Invited review c-Fos as a transcription factor: a stressful (re)view from a functional map

Kovács, Krisztina

doi:10.1016/s0197-0186(98)00023-0

Cited by 635 publications

(492 citation statements)

References 96 publications

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“…A key portion of the central response to stress appears to involve activation of neurons in the amygdala (Campeau et al 1991;Kovacs 1998;LeDoux 2000). The results presented here do not fully support the hypothesis that prenatal cocaine renders all the proposed neuronal systems hyperresponsive to stress, as the stress activation of Fos expression in the amygdala was not altered by prenatal cocaine exposure.…”

Section: Discussioncontrasting

confidence: 83%

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Male Rats Exposed to Cocaine in utero Demonstrate Elevated Expression of Fos in the Prefrontal Cortex in Response to Environment

Morrow

Elsworth

Roth

2002

Neuropsychopharmacology

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Prenatal cocaine exposure has been associated with disruption in attention and short-term memory in exposed children and in animal models. The biochemical change or changes responsible for these cognitive deficits are not known. An intriguing possibility, however, is that cocaine exposure during development disrupts the morphology or function of the frontal cortex, a region thought to contribute to cognitive and executive functions. In this report, we examined the effects of intravenous prenatal cocaineThe abuse of cocaine during pregnancy has not been associated with major anatomical birth defects; however, a significant numbers of children exposed to cocaine in utero go on to develop select cognitive deficits, such as memory deficits, impulsivity, and difficulties in modulating attention (Delaney-Black et al. 1998; DowEdwards et al. 1999). Behavioral studies in animal models of prenatal cocaine exposure have demonstrated similar deficits in memory (Choi et al. 1998a;Cutler et al. 1996;Heyser et al. 1995;Levin and Seidler 1993;Morrow et al. 2000b;Tonkiss et al. 1997;Vorhees et al. 1995) and attention (Garavan et al. 2000;Mactutus 1999;Romano and Harvey 1996). The identification of the sites and the underlying biochemical changes induced by in utero exposure to cocaine, however, remain elusive. Understanding the biochemical substrates of the behavioral deficits induced by prenatal cocaine is necessary if logical treatments for the condition are to be developed. We have chosen to use the expression of the immediateearly gene, c-fos , as a marker of neuronal activation. NO . 3 Many researchers, including in our own laboratory, have successfully used this marker to map and study stress responses (Kovacs 1998). The expression of Fos, however, does not solely indicate that the neuron has been activated but indicates that the neuron is in the process of undergoing longer-term adaptation brought about by activation.One potential candidate site for the cognitive effects of prenatal cocaine is the frontal cortex. Dysfunction in this region has been associated with disruption in cognitive processes, including memory and attention (Goldman-Rakic 1998). Additionally, deficits in shortterm working memory can be observed with altered dopaminergic function in the prefrontal cortex of rats and non-human primates (Goldman-Rakic 1998;Morrow et al. 2000c;Murphy et al. 1996). One obvious mechanism by which prenatal cocaine exposure could impact on the frontal cortex is by blockade by cocaine of the monoamine transporters, including that of dopamine, in that region. Fetal changes in monoamine levels in the developing frontal cortex could potentially result in an anatomical or functional disruption (Levitt 1998;Pendleton et al. 1998). Wang and colleagues reported changes in the GABAergic neurons in the cortex, leading to the hypothesis that prenatal cocaine exposure could result in a disruption of the excitatory/inhibitory balance (Wang et al. 1995(Wang et al. , 1996. In this current report, we investigate potential changes in th...

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Section: Discussioncontrasting

confidence: 83%

“…Many researchers, including in our own laboratory, have successfully used this marker to map and study stress responses (Kovacs 1998). The expression of Fos, however, does not solely indicate that the neuron has been activated but indicates that the neuron is in the process of undergoing longer-term adaptation brought about by activation.…”

mentioning

confidence: 99%

Male Rats Exposed to Cocaine in utero Demonstrate Elevated Expression of Fos in the Prefrontal Cortex in Response to Environment

Morrow

Elsworth

Roth

2002

Neuropsychopharmacology

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“…Kim and Diamond, 30 Pavlides et al, 70 Alfarez et al 71 and Blank et al 72 ). Patterns of Fos expression after stress in adult hippocampus have been described by several groups at both mRNA and protein level, [73][74][75][76] and others have distinguished the effects of novelty from those of stress per se. 77,78 The effects of stress on hippocampal neurons during development have been less studied.…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent

et al. 2006

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The effects of stress, including their putative contribution to pathological psychiatric conditions, are crucially governed by the age at which the stress takes place. However, the cellular and molecular foundations for the impact of stress on neuronal function, and their change with age, are unknown. For example, it is not known whether 'psychological' stress signals are perceived by similar neuronal populations at different ages, and whether they activate similar or age-specific signaling pathways that might then mediate the spectrum of stress-evoked neuronal changes. We employed restraint and restraint/noise stress to address these issues in juvenile (postnatal day 18, [P18]) and adult rats, and used phosphorylation of the transcription factor CREB (pCREB) and induction of c-fos as markers of hippocampal neuronal responses. Stress-activated neuronal populations were identified both anatomically and biochemically, and selective blockers of the stress-activated hippocampal peptide, corticotropin-releasing hormone (CRH) were used to probe the role of this molecule in stressinduced hippocampal cell activation. Stress evoked strikingly different neuronal response patterns in immature vs adult hippocampus. Expression of pCREB appeared within minutes in hippocampal CA3 pyramidal cells of P18 rats, followed by delayed induction of Fos protein in the same cell population. In contrast, basal pCREB levels were high in adult hippocampus and were not altered at 10-120 min by stress. Whereas Fos induction was elicited by stress in the adult, it was essentially confined to area CA1, with little induction in CA3. At both age groups, central pretreatment with either a nonselective blocker of CRH receptors or the CRF 1 -selective antagonist, NBI 30775, abolished stress-evoked neuronal activation. In conclusion, hippocampal neuronal responses to psychological stress are generally more rapid and robust in juvenile rats, compared to fully mature adults, and at both ages, CRH plays a key role in this process. Enhanced hippocampal response to stress during development, and particularly the activation of the transcription factor CREB, may contribute to the enduring effects of stress during this period on hippocampal function.

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“…The c-fos gene is rapidly upregulated by many stimulatory pathways and is often used as a marker to determine general neuronal activation (Kovacs 1998). Levels of c-fos increased approximately twofold in all areas of the brain examined in response to acute LSD, suggesting that LSD activates many brain areas.…”

Section: Discussionmentioning

confidence: 99%

A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain

Nichols

Sanders‐Bush

2002

Neuropsychopharmacology

136

100

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Hallucinogenic drugs such as lysergic acid diethylamide (LSD) have profound effects on humans including INTRODUCTIONLysergic acid diethylamide (LSD) is an hallucinogenic drug that transiently but powerfully alters human perception, behavior, and mood at extremely low doses. Certain aspects of the behavior elicited by acute doses of LSD closely resemble symptoms of mental disorders such as schizophrenia (Breier 1995). Despite extensive research over the past four decades, the mechanism of action of hallucinogenic drugs still largely remains a mystery. The behavioral effects of LSD are believed to arise in part from agonist activity at the 5-HT 2A , 5-HT 2C , and 5-HT 1A receptor subtypes (Burris et al. 1991; KrebsThomson et al. 1998;Titeler et al. 1988), but if, and how, these interactions affect cognitive functions remains unknown. In addition to actions at serotonin receptors, LSD has high affinity for dopamine receptors and has been shown to act as an agonist at these receptors (Giacomelli et al. 1998;Watts et al. 1995). Because LSD is a unique ligand that can simultaneously bind to serotonin and dopamine receptor subtypes implicated in both normal and abnormal human behaviors, it is an excellent tool for probing the biochemical basis for behavior.Simply increasing brain levels of serotonin, however, does not produce hallucinogenic effects. Recent work has demonstrated that while LSD binds to the same re- NO . 5 LSD-influenced Gene Expression 635 ceptor sites as the endogenous ligand serotonin, it has the capacity to activate different intracellular signaling cascades (Backstrom et al. 1999). Because intracellular signaling cascades influence gene expression, LSDinduced signaling events within cells may inappropriately alter gene expression, which in turn may lead to changes in the physiological status of the neurons, ultimately altering the processes of cognition. Certain behavioral effects of LSD resemble paranoid schizophrenia in humans. This particular subset of mood alterations occurs within the "second phase . . . of the LSD experience" as defined by Freedman, and may be specific for LSD (Freedman 1984). These delayed "second phase" effects could result from transient changes in gene expression. Thus, identifying and characterizing these genes could prove to be important in understanding mechanisms underlying how hallucinogens such as LSD alter behavior. In addition, understanding these mechanisms may lead to the identification of novel therapeutic targets for treatment of mental disorders.We took a broad approach to investigating and identifying genes that are altered by an acute dose of LSD in the mammalian brain. First, we investigated the expression of the mRNAs of the 5-HT receptor subtypes thought to mediate hallucinogenic effects in animal models (5-HT 1A,2A,2C ), as well as, specific gene expression of immediate early genes predicted to be affected by LSD. Next, we performed a DNA microarray screen to identify gene expression influenced by LSD at a more global level. For each gene identified,...

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Invited review c-Fos as a transcription factor: a stressful (re)view from a functional map

Cited by 635 publications

References 96 publications

Male Rats Exposed to Cocaine in utero Demonstrate Elevated Expression of Fos in the Prefrontal Cortex in Response to Environment

Male Rats Exposed to Cocaine in utero Demonstrate Elevated Expression of Fos in the Prefrontal Cortex in Response to Environment

Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent

A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain

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