Bai-Han Li

Localization of changes in immediate early genes in brain in relation to hydromineral balance: intravenous angiotensin II

Immediate early genes, detected by Fos- and Jun-like immunoreactivity (FLI, JLI), were induced in discrete regions of the rat brain by intravenous infusion of angiotensin II (Ang II) at dipsogenic doses. The regions included subfornical organ (SFO), organum vasculosum laminae terminalis (OVLT), median preoptic nucleus (MnPO), supraoptic nucleus (SON), and the magnocellular part of the paraventricular hypothalamus (PVH). These responses were sustained for up to 6 h of infusion. In SFO, FLI was induced preferentially in the posterior part, while JLI occurred in more central regions. Cerebroventricular (ICV) injection of the Ang II type 1 receptor (AT-1) antagonist, losartan potassium, completely prevented the FLI induced by Ang II in these brain regions. ICV injection of the Ang II type 2 receptor (AT-2) antagonist, PD 123319, did not reduce Ang II-induced FLI in SFO, OVLT and MnPO, but markedly attenuated the activation in SON and PVH. To determine whether SFO is the primary site for transduction of the circulating Ang II signal, electrolytic lesions were made in or rostral to the SFO. Rats with complete lesions showed a complete absence of Ang-induced FLI in SON and PVH. The data are discussed in terms of functional mapping of the brain regions activated by circulating Ang II and neural circuitry for water intake, including the possible role of AT-2 receptors in PVH and SON.

Dexfenfluramine induces fos-like immunoreactivity in discrete brain regions in rats

Administration of the anorectic agent, dexfenfluramine (DFEN) to rats induced dose- and time-dependent expression of Fos-like immunoreactivity in several discrete brain regions of rats. At moderate doses, the regions showing the most intense Fos immunostaining included the bed nucleus of the stria terminalis, the lateral part of the central amygdala, midline thalamic nuclei, habenular nuclei, lateral parabrachial nucleus, and nucleus of the solitary tract. It is suggested that these nuclei, many of which are known to receive gustatory or visceral input, may form part of a functional circuit via which DFEN modulates food intake. Rats that were made hungry by either food deprivation or administration of insulin also showed induction of Fos in several brain regions, but only that in the supramamillary/ventral tegmental area was suppressed by pretreatment with an anorectic dose of DFEN. The functional significance of these sites requires further investigation.

c-fos expression in the rat brain following central administration of neuropeptide Y and effects of food consumption

Administration of neuropeptide Y (NPY) intracerebroventricularly (i.c.v.) results in the release of a number of hypothalamic and pituitary hormones and stimulation of feeding and suppression of sexual behavior. In this study, we sought to identify cellular sites of NPY action by evaluating perikaryal Fos-like immunoreactivity (FLI), a marker of cellular activation, in those hypothalamic and extrahypothalamic sites previously implicated in the control of neuroendocrine function and feeding behavior. Additionally, we compared the topography of FLI in these brain sites when food was either available ad libitum or withheld after NPY injection (1 nmol/3 microliters, i.c.v.). The results showed that one hour after NPY injection a larger number of cells in the parvocellular region of the paraventricular nucleus (PVN) were FLI-positive in the absence of food consumption. However, in association with food intake, a significant number of cells were intensely stained in the magnocellular region of the PVN. An analogous increase in FLI in association with feeding was apparent in the supraoptic nucleus (SON), the dorsomedial nucleus and the bed nucleus of the stria terminalis in the hypothalamus. Among the extrahypothalamic sites, feeding facilitated FLI in a large number of cells located in the lateral subdivision of the central amygdaloid nucleus and the lateral subdivision of the solitary tract. FLI was observed in a moderate number of cells in the hypothalamic arcuate nucleus (ARC) and ventromedial nucleus, and this response was not changed by feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of dexfenfluramine-induced anorexia and c-Fos/c-Jun expression by lesion in the lateral parabrachial nucleus

The external subdivision of the lateral parabrachial nucleus (LPBE) shows strong Fos-like immunoreactivity (FLI) following anorectic doses of the indirect serotonin agonist dexfenfluramine (DFEN). In an effort to determine the contribution of the LPBE to DFEN-induced anorexia, bilateral ibotenate lesions were made in the LPBE, and the effects of the lesion on DFEN-induced anorexia and FLI as well as c-Jun-like immunoreactivity (JLI) were examined. It was found that LPBE lesion significantly attenuated DFEN anorexia: in a 1-h food intake test following 24-h food deprivation, DFEN (2 mg/kg) suppressed food intake by 60% in intact rats but only 34% in rats with LPBE lesions. In addition to this behavioral change, LPBE lesion completely abolished DFEN-induced FLI and JLI in the lateral subdivision of the central nucleus of the amygdala (CeL) and laterodorsal subdivision of the bed nucleus of stria terminalis (BSTLD), both of which showed strong FLI and JLI in intact rats. DFEN-induced FLI and JLI in other brain regions were not affected by LPBE lesion, including the ventromedial and lateral hypothalamus, caudate-putamen, and the nucleus of the solitary tract (NST). The parallel loss of DFEN-induced anorexia and FLI/JLI following LPBE lesion raises the novel possibility that LPBE-CeL/BSTLD pathway may be involved in DFEN anorexia.

The physiology and brain mechanisms of feeding

This article is designed as an introduction to the major theoretical models in the field of regulation of eating behavior, and a selective review of relevant neurobiological data. We first critically consider the paradigm of homeostasis as it relates to body energy content, and argue that additional theoretical constructs will be needed to account for the complexity of eating behavior in both nonhumans and humans. We then summarize some of the methods available to the neuroscientist in this area, and address some of their limitations. We review treatments and potential mechanisms that increase food intake, including deprivation, antimetabolites, norepinephrine, and several peptides including neuropeptide Y. We next review treatments that decrease food intake, including a variety of humoral, gastrointestinal, and pancreatic factors, as well as examine central pathways of satiety. This includes a discussion of leptin and other potential anorectic agents. We conclude with a discussion of human obesity and anorexias, and prospects for pharmacotherapy of eating disorders. We emphasize throughout that most regions of the human brain probably make some contribution to feeding behavior, and so a focus on any one area of transmitter/hormone is an unrealistic approach both in basic and applied areas.

Effects of vagotomy on cholecystokinin- and dexfenfluramine-induced fos-like immunoreactivity in the rat brain

This study compared the effects of bilateral subdiaphragmatic vagotomy on the Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat brain induced by two anorectic agents, cholecystokinin (CCK) and the serotonin agonist, dexfenfluramine (DFEN). In the nonvagotomized rats, both CCK (5 micrograms/kg, IP) and DFEN (2 mg/kg, IP) induced FLI in the nucleus of the solitary tract (NST), the external subdivision of the lateral parabrachial nuclei (LPBE), the lateral subdivision of the central amygdaloid nucleus (CeL), and the bed nucleus of the stria terminalis (BST). However, subregional distribution of the FLI induced by the two agents was different in most of these regions. Additionally, the area postrema and the medial subdivision of the hypothalamic paraventricular nucleus were preferentially activated by CCK but not DFEN, while the caudate-putamen was activated by DFEN but not CCK. Bilateral subdiaphragmatic vagotomy completely abolished CCK-induced FLI in all the brain regions but did not attenuate DFEN-induced FLI in any of these regions, including the NST. The results of the present study suggest that DFEN-activation of the NST-LPBE-CeL/BST neuraxis is not mediated by the vagus nerve. On the other hand, and consistent with a variety of other data, activation of various parts of the brain by peripherally administered CCK depends on a vagal pathway. These data are discussed in relation to a previously proposed interaction between CCK and serotonin in mediating satiety.

Cholecystokinin- and dexfenfluramine-induced anorexia compared using devazepide and c-fos expression in the rat brain

It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK in most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.

Fos induced in brain of spontaneously hypertensive rats by angiotensin II and co-localization with AT-1 receptors

The induction of Fos-like immunoreactivity (FLI) by peripheral administration of angiotensin II (Ang II) was used to determine whether central activation was greater in spontaneously hypertensive rats (SHR) than in normotensive WKY and outbred Wistar controls. FLI was induced in the same brain regions (circumventricular organs and neurosecretory hypothalamic cell groups) in all three groups of rats, but the FLI in several of these regions was markedly less in WKY than in either SHR or Wistar. This reduced responsiveness in supraoptic and paraventricular nuclei was selective to Ang II, because the FLI induced in these nuclei by hypertonic NaCl did not differ between groups. We also report that a considerable number of cells in the SON and PVH expressing FLI to these stimuli show immunostaining with an antibody to the AT-1 Ang II receptor. These data indicate that central angiotensinergic pathways may be more sensitive in SHR than WKY, and that WKY are less sensitive than outbred Wistars.

Effect of chronic dexfenfluramine on Fos in rat brain

The acute appetite suppressant effect of dexfenfluramine (DF) in rats, which may depend upon its action to release serotonin (5-HT) in the brain, often declines with repeated dosing (tolerance). The mechanisms of this tolerance remain unclear. Previously, we used Fos-like immunoreactivity (Fos-IR) to map potential brain sites activated by single injections of DF in rats. A dose of 5 mg DF/kg activated the central amygdala (CeA), bed nucleus of the stria terminalis (BST), caudate-putamen (CPu), lateral parabrachial nucleus (LPB), nucleus tractus solitarius (NST), frontal cerebral cortex and the parvocellular paraventricular hypothalamic nucleus (PVN). We now report studies using Fos-IR in an attempt to understand which regions might underlie tolerance to the action of DF. Pretreatment of rats with an escalating dosage regimen of DF (0.5-4 mg/kg, i.p.) was associated with complete loss of Fos-IR to a probe dose (5 mg DF/kg) in the cortex, CPu, PVN and NTS, and partial loss of Fos-IR in the BST, CeA and LPB. Second, repeated treatment with DF (2 mg/kg), which has been shown to produce tolerance the anorexia caused by DF but not cholecystokinin (CCK), likewise reduced Fos-IR induced in the above brain regions, but had no effect on Fos-IR induced by either CCK or the 5-HT agonist, 5-carboxamidotryptamine. Third, repeated treatment with 5-HT (2 mg/kg, s.c.) had no effect on Fos-IR induced by a probe dose of DF. These data show that regionally heterogeneous hyporesponsiveness to the induction of Fos by DF develops after repeated low doses of DF; however, the Fos response to other putative anorectics or weight reducing agents is not affected. This may be related to behavioral tolerance.

Neuropeptide Y injection into the fourth cerebroventricle stimulates c-Fos expression in the paraventricular nucleus and other nuclei in the forebrain : effect of food consumption

Injection of neuropeptide Y (NPY) into the cerebroventricular system of the rat results in a robust feeding response. In this study, we observed that NPY injection into the fourth ventricle augmented feeding and Fos-like immunoreactivity (FLI) in the paraventricular nucleus (PVN) and in other neighboring nuclei in the forebrain previously implicated in stimulation of feeding. Since the rostral transport of NPY in cerebrospinal fluid after injection into the fourth ventricle is unlikely and the topography of FLI as well as feeding behavior seen in this study are similar to those observed previously after NPY injection into the lateral cerebroventricle, these findings are in accord with the view that feeding induced by NPY injection into the fourth ventricle may also be mediated by NPY receptive elements in the forebrain.