Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex

Hale, Matthew W.; Hay‐Schmidt, Anders; Mikkelsen, Jens D.; Poulsen, Britta C.; Bouwknecht, J. Adriaan; Evans, Andrew K.; Stamper, Christopher E.; Shekhar, Anantha; Lowry, CA

doi:10.1016/j.neuroscience.2008.09.050

Cited by 76 publications

(66 citation statements)

References 47 publications

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“…(2,27) ϭ 7.45; *p Ͻ 0.05; n ϭ 12; E) without changing the total moving distance (vehicle, 3746.22 Ϯ 1168.60 cm; diazepam, 0.5 mg/kg, 3778.29 Ϯ 1316.09 cm; n ϭ 12; F (2,27) ϭ 0.56, not significant; F ). Hale et al (2008) reported that the exposure of rats to an OF arena markedly increases c-Fos expression in both TPHpositive and TPH-negative neurons in the DRL. In the present study, we confirmed this and further revealed that diazepam suppressed the OF stress-induced c-Fos expression at a dose that effectively lowered the anxiety level.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, c-Fos expression induced by OF stress in the DRD and DRV was resistant to diazepam. Because these nuclei project not only to the basolateral amygdala (Hale et al, 2008), but also to the medial prefrontal cortex and nucleus accumbens (Van Bockstaele et al, 1993), the c-Fos induction in these nuclei may be related to the cognition or novelty-seeking behaviors. Together, these findings suggest that neurons in the DRL, particularly 5-HT/GAD67 neurons, are highly sensitive to innocuous stressors, in which activation of diazepam-sensitive GABA A receptors may be involved.…”

Section: Discussionmentioning

confidence: 99%

“…Subdivisions of the DRN innervate distinct targets and receive disparate afferent inputs (Abrams et al, 2004;Lee et al, 2005Lee et al, , 2007Hale et al, 2008), including 5-HTergic interactions within the DRN (Lemos et al, 2006;Kirby et al, 2007). Neurons in the DRL have been deemed to play a distinctive, crucial role in the response to stressors.…”

Section: Discussionmentioning

confidence: 99%

“…Neurons in the DRL have been deemed to play a distinctive, crucial role in the response to stressors. Various types of stressors, including OF stress, social stress, and swim stress, along with anxiogenic drugs or reagents activates DRL neurons preferentially (Roche et al, 2003;Abrams et al, 2005;Berton et al, 2007;Hale et al, 2008;Johnson et al, 2008). 5-HTergic neurons in the ventrolateral periaqueductal gray (vlPAG), which is overlapped or embedded in the DRL, project to major sympathoexcitatory regions, the dlPAG and the RVLM, i.e., the adrenergic C1 region .…”

Section: Discussionmentioning

confidence: 99%

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Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Shikanai

Yoshida²,

Konno

et al. 2012

J. Neurosci.

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The serotonergic (5-HTergic) system arising from the dorsal raphe nucleus (DRN) is implicated in various physiological and behavioral processes, including stress responses. The DRN is comprised of several subnuclei, serving specific functions with distinct afferent and efferent connections. Furthermore, subsets of 5-HTergic neurons are known to coexpress other transmitters, including GABA, glutamate, or neuropeptides, thereby generating further heterogeneity. However, despite the growing evidence for functional variations among DRN subnuclei, relatively little is known about how they map onto neurochemical diversity of 5-HTergic neurons. In the present study, we characterized functional properties of GAD67-expressing 5-HTergic neurons (5-HT/GAD67 neurons) in the rat DRN, and compared with those of neurons expressing 5-HTergic molecules (5-HT neurons) or GAD67 alone. While 5-HT/GAD67 neurons were absent in the dorsomedial (DRD) or ventromedial (DRV) parts of the DRN, they were selectively distributed in the lateral wing of the DRN (DRL), constituting 12% of the total DRL neurons. They expressed plasmalemmal GABA transporter 1, but lacked vesicular inhibitory amino acid transporter. By using whole-cell patch-clamp recording, we found that 5-HT/GAD67 neurons had lower input resistance and firing frequency than 5-HT neurons. As revealed by c-Fos immunohistochemistry, neurons in the DRL, particularly 5-HT/GAD67 neurons, showed higher responsiveness to exposure to an open field arena than those in the DRD and DRV. By contrast, exposure to contextual fear conditioning stress showed no such regional differences. These findings indicate that 5-HT/GAD67 neurons constitute a unique neuronal population with distinctive neurochemical and electrophysiological properties and high responsiveness to innocuous stressor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Shikanai

Yoshida²,

Konno

et al. 2012

J. Neurosci.

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“…Our data demonstrate a relationship between the integrative actions of all urocortins in modulating stress responses. Increases in the above-noted anxiety indices were reported following different paradigms of stress exposure and were related to altered structure and/or functions of stress-related neurocircuits, including the amygdalar-BNST complex, septal regions, raphe nuclei serotonergic circuits, and HPA-axis regulation (29)(30)(31)(32)(33)(34)(35).…”

Section: (G and H) Asr (G)mentioning

confidence: 99%

A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery

Neufeld-Cohen

Tsoory²,

Evans³

et al. 2010

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

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Responding to stressful events requires numerous adaptive actions involving integrated changes in the central nervous and neuroendocrine systems. Numerous studies have implicated dysregulation of stress-response mechanisms in the etiology of stress-induced psychopathophysiologies. The urocortin neuropeptides are members of the corticotropin-releasing factor family and are associated with the central stress response. In the current study, a tripleknockout (tKO) mouse model lacking all three urocortin genes was generated. Intriguingly, these urocortin tKO mice exhibit increased anxiety-like behaviors 24 h following stress exposure but not under unstressed conditions or immediately following exposure to acute stress. The inability of these mutants to recover properly from the exposure to an acute stress was associated with robust alterations in the expression profile of amygdalar genes and with dysregulated serotonergic function in stress-related neurocircuits. These findings position the urocortins as essential factors in the stress-recovery process and suggest the tKO mouse line as a useful stress-sensitive mouse model. amygdala | anxiety-like behaviors | serotonergic system | corticotropinreleasing factor | corticotropin-releasing factor receptor type 2 D ysregulation of stress-response mechanisms is proposed to underlie a variety of stress-related psychopathologies (1, 2). Corticotropin-releasing factor (CRF) plays a pivotal and wellestablished role in regulating the hypothalamic-pituitary-adrenal (HPA) axis under basal and stress conditions (3, 4) and, via its type 1 receptor (CRFR1), integrates the autonomic, metabolic and behavioral stress responses (5).The CRF peptide family includes also three urocortin (Ucn) peptides (Ucn1, Ucn2, and Ucn3) that bind and activate the CRF receptor type 2 (CRFR2) with high affinity (6-12). CRF has a relatively lower affinity for CRFR2 than for CRFR1; Ucn1 has equal affinities for both; and Ucns 2 and 3 appear to be selective for CRFR2 (6-9). These receptors are distributed differently throughout the brain: CRFR1 is widely expressed in various brain regions, whereas CRFR2 expression is more localized to selected stress-related brain nuclei, such as the amygdala, the bed nucleus of the stria terminalis (BNST), the lateral septum (LS), and the dorsal raphe nucleus (DRN) (13,14).Evidence from studies using competitive peptides or smallmolecule CRF/urocortin receptor antagonists suggested that the brain CRF/urocortin systems play diverse roles in mediating behavioral responses to stress (15). Based on the complementary behavioral phenotypes of CRFR1-and CRFR2-deficient (KO) mice, opposing roles were suggested for the two CRF receptors systems in modulating anxiety-like behaviors. CRFR1KO mice display decreased anxiety-like behaviors coupled with an impaired HPA axis stress response (16, 17), whereas CRFR2KO mice show increased anxiety-like behaviors and an accelerated HPA-axis response to stress (18,19). Thus, the CRF-CRFR1 system has been suggested as critical for initiating str...

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Neuroglobin deficiency increases seizure susceptibility but does not affect basal behavior in mice

Gøtzsche

Hundahl

Hay‐Schmidt

2022

J of Neuroscience Research

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Neuroglobin (Ngb) is found in the neurones of several different brain areas and is known to bind oxygen and other gaseous molecules and reactive oxygen species (ROS) in vitro, but it does not seem to act as a respiratory molecule for neurones.Using male and female Ngb-knockout (KO) mice, we addressed the role of Ngb in neuronal brain activity using behavioral tests but found no differences in general behaviors, memory processes, and anxiety−/depression-like behaviors. Oxidative stress and ROS play key roles in epileptogenesis, and oxidative injury produced by an excessive production of free radicals is involved in the initiation and progression of epilepsy. The ROS binding properties led us to hypothesize that lack of Ngb could affect central coping with excitatory stimuli. We consequently explored whether exposure to the excitatory molecule kainate (KA) would increase severity of seizures in mice lacking Ngb. We found that the duration and severity of seizures were increased, while the latency time to develop seizures was shortened in Ngb-KO compared to wildtype adult female mice. Consistently, c-fos expression after KA was significantly increased in Ngb-KO mice in the amygdala and piriform cortex, regions rich in Ngb and known to be centrally involved in seizure generation. Moreover, the measured c-fos expression levels were correlated with seizure susceptibility. With these new findings combined with previous studies we propose that Ngb could constitute an intrinsic defense mechanism against neuronal hyperexcitability and oxidative stress by buffering of ROS in amygdala and other Ngb-containing brain regions.

show abstract

Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex

Cited by 76 publications

References 47 publications

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery

Neuroglobin deficiency increases seizure susceptibility but does not affect basal behavior in mice

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