration of ethanol on cerebral glucose utilization in adult alcohol-preferring and alcohol-nonpreferring rats.
Local cerebral glucose utilization (LCGU) rates, as determined by the [(14)C]-2-deoxyglucose (2-DG) technique, were examined after acute ethanol administration within selected brain regions of alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. Adult male P and NP rats were injected with saline, 0.25 g/kg, or 1.0 g/kg ethanol, intraperitoneally (ip), 10 min before an intravenous bolus of [(14)C]2-DG (125 microCi/kg). Timed arterial blood samples were collected over 45 min and assayed for plasma glucose, ethanol, and [(14)C]2-DG levels. Image densities were determined using quantitative autoradiography and LCGU values calculated. Data were collected from several key limbic, basal ganglionic, cortical, and subcortical structures. Low-dose ethanol (0.25 g/kg) significantly decreased LCGU rates in several brain regions including the medial prefrontal cortex, olfactory tubercles, and the CA1 subregion of the hippocampus of P rats. Low-dose ethanol had no significant effects on LCGU rates in the NP rats. Moderate-dose ethanol (1.0 g/kg) also significantly lowered LCGU rates in many brain regions of P rats, including key limbic structures, such as the medial prefrontal cortex, olfactory tubercles, ventral tegmental area, basolateral nucleus of the amygdala, lateral septum, and ventral pallidum. Moderate-dose ethanol also significantly lowered LCGU rates in the medial prefrontal cortex as well as in the habenula of NP rats. All other regions were unaffected in the NP rats. These findings support the suggestion that certain central nervous system regions of P rats may be more sensitive than those of NP rats to the effects of low to intermediate doses of ethanol.
Alcohol Drinking↗
Calcium, magnesium and the electrical activity of guinea-pig olfactory coex in vitro.
1. Evoked electrical activity was observed in slices from guinea-pig olfactory cortex maintained in vitro. This evoked activity was studied in saline solutions containing various concentrations of Ca(2+) and Mg(2+).2. The evoked potentials recorded from the surface of the prepiriform cortex comprised a negative wave (N-wave) of about 10-15 msec duration upon which a variable number of short duration positive notches were superimposed. The N-wave was identified as a population excitatory post-synaptic potential (EPSP) of the olfactory cortex neurones and the positive notches were identified with synchronous discharge of cortical neurones.3. The relation between the EPSP amplitude and saline Ca(2+) concentration was sigmoid. The N-wave amplitude (EPSP) was proportional to [Ca(2+)](o) (n). When saline Ca(2+) was between 0.4 and 1 mMn averaged 2.5 (range 1.5-4.3).4. The EPSP amplitude was reduced by increasing saline [Mg(2+)]. High Mg(2+) salines (about 10 mM) abolished the EPSP.5. Both Ca(2+) and Mg(2+) in high concentrations depressed the positive notches.6. Salines containing little or no Ca(2+) and Mg(2+) caused the preparation to show signs of hyperexcitability. Under these conditions the evoked potentials were very variable and unstable. ;Ca(2+)-free' salines caused a reversible loss of excitability.7. The results indicated that Ca(2+) and Mg(2+) had antagonistic effects on the release of the transmitter substance(s). Increased Ca(2+) concentrations increased the output of transmitter, increased Mg(2+) concentrations reduced the output of transmitter. Both Ca(2+) and Mg(2+) in increasing concentration increased the threshold for action potential generation.
Action Potentials↗
Differential proliferative response in the postischemic hippocampus, temporal cortex, and olfactory bulb of young adult macaque monkeys.
We investigated the fate of proliferating cells in the adult monkey brain after global ischemia. We used the thymidine analogue bromodeoxyuridine (BrdU) to label S-phase cells and their progeny in Japanese macaques subjected to global cerebral ischemia for 20 min or to a sham operation. Subsequently, newly generated cells were identified by BrdU immunohistochemistry, and their immunophenotype was determined quantitatively, using specific markers. The ischemic insult significantly increased the number of proliferating cells in the hippocampus and temporal neocortex, where the majority BrdU-labeled cells expressed markers for microglia (Iba1, CD68, and Ham56) or astrocytes (S-100beta and glial fibrillary acidic protein [GFAP]). In contrast, the proliferation level in the parahippocampal region remained unchanged. This discrepancy prompted us to investigate the postischemic response in the olfactory bulb, a well-known site of adult cell generation that is anatomically distant from the above-mentioned regions but that is also subjected to the global ischemic insult. The olfactory bulb contained clusters of proliferating cells expressing markers for neural (Musashi1 and Nestin) and/or neuronal (class III beta-tubulin) progenitors; these were immunophenotypically distinct from other cell types. Their number and distribution were unaltered by ischemia. Our results demonstrate that cell proliferation and differentiation in the adult macaque brain and olfactory bulb are differentially affected by a common insult.
Animals↗
The functional anatomy of limbic status epilepticus in the rat. I. Patterns of 14C-2-deoxyglucose uptake and Fos immunocytochemistry.
Limbic status epilepticus was induced in awake, unrestrained rats by electrically stimulating the olfactory cortex or the basal amygdaloid nucleus for about 40 min. One of four stable forms of status was induced, which were distinguished on the basis of their behavioral and EEG manifestations, and their distinct patterns of 14C-2-deoxyglucose uptake and Fos-like immunoreactivity. Type I status was characterized by sporadic EEG discharges and the activation of the amygdalohippocampal area, but had no overt behavioral manifestation. Type II status involved incessant exploratory behaviors, single EEG discharges, and the additional activation of the basal amygdaloid nucleus, some of its efferent projections, and parts of the olfactory cortex. Type III status included all of these same patterns, plus the episodic development of ictal EEG activity associated with facial and forelimb clonus, and the concurrent recruitment of the entire amygdala, ventral hippocampal formation, prefrontal, insular, and olfactory cortices, and related subcortical structures. Type IV status was characterized by generalized clonus, unremitting ictal EEG discharges, and the additional activation of most of the dorsolateral neocortex, neostriatum, and thalamus. In each case of status type I, II, or III, the same anatomical structures that displayed high levels of 14C-2-deoxyglucose uptake also contained many cells that were immunoreactive for Fos, with the exception of the parataenial and mediodorsal thalamic nuclei and the substantia nigra pars reticularis. Thus, the overall patterns of 14C-2-deoxyglucose uptake and Fos-like immunoreactivity from the same animals displayed a remarkable degree of correspondence. The major results indicate that different levels of status are related to the activation of discrete epileptogenic foci, and the capacity of such foci to interact with a distinct set of interconnected anatomical structures. It is suggested that the behavioral manifestations of limbic status epilepticus may be explained by influences of limbic structures in the ventral forebrain upon lower motor elements in the brainstem and spinal cord, without the participation of the "pyramidal" motor system.
Amygdala↗
Absence of excitotoxic neuropathology in microencephalic rats after systemic kainic acid administration.
We have s.c. injected with kainic acid (12 mg/kg) normal adult rats as well as rats rendered microencephalic by selectively timed administration of the DNA alkylating agent methylazoxymethanol acetate (MAM) to the mother during pregnancy. Histological examination of the brains revealed that normal animals underwent neurodegeneration in brain regions sensitive to kainic acid excitotoxicity, such as the olfactory cortex and the hippocampus, while no damage was apparent in the same regions of microencephalic rats. Evaluation of the neurotoxic outcome consequent to the excitotoxic stimulation, was quantitatively performed by measuring the levels of appropriate neurochemical markers 15 days after kainic acid injection. In normal animals, this resulted in significant decrease (up to 60% in the olfactory cortex and 30% in the hippocampus) of markers related to glutamatergic and GABAergic neurons, whereas in MAM-treated rats the same markers were not significantly affected, thus demonstrating a substantial protection against the excitotoxic insult in the microencephalic condition.
Animals↗
The olfactory system and Alzheimer's disease.
Alzheimer's disease (AD) is considered to be the number one health problem and seems to be reaching epidemic proportion in the USA. The cause of AD is not known, a reliable animal model of the disease has not been found and appropriate treatment of this dementia is wanting. The present review focuses on the possibility that a virus or exogenous toxic materials may gain access to the CNS using the olfactory mucosa as a portal of entry. Anterograde and retrograde transport of the virus/zeolites to olfactory forebrain regions, which receive primary and secondary projections from the main olfactory bulb (MOB) and which, in turn, project centrifugal axons to the MOB, may initiate cell degeneration at such loci. Pathological changes may, thus, be initially confined to projecting and intrinsic neurons localized in cortical and subcortical olfactory structures; arguments are advanced which favor the view that excitotoxic phenomena could be mainly responsible for the overall degenerative picture. Neurotoxic activity may follow infection by the virus itself, be facilitated by loss of GABAergic terminals in olfactory cortex, develop following repeated episodes of physiological long term potentiation (which unmasks NMDA receptors) or be due to excessive release, faculty re-uptake or altered glutamate receptor sensitivity. Furthermore, a reduction in central inhibitory inputs to the MOB might then result in disinhibition of mitral/tufted neurons and enhance the excitotoxic phenomena in the MOB projecting field. Within this context, and in line with recent studies, it is believed that pathology begins at cortical (mainly olfactory) regions, basal forebrain neurons being secondarily affected due to retrograde degeneration. In addition, failure to produce a critical level of neurotrophic factors by a damaged MOB and olfactory cortex, could adversely affect survival of basal cholinergic neurons which innervate both regions. Support for these hypothesis is provided, first, by recent reports on pathological findings in AD brains which seem to involve preferentially the olfactory and entorhinal cortices, the olfactory amygdala and the hippocampus, all of which receive primary or secondary projections from the MOB; secondly, by the presence of severe olfactory deficits in the early stages of the disease, mainly of a discriminatory nature, which points to a malfunction of central olfactory structures.
Alzheimer Disease↗
A neural network model of general olfactory coding in the insect antennal lobe.
A central problem in olfaction is understanding how the quality of olfactory stimuli is encoded in the insect antennal lobe (or in the analogously structured vertebrate olfactory bulb) for perceptual processing in the mushroom bodies of the insect protocerebrum (or in the vertebrate olfactory cortex). In the study reported here, a relatively simple neural network model, inspired by our current knowledge of the insect antennal lobes, is used to investigate how each of several features and elements of the network, such as synapse strengths, feedback circuits and the steepness of neural activation functions, influences the formation of an olfactory code in neurons that project from the antennal lobes to the mushroom bodies (or from mitral cells to olfactory cortex). An optimal code in these projection neurons (PNs) should minimize potential errors by the mushroom bodies in misidentifying the quality of an odor across a range of concentrations while maximizing the ability of the mushroom bodies to resolve odors of different quality. Simulation studies demonstrate that the network is able to produce codes independent or virtually independent of concentration over a given range. The extent of this range is moderately dependent on a parameter that characterizes how long it takes for the voltage in an activated neuron to decay back to its resting potential, strongly dependent on the strength of excitatory feedback by the PNs onto antennal lobe intrinsic neurons (INs), and overwhelmingly dependent on the slope of the activation function that transforms the voltage of depolarized neurons into the rate at which spikes are produced. Although the code in the PNs is degraded by large variations in the concentration of odor stimuli, good performance levels are maintained when the complexity of stimuli, as measured by the number of component odorants, is doubled. When excitatory feedback from the PNs to the INs is strong, the activity in the PNs undergoes transitions from initial states to stimulus-specific equilibrium states that are maintained once the stimulus is removed. When this PN-IN feedback is weak the PNs are more likely to relax back to a stimulus-independent equilibrium state, in which case the code is not maintained beyond the application of the stimulus. Thus, for the architecture simulated here, strong feedback from the PNs onto the INs, together with step-like neuronal activation functions, could well be important in producing easily discriminable odor quality codes that are invariant over several orders of magnitude in stimulus concentration.
Animals↗
A study of the possible mechanisms underlying the convulsant actions of a linear expanded xanthine.
The actions of a mixture of the 4- and 9-chloro derivatives of the linear expanded xanthine 5,7-diethyl-2-chloroimidazo[4,5-g]quinazoline-6,8 (5H,7H)-dione (chloro-DCQD) on the isolated olfactory cortex slice of the rat have been investigated. Chloro-DCQD evoked a slowly-developing depolarization which intensified over a drug application period of at least 4 min. A pharmacological investigation of the response showed that it was not mediated by blockade of potassium channels or activation of voltage-gated sodium channels, by a stimulant action at receptors to gamma-aminobutyric acid (GABA), excitatory amino acids or acetylcholine, or by antagonism of adenosine receptors. Chloro-DCQD (2.5 mM) potentiated responses evoked by N-methyl-D-aspartate (NMDA), L-aspartate and L-glutamate, probably by overcoming the magnesium ion block of the ion channel of the NMDA receptor complex. Chloro-DCQD (2.5 or 5 mM) also increased pyramidal cell excitability and abolished GABA-mediated postsynaptic inhibition but did not affect the excitability of, or neurotransmitter release from, the terminals of the lateral olfactory tract. Chloro-DCQD competitively antagonized the inhibitory actions of adenosine on the olfactory cortex. These effects are consistent with the reported convulsant actions of chloro-DCQD.
Animals↗