FIG 4 - uploaded by Miklós Palkovits
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(a) Coronal section of the medulla oblongata indicating the location of the knife incision. Al, catecholaminergic cell group; c, parvicellular reticular nucleus; 10, inferior olive; nts, nucleus of the solitary tract; P, pyramidal tract; ro, raphe obscurus; th, nucleus prepositus hypoglossi; tsV, spinal tract of the trigeminal nerve; V, vermis. (b) Accumulation of CRF-immunostained material in fibers of the olivocerebellar tract proximal to the knife incision (*). The size and topography of this enlarged region are indicated on a by the small rectangle. (Bar, 100 g.m.) (c) CRF-immunostained neurons in the inferior olive contralateral to the knife incision. (d) The level of CRF mRNA is decreased on the contralateral (right) side, especially over the dorsomedial cell column and the principal olive nucleus. c and d correspond to an area indicated by the large rectangle on a. Arrows indicate the midline, and a star marks the knife incision. P, pyramidal tract. (Bar = 500 gm.)
Source publication
The presence of corticotropin-releasing factor (CRF) in the olivocerebellar system was demonstrated in rats by light- and electron-microscopic immunohistochemistry, as well as by in situ hybridization histochemistry. CRF-like immunoreactivity was present in each portion of the olivocerebellar system: In colchicine-treated rats, CRF-immunostained ce...
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The olivocerebellar projection is organized into an intricate topographical connection from the inferior olive (IO) subdivisions to the longitudinally-striped compartments of cerebellar Purkinje Cells (PCs), to play an essential role in cerebellar coordination and learning. However, the central mechanisms for forming topography need to be clarified...
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Background
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Citations
... CRF, also called the stress hormone, is the major neuromodulator during the stress response. CRFergic neurons are found in the amygdala, thalamus, hypothalamus, and various brain stem nuclei [3,35]. CRFergic mossy fibers from such brain regions project into the cerebellum, suggesting that CRF is involved in the regulation of cerebellar circuit function and motor behavior in response to stressful challenges [5]. ...
Background
Corticotropin-releasing factor (CRF) is the major neuromodulator orchestrating the stress response, and is secreted by neurons in various regions of the brain. Cerebellar CRF is released by afferents from inferior olivary neurons and other brainstem nuclei in response to stressful challenges, and contributes to modulation of synaptic plasticity and motor learning behavior via its receptors. We recently found that CRF modulates facial stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission via CRF type 1 receptor (CRF-R1) in vivo in mice, suggesting that CRF modulates sensory stimulation-evoked MLI-PC synaptic plasticity. However, the mechanism of how CRF modulates MLI-PC synaptic plasticity is unclear. We investigated the effect of CRF on facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological methods.
Results
Facial stimulation at 1 Hz induced LTD of MLI-PC synaptic transmission under control conditions, but not in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by application of a selective CRF-R1 antagonist, BMS-763,534 (200 nM), but it was not restored by application of a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Blocking cannabinoid type 1 (CB1) receptor abolished the facial stimulation-induced MLI-PC LTD, and revealed a CRF-triggered MLI-PC long-term potentiation (LTP) via CRF-R1. Notably, either inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca²⁺ with cyclopiazonic acid (100 µM), completely prevented CRF-triggered MLI-PC LTP in mouse cerebellar cortex in vivo.
Conclusions
The present results indicated that CRF blocked sensory stimulation-induced opioid-dependent MLI-PC LTD by triggering MLI-PC LTP through CRF-R1/PKC and intracellular Ca²⁺ signaling pathway in mouse cerebellar cortex. These results suggest that activation of CRF-R1 opposes opioid-mediated cerebellar MLI-PC plasticity in vivo in mice.
... Corticotropin-releasing factor (CRF) exists in the CF (Palkovits et al. 1987;Sakanaka et al. 1987;Cummings et al. 1994), so that CRF can be released from CF terminals. On the other hand, mRNA of CRF receptors is detected in Purkinje cells (Chang et al. 1993;Potter et al. 1994). ...
... Corticotropin-releasing factor (CRF) exists in the CF (Palkovits et al. 1987;Sakanaka et al. 1987;Cummings et al. 1994), so that CRF can be released from CF terminals. On the other hand, mRNA of CRF receptors is detected in Purkinje cells (Chang et al. 1993;Potter et al. 1994). ...
... Corticotropin releasing factor (CRF) is a neuropeptide, which is founds in hypothalamus, cerebral cortex, amygdala, cerebellum and spinal cord (Luo et al., 1994;Palkovits et al., 1987;Barnack et al., 1990;Tian and Bishop, 2003; Ezra-Nevo et al., 2018a). CRF plays important functions in regulation of ionic current, synaptic transmission and long-term plasticity via its receptors (Palkovits et al., 1987;Barnack et al., 1990; Miyata et al., 1999;Tian and Bishop, 2003). ...
... Corticotropin releasing factor (CRF) is a neuropeptide, which is founds in hypothalamus, cerebral cortex, amygdala, cerebellum and spinal cord (Luo et al., 1994;Palkovits et al., 1987;Barnack et al., 1990;Tian and Bishop, 2003; Ezra-Nevo et al., 2018a). CRF plays important functions in regulation of ionic current, synaptic transmission and long-term plasticity via its receptors (Palkovits et al., 1987;Barnack et al., 1990; Miyata et al., 1999;Tian and Bishop, 2003). which are G protein-coupled receptors, and named CRF-R1 and CRF-R2 (Chen et al., 1993). ...
Background
Corticotropin-releasing factor (CRF) is an important neuromodulator in cerebellar cortex, which plays critical roles in modulating synaptic transmission and plasticity via its receptors. Activation of cannabinoid receptor 1 (CB1) controls the sensory stimulation-induced interneuron–Purkinje cell long-term depression (MLI-PC LTD) in mouse cerebellar cortex. However, the cellular actions of CRF on MLI-PC LTD are poor understand. We here investigated the effect of CRF on the facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological method.
Results
Facial stimulation at 1Hz induced a LTD of MLI-PC synaptic transmission under control conditions, but it was not induced in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by a selective CRF-R1 antagonist, BMS-763534 (BMS, 200 nM), but it was not restored by a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Blocking cannabinoid type 1 (CB1) receptor, abolished the facial stimulation-induced MLI-PC LTD, and revealed a CRF-R1 receptor activation-dependent MLI-PC long-term potentiation (LTP). However, the CRF-R1 receptor activation-dependent MLI-PC LTP was abolished by inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca²⁺ with cyclopiazonic acid (100 µM).
Conclusions
The present results indicate that CRF opposes the CB1 receptor-dependent MLI-PC LTD produced by the facial stimulation train, which may be caused by triggering a MLI-PC LTP through CRF-R1/PKC and intracellular Ca²⁺ signaling pathway in mouse cerebellar cortex. Our results suggest that CRF-R1 and CB1 receptor play oppose actions on facial stimulation-induced cerebellar MLI-PC plasticity in vivo in mice.
... Corticotropin-releasing factor (CRF) is synthesized and secreted in many regions of the central nervous system and is distributed in the hypothalamus, cerebral cortex, amygdala, cerebellum, and spinal cord (Palkovits et al., 1987;Barmack and Young, 1990;Luo et al., 1994;Tian and Bishop, 2003;Ezra-Nevo et al., 2018b). In the mammalian brain, CRF is released following stress and subsequently stimulates the release of adrenocorticotropic hormone from the anterior pituitary, which has a critical role in coordinating the physiological and behavioral responses to stressors (Vale et al., 1981;Antoni, 1986;Luo et al., 1994;Hauger et al., 2009). ...
... Our previous results demonstrated that CRF acted on presynaptic CRF-R2 of cerebellar PCs, resulting in an increase in glutamate release via PKA pathway, which contributed to modulation of the cerebellar PCs outputs in vivo in mice . Moreover, the release of CRF from climbing fibers can be reliably induced by direct electrical or chemical stimulation of the inferior olive, as well as by stimulation of specific sensory afferents (Palkovits et al., 1987;Barmack and Young, 1990;Tian and Bishop, 2003), and the reduction in CRF levels of the inferior olive nucleus is sufficient to induce motor deficiency under challenging conditions, irrespective of basal locomotion or anxiety-like behavior (Ezra-Nevo et al., 2018b). Moreover, CRFergic fibers project to granular layer as mossy fibers to regulate their synaptic transmission and plasticity (Chen et al., 2000;Refojo et al., 2011;K`ùhne et al., 2012), and it acts as critical roles in regulating particular forms of cerebellar learning both at the cellular and behavioral levels, but without an effect on baseline motor skills (Ezra-Nevo et al., 2018a). ...
Corticotropin-releasing factor (CRF) is an important neuromodulator in central nervous system that modulates neuronal activity via its receptors during stress responses. In cerebellar cortex, CRF modulates the simple spike (SS) firing activity of Purkinje cells (PCs) has been previously demonstrated, whereas the effect of CRF on the molecular layer interneuron (MLI)–PC synaptic transmission is still unknown. In this study, we examined the effect of CRF on the facial stimulation–evoked cerebellar cortical MLI-PC synaptic transmission in urethane-anesthetized mice by in vivo cell-attached recording, neurobiotin juxtacellular labeling, immunohistochemistry techniques, and pharmacological method. Cell-attached recordings from cerebellar PCs showed that air-puff stimulation of ipsilateral whisker pad evoked a sequence of tiny parallel fiber volley (N1) followed by MLI-PC synaptic transmission (P1). Microapplication of CRF in cerebellar cortical molecular layer induced increases in amplitude of P1 and pause of SS firing. The CRF decreases in amplitude of P1 waveform were in a dose-dependent manner with the EC 50 of 241 nM. The effects of CRF on amplitude of P1 and pause of SS firing were abolished by either a non-selective CRF receptor antagonist, α-helical CRF-(9-14), or a selective CRF-R1 antagonist, BMS-763534 (BMS, 200 nM), but were not prevented by a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Notably, application CRF not only induced a significant increase in spontaneous spike firing rate, but also produced a significant increase in the number of the facial stimulation–evoked action potential in MLIs. The effect of CRF on the activity of MLIs was blocked by the selective CRF-R1 antagonist, and the MLIs expressed the CRF-R1 imunoreactivity. These results indicate that CRF increases excitability of MLIs via CRF-R1, resulting in an enhancement of the facial stimulation–evoked MLI-PC synaptic transmission in vivo in mice.
... In mammalian cerebellar cortex, climbing fibers produce and release CRF onto Purkinje cells (PCs; Palkovits et al., 1987). The release of CRF from climbing fibers can be reliably induced by direct electrical or chemical stimulation of the inferior olive, as well as by stimulation of specific sensory afferents (Barmack and Young, 1990;Tian and Bishop, 2003). ...
... In the cerebellar cortex CRF is released from climbing fibers to PCs during direct electrical or chemical stimulation of the inferior olive, as well as by stimulation of sensory afferents (Palkovits et al., 1987;Barmack and Young, 1990;Tian and Bishop, 2003), and modulates spontaneous and glutamate-induced activity in cerebellar PCs (Fox and Gruol, 1993). Consistent with previous studies (Bishop et al., 2000;Dautzenberg and Hauger, 2002;Libster et al., 2015), our results show that molecular layer micro-application of CRF dose-dependently increases the SS firing rate of cerebellar PCs in the absence of GABA A receptor activity. ...
Corticotropin-releasing factor (CRF) is a major neuromodulator that modulates cerebellar neuronal activity via CRF receptors during stress responses. In the cerebellar cortex, CRF dose-dependently increases the simple spike (SS) firing rate of Purkinje cells (PCs), while the synaptic mechanisms of this are still unclear. We here investigated the effect of CRF on the spontaneous SS activity of cerebellar PCs in urethane-anesthetized mice by in vivo electrophysiological recording and pharmacological methods. Cell-attached recordings from PCs showed that micro-application of CRF in cerebellar cortical molecular layer induced a dose-dependent increase in SS firing rate in the absence of GABAA receptor activity. The CRF-induced increase in SS firing rate was completely blocked by a nonselective CRF receptor antagonist, α-helical CRF-(9–14). Nevertheless, application of either a selective CRF-R1 antagonist, BMS-763534 (BMS, 200 nM) or a selective CRF-R2 antagonist, antisauvagine-30 (200 nM) significantly attenuated, but failed to abolished the CRF-induced increase in PCs SS firing rate. In vivo whole-cell patch-clamp recordings from PCs showed that molecular layer application of CRF significantly increased the frequency, but not amplitude, of miniature postsynaptic currents (mEPSCs). The CRF-induced increase in the frequency of mEPSCs was abolished by a CRF-R2 antagonist, as well as protein kinase A (PKA) inhibitors. These results suggested that CRF acted on presynaptic CRF-R2 of cerebellar PCs resulting in an increase of glutamate release through PKA signaling pathway, which contributed to modulation of the cerebellar PCs outputs in Vivo in mice.
... These systems may be particularly important in situations where an organism must mobilize not only the hypothalamic-pituitary-adrenal (HPA) system, but also the central nervous system in response to environmental challenge 1,2,5 . Interestingly, it has been repeatedly demonstrated that CRF is prominently expressed in the inferior olive (IO) of various species from rodents to primates, as well as localized in the fibers descending from the IO, namely, the climbing fibers (CFs) [6][7][8][9][10][11][12][13][14][15][16][17] . ...
... IO-CRF KD and control mice motor performance was tested using the rotarod. h Although on average IO-CRF KD lasted less time on the rotarod compared to control mice, no overall significant differences were detected between the groups, but significant difference in latency to fall was seen at the highest velocity (20 rpm; n = 10, 9). i Maximal velocity reached on the rotarod was significantly higher for control than KD mice (n = 10, 9). ...
A well-coordinated stress response is pivotal for an organisms’ survival. Corticotropin-releasing factor (CRF) is an essential component of the emotional and neuroendocrine stress response, however its role in cerebellar functions is poorly understood. Here, we explore the role of CRF in the inferior olive (IO) nucleus, which is a major source of input to the cerebellum. Using a CRF reporter line, in situ hybridization and immunohistochemistry, we demonstrate very high levels of the CRF neuropeptide expression throughout the IO sub-regions. By generating and characterizing IO-specific CRF knockdown and partial IO-CRF knockout, we demonstrate that reduction in IO-CRF levels is sufficient to induce motor deficiency under challenging conditions, irrespective of basal locomotion or anxiety-like behavior. Furthermore, we show that chronic social defeat stress induces a persistent decrease in IO-CRF levels, and that IO-CRF mRNA is upregulated shortly following stressful situations that demand a complex motor response. Taken together our results indicate a role for IO-CRF in challenge-induced motor responses.
... CRF-containing cells are found in many common brainstem nuclei across species including: the medial and lateral parabrachial nucleus (PB), the lateral dorsal tegmental nucleus (LDtg), locus coeruleus (LC), pedunculopontine tegmental nucleus (PTg), the inferior colliculus, the central linear nucleus, the median raphe nucleus (MR), the nucleus of the solitary tract (STn), and inferior olive. The main discrepancies across these regions in mouse, rat and monkey tend to be mainly related to relative densities of CRF-labeled cells (Alon et al., 2009;Cha and Foote, 1988;Cummings et al., 1983;Foote and Cha, 1988;Kono et al., 2017;Merchenthaler et al., 1982Merchenthaler et al., , 1984Olschowka et al., 1982;Palkovits et al., 1987;Powers et al., 1987;Sakanaka et al., 1987b;Swanson et al., 1983), and may also arise because of different ages at assessment (e.g., Chang et al., 1996). Rodents additionally have CRFlabeled cells in midline parts of the superior colliculus, the superior olive, and surrounding the cochlear nerve nuclei, which primates lack (Imaki et al., 1991a;Sakanaka et al., 1987b). ...
Corticotropin-releasing factor (CRF) is a neuropeptide that mediates the stress response. Long known to contribute to regulation of the adrenal stress response initiated in the hypothalamic-pituitary axis (HPA), a complex pattern of extrahypothalamic CRF expression is also described in rodents and primates. Cross-talk between the CRF and midbrain dopamine (DA) systems links the stress response to DA regulation. Classically CRF+ cells in the extended amygdala and paraventricular nucleus (PVN) are considered the main source of this input, principally targeting the ventral tegmental area (VTA). However, the anatomic complexity of both the DA and CRF system has been increasingly elaborated in the last decade. The DA neurons are now recognized as having diverse molecular, connectional and physiologic properties, predicted by their anatomic location. At the same time, the broad distribution of CRF cells in the brain has been increasingly delineated using different species and techniques. Here, we review updated information on both CRF localization and newer conceptualizations of the DA system to reconsider the CRF-DA interface.
... Notably, the very conspicuous expression of Venus in these nuclei paralleled the strong expression of CRF mRNA both in rats (Asan et al. 2005;Chang et al. 1996) and in mice (Alon et al. 2009;Asan et al. 2005;Keegan et al. 1994). Therefore, Venus may serve as a marker for CRF-producing neurons, even if it is hard to recognize them by immunohistochemistry (Asan et al. 2005;Palkovits et al. 1987;Wang et al. 2011). The Venus protein may not undergo exocytosis, and it may be metabolized through a distinct pathway from that of CRF, which may partly explain why Venus-expression is sometimes clearly observed despite the paucity of CRF-ir neurons. ...
... The Venus-containing fibers, originating from the IO, follow the course of the olivocerebellar fibers. Specifically, they run along the surface layer of the medulla after leaving the hilum of the IO and decussating in the midline (Palkovits et al. 1987). They then ascend via the inferior cerebellar peduncle, and run through the white matter of the folium to reach the cerebellar cortex. ...
... CRF-ir neurons were not always explicitly observed in the IO of rats (Merchenthaler 1983, Swanson et al. 1983, and CRF neurons can only be stained immunohistochemically after colchicine treatment (Palkovits et al. 1987). In contrast, CRF mRNA was observed to be expressed prominently in the IO in both rats (Chang et al. 1996) and mice (Keegan et al. 1994), as was discussed in the preceding section. ...
We examined the morphological features of corticotropin-releasing factor (CRF) neurons in a mouse line in which modified yellow fluorescent protein (Venus) was expressed under the CRF promoter. We previously generated the CRF-Venus knock-in mouse, in which Venus is inserted into the CRF gene locus by homologous recombination. In the present study, the neomycin phosphotransferase gene (Neo), driven by the pgk-1 promoter, was deleted from the CRF-Venus mouse genome, and a CRF-Venus∆Neo mouse was generated. Venus expression is much more prominent in the CRF-Venus∆Neo mouse when compared to the CRF-Venus mouse. In addition, most Venus-expressing neurons co-express CRF mRNA. Venus-expressing neurons constitute a discrete population of neuroendocrine neurons in the paraventricular nucleus of the hypothalamus (PVH) that project to the median eminence. Venus-expressing neurons were also found in brain regions outside the neuroendocrine PVH, including the olfactory bulb, the piriform cortex (Pir), the extended amygdala, the hippocampus, the neocortices, Barrington's nucleus, the midbrain/pontine dorsal tegmentum, the periaqueductal gray, and the inferior olivary nucleus (IO). Venus-expressing perikarya co-expressing CRF mRNA could be observed clearly even in regions where CRF-immunoreactive perikarya could hardly be identified. We demonstrated that the CRF neurons contain glutamate in the Pir and IO, while they contain gamma-aminobutyric acid in the neocortex, the bed nucleus of the stria terminalis, the hippocampus, and the amygdala. A population of CRF neurons was demonstrated to be cholinergic in the midbrain tegmentum. The CRF-Venus∆Neo mouse may be useful for studying the structural and functional properties of CRF neurons in the mouse brain.
... Cerebellar involvement in the stress response is also well documented (Baldacara et al. 2011;Liu et al. 2010;Strick et al. 2009). Neurons of the inferior olive targeting the cerebellar Purkinje neurons (PNs) produce CRF (Palkovits et al. 1987), suggesting that CRF plays a role in the information processing within the cerebellum. Its release from climbing fibers can be induced by electrical or chemical stimulation of the inferior olive, as well as by specific sensory stimulation (Barmack et al. 1993;Barmack and Young 1990;Beitz and Saxon 2004;Tian and Bishop 2003). ...
Corticotropin releasing factor (CRF) is a neuromodulator closely associated with stress responses. It is synthesized and released in the central nervous system by various neurons, including neurons of the inferior olive. The targets of inferior olivary neurons, the cerebellar Purkinje neurons, are endowed with CRF receptors. CRF increases the excitability of Purkinje neurons in vivo but the biophysical mechanism is not clear. Here we examine the effect of CRF on the firing properties of Purkinje neurons using acute rat cerebellar slices. CRF increased the Purkinje neuron firing rate, regardless of whether they were firing tonically or switching between firing and quiescent periods. Current- and voltage-clamp experiments showed that the increase in firing rate was associated with a voltage shift of the activation curve of the persistent sodium current and hyperpolarizing activated current (Ih) as well as activation of voltage dependent potassium current. The multiple effects on various ionic currents, which are in agreement with the possibility that activation of CRF receptors triggers several intracellular pathways, are manifested as an increase excitability of PN.
