Locus Ceruleus Regions Research Articles

The Central Amygdala Corticotropin-releasing hormone (CRH) Neurons Modulation of Anxiety-like Behavior and Hippocampus-dependent Memory in Mice

The encoding, consolidation and retrieval of memories is a multifaceted process that depends strongly on the optimal level of arousal but high levels of arousal may trigger anxiety, which negatively impacts the memory processing by the brain. We investigated the role of CRH neurons in the central amygdala (CeA) for their capacity to modulate both, the anxiety-like behavior and hippocampus-dependent memory. First, we activated the CRH neurons in CeA using cre-dependent AAV-DREADD in CRH-cre mice. The activation of CeA CRH neurons increased the anxiety-like behavior in Elevated-O maze (O-maze) and Light-Dark box (LDB). The activation of the CeA CRH also decreased Y-maze memory performance and the discrimination index in novel object recognition test (NOR). The inhibition of CeA CRH neurons with AAV-DREADD had the opposite effects on the anxiety-like behavior and the memory tests. Next, we used a combination of retrograde cre virus injected into locus ceruleus (LC) and cre-dependent AAV-DREADD injected into the CeA. While the excitation of the CeA neurons that project to LC increased the anxiety-like behavior, it also led to a better performance on the memory tests. The behavioral and memory effects were accompanied by increased c-Fos expression in the LC region. Pretreatment with CRH1 receptor antagonist antalarmin hydrochloride blocked the effects that were observed after the activation of the CeA projections to LC. Our findings highlight the role of CeA CRH neuronal population not only as a generator of anxiety but also demonstrate their role in the control of hippocampus-dependent memory.

Commentaries on Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites

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Depression in an animal model: focus on the locus ceruleus.

When rats are exposed to highly stressful events over which they have no control, they subsequently show many of the symptoms seen in depression in humans. In the attempt to discover neurochemical factors underlying depression, the neurochemical basis of stress-induced behavioural depression in rats has been studied extensively. Initial research (1968-1976) indicated that behavioural depression in this model was produced by alteration of noradrenaline (NA) concentrations in the brain. More recent research has indicated that the critical change may be a large depletion of NA in the locus ceruleus (LC). Behavioural depression may result when such NA depletion is sufficient to reduce NA release in the LC region, leading to a 'functional blockade' of inhibitory alpha 2-receptors in that brain region. Studies have now shown that behavioural depression after uncontrollable shock can be mimicked by pharmacological blockade of alpha 2-receptors in the LC region. Conversely, behavioural depression can be eliminated by either infusion of clonidine into the LC to replace at the alpha 2-receptors the NA depleted after uncontrollable shock, or infusion of pargyline into the LC to prevent the depletion of NA that otherwise follows uncontrollable shock. If alpha 2-receptors are functionally blocked in depression, then release of NA in regions innervated by the LC should be increased and stimulation of postsynaptic adrenoceptors outside the LC should be higher than normal. Thus, higher-than-normal stimulation of postsynaptic NA receptors should also produce behavioural depression; this has been demonstrated.

Noradrenergic neurons from the locus ceruleus in dissociated cell culture: culture methods, morphology, and electrophysiology

We have developed a dissociated primary cell culture of noradrenergic neurons from the locus ceruleus of postnatal (1- to 5-d-old) mice or rats. Slices of the brain stem were made on a Vibratome. Then the region of locus ceruleus, which was identified by observing the slices under a dissecting microscope, was dissected out from the slices. The removed fragments of brain slices were dissociated and cultured up to 3 weeks on a non-neuronal feeder layer, which consisted predominantly of astroglial cells, or on a fibronectin-treated collagen substratum. After 2 weeks of culture, about 70% of total neuronlike cells revealed positive catecholamine histofluorescence, indicating that they were probably noradrenergic neurons. About 98% of large- and medium-sized cultured neurons (soma diameter greater than or equal to 20 microns) was histofluorescence positive. The fluorescence-positive cells had long processes rich in varicosities, and the shape of their soma was either multipolar or fusiform. Electron microscopy using permanganate fixation revealed that the varicosities along their processes had small granular vesicles, which may contain norepinephrine. Physiological properties of these noradrenergic neurons were investigated with intracellular microelectrodes or with the whole-cell version of the patch clamp. We observed that many cells were producing spontaneous firing. Many of these spontaneously firing cells had no obvious contact with neighboring cells. The neurons were depolarized when glutamate was applied by pressure ejection. They also responded to GABA and glycine with either hyperpolarization or depolarization, and these responses were antagonized by picrotoxin and strychnine. Application of substance P generally produced depolarization with an increase in input resistance. The neurons responded with hyperpolarization to somatostatin, beta-endorphin, and enkephalin. This culture system will become a useful tool for elucidating the cellular and molecular properties of the central noradrenergic neurons.

Dorsolateral pontine inhibition of dorsal horn cell responses to cutaneous stimulation: lack of dependence on catecholaminergic systems in cat.

The effect of stimulating the dorsolateral pons (DLP) in the region of locus ceruleus (LC) on lumbar dorsal horn cell responses to innocuous and noxious cutaneous stimuli was assessed and the dependence of these effects on intact pontospinal catecholaminergic systems was tested in chloralose-anesthetized cats. DLP stimulation inhibited the responses of dorsal horn cells to both noxious and innocuous skin stimuli. The inhibitory effect was most prominent when the responses to noxious stimuli were tested. The thresholds for eliciting DLP-spinal inhibition were lowest (less than 30 microA) in the region of LC. The inhibitory effect was found in both ipsilateral and contralateral dorsal horns. The DLP-spinal inhibition was unaltered by depletion of spinal catecholamines brought about by repeated lumbar intrathecal administration of 6-hydroxydopamine or systemic administration of reserpine. We conclude that the DLP-dorsal horn inhibition is not related to a catecholaminergic ceruleospinal system in the cat and that the dependence of pain modulation by catecholamine systems is a reflection of other descending pathways.

Locus ceruleus region: Effects on behavior of cholinergic, noradrenergic, and opiate drugs injected intracerebrally into freely moving cats

Behavioral effects of intracerebral injections of small amounts of cholinergic, noradrenergic, and opiate agents into 125 sites in and around the locus ceruleus of the cat were investigated. Many effects were found that could be related to different regions. Carbachol caused atonia comparable to the atonia during paradoxical sleep; the most effective regions were the nucleus pontis centralis caudalis and the subceruleus region. Carbachol injected into the nucleus pontis centralis oralis caused defense reactions like hissing and growling and disturbed vocalizations. Micturation and defecation were elicited by carbachol injected near the nucleus laterodorsalis tegmenti. Carbachol caused ipsiversive and contraversive circling when injected in or near the region of the norepinephrine-containing cell bodies; this circling was probably not due to the NE cells. α-Noradrenergic and opiate agonists injected into the part of the nucleus pontis centralis oralis just rostral to the locus ceruleus caused behavioral inactivation. α-Noradrenergic agonists caused vomiting; the most effective region was the fourth ventricle. Naloxone injected intracerebrally in morphine-treated cats antagonized the morphine-induced stereotyped behavior and part of the behavioral disturbance; it is suggested that this is due to the NE cells: An adequate sensorimotor coordination was dependent on an intact central NE transmission. It is suggested that the locus ceruleus acts as a sympathetic nucleus situated in the brain with extensive parts of the central nervous system as its target regions.