The participation of cholinergic systems of the nucleus accumbens in the differentiation of acoustic signals in dogs

>The influence of microinjections of the choline agonist, carbocholine (0.05–0.1 g), into the nucleus accumbens (Acc) of the right and left hemispheres on the realization of an instrumental defense reflex associated with the maintenance of a specific posture, and on the differentiation of acoustic signals in a defense situation, was studied in chronic experiments in five dogs. It was demonstrated that the injection of fairly small doses of carbocholine (CbCh) into the Acc of the left and right hemispheres improves the differentiation of acoustic signals in the defense situation. The introduction of fairly small doses of CbCh also improves the values of the criteria of the execution of the instrumental defense reaction associated with the maintenance of a specific posture. The changes observed are prolonged in character. Analysis of the motoric components of the instrumental responses made it possible to evaluate objectively the contribution of the motor and sensory mechanisms to those changes which were elicited by the microinjections of CbCh into the Acc, and to reach conclusion regarding an important role of the cholinergic system of the nucleus accumbens in sensory processes associated with the initiation and realization of instrumental responses to defense and differential signals, and especially in the regulation of attention to significant stimuli.Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 42, No. 5, pp. 919–929, September–October, 1992.     

Calcium-binding protein immunoreactivity delineates the intralaminar nuclei of the thalamus in the human brain

Immunohistochemical studies have shown that the three calcium-binding proteins (calbindin-D28k, calretinin and parvalbumin) are heterogeneously distributed in the mammalian brain and are useful for delineating nuclear boundaries. We have investigated the distribution of the three calcium-binding proteins in the human thalamus in order to assist in the delineation of the equivocal nuclear boundaries of the intralaminar nuclei of the thalamus. The results show that each of the "functional" nuclear complexes in the human thalamus demonstrates a characteristic pattern of calcium-binding protein immunoreactivity. In particular, the intralaminar nuclei are characterized by a unique combination of calcium-binding protein staining which clearly delineates the component nuclei in this complex from the other nuclei of the human thalamus. The anterior group of intralaminar nuclei (central lateral nucleus, paracentral nucleus and central medial nucleus) showed intense staining for both calbindin-D28k and calretinin. By contrast, the posterior group of intralaminar nuclei (centre median nucleus and parafascicular nucleus) showed a complementary pattern of staining; the centre median nucleus showed immunoreactivity only for one calcium-binding protein, parvalbumin, while the parafascicular nucleus showed immunoreactivity for both calbindin-D28k and calretinin. No other nucleus in the human thalamus showed these particular combinations of calcium-binding protein staining. Since the intralaminar nuclei also have unique topographically organized connectional affiliations with both the cerebral cortex and the basal ganglia, these results suggest that the calcium-binding proteins may play an important role in the influence of the intralaminar nuclei on interactions between the cerebral cortex and the basal ganglia.     

Distribution and density of GABA cells in intralaminar and adjacent nuclei of monkey thalamus

The density of GABA-immunoreactive neurons was examined in the intralaminar and certain principal relay nuclei of the macaque monkey thalamus. Counts were made in 10-microns-thick frozen sections and in 1-micron-thick plastic sections and stereological formulae applied to obtain an accurate assessment of the volumetric density of GABA cells in the nuclei. It was found that GABA-immunoreactive cells account for at least 27% of the cells per unit area of all the thalamic nuclei investigated and up to as much as 50% by unit volume. The intralaminar nuclei show only slightly fewer GABA cells than the principal relay nuclei. Previous reports of their absence or relatively low numbers in the intralaminar nuclei probably stem from their smaller size, relatively weaker immunoreactive staining and from failure to apply stereometric formulae that reveal the density of neurons per volume of tissue. These results suggest that the cellular elements of the intralaminar nuclei are not fundamentally different from those of the principal relay nuclei of the thalamus.     

Role of the cholinergic system of the neostriatum in regulating several forms of defensive behavior

Studies were carried out on the effects of microinjection of carbacholine, a choline receptor agonist, into the dorsal striatum on the discrimination of sensory signals in chronic experiments on dogs with an operant defensive reflex involving maintenance of a flexor pose and in rats trained to a conditioned active escape reflex (CAER) in a T-maze; the sensory signals involved were important in the behavioral situations used. Carbacholine microinjection improved the process of discrimination, with an increase in the number of correct responses in rats in the T-maze discrimination-requiring CAER, and with improvements in responses to differentiation stimuli in the operant defensive reflex requiring maintenance of a defined pose in dogs. The efficiency of the effect dependend on the level of training. There were two situations in which responses did not improve: when there was no signal discrimination in background conditions before microinjection, and in conditions of complete differentiation of the signals, i.e., complete training. It would appear that the neostriatum is not involved in the behavioral reactions in either of these situations, and this may result primarily from low levels of neuronal activity in response to these signals. I. P. Pavlov Institute of Physiology, Russian Academy of Sciences I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg. Translated from Fiziologicheskii Zhurnal im. I. M. Sechenova, Vol. 81, No. 4, pp. 43–50, April, 1995.     

Role of the intralaminar thalamic nuclei in the potentiation of inhibition induced by caudate nucleus stimulation

Neuroscience and Behavioral Physiology -     

Effects of the cholinergic system of the rat neostriatum on learning active escape in normal animals and in animals with lesions to the intralaminar thalamic nuclei

Studies were carried out into the role of the parafascicular (Pf) nuclei of the rat thalamus in learning a conditioned active escape reflex (CAER) in a T-maze, a reflex associated with discrimination of visual stimuli, and into the regulatory effect on this learning process of activation of the neostriatal cholinergic system. The following results were obtained using 57 Sprague-Dawley rats divided into a number of experimental groups: 1) bilateral microinjection of carbacholine (0.03 μg) into the neostriatum on days 4, 5, and 6 of training produced significant (p<0.01) increases in the proportion of correct discriminant CAER performances; 2) bilateral lesioning of the Pf nuclei led to irreversible disruption of the previously learned CAER. Rats with initially bilaterally lesioned Pf nuclei did not learn the discriminant CAER at all after 10 days of training (16 combinations), and microinjection of carbacholine into the neostriatum of these animals was ineffective. It is concluded that the integrity of the afferent input into the Pf nuclei of the thalamus is an important factor for activation of the neuronal background of the neostriatum, and is required for cholinergic activation of the neostriatum to be effective. Laboratory for the Physiology of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 St. Petersburg. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 82, No. 2, pp. 1–12, February, 1996.     

The integrative role of the intralaminar system of the thalamus in visual orientation and perception in the cat

Summary Electrical stimulation with repetitive pulses (6/sec) was applied to the internal medullary lamina and produced tonic contraversive turning movements of eyes and head which were associated with recruiting responses in the visual cortex.Optical gratings of a spatial frequency of 0.5 c/deg which alternated with diffuse illumination of equal intensity were then presented to the animal during conjugated adversive eye movements induced by intralaminar stimulation with continuous sine-wave alternating currents of 5000 c.p.s. The head of the animal was fixed except for rotation in the horizontal plane. Prior to intralaminar stimulation it was turned in the direction opposite to the induced eye movements so that the animal always viewed the central area of the screen.The potential recorded in the visual cortex in response to the gratings consisted of an initial positive-negative potential of the order of 20 V followed by later deflections of irregular shape. The size of this initial potential was measured during induced gazing and in the absence of intralaminar stimulation. A significantly greater potential in response to the gratings was found during gazing. Diminishing the visual acuity of the animal resulted in a marked decrease of the initial potential and in this condition very little increase was obtained during gazing. No enhancement of the potential was seen when stimulation was applied to other thalamic structures that yielded no visual orientation.It is concluded that perception of contrast is improved during visual orientation and that the effect is due to a concomitant activation of unspecific intralaminar afferents to the visual cortex.     

Role of intralaminar thalamus in gaze mechanisms: evidence from electrical stimulation and fiber-sparing lesions in cat

Summary Information on eye movement related activity in the internal medullary lamina (IML) of the thalamus is consistent with an IML role in the control of eye movements, or with its serving to convey information to the forebrain on impending events in the oculomotor system. Interpretation is impeded by the fact that eye movements evoked by electrical stimulation of the IML might be triggered by antidromic activation of projections to the IML from brainstem preoculomotor centers. In order to address this issue, thesholds for the elicitation of eye movements and cortical recruiting responses (as a marker for IML integrity) were studied before and after destruction of IML neuronal populations by the fiber-sparing neurotoxin ibotenic acid. Experiments were performed in alert cats chronically implanted with a scleral search coil for the monitoring of eye movements and an electrode-cannula assembly that permitted threshold determinations and drug injections at the stimulating site without any movement of probes in the tissue. Drastic elevation of the threshold for cortical recruiting responses, but not for eye movements following ibotenic acid destruction of IML neurons uncomplicated by myelin damage at the site of stimulation suggests an antidromic route for eye movements elicited by IML stimulation.Supported by USPHS grant NS 4955     

The features of the participation of the cholinergic mechanisms of the accumbens and caudate nuclei in the regulation of an instrumental defense reflex in dogs

The influence of microinjections of carbacholine (0.1, 0.05, and 1.0 μg) into the dorsal striatum (head of the caudate nucleus) and the ventral striatum (nucleus accumbens) on the motor components of the instrumental response and the criteria of execution of an instrumental task was studied in chronic experiments in eight dogs, based on a model of an instrumental defense reflex associated with the maintenance of a specific posture. The varied participation of the cholinoreactive structures of the caudate and accumbens nuclei in the regulation of the instrumental defense reflex was demonstrated in the dogs. Data were obtained indicating that the cholinoreactive system of the contralateral head of the caudate nucleus is structurally included in the regulation of the motor components of the instrumental response, of the main component of the reorganization of posture (the “disburdening” of the working extremity), and in the regulation of the tonic component of the voluntary movement and of its form. At the same time, the injection of carbacholine into the nucleus accumbens exerted, rather, a nonspecific activating influence on the motor systems. An improvement in attention to significant stimuli and the prolongation of the observed effects were also features of the activation of the cholinoreactive system of this nucleus. These changes took place in the case of both ipsi- and contralateral influences; this makes it possible to consider the inclusion mainly of sensory mechanisms in the realization of these influences. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 79, No. 7, pp. 29–40, July, 1993.     

胆碱能抗炎通路在电针预处理调控脑缺血再灌注大鼠小胶质细胞活化状态中的作用

目的:观察电针预处理对大鼠脑缺血再灌注后小胶质细胞活化状态的影响并探讨其机制。方法:成年雄性SD大鼠随机分为7组,分别为假手术组(Sham),脑缺血再灌注组(MCAO),电针(EA)+MCAO组,烟碱型乙酰胆碱受体α7亚单位(α7nAChR)PHA-543,613+MCAO组,溶剂(Vehicle)+MCAO组,α7nAChR抑制剂α-BGT+EA+MCAO组,溶剂+EA+MCAO组。脑缺血再灌注后3 d取材,运用Western Blot技术以及免疫荧光技术检测脑缺血半暗带小胶质细胞经典激活状态(M1型)及选择性激活状态(M2型)特异性标志分子的表达水平。结果:(1)与MCAO组比较,电针预处理组(EA+MCAO)M1型小胶质细胞标志分子iNOS表达下调(P0.05),M2型小胶质细胞标志分子Arginase表达上调(P0.05);(2)α7nAChR激动剂PHA-543,613可模拟电针预处理的作用,使小胶质细胞由M1型向M2型转化;α7nAChR抑制剂α-BGT逆转了电针促进小胶质细胞由M1型向M2型转化的作用。结论:电针预处理可以使脑缺血再灌注后小胶质细胞由M1型向M2型转化,α7nAChR参与了电针预处理对小胶质细胞活化状态改变的过程。     

Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb

Neurogenesis in the subgranular zone of the hippocampal dentate gyrus and olfactory bulbs continues into adulthood and has been implicated in the cognitive function of the adult brain. The basal forebrain cholinergic system has been suggested to play a role in regulating neurogenesis as well as learning and memory in these regions. Herein, we report that highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive immature cells as well as neuronal nuclei (NeuN)-positive mature neurons in the dentate gyrus and olfactory bulb express multiple acetylcholine receptor subunits and make contact with cholinergic fibers. To examine the function of acetylcholine in neurogenesis, we used donepezil (Aricept), a potent and selective acetylcholinesterase inhibitor that improves cognitive impairment in Alzheimer's disease. Intraperitoneal administrations of donepezil significantly enhanced the survival of newborn neurons, but not proliferation of neural progenitor cells in the subgranular zone or the subventricular zone of normal mice. Moreover, donepezil treatment reversed the chronic stress-induced decrease in neurogenesis. Taken together, these results suggest that activation of the cholinergic system promotes survival of newborn neurons in the adult dentate gyrus and olfactory bulb under both normal and stressed conditions.     

Behavior of rats during chronic activation and blockade of the neostriatal opiate system

The effects of daily microinjections (MI), over the course of three weeks, bilaterally into the rostral striatum, of morphine, promedol, native leu-enkephalin and its synthetic tetrapeptide analogs were studied in experiments on rats. Naloxone was used as an antagonist. An active avoidance conditioned reflex was developed preliminarily in a shuttle box. A decrease in the accuracy of the realization and an increase in the latent period of the reflex were observed after the first MI of morphine and enkephalins. The effect in the most stable aminated ornithine-containing tetrapeptides proved to be the strongest. A search stereotypy and increased motoric activity were recorded in the rats during the development of the chronic effects of the activators of the opiate system. A clear correlation was not found between the motor and conditioned reflex shifts. The blockade of the opiate receptors with naloxone did not lead to substantial changes in behavior. The data obtained confirm the current hypothesis regarding the important role of the enkephalinergic system of the neostriatum in the regulation of complex forms of behavior and its close functional association with the dopaminergic system. I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 44, No. 2, pp. 283–290, March–April, 1994.     

Role of the ubiquitin system in regulating ion transport

Ion channels and transporters play a critical role in ion and fluid homeostasis and thus in normal animal physiology and pathology. Tight regulation of these transmembrane proteins is therefore essential. In recent years, many studies have focused their attention on the role of the ubiquitin system in regulating ion channels and transporters, initialed by the discoveries of the role of this system in processing of Cystic Fibrosis Transmembrane Regulator (CFTR), and in regulating endocytosis of the epithelial Na(+) channel (ENaC) by the Nedd4 family of ubiquitin ligases (mainly Nedd4-2). In this review, we discuss the role of the ubiquitin system in ER Associated Degradation (ERAD) of ion channels, and in the regulation of endocytosis and lysosomal sorting of ion channels and transporters, focusing primarily in mammalian cells. We also briefly discuss the role of ubiquitin like molecules (such as SUMO) in such regulation, for which much less is known so far.