Influence of cholinergic and adrenergic agents of the electric activity of the brain and the heart under hypoxia

Injection of adrenergic and cholinergic agents to animals in the normal athmospheric conditions did not tigger drastic changes on the electric activity of the brain and heart. Acutehipoxia demands high adaptability from the body. In such conditions stimulation of reticular formation and hypothalamus produces different changes in the EEG and ECG activity whith injecting adrenergic and cholinergic agents. It was determined that cholinergic influence are effective in the regulation of electrical brain activity while adrenergics are more important for the realization of descending influences of the truncus cerebri vegetative centers and are less active in the modulation of the cerebral cortex activity.     

Neuropharmacologic analysis of the process of developing extinctive inhibition in the lobectomized cat

Pharmacological action on cholinergic and monoaminergic brain structures in the process of food-procuring reflex extinction was studied in intact and lobectomized cats. Growing stimulation of cholinergic structures of lobectomized animals caused consecutive behavioural changes similar to those appearing during development of active reaction of intact animals to cancellation of the reflex reinforcement. In both cases influences on monoaminergic systems produced analogous effects, but suppressing influence of haloperidol injection on food-procuring activity of lobectomized cats was significantly weakened. Conclusion is made that the development of active reaction of the animal to cancellation of food reinforcement is due to an increasing activation of brain cholinergic structures and consecutive activation of monoaminergic structures. Disturbance of extinction functions in lobectomized cats may be connected with disturbance of monoaminergic systems balance as a result of hyperactivity of dopaminergic structures.     

The Effects of Acetylcholine on the Turnover of Phosphatidic Acid and Phosphoinositide in Sympathetic Ganglia, and in Various Parts of the Central Nervous System in Vitro

The effect of acetylcholine on the incorporation of P³² into the individual phosphatides in slices of various structures of the nervous system has been studied. There was a marked stimulation of P³² incorporation into phosphoinositide and phosphatidic acid, but not into phosphatidyl choline and phosphatidyl ethanolamine, in the cat stellate and celiac ganglia in vitro. Acetylcholine stimulated P³² incorporation into certain phosphatides, primarily phosphoinositide and phosphatidic acid, in several structures of the cat and guinea pig brain; there was little or no effect of acetylcholine on phosphatide turnover in the inferior corpora quadrigsemina and cerebellar cortex. The suggestion is made that the phospholipid effect can best be explained as being concerned with the active transport of sodium ions out of the cell across the postsynaptic membrane of cholinergic neurons in response to acetylcholine.     

Mechanisms and models of REM sleep control

The first sections of this paper survey the history and recent developments relevant to the major neurotransmitters and neuromodulators involved in REM sleep control. The last portion of this paper proposes a structural model of cellular interaction that produces the REM sleep cycle, and constitutes a further revision of the reciprocal interaction model This paper proposes seven criteria to define a causal role in REM sleep control for putative neuro-transmitters/modulators. The principal criteria are measurements during behavioral state changes of the extracellular concentrations of the putative substances, and electrophysiological recording of their neuronal source. A cautionary note is that, while pharmacological manipulations are suggestive, they alone do not provide definitive causal evidence. The extensive body of in vivo and in vitro evidence supporting cholinergic promotion of REM sleep via LDT/PPT neuronal activity is surveyed. An interesting question raised by some studies is whether cholinergic influences in rat are less puissant than in cat. At least some of the apparent lesser REM-inducing effect of carbachol in the rat may be due to incomplete control of circadian influences; almost all experiments have been run only in the daytime, inactive period, when REM sleep is more prominent, rather than in the REM-sparse nighttime inactive period. Monoaminergic inhibition of cholinergic neurons, once thought to be the most shaky proposal of the reciprocal interaction model, now enjoys considerable support from both in vivo and in vitro data. However, the observed time course of monoaminergic neurons, their "turning off" discharge activity as REM sleep is approached and entered would seem to be difficult to produce from feedback inhibition, as originally postulated by the reciprocal interaction model. New data suggest the possibility that GABAergic inhibition of Locus Coeruleus and Dorsal Raphe monoaminergic neurons may account for the "REM-off" neurons turning off. However, the source(s) of GABAergic influences suggested by anatomical studies has yet to be definitively identified by electrophysiological recordings of GABAergic neurons that show the requisite inverse time course of activity relative to monoaminergic neurons. New and still preliminary microdialysis data suggest that reticular formation neurons, the effector neurons for REM sleep phenomena, might be disinhibited during REM sleep by decreased GABAergic influence, perhaps stemming from REM-on cholinergic neuronal inhibition of reticular formation GABAergic neurons. Whether the postulated cholinergic inhibition of GABAergic neurons is present is testable with in vitro recordings and double labeling. Taking into account the observed data on neuro-modulators/transmitters, a structural model incorporating interaction of REM-on and REM-off neurons and GABAergic influences is proposed. Finally, with respect to orexin and REM sleep, it is hypothesized that orexinergic activity may be a principal factor controlling REM sleep's absence from the active period in strongly circadian animals such as rat and man.     

Thalamo-Basal Ganglia Connectivity in Postmenopausal Women Receiving Estrogen Therapy

Cumulative data on the effects of estrogen therapy (ET) on brain function in postmenopausal women suggests that ET influences cerebral metabolism and may protect against age-related declines in various domains of cognitive function. The beneficial cognitive effects of ET may relate to its modulation of the thalamic-striatum cholinergic and dopaminergic systems, as the activity of both neurotransmitter systems in the thalamus appears to be positively influenced by estrogen. In the current study, we attempted to evaluated regional cerebral brain metabolism utilizing [18F]-fluorodeoxyglucose positron emission tomography in 11 healthy recently-postmenopausal women on ET (ET+) in comparison to 11 recently-postmenopausal and ET-naïve women (ET?) in order to assess the effects of ET on cholinergic and dopaminergic system regulation. Results showed thalamo-basal ganglia connectivity among ET+ women but not among ET? women. The presence of connectivity in the thalamo-striatal pathway in recently postmenopausal women suggests estrogen effects in preserving integrity of the cholinergic and dopaminergic systems. The results also suggest that ET initiated at or near the menopausal transition may modulate brain aging by mediating complex sensory-motor functions.     

Cholinergic neuromodulation of inhibitory interneurons facilitates functional integration in whole-brain models

Segregation and integration are two fundamental principles of brain structural and functional organization. Neuroimaging studies have shown that the brain transits between different functionally segregated and integrated states, and neuromodulatory systems have been proposed as key to facilitate these transitions. Although whole-brain computational models have reproduced this neuromodulatory effect, the role of local inhibitory circuits and their cholinergic modulation has not been studied. In this article, we consider a Jansen & Rit whole-brain model in a network interconnected using a human connectome, and study the influence of the cholinergic and noradrenergic neuromodulatory systems on the segregation/integration balance. In our model, we introduce a local inhibitory feedback as a plausible biophysical mechanism that enables the integration of whole-brain activity, and that interacts with the other neuromodulatory influences to facilitate the transition between different functional segregation/integration regimes in the brain.     

Cholinergic mechanisms of the hypothalamus medial preoptic area in control of thermoregulation and of wakefulness-sleep states in pigeons

The data obtained show that cholinergic mechanisms of the medial preoptic area of hypothalamus participate in control of wakefulness-sleep states and thermoregulation parameters in pigeons. Muscarinic and nicotinic cholinergic receptors are established to be involved in the wakefulness maintenance. The muscarinic cholinergic receptor activation of the medial preoptic area is accompanied by an elevation of the brain temperature, by development of peripheral vasoconstriction, and by an in increase in level of the muscle contractile activity. During the nicotinic cholinergic receptor activation of the area, a decrease in the brain temperature and an increase in level of the muscle contractile activity are found. A comparative analysis of experiments and early investigation suggests that during the cholinergic receptors activation changes in the brain temperature of pigeons depend on type of the cholinergic receptors but not on their localization in the preoptic area of hypothalamus.     

Neuropharmacological analysis of the compensatory-recovery processes in deficiency of the generalization function in lobectomized cats

Compensatory-recovery abilities of the cat brain were studied in free behaviour under frontal deficiency by means of parenteral pharmacological influence on dopamin-, cholin- and GABA-ergic systems. Activation of dopaminergic structures in lobectomized cats restored complex forms of generalization, and GABA-ergic system stimulation improved simple forms of generalization. Excitation of cholinergic formations deepened decompensation of generalization function.     

Opioid receptor subtypes that mediate a microwave-induced decrease in central cholinergic activity in the rat.

We performed experiments to investigate subtypes of opioid receptors in the brain involved in the effect of acute (45 min) pulsed microwave exposure (2,450-MHz, 2-microseconds pulses, 500 pps, average power density 1 mW/cm2, peak-power density, 1 W/cm2, average whole body SAR 0.6 W/kg) on cholinergic activity in the rat brain. Rats were pretreated by microinjection of specific antagonists of mu, delta, and kappa opioid-receptors into the lateral cerebroventricle before exposure to microwaves. The data showed that all three subtypes of opioid receptors are involved in the microwave-induced decrease in cholinergic activity in the hippocampus. However, the microwave-induced decrease in cholinergic activity in the frontal cortex was not significantly affected by any of the drug treatments, confirming our previous conclusion that the effect of microwaves on the frontal cortex is not mediated by endogenous opioids.     

Down''s Syndrome Individuals Begin Life with Normal Levels of Brain Cholinergic Markers

We measured the activities of the cholinergic marker enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in autopsied brains of seven infants (age range 3 months to 1 year) with Down's syndrome (DS), a disorder in which virtually all individuals will develop by middle age the neuropathological changes of Alzheimer's disease accompanied by a marked brain cholinergic reduction. When compared with age-matched controls cholinergic enzyme activity was normal in all brain regions of the individuals with infant DS with the exception of above-normal activity in the putamen (ChAT) and the occipital cortex (AChE). Our neurochemical observations suggest that DS individuals begin life with a normal complement of brain cholinergic neurons. This opens the possibility of early therapeutic intervention to prevent the development of brain cholinergic changes in patients with DS.     

The effects of some porphyrinogenic drugs on the brain cholinergic system.

In central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyse acetylcholine. Diminished cholinesterase activity is known to alter several mental and psychomotor functions. The symptoms of cholinergic crisis and those observed during acute attacks of acute intermittent porphyria are very similar. The aim of this study was to investigate if there could be a link between the action of some porphyrinogenic drugs on brain and the alteration of the cholinergic system. To this end, AChE and BuChE activities were assayed in whole and different brain areas. Muscarinic acetylcholine receptor (mAChR) levels were also measured. Results obtained indicate that the porphyrinogenic drugs tested affect central cholinergic transmission. Quantification of mAChR gave quite different levels depending on the xenobiotic. Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced. Acute and chronic isoflurane anaesthesia diminished BuChE activity by 70-90% in whole brain instead cerebellum and hippocampus mAChR levels were only altered by chronic enflurane anaesthesia. Differential inhibition of cholinesterases in the brain regions and their consequent effects may be of importance to the knowledge of the mechanisms of neurotoxicity of porphyrinogenic drugs.     

Evidence for a cerebral cholinergic system and suggested pharmacological patterns of neural organization in the prostomium of the polychaete Nereis virens (SARS)

The histological visualization of choline acetyltransferase (CAT) and acetylcholinesterase (AChE) on frozen sections of prostomia of Nereis virens indicate a concentration of cholinergic activity in the anterior brain. Components are probably sensory epithelial cells with cholinergic axons entering the brain in cephalic nerves and efferent cholinergic axons to prostomial muscle leaving the brain in the same nerves. There are also subepidermal cholinergic cells that may be second order motor neurons serving epidermal mucous cells. The smaller, second lobe of the corpora pedunculata and its associated vertical fibre tract are CAT⁴ and appear continuous, on each side of the cerebral ganglion, with a dorsal and a ventral longitudinal bundle of AChE⁺ fibers. This system tapers to nothing at the level of the posterior eyes. There is a small AChE⁺ component to each optic nerve and AChE is present in the nuchal epithelium. These observations are discussed in relation to earlier studies on aminergic and neurosecretory activity in the same ganglion.     

Multiple forms of choline acetyltransferase in several species demonstrated by isoelectric focusing

1. The behaviour of choline acetyltransferase from pigeon, guinea-pig, rat and cat brain on isoelectric focusing was studied. 2. Choline acetyltransferase from pigeon and guinea-pig brain showed single peaks with isoelectric points at pH6.6 and 6.8 respectively. Only one molecular form of the enzyme was therefore detected in these species. 3. Three peaks of choline acetyltransferase activities with isoelectric points 7.3-7.6, 7.7-7.9 and 8.3 were obtained with enzyme preparations from rat brain. 4. The separate identities of each of the three forms were confirmed by refocusing. 5. Choline acetyltransferase activity from a high-speed supernatant of rat brain homogenate was distributed similarly to a partially purified enzyme preparation from rat brain in the isoelectric gradient. 6. The enzyme activities from cat brain were separated into two distinct peaks with isoelectric points 7.0 and 8.4, and a possible third peak with isoelectric point 7.6. 7. The two main peaks showed considerable differences in stability on storage, and their identities were confirmed by refocusing. 8. The distribution of the enzyme activities was unaltered by isoelectric focusing in the presence of 3m-urea. 9. The apparent K(m) for choline of choline acetyltransferase from rat, cat and guinea-pig brain was 0.8mm, whereas for the pigeon enzyme it was 0.4mm.     

REGIONAL CHANGES IN RAT BRAIN CHOLINE ACETYLTRANSFERASE AND ACETYLCHOLINESTERASE ACTIVITY RESULTING FROM UNDERNUTRITION IMPOSED DURING DIFFERENT PERIODS OF DEVELOPMENT1

Abstract— The severity of mental changes in malnourished children is related to both the period of development when the malnutrition occurs and the amount of environmental stimulation. In the present study the effect of imposing protein undernutrition during the period of gestation or postweaning period, and protein-energy undernutrition during the suckling period on cholinergic enzyme activity was investigated in the rat. Six different dietary treatments were given and the activity of ChAc, ChE, and AChE determined in the forebrain, brainstem, and cerebellum of male rats on day 49. Undernutrition imposed during gestation, suckling or postweaning all resulted in changes in cholinergic enzyme activity. The direction and degree of change of enzyme activity depended on the period when undernutrition was imposed as well as the brain region. In the forebrain ChE and AChE activities were altered, in the brainstem, ChAc, ChE and AChE activities were altered, and in the cerebellum ChAc activity was altered. The effect on the activity of the individual cholinergic enzymes was complex and was not the same in the different regions of the brain or even for the same brain region exposed to undernutrition during different periods of development. These results along with earlier work indicate that cholinergic enzyme activity in brain of undernourished rats can be altered by both the period of development when undernutrition is imposed and the amount of environmental stimulation.     

The neurotoxic actions of quinolinic acid in the central nervous system

Excitotoxins such as kainic acid, ibotenic acid, and quinolinic acid are a group of molecules structurally related to glutamate or aspartate. They are capable of exciting neurons and producing axon sparing neuronal degeneration. Quinolinic acid (QUIN), an endogenous metabolite of the amino acid, tryptophan, has been detected in brain and its concentration increases with age. The content of QUIN in the brain and the activity of the enzymes involved in its synthesis and metabolism show a regional distribution. The neuroexcitatory action of QUIN is antagonized by magnesium (Mg2+) and the aminophosphonates, proposed N-methyl-D-aspartate (NMDA) receptor antagonists, suggesting that QUIN acts at the Mg2+ -sensitive NMDA receptor. Like its excitatory effects, QUIN's neurotoxic actions in the striatum are antagonized by the aminophosphonates. This suggests that QUIN neurotoxicity involves the NMDA receptor and (or) another receptor sensitive to the aminophosphonates. The neuroexcitatory and neurotoxic effects of QUIN are antagonized by kynurenic acid (KYN), another metabolite of tryptophan. QUIN toxicity is dependent on excitatory amino acid afferents and shows a regional variation in the brain. Local injection of QUIN into the nucleus basalis magnocellularis (NBM) results in a dose-dependent reduction in cortical cholinergic markers including the evoked release of acetylcholine. A significant reduction in cortical cholinergic function is maintained over a 3-month period. Coinjection of an equimolar ratio of QUIN and KYN into the NBM results in complete protection against QUIN-induced neurodegeneration and decreases in cortical cholinergic markers. In contrast, focal injections of QUIN into the frontoparietal cortex do not alter cortical cholinergic function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative autoradiographic analysis of muscarinic receptors and quantitative histochemistry of acetylcholinesterase in the rat brain after trimethyltin intoxication

The influence of trimethyl tin (TMT) intoxication on muscarinic cholinergic receptors and histochemistry of acetylcholinesterase (AChE) in the rat brain 21 days after treatment was studied. The topographical distribution and reduction in muscarinic receptor sites were analysed by means of quantitative receptor autoradiography using [³H]quinuclidinyl benzilate (QNB). TMT treatment produced a decrease in cholinergic receptors in a large number of brain regions.

The quantitative distribution of AChE was examined in over 60 regions following TMT intoxication. The activity of AChE was significantly affected. Reduced AChE content was found in several brain regions following TMT intoxication. The effect on AChE content was confined to cholinergic terminal areas, e.g. the hippocampus, while in the area dentata a significant increase in AChE content was detected.

The results are interpreted in terms of TMT producing disruption of the cholinergic system with implications for a neuroanatomical basis of impaired memory mechanisms.     

Laminar Distributions of Choline Acetyltransferase and Acetylcholinesterase Activities in the Inner Plexiform Layer of Rat Retina

Choline acetyltransferase and acetylcholinesterase activities were measured in samples taken at 7-micron increments through the inner plexiform layer of rat retina. These enzyme activities were not uniformly distributed through the depth of the inner plexiform layer. Peaks of choline acetyltransferase activity occurred at about one-third and peaks of acetylcholinesterase activity at about one-fifth of the depth into the inner plexiform layer from either side. The positions of the two peaks of choline acetyltransferase activity most likely correspond to the locations of processes from cholinergic amacrine somata in the inner nuclear layer, which spread in sublamina a, and processes from cholinergic amacrine somata "displaced" in the ganglion cell layer which spread in sublamina b of the inner plexiform layer. The peaks of acetylcholinesterase activity may in addition correspond to the processes of cholinoceptive amacrine and ganglion cells. The magnitudes of choline acetyltransferase and acetylcholinesterase activities are as high as found anywhere in rat brain, emphasizing the important role of cholinergic mechanisms in visual processing through the rat inner plexiform layer.     

Pulmonary stretch receptors activity during thermal polypnea (author's transl)]

1 We have studied the unit activity of 88 pulmonary stretch receptors (RPI) in the vagus nerve of the cat by using the single fibre technique. 2 In spite of a 38% decrease in tidal volume, the discharge frequency of RPI is statistically unchanged during polypnea, However, RPI are recruited earlier, but their discharge overlaps expiration. 3 Individual influences of tidal volume, temperature, and FACO2 on RPI activities are tested. During polypnea, the excitatory influences of hyperthermia and hypocapnia act against the depressing action of tidal volume reduction: RPI are still active. 4 During polypnea, respiratory rhythm and tidal volume are unchanged after bivagotomy. RPI activity seems functionally insignificant. This result suggests that the thermally induced respiratory response is mediated by structures in the upper brain stem (probably the preoptic anterior hypothalamus) and is not dependent on the integrity of the vagus nerve.     

Long non-coding RNA BDNF-AS modulates osteogenic differentiation of bone marrow-derived mesenchymal stem cells

Chagas disease is an acute or chronic illness that causes severe inflammatory response, and consequently, it may activate the inflammatory cholinergic pathway, which is regulated by cholinesterases, including the acetylcholinesterase. This enzyme is responsible for the regulation of acetylcholine levels, an anti-inflammatory molecule linked to the inflammatory response during parasitic diseases. Thus, the aim of this study was to investigate whether Trypanosoma cruzi infection can alter the activity of acetylcholinesterase and acetylcholine levels in mice, and whether these alterations are linked to the inflammatory cholinergic signaling pathway. Twenty-four mice were divided into two groups: uninfected (control group, n = 12) and infected by T. cruzi, Y strain (n = 12). The animals developed acute disease with a peak of parasitemia on day 7 post-infection (PI). Blood, lymphocytes, and brain were analyzed on days 6 and 12 post-infection. In the brain, acetylcholine and nitric oxide levels, myeloperoxidase activity, and histopathology were analyzed. In total blood and brain, acetylcholinesterase activity decreased at both times. On the other hand, acetylcholinesterase activity in lymphocytes increased on day 6 PI compared with the control group. Infection by T. cruzi increased acetylcholine and nitric oxide levels and histopathological damage in the brain of mice associated to increased myeloperoxidase activity. Therefore, an intense inflammatory response in mice with acute Chagas disease in the central nervous system caused an anti-inflammatory response by the activation of the cholinergic inflammatory pathway.     

Cholinergic fiber growth in co-cultures of CNS tissue.

In co-cultures prepared from the septum and the hippocampus, cholinergic fibers originating in the septal slices grew into the neighboring hippocampal tissue and established functional cholinergic connections with pyramidal cells. To get further insight into the mechanisms governing cholinergic fiber growth, we have added TTX to the growth medium (2 x 10(-7) M) to block propagated electrical activity. Under these conditions, considerably fewer cholinergic cells appeared to survive. A few cholinergic fibers still invaded hippocampal target tissue, but their number was markedly reduced compared with control cultures. Simultaneous application of NGF together with TTX, however, not only increased enzyme levels and enhanced survival of cholinergic neurons, but also led to hippocampal ingrowth in virtually all septo-hippocampal co-cultures. These data, therefore, suggest, that in the absence of spiking activity, cholinergic fibers are capable of growing into a co-cultured target tissue. To test the specificity of growth of septal cholinergic fibers, we have co-cultured septal slices with slices of various brain areas which in situ lack a major cholinergic innervation, in particular the cerebellum. In the vast majority of such co-cultures, cholinergic fibers remained restricted within the septal slices, without innervating cerebellar tissue. This failure might in part be related to the lack of trophic factors released by the target tissue. We have, therefore, grown septo-cerebellar cultures in the presence and absence of NGF. Following application of 100 ng/ml NGF during the entire growth of the cultures, numerous AChE-positive fibers originating in the septal slices invaded the co-cultured cerebellar slices.(ABSTRACT TRUNCATED AT 250 WORDS)