Predator stress engages corticotropin-releasing factor and opioid systems to alter the operating mode of locus coeruleus norepinephrine neurons - PubMed (original) (raw)

Predator stress engages corticotropin-releasing factor and opioid systems to alter the operating mode of locus coeruleus norepinephrine neurons

Andre L Curtis et al. Neuropharmacology. 2012 Mar.

Abstract

The norepinephrine nucleus, locus coeruleus (LC), has been implicated in cognitive aspects of the stress response, in part through its regulation by the stress-related neuropeptide, corticotropin-releasing factor (CRF). LC neurons discharge in tonic and phasic modes that differentially modulate attention and behavior. Here, the effects of exposure to an ethologically relevant stressor, predator odor, on spontaneous (tonic) and auditory-evoked (phasic) LC discharge were characterized in unanesthetized rats. Similar to the effects of CRF, stressor presentation increased tonic LC discharge and decreased phasic auditory-evoked discharge, thereby decreasing the signal-to-noise ratio of the sensory response. This stress-induced shift in LC discharge toward a high tonic mode was prevented by a CRF antagonist. Moreover, CRF antagonism during stress unmasked a large decrease in tonic discharge rate that was opioid mediated because it was prevented by pretreatment with the opiate antagonist, naloxone. Elimination of both CRF and opioid influences with an antagonist combination rendered LC activity unaffected by the stressor. These results demonstrate that both CRF and opioid afferents are engaged during stress to fine-tune LC activity. The predominant CRF influence shifts the operational mode of LC activity toward a high tonic state that is thought to facilitate behavioral flexibility and may be adaptive in coping with the stressor. Simultaneously, stress engages an opposing opioid influence that restrains the CRF influence and may facilitate recovery toward pre-stress levels of activity. Changes in the balance of CRF:opioid regulation of the LC could have consequences for stress vulnerability.

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Figures

Figure 1

Discrimination of single units from LC recordings. a) Accumulated waveforms of three units discriminated from a multiunit analog record by the wavemark template matching algorithm. b) Cluster plot of the principal component analysis for the three representative waveform sets in a. Each waveform in the template is represented by a color-coded event dot in the principal component space, thereby generating its respective principal component cluster. The ellipsoids around the clusters are three-dimensional representations of 2 SD from cluster centrality. The lack of overlap of the ellipsoids suggests that the clusters represent single units. c) The histograms are inter-spike interval autocorrelograms that are color-matched with their associated set of waveforms (a) and component clusters (b). The abscissae indicate time in milliseconds, whereas the ordinates indicate number of intervals per bin. For LC neurons, the onset of the relative refractory period is 3 ms, suggesting that at least 2 ms to the left of 0 and 2 ms to the right of 0 should be devoid of spike interval histograms in an autocorrelogram of a single LC unit.

Figure 2

Histological verification of a recording site in the LC. Photomicrograph showing a coronal section stained with neutral red at the level of the LC. The arrows point to the LC. The darkened region within the LC is the Prussian blue stain produced by deposited metal ions reacting with potassium ferrocyanide. The arrowheads indicate the location of soma of the mesencephalic trigeminal nucleus lateral to the LC. V= Ventricle, CB=cerebellum. (Scale bar, 100 μm.)

Figure 3

Effect of TMT exposure on LC tonic and auditory-evoked activity. a) Shown are the average PSTHs (n=22 cells from 4 rats) generated before (Pre-vehicle) and immediately after (Post-vehicle) pipetting water into the caps. b) The average PSTHs (n=25 cells from same 4 rats) generated before (Pre-) and immediately after (Post-) introduction of TMT.

Figure 4

Effect of antagonizing CRF and/or endogenous opioids on LC activity during TMT exposure. a) Mean PSTHs (n=28 cells, 3 rats) generated before and after ACSF (3 μl, i.c.v.) pretreatment followed by TMT exposure. Note the increase in tonic discharge rate and decrease in evoked discharge rate similar to that see in Figure 3b. b) Mean PSTHs (26 cells; 4 rats) generated before and after pretreatment with DPheCRF12–41 followed by TMT exposure. Note that with CRF antagonist pretreatment evoked discharge is not decreased by TMT and a large decrease in tonic activity is apparent. c) Mean PSTHs (32 cells; 3 rats) generated before and after pretreatment with a combination of DPheCRF12–41 and naloxone followed by TMT exposure. Note that TMT appears to have no effect on LC activity in rats pretreated with the antagonist combination. The abscissae indicate time in seconds before and after the auditory stimulus, which starts at 0.5 s (arrowhead), and the ordinates indicate the averaged number of cumulative discharges across all units in the group in each 8 ms bin.

Figure 5

Representative cross correlograms from pairs of LC neurons recorded on the same wire. a) Correlograms for the same cell pair before and after exposure to TMT. The peak Z scores were 2.97 and 4.89 before and after TMT, respectively. b) Correlograms for the same cell pair before and after TMT in a rat that was pretreated with DPheCRF12–41 prior to TMT exposure. The peak Z scores were 3.12 and 9.52 before and after TMT, respectively. Note the large peak indicative of greater synchrony between cells after TMT exposure in the rat pretreated with DPheCRF12–41. The abscissae indicate interspike intervals in 50 ms bins and the ordinates indicate the number of counts/bin.

Figure 6

Schematic depicting how LC discharge mode is influenced by different afferent inputs. In awake but unstressed conditions, salient sensory stimuli engage glutamatergic afferents that phasically drive LC neurons. Stress engages parallel CRF and endogenous opioid inputs to the LC. The CRF input shifts LC discharge to a high tonic-low phasic mode that has been suggested to facilitate behavioral flexibility. At the same time the opioid input provides a brake on LC discharge, which if eliminated, would result in an even greater tonic activation by the stress.

References

1. Abercrombie ED, Jacobs BL. Single unit response of noradrenergic neurons in locus coeruleus of freely moving cats. I Acutely presented stressful and nonstressful stimuli. J Neurosci. 1987;7:2837–2843. - PMC - PubMed
1. Abercrombie ED, Jacobs BL. Systemic naloxone administration potentiates locus coeruleus noradrenergic neuronal activity under stressful but not non-stressful conditions. Brain Res. 1988;441:362–366. - PubMed
1. Aghajanian GK, Wang YY. Common alpha2 and opiate effector mechanisms in the locus coeruleus: intracellular studies in brain slices. Neuropharmacology. 1987;26:793–399. - PubMed
1. Aston-Jones G, Bloom FE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci. 1981a;1:876–886. - PMC - PubMed
1. Aston-Jones G, Bloom FE. Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J Neurosci. 1981b;1:887–900. - PMC - PubMed

Predator stress engages corticotropin-releasing factor and opioid systems to alter the operating mode of locus coeruleus norepinephrine neurons - PubMed (original) (raw)