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T J Marczynski

Publications and source records attributed to T J Marczynski.

At least 19 recordsLinked to original sources
PubMed1998

GABAergic deafferentation hypothesis of brain aging and Alzheimer's disease revisited.

Considering the mechanisms responsible for age- and Alzheimer's disease (AD)-related neuronal degeneration, little attention was paid to the opposing relationships between the energy-rich phosphates, mainly the availability of the adenosine triphosphate (ATP), and the activity of the glutamic acid decarboxylase (GAD), the rate-limiting enzyme synthesizing the gamma-amino butyric acid (GABA). Here, it is postulated that in all neuronal phenotypes the declining ATP-mediated negative control of GABA synthesis gradually declines and results in age- and AD-related increases of GABA synthesis. The Ca2+-independent carrier-mediated GABA release interferes with Ca2+-dependent exocytotic release of all transmitter-modulators, because the interstitial (ambient) GABA acts on axonal preterminal and terminal varicosities endowed with depolarizing GABA(A)-benzodiazepine receptors; this makes GABA the "executor" of virtually all age- and AD-related neurodegenerative processes. Such a role of GABA is diametrically opposite to that in the perinatal phase, when the carrier-mediated GABA release, acting on GABA(A)/chloride ionophore receptors, positively controls chemotactic migration of neuronal precursor cells, has trophic actions and initiates synaptogenesis, thereby enabling retrograde axonal transport of target produced factors that trigger differentiation of neuronal phenotypes. However, with advancing age, and prematurely in AD, the declining mitochondrial ATP synthesis unleashes GABA synthesis, and its carrier-mediated release blocks Ca2+-dependent exocytotic release of all transmitter-modulators, leading to dystrophy of chronically depolarized axon terminals and block of retrograde transport of target-produced trophins, causing "starvation" and death of neuronal somata. The above scenario is consistent with the following observations: 1) a 10-month daily administration to aging rats of the GABA-chloride ionophore antagonist, pentylenetetrazol, or of the BDZ antagonist, flumazenil (FL), each forestalls the age-related decline in cognitive functions and losses of hippocampal neurons; 2) the brains of aging rats, relative to young animals, and the postmortem brains of AD patients, relative to age-matched controls, show up to two-fold increases in GABA synthesis; 3) the aging humans and those showing symptoms of AD, as well as the aging nonhuman primates and rodents--all show in the forebrain dystrophic axonal varicosities, losses of transmitter vesicles, and swollen mitochondria. These markers, currently regarded as the earliest signs of aging and AD, can be reproduced in vitro cell cultures by 1 microM GABA; the development of these markers can be prevented by substituting Cl- with SO4(2-); 4) the extrasynaptic GABA suppresses the membrane Na+, K+-ATPase and ion pumping, while the resulting depolarization of soma-dendrites relieves the "protective" voltage-dependent Mg2+ control of the N-methyl-D-aspartate (NMDA) channels, thereby enabling Ca2+-dependent persistent toxic actions of the excitatory amino acids (EAA); and 5) in whole-cell patch-clamp recording from neurons of aging rats, relative to young rats, the application of 3 microM GABA, causes twofold increases in the whole-cell membrane Cl- conductances and a loss of the physiologically important neuronal ability to desensitize to repeated GABA applications. These age-related alterations in neuronal membrane functions are amplified by 150% in the presence of agonists of BDZ recognition sites located on GABA receptor. The GABA deafferentation hypothesis also accounts for the age- and AD-related degeneration in the forebrain ascending cholinergic, glutamatergic, and the ascending mesencephalic monoaminergic system, despite that the latter, to foster the distribution-utilization of locally produced trophins, evolved syncytium-like connectivities among neuronal somata, axon collaterals, and dendrites, to bidirectionally transport trophins. (ABSTRACT TRUNCATED)

Aging↗
PubMed1993

A low-noise preamplifier for multisite recording of brain multi-unit activity in freely moving animals.

A novel FET instrumentation amplifier is described which, as compared to most traditional operational FET preamplifiers, is characterized by an about 7-10 times lower intrinsic electronic noise and a higher common mode rejection. This allows discrimination of single units from multi-unit recording, even if the action potential amplitudes are as small as 20-30 microV and the units are located more than 100 microns away from the electrode tips. Such a distant and chronic recording may be expected to reduce the possibility of mechanical interference with functions of neuronal membrane and its immediate environment, and may be suitable for studying changes in functional connectivities among neurons during the animal's behavior and learning.

Action Potentials↗
PubMed1991

Chronic administration of flumazenil (Ro 15-1788) enhances non-appetitive exploratory behavior of rats.

The effects of chronic administration of the benzodiazepine receptor antagonist, flumazenil (Ro 15-1788; 4 mg/kg/day for 14 days in drinking water) on the performance of adult rats in the 12-arm radial maze were studied. Relative to controls, the animals treated with flumazenil showed an increase (P less than 0.002) in non-appetitively motived exploratory behavior, so called because it occurred in 88% of instances in non-baited alleys, facing the well-illuminated "enriched environment" of the center of the room, as opposed to the baited alleys, facing the "dull" corner of the room. This behavior emerged between day 5 and 7 of treatment with the drug, it continued to increase over the period of treatment with drug (P less than 0.002), and reached its peak at day 3, after withdrawal of the drug (P less than 0.008; a longer duration was not investigated). The occurrence of non-appetitively motivated exploratory behavior was inversely correlated with the scores for urination/defecation (P less than 0.003) and, therefore, most likely reflected the anxiolytic action of flumazenil. During treatment with drug or vehicle, the control and the drug groups made comparable numbers of "working memory" errors (P = 0.17). However, upon withdrawal of drug and introduction of alley gates (to confine the animal for 10 sec to the center platform, after an alley was explored), the working memory errors of the rats exposed to the drug, remained unchanged (P = 0.35), relative to the preceding three trials, while the performance of the control group was disrupted, as shown by an increase in the numbers of errors (P less than 0.004). At day seven of treatment with drug, the emergence of exploratory behavior was associated with an increased density and/or affinity of benzodiazepine receptors in cortex, hippocampus and brain stem, while three days after withdrawal of drug, when the exploratory behavior reached its peak, there was a reduction in GABA-enhanced binding of [3H]flunitrazepam in the cortex.

Animals↗
PubMed1991

Chronic Ro 15-1788 treatment increases REM sleep in rats.

Administration of Ro 15-1788, a benzodiazepine antagonist (3.6 mg/kg/day in drinking water for 14 days), increased total sleep and rapid eye movement (REM) sleep in rats. Standard six-hour EEG recording periods were obtained on day 0, 1, 3, 7, 10, 14, as well as 24 and 72 hours following withdrawal. Enhanced REM sleep reached significance on day 7 of continuous drug treatment and remained significantly increased on day 10 and 14, as well as at 24 and 72 hours following drug withdrawal. The present data show that chronic administration of Ro 15-1788 increases total sleep time due to increases in REM sleep. The actions of Ro 15-1788 presumably occur through either adenosinergic or cholinergic mechanisms.

Analysis of Variance↗
PubMed1990

Chronic exposure to flumazenil: anxiolytic effect and increased exploratory behavior.

The aim of the present study was to define the behavioral correlates of chronic exposure of adult rats to flumazenil (4 mg/kg/day X 21 days in drinking water). In the holeboard test, performed on day 13 of drug treatment, the animals showed a significantly greater interest for the holes under which objects were placed than for the holes without objects (p less than 0.03), while there was no such difference in the control group. In the plus-maze test, the flumazenil-treated animals spent significantly more time on open arms and left less fecal boluses than the controls when tested in the third week of treatment and 24 hours after flumazenil withdrawal. In the drinking-punishment test, conducted on days 3, 6 and 10 after drug withdrawal, the drug-exposed animals, following shock experience, did not significantly alter their unpunished drinking in subsequent trials, while the control rats significantly reduced (p less than 0.003) their unpunished drinking. Also, the punished drinking revealed a significant "anticonflict" effect of prior exposure to flumazenil (p less than 0.006) which was still observed 6 days after drug withdrawal. There were no group differences in the home-cage food and water consumption during flumazenil treatment; also, the drug treatment had no effect on nociceptive threshold. In summary, chronic treatment with a benzodiazepine receptor antagonist, flumazenil, increased exploratory activity and had a lasting anxiolytic effect.

Animals↗
PubMed1989

Chronic exposure to Ro 15-1788: differential effect on flunitrazepam binding to cortex and hippocampus.

The time course of changes in specific [3H]flunitrazepam binding following 2 weeks of treatment with the benzodiazepine antagonist Ro 15-1788 (2.7 and 4 mg/kg per day in drinking water) was studied in the rat neocortical and hippocampal synaptosomal membranes. Such a treatment produced regional increases in the density of benzodiazepine sites, which remained for up to 24 and 48 h after drug withdrawal in the hippocampus and cortex, respectively; the dissociation constant (Kd) was unchanged. In addition, a significant reduction in GABA enhanced [3H]flunitrazepam binding to cortical, but not to hippocampal, membranes from Ro 15-1788-treated animals was found 72 h after drug withdrawal. These data show that there is a regional difference in responses of the GABA/benzodiazepine receptor complex following chronic in vivo exposure to Ro 15-1788 and that, beside the increases in the maximal binding (Bmax) of [3H]flunitrazepam the coupling between the GABA and the benzodiazepine recognition sites was also affected.

Animals↗
PubMed1989

Adenosine presynaptic inhibition and transmitter "spillover": a new hypothesis of etiopathogenesis of narcolepsy.

Neurobiologic and clinical evidence has been discussed in order to propose a new hypothesis explaining the precipitous nature of narcoleptic attacks. It is postulated that narcoleptic episodes are triggered by a surge in the tone of the arousal system which temporarily overcomes the abnormal tonic inhibitory influences of adenosine on presynaptic terminals of the arousal system. As a result, abnormally high levels of accumulated transmitters "spillover" onto supersensitive postsynaptic receptors both in the brain and spinal cord. Such a state reduces the tone of the skeletal muscles and blocks the thalamo-cortical association system, causing a hypnagogic state incompatible with adaptive and cognitive functions. An agent selectively blocking A1 receptors would constitute the most appropriate treatment of narcolepsy. In theory, the hereditary predisposition toward narcolepsy could be corrected by perinatal treatment with an agonist of A1 receptors, thus causing an enduring down-regulation of the genome expression that regulates the ontogeny and proliferation of the A1 receptors.

Acetylcholinesterase↗
PubMed1988

Animal models of chronic anxiety and "fearlessness".

Three behavioral animal models have been described: a feline and a rodent model of chronic anxiety, and a rodent model of "fearless" behavior. The models have been obtained by pre- or perinatal exposure to diazepam (DZ) or RO 15-1788 which produced enduring postnatal deficits or enrichment, respectively, of brain benzodiazepine (BDZ) receptors. The receptor-deficient one-year-old cat progenies showed hyperarousal, unabated restless behavior, delayed acquisition of instrumentally conditioned behavior, bizarre escape responses and absence or reduced alpha-like EEG activity. The receptor-deficient rat progencies, studied at the age of 5-6 months, showed a reduction of time spent in deep slow wave sleep, and inability to habituate to novel environment, such as the radial arm maze. In the maze, the behavior of these progenies was characterized by delayed and incomplete exploratory activity often terminated by sudden escape, numerous fecal deposits and significantly more frequent than normal errors of "working memory." On the other hand, in all aspects, the receptor-enriched progenies were superior to the control animals as well as to the receptor-deficient group, particularly when the animals were challenged by novel and "intimidating" visual and/or auditory stimuli. In addition, 12 out of 51 receptor-deficient rats reared for 18 months developed mammary fibroadenomas, while no such tumors were found in the group of 44 vehicle-exposed control animals. Increased density and affinity of BDZ brain receptors was also observed after adult rats were treated with RO 15-1788 administered water for 7 or 14 days.

Animals↗
PubMed1986

Enduring effects of prenatal diazepam on the behavior, EEG, and brain receptors of the adult cat progeny.

Pregnant cats were treated with a benzodiazepine receptor agonist, diazepam (DZ; Valium; average dose of 0.4 mg/kg/day, i.m.) between day 20 through day 53 of gestation in an attempt to alter the ontogenesis of the benzodiazepine receptors. As tested in fully developed one-year-old progenies, prenatal exposure to DZ resulted in a behavioral syndrome of hyperactivity, aggressiveness, behavioral signs of chronic anxiety, inability to habituate to novel environment, suppression or absence of the reward-induced alpha-like (7 to 11 Hz) electroencephalographic patterns during operantly conditioned behavior (bar pressing for 1 ml of milk reward), and deficits in the numbers of benzodiazepine receptors in the hypothalamus (-47%), fronto-orbital cortex (-33%) and postcentral cortex (-19%).

Agonistic Behavior↗
PubMed1985

Prenatal exposure to diazepam results in enduring reductions in brain receptors and deep slow wave sleep.

After prenatal exposure to diazepam (Valium), mature rats at 4 months of age displayed slow wave sleep (SWS) electroencephalographic patterns indicating impaired synchronization and SWS mechanisms. These animals spent a much greater portion of their SWS in the lighter SWS I, as compared to the control group which showed a predominance of the deeper SWS II. At one year of age, the diazepam-exposed rats had much fewer diazepam-specific binding sites in the thalamus than the vehicle-exposed controls. These results provide first evidence for a physiological role for benzodiazepine receptors by showing that prenatal exposure to diazepam has an enduring and detrimental effect on their ontogenesis and sleep mechanisms.

Animals↗
PubMed1984

Sleep and purposive behavior: inverse deviations from randomness of neuronal firing patterns in the feline thalamus. A new form of homeostasis?

In behaving cats trained to press a bar for small aliquots of milk reward, single neuronal firing patterns were monitored from the nucleus reticularis (NR) thalami during bar bressing (BP), subsequent quiet wakefulness with EEG spindles (S- QW ), grooming behavior (GR) and slow-wave sleep (SWS). The temporal patterns in the neuronal spike trains were analyzed using a non-parametric method based on relative relations between sequential spike intervals. The deviations of pattern occurrences from the random model were quantified. During BP, specific patterns occurred much more often while others occurred much less often than predicted by the random model. Patterns that were dominant during BP, were selectively suppressed or virtually eliminated during S- QW , GR and SWS, despite the increased firing rate; and, vice versa, patterns that were suppressed below chance level during BP, became dominant during S- QW , GR and SWS. The magnitudes of these inversions of the statistical distribution of patterns were not random but graded and positively correlated, thus indicating that they were homeostatically controlled. Since the inversions were already evident shortly after the satiated ceased bar pressing, they may be related to the 'need' for sleep. On the basis of the known mechanisms of pattern generation and changes in receptors for putative transmitters, it was postulated that the inversions of pattern distribution are related to the recuperative function of SWS, i.e. resensitization of receptors that had been desensitized during the animal's stereotypic BP performance. The NR and other neuronal ensembles seem to constitute an oscillatory system with two modes of reciprocal connectivities : one is supporting wakefulness and emission of specific firing patterns, and the other is incompatible with wakefulness and instead is associated with inversion of statistical distribution of firing patterns and recuperative function of SWS.

Animals↗
PubMed1983

Sleep-wakefulness: inverse deviation from randomness of neuronal firing patterns in the feline thalamus. A new form of homeostasis?

During stereotypic goal-directed behavior, neurons in the feline nucleus reticularis thalami emitted specific temporal patterns, while other patterns occurred much less often than predicted by the random model. During subsequent slow wave sleep, the mean firing rate increased, but the patterns that were emitted during behavior were eliminated or suppressed far below chance level, while those that were previously suppressed became dominant.

Action Potentials↗
PubMed1982

Phasic loss of constraints in timing of neuronal spikes in the feline centrum medianum during EEG alpha-like activity.

In unrestrained cats, temporal patterns of single neuronal firing in the centrum medianum-parafascicular complex (CM-Pf) of thalamus were studied during a state of motionless quiet wakefulness. The spike trains from each neuron were electronically divided into episodes that occurred during desynchronized EEG and those that occurred during bursts of 6-14 Hz EEG spindles or alpha-like activity over the parieto-occipital cortex and in the CM-Pf. Contrary to expectations based on the theory of inhibitory phasing of neuronal activity, the episodes of synchronized quiet wakefulness (S-QW) were associated with independent and random distribution of spike intervals, although they tended to occur in clusters. During episodes of desynchronized quiet wakefulness (D-QW), significant temporal patterns were emitted by most neurons studied. The results suggest that: (a) during D-QW and increased levels of vigilance, temporal patterns are generated by cognitive processes and enhanced specific connectivities between CM-Pf neurons and other systems; (b) if connectivity is defined as increased certainty of synaptic transmission and iterative activation of the same pathways, then the assumption that the gross EEG thalamo-cortical synchronization represents increased connectivities between the CM-Pf neurons and other systems, may be erroneous; and (c) since temporal patterns of single neuronal discharges are determined by specific spatio-temporal distribution of synaptic drive, therefore during EEG spindles, most EPSP-IPSP sequences impinging upon CM-Pf neurons are conveyed by randomly varying polysynaptic pathways and have random spatio-temporal distribution on the soma and dendrites. In light of other observations, such a process is equivalent to an active introduction of uncertainty or 'entropy' into the information processing system, a state which may be important in preserving plasticity of operational modes of CM-Pf neurons and those with which they directly and/or indirectly interact.

Action Potentials↗
PubMed1982

Visual attention and neuronal firing patterns in the feline pulvinar nucleus of thalamus.

In behaving cats, temporal patterns of neuronal firing were studied during slow wave sleep (SWS), motionless quiet wakefulness (QW) coupled with specific direction of the animal's attention, and during bar pressing performance (BP) for milk reward. The analysis was based on relative relations between sequential spike intervals. The strength of the method is based on the fact that the probabilities of occurrence of patterns are determined by the history of a spike train. During SWS, the neuronal firing modes closely followed the theoretical model of independent distribution of intervals, whereas during QW and BP specific for each neuron departures from the model, i.e., patterning was observed. Most importantly, in seven chronically studied neurons idiosyncratic patterns were related to direction of the animal's attention, and, very likely, to the visual forms the animals gazed at, because the patterns disappeared in the dark and during SWS without major changes in the mean firing rate. The replications of patterns upon recurrence of a particular direction of attention was proven statistically. The constancy and idiosyncrasy of these patterns were apparent even though the comparable episodes occurred several hours apart, and the animals slept and/or ate in between, and the distance, i.e., the retinal size of visual forms varied from one episode to another. On the basis of correlative evidence, it was argued that, compared to more abstract modes of information processing, the identification and quantification of patterns based on relative relations between intervals require the least amount of storage of intermediate results. Hence, these patterns are likely to represent a simple and phylogenetically old principle of communication between neurons. It was postulated that the idiosyncrasy and invariance of patterns may play a role in constancy of feature extraction and Gestalt perception.

Animals↗
PubMed1981

The magnitude of post-reinforcement EEG synchronization (PRS) in cats reflects learning ability.

Electrocortical alpha-like activity, termed post-reinforcement synchronization (PRS), observed during operantly behavior, was quantified in 25 cats and plotted against the number of training sessions required for each to learn to press a lever for milk reward. A significant correlation (r = 0.77; P less than 0.001) was found between PRS magnitude and learning ability. The time required for learning correlated with the amount of perseveration in partially reinforced, i.e. ineffective, behavioral modes.

Animals↗
PubMed1980

Neuronal firing patterns in the feline hippocampus during sleep and wakefulness.

The study addressed the problem of information transmission in mammalian brain as reflected in the emergence or disappearance of temporal patterns in extracellularly monitored single action potentials from the dorsal hippocampus of unrestrained cats during slow wave sleep (SWS), rapid eye movement sleep (REM), and motionless quiet wakefulness (QW). The spike trains were analyzed with a nonparametric technique. Chi-square statistics were used to measure deviation of firing patterns from the theoretical model which is based on the assumption that the intervals are random and/or independent from each other. The plots of the chi-square values for a given set of patterns represented the neuronal 'signatures' characteristic of a behavioral state. During SWS most neurons followed the theoretical model, i.e. their 'signatures' were flat and statistically non-significant. However, during REM sleep and QW their firing modes showed specific deviations from the theoretical model: some patterns occurred more often while others less often than expected, thus generating large and statistically significant 'signatures'. During REM sleep some neurons shared similar tendencies in their departures from the theoretical model. However, during QW the same neurons developed their individual 'signatures' which were significantly different from each other. Hence, the QW episodes were characterized by a greater differentiation of neuronal firing patterns. The mean firing rate and the shape of the time interval histogram were not necessarily correlated with the emergence of specific temporal patterns in spike trains. The results suggest that information transmission from one neuron to another depends on the emergence of repetitive and specific temporal patterns. The strong tendency of most neurons to lapse during SWS into a firing mode that closely follows the theoretical model constitutes the basis for a working hypothesis which states that the essence of SWS recovery in cognitive systems is the disappearance of temporal patterns, and that the 'noisy' interactions between neurons plays an important role in the recuperative processes.

Animals↗