Iron and mechanisms of emotional behavior

Iron is required for appropriate behavioral organization. Iron deficiency results in poor brain myelination and impaired monoamine metabolism. Glutamate and γ-aminobutyric acid homeostasis is modified by changes in brain iron status. Such changes produce not only deficits in memory/learning capacity and motor skills, but also emotional and psychological problems. An accumulating body of evidence indicates that both energy metabolism and neurotransmitter homeostasis influence emotional behavior, and both functions are influenced by brain iron status. Like other neurobehavioral aspects, the influence of iron metabolism on mechanisms of emotional behavior is multifactorial: brain region-specific control of behavior, regulation of neurotransmitters and associated proteins, temporal and regional differences in iron requirements, oxidative stress responses to excess iron, sex differences in metabolism, and interactions between iron and other metals. To better understand the role that brain iron plays in emotional behavior and mental health, this review discusses the pathologies associated with anxiety and other emotional disorders with respect to body iron status.     

长寿型啮齿类动物的抗肿瘤机制

啮齿类动物是广泛应用于生物医学的重要模式动物,包括先天性胸腺缺陷型的裸鼠、不患癌的裸鼹鼠(Heterocephalus glaber)和盲鼹鼠(Spalax galili)等。哺乳动物的衰老过程与癌症发生率有关,衰老的程度与患癌机率呈正相关。由于啮齿类动物约占哺乳动物的40%,因此研究长寿型啮齿类动物抗肿瘤机制对于抗癌机制的研究具有十分重要的作用。复制性衰老是啮齿类动物中普遍存在的抗肿瘤机制,但在裸鼹鼠和盲鼹鼠体内发现了独特的抗肿瘤机制：盲鼹鼠主要的抗肿瘤机制是由细胞释放IFN-β,激活p53和Rb信号通路,进而导致细胞集中性死亡;裸鼹鼠的抗肿瘤机制是由高分子量透明质酸引起的早期接触性抑制介导。此外,裸鼹鼠和盲鼹鼠的基因组中还含有高表达与调节细胞死亡和抗炎机制相关的基因。本文对裸鼹鼠和盲鼹鼠的独特抗肿瘤机制进行了综述,以期为该领域的相关研究提供参考。     

Possible mechanisms of amygdala participation in the regulation of gastric motor activity

Mechanisms of the amygdala central nucleus (CNA) influence on gastric motor reflex activity were studied in electrophysiological and neuroanatomical experiments in Wistar rats. In the anaesthetized animals, electrical stimulation of the CNA affected spontaneous gastric motility and caused inhibitory as well as excitatory changes of vagus-induced gastric relaxation. The most significant and mainly inhibitory effects were observed under the stimulation of the medial CNA. Microinjection of the anterograde tracer Phaseolus vulgaris-leucoagglutimn (PHA-L) into the different divisions of the CNA revealed direct projections from its dorso-medial portion to the gastric related area of the dorsal vagal complex. Electrical stimulation of this amygdaloid area was found to change activity of the bulbar gastric related neurons. Inhibitory and excitatory changes of their vagus-induced responses under the amigdala stimulation were manifested as a general modulation of all phases of the reaction or a selective modulation of some of them. These mechanisms may underlie the amygdalo-fugal modulation of gastric motor reflex activity.     

Effects of CCK-8 in the nucleus accumbens

The electrophysiological effects of CCK-8 were studied in the rabbit nucleus accumbens. CCK-8 was found to influence neurotransmitter (modulator) systems so as to enhance their action. For example, CCK-8 enhanced the effects of stimulation of the glutaminergic pathways, the fimbria. In addition, when CCK-8 was co-administered with dopamine and acetylcholine, their suppressive effect on the fimbria evoked response was enhanced. Therefore, CCK-8 appears to be capable of enhancing the influence of multiple neurotransmitter (modulator) systems.     

Differential bile-pancreatic secretory effects of CCK-58 and CCK-8

In this work, we 1) synthesized rat CCK-58, 2) determined the amounts and forms of rat CCK in whole blood after stimulation of its release by casein, 3) determined the potency of CCK-8 and CCK-58 peptides to displace labeled CCK-8 from CCK(A) and CCK(B) receptors transfected into Chinese hamster ovary (CHO) cells, and 4) examined the biological actions of CCK-8 and rat CCK-58 in an anesthetized rat model. CCK-58 was the only detected endocrine form of CCK in rat blood. Synthetic rat CCK-58 was less potent than CCK-8 for displacing the label from CCK(A) and CCK(B) receptors in transfected CHO cells. However, rat CCK-58 was more potent than CCK-8 for stimulation of pancreatic protein secretion in the anesthetized rat. In addition, CCK-58 but not CCK-8 stimulated fluid secretion in this anesthetized rat model. These data suggest that regions outside the COOH terminus of rat CCK-58 influence the expression of CCK biological activity. The presence of only CCK-58 in the circulation and the fact that its biological activity differs from CCK-8 suggests that CCK-58 deserves scrutiny in other physiological models of CCK activity.     

Neuroendocrine mechanisms of participation of the raphe nuclei in the development of hypertensive reactions in emotional stress

The experiments on cats and rabbits have studied electroencephalographic, endocrine and blood pressure responses to stress (5-hour immobilization with electrical foot shock) before and after coagulation of the midbrain nuclei raphe. Blood pressure and adrenal responses in advanced (4-hour) stress were elevated in intact animals, the responses attenuating after coagulation of the nuclei raphe. Background bioelectrical activity of the midbrain reticular formation and hypothalamus was found to be activated in the operated animals. Stress was followed by the reduction in bioelectrical changes of the above subcortical structures with the parallel development of "burst" activity in the dorsal hippocamp.     

The participation of GFAD-synthesizing neurons in behavior regulation in the snail (Helix lucorum L.)

It was shown earlier that some neurons in Helix CNS express the mRNA of the precursor of neuropeptide GFAD. Using the data obtained with the help of the whole-mount in situ hybridization, we tried to identify a group of such neurons, namely, the pedal caudo-ventral group and to determine their possible functions. The local extracellular stimulation of the pedal caudo-ventral group resulted in movements of reproductive organs in the semi-intact preparation and suppressed the activity of the modulatory neurons controlling feeding and defensive behavior. Application of synthetic peptide GFAD (10(-8) mol/l) also activated movements of the reproductive organs and suppressed the activity of the modulatory neuron controlling feeding behavior. Stimulation of the labial nerves resulted in suppression of caudo-ventral neurons with simultaneous activation of the modulatory neuron controlling feeding behavior. The obtained evidence suggests that the caudo-ventral neurons can regulate movements of the reproductive organs and also coordinate different functions in realization of the integral sexual behavior. This group of neurons inhibits the modulatory neurons controlling the forms of behavior incompatible with courtship, i.e., feeding and defensive forms.     

Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms

Previous reports suggest that glucagon-like peptide (GLP-1), a peptide secreted from the distal small intestine, is an endocrine satiation signal. Nevertheless, there are conflicting reports regarding the site where circulating GLP-1 acts to reduce food intake. To test the hypothesis that vagal afferents are necessary for reduction of food intake by circulating GLP-1, we measured intake of 15% sucrose during intravenous GLP-1 infusion in intact, vagotomized, and capsaicin-treated rats. We also measured sucrose intake during intravenous infusion of cholecystokinin, a peptide known to reduce food intake via abdominal vagal afferents. We found that reduction of intake by GLP-1 was not diminished by capsaicin treatment or vagotomy. In fact, reduction of sucrose intake by our highest GLP-1 dose was enhanced in vagotomized and capsaicin-treated rats. Intravenous GLP-1 induced comparable increases of hindbrain c-Fos immunoreactivity in intact, capsaicin-treated, and vagotomized rats. Plasma concentrations of active GLP-1 in capsaicin-treated rats did not differ from those of controls during the intravenous infusions. Finally, capsaicin treatment was not associated with altered GLP-1R mRNA in the brain, but nodose ganglia GLP-1R mRNA was significantly reduced in capsaicin-treated rats. Although reduction of food intake by intraperitoneal cholecystokinin was abolished in vagotomized and capsaicin-treated rats, reduction of intake by intravenous cholecystokinin was only partially attenuated. These results indicate that vagal or capsaicin-sensitive neurons are not necessary for reduction of food intake by circulating (endocrine) GLP-1, or cholecystokinin. Vagal participation in satiation by these peptides may be limited to paracrine effects exerted near the sites of their secretion.     

Dopaminergic mechanisms of the neostriatum in the corticoliberin regulation of adaptive behavior

Administration of corticotropin-releasing Hormone (CRH) to dorsal striatum in the course of active avoidance and open-field behaviour of genetically selected rats exerted different effects on adaptive behaviour of high-acquisition (KHA) and low-acquisition (KLA) rats. The findings suggest an important role of striatal dopamine in behavioural effect of the CRH.     

The structural organization and neurochemical mechanisms of the participation of the nucleus accumbens in the interaction of the limbic and motor systems and in the regulation of motor behavior]

The review of own and literature data devoted to structural and neurochemical organization of the nucleus accumbens (Acc) as well as spatial organization of their projection fibers in comparison with nucleus caudatus (neostriatum) has been presented. The facts concerned with correlations revealed between both the cell clusters and histochemical compartments as well as the compartmental organization of afferent and efferent striatal connections were analyzed. The presented data propose the existence of sensorimotor and limbic parts of the dorsal and ventral striatum, which are involved in the parallelly functioning systems. The common and different signs of these two systems and its role in the regulation of the movement behaviour has been proposed. A lot of attention also was payed to the Acc and the neostriatum interaction. The many pathways by which Acc can influence neostriatum functions and therefore the motor activity controlled by the neostriatum are discussed. It was shown that the Acc can influence on the striatal synaptic DA release. The sign of this influence depended upon DA/glutamic acid interactions in the Acc. It was stressed that the influence of Acc on striatal DA-ergic system is very likely mediated via kainate/quisqualate (but not NMDA) inputs of the neostriatum. The balance of DA-ergic mechanisms of neostriatum and Acc as important basis of animals adequate behaviour in conditioning situation was proposed. The disbalance of these mechanisms could leads to pathology.     

NMR evidence for different conformations of the bioactive region of rat CCK-8 and CCK-58

Sulfated CCK-58 and CCK-8 have identical bioactive C-terminal primary sequences but distinct C-terminal solution structures and different bioactivities. To examine structural differences in greater detail, rat CCK-58 and -8 were synthesized with isotopic enrichment of C-terminal residues with (15)N at alpha-amino nitrogens. Proton and nitrogen chemical shift assignments of peptide solutions were obtained by homo- and heteronuclear NMR methods. These data show that the tertiary structure ensembles of C-terminal CCK-8 and CCK-58 differ significantly. Thus, distinct solution conformations may explain differences in CCK(A) and CCK(B) receptor interactions of large and small molecular forms of CCK.     

Transgenic and knockout rodents: Novel insights into mechanisms of body weight regulation

Transgenic animals that over- or underexpress a protein of interest have been used to study obesity development, prevention, and susceptibility to diet-induced obesity such as a high-fat diet. Several transgenic models are resistant to diet-induced obesity including those that overexpress the insulin-sensitive glucose transporter, GLUT4, in adipose tissue only. In this animal there is increased adipose tissue mass but the animal maintains its insulin sensitivity. The overexpression of lipoprotein lipase (LPL) in skeletal muscle and the elimination of a protein kinase A subunit both resulted in lean and obesity resistant animals. By directing the production of the diphtheria toxin A chain to adipose tissue only the resulting animals not only had less adipose tissue mass but were resistant to MSG-induced obesity. Conversely, transgenic models with decreased brown adipose tissue or its function have all resulted in obese animals, highlighting the importance of thermoregulation in body weight maintenance. The use of transgenic technology in the field of obesity has emphasized the regional differences among fat pads as well as the dissimilarity between genders in fuel metabolism. Several transgenic models have separated obesity from insulin resistance allowing the importance of each state to be studied individually. Results using transgenic animals have re-emphasized that obesity is a polygenic disease.     

CCK-8 induces fever-like regulated hyperthermia and symptoms of sickness behavior in mice: A biotelemetric study

In earlier studies it has been found that rats respond to intracerebroventricular (i.c.v.) injection of cholecystokinin-octapeptide (CCK-8) with a febrile response characterized by rises of heat production and core temperature together with tail-skin vasoconstriction mediated by CCK2 receptors. Biotelemetric investigations of the same species have additionally shown that CCK-induced fever is accompanied by decreased locomotor activity. Similar data for mice have not been reported so far. In the present studies C57BL/6 mice were infused i.c.v. for 3 days with CCK-8 to see effects on body core temperature, locomotor activity, food intake and body weight. Biotelemetric monitoring disclosed a rise in daylight core temperature and a fall of night-time locomotor activity both lasting beyond the time of i.c.v. infusions. Food intake was suppressed only during infusion, while a significant decrease of body weight was sustained after the end of CCK-8 infusion. It is concluded that similar to rats mice also respond to i.c.v. infusion of CCK-8 with a fever-like (regulated) hyperthermia and some components of sickness behavior as measured by biotelemetry, and thus a CCK-mediated mechanism may contribute to fever genesis also in mice.     

Enzymatic condensation of cholecystokinin CCK-8 (4-6) and CCK-8 (7-8) peptide fragments in organic media

The kinetically controlled condensation reaction of Z-Gly-Trp-Met-OR(1) (R(1): Et, Al, Cam) and H-Asp-(OR(2))-Phe-NH(2) (R(2): H, Bu(t)) catalyzed by alpha-chymotrypsin deposited onto polyamide in organic media was studied. The effect of the drying process of the enzyme-support preparation, substrate concentrations, reaction medium, acyl donor, and nucleophile structure on both enzymatic activity and pentapeptide yield was investigated. The immobilized preparation directly equilibrated at a(w) = 0.113, gave higher enzymatic activities than dried with vacuum first, and then equilibrated at a(w) = 0.113. The addition of triethylamine to the reaction medium increased dramatically the enzymatic activity. However, the pentapeptide yield was affected neither by the drying procedure nor by the addition of triethylamine. The donor ester Z-Gly-Trp-Met-OAl gave initial reaction rates 2.6 times higher than the conventional ethyl ester derivative but rendered similar yields. The best results were obtained using Z-Gly-Trp-Met-OCam as acyl-donor ester; 80% yield and initial reaction rates 4 times higher than the ethyl ester derivative. In all cases, acetonitrile containing Tris-HCl 50 mM pH 9 buffer (0.5% v/v) and triethylamine (0.5% v/v) was found to be the best reaction system. Under these conditions, it was possible to use the nucleophile H-Asp-Phe-NH(2) with beta-unprotected aspartic acid residue. In this case, 50% yield was obtained, but economic considerations could lead to select it as nucleophile. Finally, the fragment condensation reaction was carried out at gram scale, obtaining a 39% yield which included the reaction, removal of protecting groups and purification steps. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 56: 456-463, 1997.     

Degradation of CCK-8 by rat synaptosomal peptidases

By use of an antiserum raised against conjugated ovine corticotropin releasing factor (CRF_1–41), nerve fibres can be stained immunocytochemically in the external zone of the median eminence of rats. The presence of CRF-immunoreactive (CRF_i) nerve fibres and the plasma corticosterone response to ether stress were studied in rats 6–7 days after making various types of lesions in the hypothalamus. Complete anterolateral deafferentation of the mediobasal hypothalamus caused complete disappearance of CRF_i fibres from the median eminence and blocked the corticosterone response to stress. Incomplete anterolateral hypothalamic deafferentation did not prevent the stress-induced increase of corticosterone and in these rats, part of the CRF_i nerve fibres remained intact. A horizontal cut placed ventral to the paraventricular nuclei, completely prevented the corticosterone response in those rats that showed a complete disappearance of CRF_i nerve fibres from the median eminence. Some rats however, still exhibited CRF_i nerve fibres and these animals responded to stress with increased corticosterone levels. A similar horizontal cut made just dorsal to the paraventricular nuclei affected neither the corticosterone response to stress nor the appearance of CRF_i nerve fibres in the median eminence. We conclude that the presence of CRF_i nerve fibres in the median eminence is a prerequisite for rats to show a pituitary-adrenal response to ether stress and therefore represents the first functional evidence for the role of these hypothalamic CRF_i-neurons.     

Sexual behavior in male rodents

The hormonal factors and neural circuitry that control copulation are similar across rodent species, although there are differences in specific behavior patterns. Both estradiol (E) and dihydrotestosterone (DHT) contribute to the activation of mating, although E is more important for copulation and DHT for genital reflexes. Hormonal activation of the medial preoptic area (MPOA) is most effective, although implants in the medial amygdala (MeA) can also stimulate mounting in castrates. Chemosensory inputs from the main and accessory olfactory systems are the most important stimuli for mating in rodents, especially in hamsters, although genitosensory input also contributes. Dopamine agonists facilitate sexual behavior, and serotonin (5-HT) is generally inhibitory, though certain 5-HT receptor subtypes facilitate erection or ejaculation. Norepinephrine agonists and opiates have dose-dependent effects, with low doses facilitating and high doses inhibiting behavior.     

The involvement of suprachiasmatic nuclei in the regulation of estrous cycles in rodents

Originally suprachiasmatic nuclei (SCN) were considered the main center of signals regulating the cyclic function of female reproduction, especially the gating of the LH surge. It was confirmed in the rat but not in the hamster. Some recent data show that multiple and complex interactions and processes underlie the occurrence of this very important and crucial event in female reproduction: the LH surge. Thanks to such multiway and multifactor control, the LH surge and the resulting ovulation occur regularly when "the time window" opens. Involvement of the SCN and other nuclei of the respective area in the regulation of rhythmic reproductive phenomena in female rats and hamsters is discussed.