Cummings S, Elde R, Ells J, Lindall A. Corticotropin-releasing factor immunoreactivity is widely distributed within the central nervous system of the rat: an immunohistochemical study. J Neurosci 3: 1355-1368


The discovery of a 41-amino acid peptide with potent corticotropin-releasing factor properties has prompted a search for neurons that contain this substance and potentially utilize it in intercellular communication. The present study utilized immunohistochemical methods and an antiserum directed against a synthetic replica of ovine corticotropin-releasing factor. The rat hypothalamus was found to contain striking immunoreactive groups of neuronal perikarya within the paraventricular, periventricular, and anterior hypothalamic nuclei, some of which are likely to project to the external layer of the median eminence and thereby comprise a hypophysiotropic system. Certain other hypothalamic nuclei, as well as many other regions of the central nervous system, were found to contain corticotropin-releasing factor-immunoreactive neurons. Among the most prominent of these were neurons in the bed nucleus of stria terminalis, the central nucleus of the amygdala, the region of the dorsal raphe, locus ceruleus, the external cuneate nucleus, and the medullary reticular formation. Thus, corticotropin-releasing factor, like many other neurohormones and peptides, may participate in neuroendocrine regulation as well as play a role as a neurotransmitter-like substance in numerous extrahypothalamic circuits.

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    • "The central nucleus of the amygdala (CeA) is a key component of an extended brain circuitry involved in stress responses and anxiety-like behaviors and is an important structure for CRF-mediated responses as it contains one of the highest concentrations of CRF immunoreactive neurons outside of the PVN (Cummings et al., 1983; Swanson et al., 1983; Cassell and Gray, 1989; Shimada et al., 1989). Numerous studies have shown that a wide variety of stressors and anxiogenic stimuli activate neurons of the CeA as measured by increased expression of the early immediate gene c-fos (Hayward et al., 1990; Campeau et al., 1991; Honkaniemi et al., 1992; Funk et al., 2003; Asok et al., 2013) supporting the notion that stressors act, at least in part, through the CeA. "
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    ABSTRACT: Corticotropin releasing factor (CRF) is a primary mediator of endocrine, autonomic and behavioral stress responses. Studies in both humans and animal models have implicated CRF in a wide-variety of psychiatric conditions including anxiety disorders such as post-traumatic stress disorder (PTSD), depression, sleep disorders and addiction among others. The central nucleus of the amygdala (CeA), a key limbic structure with one of the highest concentrations of CRF-producing cells outside of the hypothalamus, has been implicated in anxiety-like behavior and a number of stress-induced disorders. This study investigated the specific role of CRF in the CeA on both endocrine and behavioral responses to stress. We used RNA Interference (RNAi) techniques to locally and specifically knockdown CRF expression in CeA. Behavior was assessed using the elevated plus maze (EPM) and open field test (OF). Knocking down CRF expression in the CeA had no significant effect on measures of anxiety-like behavior in these tests. However, it did have an effect on grooming behavior, a CRF-induced behavior. Prior exposure to a stressor sensitized an amygdalar CRF effect on stress-induced HPA activation. In these stress-challenged animals silencing CRF in the CeA significantly attenuated corticosterone responses to a subsequent behavioral stressor. Thus, it appears that while CRF projecting from the CeA does not play a significant role in the expression stress-induced anxiety-like behaviors on the EPM and OF it does play a critical role in stress-induced HPA activation.
    Frontiers in Neuroscience 10/2013; 7(7):195. DOI:10.3389/fnins.2013.00195 · 3.66 Impact Factor
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    • "CRF that is synthesized and released by PVN neurons plays a major role in regulating activity of the hypothalamic-pituitary-adrenal (HPA) axis and triggers the classic endocrine stress response (Vale et al., 1981; Rivier and Vale, 1983), whereas outside the HPA axis CRF acts not as a hormone, but as a modulator of synaptic transmission at pre-and postsynaptic sites within specific central neuronal circuits (Lowry and Moore, 2006; Orozco-Cabal et al., 2006). In the BNST, the highest concentration of CRF neurons are found in the oval and fusiform nuclei (Cummings et al., 1983; Morin et al., 1999), which is also rich in CRF fibers and terminals, many of which originate from the CeA (Cummings et al., 1983; Sakanaka et al., 1986; Morin et al., 1999). Growing evidence suggests that CRF neurons of the anterolateral cell group of the BNST, BNST ALG , play a major role in the affective response to stressors (Lee and Davis, 1997; Liang et al., 2001; Nijsen et al., 2001; Ciccocioppo et al., 2003; Sahuque et al., 2006; Dabrowska et al., 2013), and that dysfunction of this CRF system contributes to the etiology of several psychiatric disorders, including depression (Crestani et al., 2010), anxiety-disorders (Walker et al., 2009), as well as addiction (Koob, 2010). "
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    ABSTRACT: Corticotrophin-releasing factor (CRF) plays a key role in initiating many of the endocrine, autonomic, and behavioral responses to stress. CRF-containing neurons of the paraventricular nucleus of the hypothalamus (PVN) are classically involved in regulating endocrine function through activation of the stress axis. However, CRF is also thought to play a critical role in mediating anxiety-like responses to environmental stressors, and dysfunction of the CRF system in extra-hypothalamic brain regions, like the bed nucleus of stria terminalis (BNST), has been linked to the etiology of many psychiatric disorders including anxiety and depression. Thus, although CRF neurons of the PVN and BNST share a common neuropeptide phenotype, they may represent two functionally diverse neuronal populations. Here, we employed dual-immunofluorescence, single-cell RT-PCR, and electrophysiological techniques to further examine this question and report that CRF neurons of the PVN and BNST are fundamentally different such that PVN CRF neurons are glutamatergic, whereas BNST CRF neurons are GABAergic. Moreover, these two neuronal populations can be further distinguished based on their electrophysiological properties, their co-expression of peptide neurotransmitters such as oxytocin and arginine-vasopressin, and their cognate receptors. Our results suggest that CRF neurons in the PVN and the BNST would not only differ in their response to local neurotransmitter release, but also in their action on downstream target structures.
    Frontiers in Neuroscience 08/2013; 7(7):156. DOI:10.3389/fnins.2013.00156 · 3.66 Impact Factor
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    • "Fourth, an increase of 5-HT may regulate the processing of stress via the activation of pituitary and adrenal functions (Vernikos-Danellis et al., 1977), which have bi-directional interactions with the 5-HT system. There is a dense projection of corticotropin-releasing factor (CRF) neurons to the raphé nuclei in rats (Cummings et al., 1983; Lowry et al., 2008) and humans (Austin et al., 1997). A subpopulation of CRF-containing neurons is present in the dorsomedial part of the DRN, and dual-labeling immunohistochemistry revealed that almost all CRF-containing neurons are serotonergic (Commons et al., 2003). "
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    ABSTRACT: Pharmacological experiments have shown that the modulation of brain serotonin levels has a strong impact on value-based decision making. Anatomical and physiological evidence also revealed that the dorsal raphé nucleus (DRN), a major source of serotonin, and the dopamine system receive common inputs from brain regions associated with appetitive and aversive information processing. The serotonin and dopamine systems also have reciprocal functional influences on each other. However, the specific mechanism by which serotonin affects value-based decision making is not clear. To understand the information carried by the DRN for reward-seeking behavior, we measured single neuron activity in the primate DRN during the performance of saccade tasks to obtain different amounts of a reward. We found that DRN neuronal activity was characterized by tonic modulation that was altered by the expected and received reward value. Consistent reward-dependent modulation across different task periods suggested that DRN activity kept track of the reward value throughout a trial. The DRN was also characterized by modulation of its activity in the opposite direction by different neuronal subgroups, one firing strongly for the prediction and receipt of large rewards, with the other firing strongly for small rewards. Conversely, putative dopamine neurons showed positive phasic responses to reward-indicating cues and the receipt of an unexpected reward amount, which supports the reward prediction error signal hypothesis of dopamine. I suggest that the tonic reward monitoring signal of the DRN, possibly together with its interaction with the dopamine system, reports a continuous level of motivation throughout the performance of a task. Such a signal may provide "reward context" information to the targets of DRN projections, where it may be integrated further with incoming motivationally salient information.
    Frontiers in Integrative Neuroscience 08/2013; 7:60. DOI:10.3389/fnint.2013.00060
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