Colocalization of Peptide and Glucocorticoid Receptor Immunoreactivities in Rat Central Amygdaloid Nucleus

Honkaniemi, Jari; Pelto‐Huikko, Markku; Rechardt, Leena; Isola, Jorma; Lammi, Antti; Fuxé, Kjell; Gustafsson, Jan‐Åke; Wikström, Ann–Charlotte; Hökfelt, Tomas

doi:10.1159/000126156

Cited by 100 publications

(52 citation statements)

References 30 publications

(36 reference statements)

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“…The finding that the PER2 expression in the CEA and BNST-OV is abolished by adrenalectomy suggests that the rhythm of PER2 is modulated by glucocorticoids, which is consistent with evidence that Per gene expression in peripheral tissues is sensitive to glucocorticoids (54,55). Furthermore, these regions contain high densities of glucocorticoid receptors, and glucocorticoids are known to modulate cell morphology and the expression of peptides such as corticotropin-releasing factor (CRF) and enkephalin (ENK) in these regions (31,(56)(57)(58)(59)(60)(61)(62). Preliminary evidence indicates that corticosterone added to the drinking water can restore PER2 rhythms in the CEA and BNST-OV of adrenalectomized, SCNintact rats.…”

Section: Discussionsupporting

confidence: 78%

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The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2

Lamont

Robinson

Stewart

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

216

231

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There is considerable evidence that circadian rhythms in mammals can be modulated by emotional state, but how emotional state modulates specific circadian outputs is poorly understood. We analyzed the expression of the circadian clock protein Period2 (PER2) in three regions of the limbic forebrain known to play key roles in emotional regulation, the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA), and the dentate gyrus (DG). We report here that cells in all three regions exhibit daily rhythms in expression of PER2 that are under the control of the master clock, the suprachiasmatic nucleus (SCN). The rhythm in the CEA and the rhythms in the BLA and DG are diametrically opposite in phase and are differentially affected by adrenalectomy. Adrenalectomy completely abolished the PER2 rhythm in the CEA but had no effect on the PER2 rhythms in the BLA and DG. We previously reported a rhythm in PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis that is identical in phase and sensitivity to adrenalectomy to that found in the CEA. Together, these findings show that key structures of the limbic forebrain exhibit daily oscillations in clock gene expression that are controlled not only by input from the SCN but, importantly, by hormonal and neurochemical changes that normally accompany motivational and emotional states. Thus, cells within these areas are strategically positioned to integrate the inputs from the SCN and emotional states to modulate circadian rhythms downstream from the SCN clock.hippocampus ͉ suprachiasmatic nucleus ͉ oval nucleus ͉ circadian clock I n mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is recognized as a master clock responsible for the regulation of all behavioral and physiological circadian rhythms (1). The rhythm of the SCN, although sensitive to the daily cycle of light, is relatively invulnerable to environmental challenges and changes in physiology (2, 3). Yet it is recognized that stressors and changes in emotional states can have disruptive effects on behavioral and physiological rhythms (4-8). Furthermore, disruptions of circadian rhythms have negative effects on mood and well being, as observed during jet lag or shift work (9, 10).Although the SCN is the only clock structure required for the generation of circadian rhythmicity, recent studies show that circadian rhythms in expression of clock genes, such as Per1 and Per2, can be found in other brain regions that participate in the control of specific behavioral and physiological outputs. These include, but are not limited to, the striatum, paraventricular hypothalamic nucleus, arcuate nucleus, preoptic area, and olfactory bulbs (11-17). The study of clock genes in these and other functionally defined brain regions may help to determine how the SCN clock controls specific circadian rhythms and, importantly, may contribute to an understanding of how diverse experiences and pathological conditions can affect circadian rhythms downstream from the SCN clock.We found recently th...

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Section: Discussionsupporting

confidence: 78%

“…Cells in the CEA, BLA, and DG express glucocorticoid receptors and exhibit a range of responses to endogenous and exogenous glucocorticoids (31)(32)(33)(34)(35)(36). Here, we found that in adrenalectomized rats, the rhythm in PER2 in the CEA was abolished (F [3,18] ϭ 0.91, P ϭ 0.45) (Fig.…”

Section: Resultsmentioning

confidence: 57%

The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2

Lamont

Robinson

Stewart

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

216

231

View full text Add to dashboard Cite

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“…56,57 Further studies have determined that, in parallel with the expression of PPTA, both the expression and activity of fos and jun are unregulated in the amygdala in response to stress. 57,58 In addition, the highly conserved binding sites of the C/EBP protein are represented twice in ECR1. This observation is interesting as mice deficient for members of the C/EPB family display increased fear responses when challenged with specific stimuli.…”

Section: Discussionmentioning

confidence: 99%

A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P

et al. 2006

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The neuropeptide substance P (SP), encoded by the preprotachykinin-A (PPTA) gene, is expressed in the central and medial amygdaloid nucleus, where it plays a critical role in modulating fear and anxiety related behaviour. Determining the regulatory systems that support PPTA expression in the amygdala may provide important insights into the causes of depression and anxiety related disorders and will provide avenues for the development of novel therapies. In order to identify the tissue specific regulatory element responsible for supporting expression of the PPTA gene in the amygdala, we used long-range comparative genomics in combination with transgenic analysis and immunohistochemistry. By comparing human and chicken genomes, it was possible to detect and characterise a highly conserved long-range enhancer that supported tissue specific expression in SP expressing cells of the medial and central amygdaloid bodies (ECR1; 158.5 kb 5 0 of human PPTA ORF). Further bioinformatic analysis using the TRANSFAC database indicated that the ECR1 element contained multiple and highly conserved consensus binding sequences of transcription factors (TFs) such as MEIS1. The results of immunohistochemical analysis of transgenic lines were consistent with the hypothesis that the MEIS1 TF interacts with and maintains ECR1 activity in the central amygdala in vivo. The discovery of ECR1 and the in vivo functional relationship with MEIS1 inferred by our studies suggests a mechanism to the regulatory systems that control PPTA expression in the amygdala. Uncovering these mechanisms may play an important role in the future development of tissue specific therapies for the treatment of anxiety and depression.

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“…Many neurons in the central amygdala express neuropeptides including enkephalin (see Petrovich and Swanson 1997;Honkaniemi et al 1992), and it is currently unclear if neurons expressing human preproenkephalin are normally enkephalinergic, or if opioid peptides have been added to their neurotransmitter repertoire. Moreover, neurons of the lateral region of the central nucleus have strong projections to the medial portion of the central nucleus, as well as the parabrachial nucleus and the bed nucleus of the stria terminalis (Petrovich and Swanson 1997).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Proenkephalin in the Amygdala Potentiates the Anxiolytic Effects of Benzodiazepines

Wen

Wilson

2000

Neuropsychopharmacology

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To elucidate the role of opioid peptides in control of the anxiety-like behavior and anxiety-reducing actions of benzodiazepines, a recombinant, replication-defective herpes virus (SHPE) carrying human preproenkephalin cDNA was delivered to rat amygdala. Viral infection resulted in a strong, localized transgene expression after 2-4 days which diminished after one week. Anxiety-like behavior and the anxiolytic effect of diazepam were assessed three days afterIn addition to its well known role in mediating fear and anxiety responses (Davis et al. 1994), the amygdala may also be a key neural substrate for the anxiolytic actions of benzodiazepines. Benzodiazepines (BZs) are believed to induce their anxiolytic properties by binding to GABA/benzodiazepine receptors in the brain (Haefely 1990). In addition, the amygdala has a high density of GABA/benzodiazepine receptors (Young and Kuhar 1980;Richards and Mohler 1984). Local infusion of benzodiazepine agonists into the amygdala produces anxiolytic effects which can be blocked by co-administration of GABA A or benzodiazepine antagonists (Scheel-Kruger and Petersen 1982;Petersen et al. 1985; Treit 1994, 1995). Furthermore, the anxietyreducing actions of systemic benzodiazepines can be blocked by intra-amygdala injection of GABA/benzodiazepine antagonists (Sanders and Shekhar 1995).The amygdala also has high levels of endogenous opioid peptides and opioid receptors (Loughlin et al. 1995), and opioid mechanisms have been implicated in many biological functions, including nociception, memory, and fear conditioning (Good and Westbrook 1995;McGaugh et al. 1996;Valverde et al. 1996). A partial anxiolytic action has been reported following microinjection of morphine into amygdala (File and Rodgers 1979).Although opioid agonists are not used as anxiolytics in general, recent evidence strongly indicates a role for endogenous opioid peptides in the control of stress and anxiety (Olson et al. 1996). Preproenkephalin knockout (Konig et al. 1996), and some novel -opioid agonists show anxiolytic properties (Privette and Terrian 1995). Several lines of evidence also indicate the involvement of endogenous opioid peptides in various aspects of benzodiazepine action, including their influences on food intake, locomotor activity, conflict, and anxiety-like behaviors (Millan and Duka 1981;Cooper 1983;Nowakowska and Chodera 1990). Interestingly, clinical studies suggest interactions between responses to benzodiazepines and opioids in humans (Darke et al. 1993). The anxiolytic effects of benzodiazepines can be blocked by opioid antagonists in both humans and laboratory animals (Billingsley and Kubena 1978;Koob et al. 1980;Duka et al. 1981Duka et al. , 1982Agmo et al 1995;Tsuda et al. 1996).Prior studies using herpes virus-mediated gene transfer demonstrated that overexpression of proenkephalin in amygdala produced antinociceptive effects, and illustrated the usefulness of this methodology for examining the role of neuropeptides in behavioral responses (Kang et al. 1998). To investigate if mo...

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Colocalization of Peptide and Glucocorticoid Receptor Immunoreactivities in Rat Central Amygdaloid Nucleus

Cited by 100 publications

References 30 publications

The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2

The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2

A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P

Overexpression of Proenkephalin in the Amygdala Potentiates the Anxiolytic Effects of Benzodiazepines

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