Kainic acid-induced early genes activation and neuronal death in the medial extended amygdala of rats

The medial extended amygdala modulates pheromonal perception, influencing emotional and social behavior. As the amygdala is part of neuronal circuits that are very sensitive to excitability, its neurons are targets of seizures in temporal lobe epilepsy. It has been suggested that the hippocampus is strongly involved this pathology. There is less consistent information, however, on the effects of this disease in the amygdala. The effects of status epilepticus on the medial extended amygdala were analyzed by immunohistochemistry for neural stress and by the amino-cupric-silver technique for neuronal death in rats after kainic acid (KA) administration. Sixty adult Wistar male rats were used. Thirty animals received an injection of KA, and 30 were injected with saline. After 2, 4, 12, 24 and 48 h survival the brains were stained for Fos and FosB and for neuronal death.In the present study we show that KA induces Fos and FosB expression in neurons of the medial extended amygdala after 2, 4-48 h, with time courses that are different between them and from control animals. While Fos-IR peaks at 2-4 h post KA and then decreases, FosB-IR increases in the same period reaching its highest expression at 24-48 h. Moreover, KA injection produced massive neuronal death with a peak at 24 h. This neurodegeneration paralleled FosB-IR protein expression.These findings show that KA produces neuronal stress and activation of early genes and neuronal death in the medial extended amygdala, demonstrating the vulnerability of its neurons to the epileptogenic effects of KA.     

大鼠弥漫性轴索损伤后Fos蛋白表达的研究

目的观察大鼠弥漫性轴索损伤（DAI）后不同时间Fos蛋白在脑皮质、脑干的表达,进一步阐明脑损伤后弥漫轴索损伤的发生机制。方法45只大鼠随机分为两组,正常对照组（5只）和损伤组（40只）。损伤组复制Marmarou DAI模型,通过免疫组织化学方法,观察伤后不同时间脑皮质、脑于神经元Fos蛋白表达。结果外伤后0．5hFos蛋白表达开始增加,1d达到高峰,以后逐渐下降,12d后基本消失。与正常对照组相比,损伤组伤后0．5、1、4、12h、1、4dFos阳性神经元数明显增多（P〈0．01）。结论DAI的形成和发展与伤后的时间存在明显相关关系。     

Prenatal stress alters the negative correlation between neuronal activation in limbic regions and behavioral responses in rats exposed to high and low anxiogenic environments

Behavioral adaptation to an anxiogenic environment involves the activity of various interconnected limbic regions, such as the amygdala, hippocampus and prefrontal cortex. Prenatal stress (PS) in rats affects the ability to cope with environmental challenges and alters brain plasticity, leading to long-lasting behavioral and neurobiological alterations. We examined in PS and control animals whether behavioral reactivity was correlated to neuronal activation by assessing Fos protein expression in limbic regions of rats exposed to a low or high anxiogenic environment (the closed and open arms of an elevated plus maze, respectively). A negative correlation was found between behavioral and neuronal activation, with a lower behavioral reactivity and a higher neuronal response observed in rats exposed to the more anxiogenic environment (the open arm) with respect to the less anxiogenic environment (the closed arm). Interestingly, the variation in the neurobehavioral response between the two arms of the maze was less pronounced in rats that had been subjected to PS. This study provides a remarkable example of how long-lasting changes in brain plasticity induced by PS affect the ability of limbic neurons to cope with anxiogenic stimuli of different strength.     

Alpha-7 nicotinic acetylcholine receptor agonists selectively activate limbic regions of the rat forebrain: an effect similar to antipsychotics

It is considered that activation of nicotinic alpha7 receptors (alpha7 nAChR) is useful for the treatment of cognitive disturbances in schizophrenia and Alzheimer's disease. Recently, selective alpha7 nAChR agonists have been discovered and are used to validate the alpha7 nAChR as a drug target for the treatment of cognitive disturbances in schizophrenia. One important feature shared by all known antipsychotics is their capacity to induce expression of the neuronal immediate-early gene c-fos in the limbic forebrain. Using two novel and selective alpha7 nAChR agonists, PNU-282987 and SSR180711, we investigated their ability to induce c-Fos expression in the limbic forebrain with particular emphasis on the same regions reported to be activated by antipsychotics. Both alpha7 nAChR agonists increased c-Fos dose-dependently in the prefrontal cortex and the shell of nucleus accumbens, while leaving the core of nucleus accumbens and the dorsolateral striatum unaffected. The accumbal and cortical effect of SSR180711 was blocked completely by pre-administration of the alpha7 nAChR antagonist methyllycaconitine. Also, SSR180711 displayed no c-Fos-inducing effect in alpha7 nAChR knock-out mice. In conclusion, these results show that selective pharmacologic stimulation of alpha7 nAChR function results in activation of forebrain regions similar to conventional antipsychotics.     

Grueneberg ganglion neurons respond to cool ambient temperatures

The Grueneberg ganglion (GG) - a neuronal cell cluster of unknown function localized to the vestibule of the anterior nasal cavity - is considered as a chemosensory compartment based on the expression of olfactory receptors and the olfactory marker protein. Axonal projection of GG neurons to so-called 'necklace glomeruli' in the olfactory bulb of the brain, which are thought to be important for suckling behaviour in rodent pups, has led to the hypothesis that the GG might be involved in mother/child interactions. To survey potential activation of GG neurons in living animals during the course of mother/child interactions, expression of the activity-dependent gene c-Fos in the GG of neonatal mouse pups was monitored in the presence and absence of the dam. It was found that GG neurons were only activated in the absence of the mother. Moreover, GG activation was independent from olfactory cues as revealed by naris occlusion. Searching for stimuli eliciting GG activity in pups separated from the dam, cool ambient temperatures were found to induce strong c-Fos expression in GG neurons whereas warmer temperatures did not. These coolness-induced responses were only observed in a distinct subset of GG neurons characterized by the expression of the olfactory receptor V2r83. Finally, GG responsiveness to coolness was remarkably reduced in older stages. In summary, these findings suggest that the GG of neonatal mice is activated by cool ambient temperatures to which they are exposed in the absence of their dam, indicating that the GG might function as a thermosensor.     

Differential involvement of 3′, 5′-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos and tyrosine hydroxylase expression in the heart after naloxone induced morphine withdrawal

We previously demonstrated that morphine withdrawal induced hyperactivity of the heart by the activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline (NA) turnover and Fos expression. We investigated whether cAMP-dependent protein kinase (PKA) plays a role in this process by estimating changes in PKA immunoreactivity and the influence of inhibitor of PKA on Fos protein expression, tyrosine hydroxylase (TH) immunoreactivity levels and NA turnover in the left and right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (5 mg/kg). When opioid withdrawal was precipitated, an increase in PKA immunoreactivity and phospho-CREB (cyclic AMP response element protein) levels were observed in the heart. Moreover, morphine withdrawal induces Fos expression, an enhancement of NA turnover and an increase in the total TH levels. When the selective PKA inhibitor HA-1004 was infused, concomitantly with morphine pellets, it diminished the increase in NA turnover and the total TH levels observed in morphine-withdrawn rats. However, this inhibitor neither modifies the morphine withdrawal induced Fos expression nor the increase of nonphosphorylated TH levels. The present findings indicate that an up-regulated PKA-dependent transduction pathway might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal and suggest that Fos is not a target of PKA at heart levels.     

Impaired activation of celiac ganglion neurons in vivo after damage to their sympathetic nerve terminals

Because damage to sympathetic nerve terminals occurs in a variety of diseases, we tested the hypothesis that nerve terminal damage per se is sufficient to impair ganglionic neurotransmission in vivo. First, we measured the effect of nerve terminal damage produced by the sympathetic nerve terminal toxin 6-hydroxydopamine (6-OHDA) on ganglionic levels of several neurotrophins thought to promote neurotransmission. 6-OHDA-induced nerve terminal damage did not decrease the expression of neurotrophin-4 or brain-derived neurotrophic factor mRNA in the celiac ganglia but did decrease the ganglionic content of both nerve growth factor protein (nadir = -63%) and the mRNA of the alpha-3 subunit of the nicotinic cholinergic receptor (nadir = -49%), a subunit required for neurotransmission. Next, we tested whether this degree of receptor deficiency was sufficient to impair activation of celiac ganglia neurons. Impaired fos mRNA responses to nicotine administration in the celiac ganglia of 6-OHDA-pretreated rats correlated temporally with suppressed expression of functional nicotinic receptors. We verified by Fos protein immunohistochemistry that this ganglionic impairment was specific to principal ganglionic neurons. Last, we tested whether centrally initiated ganglionic neurotransmission is also impaired following nerve terminal damage. The principal neurons in rat celiac ganglia were reflexively activated by 2-deoxy-glucose-induced glucopenia, and the Fos response in the celiac ganglia was markedly inhibited by pretreatment with 6-OHDA. We conclude that sympathetic nerve terminal damage per se is sufficient to impair ganglionic neurotransmission in vivo and that decreased nicotinic receptor production is a likely mediator.     

Differential fos activation in virgin and lactating mice in response to an intruder

Lactating (L) mice display fierce aggression towards novel, male mice, while virgin (V) mice do not. This study compares patterns of brain activation in V and L mice in response to a novel intruder using immunohistochemical detection of Fos (Fos-IR). Animals were sampled 120 min after either a sham or real 10 min test with a male intruder. L mice were aggressive towards intruders, but V mice were not. In general, Fos-IR for both groups increased with exposure to an intruder, with L mice showing higher increases in Fos-IR than V mice. In only medial preoptic nucleus and ventral portion of bed nucleus of stria terminalis (BNST) was Fos-IR significantly increased in both groups with testing. In V mice, testing resulted in Fos-IR increases in an additional 10 regions examined that did not reach significance in L mice, including lateral septum, lateral and medial preoptic areas, and anterior hypothalamus. Fos-IR also increased with testing in nine regions unique to L mice, including the mitral and granular layers of accessory olfactory bulb, regions of the amygdala, dorsal BNST, and caudal portions of the hypothalamic attack area. These increases in Fos-IR with testing suggest alterations in the circuitry governing response to pheromonal cues and imply some commonalities between the circuitries governing maternal aggression and intermale aggression. These results support the hypothesis that pregnancy and lactation induce substantial changes in brain circuitry and function; changes that enable maternal defense of offspring by altering the neural response to an intruder male.