Corticotropin-releasing factor acting at the locus coeruleus disrupts thalamic and cortical sensory-evoked responses

Abstract

Stress and stress-related psychiatric disorders, including post-traumatic stress disorder, are associated with disruptions in sensory information processing. The neuropeptide, corticotropin-releasing factor (CRF), coordinates the physiological and behavioral responses to stress, in part, by activating the locus coeruleus-norepinephrine (LC-NE) projection system. Although the LC-NE system is an important modulator of sensory information processing, to date, the consequences of CRF activation of this system on sensory signal processing are poorly understood. The current study examined the dose-dependent actions of CRF at the LC on spontaneous and sensory-evoked discharge of neurons within the thalamus and cortex of the vibrissa somatosensory system in the awake, freely moving rat. Peri-LC infusions of CRF resulted in a dose-dependent suppression of sensory-evoked discharge in ventral posterior medial thalamic and barrel field cortical neurons. A concurrent increase in spontaneous activity was observed. This latter action is generally not found with iontophoretic application of NE to target neurons or stimulation of the LC-NE pathway. Net decreases in signal-to-noise of sensory-evoked responses within both regions suggest that under conditions associated with CRF release at the LC, including stress, the transfer of afferent information within sensory systems is impaired. Acutely, a suppression of certain types of sensory information may represent an adaptive response to an immediate unexpected stressor. Persistence of such effects could contribute to abnormalities of information processing seen in sensorimotor gating associated with stress and stress-related psychopathology.

Figure 1

Example photomicrographs of the final electrode and infusion locations. (a) × 40 photomicrograph of the barrelfield (BF) cortex with a Prussian blue reaction product indicating the final location of the recording electrode placed in layer V (Black Bar). (b) × 40 photomicrograph somatosensory thalamus with a Prussian blue reaction product indicating the final location of three neighboring recording electrodes placed in the vibrissae VPm subdivision of the thalamus. Electrodes are separated by >100 μm. Bar=200 μm (c) × 100 photomicrograph of the pons illustrating the track of the infusion needle lateral to the LC. Bar=200 μm. (I-VI, cortical lamina; CC, corpus callosum; HPC, hippocampus; ic, internal capsule; VPL, ventral posterolateral; VPm, ventral posteromedial; PO, posterior thalamic group; Me5, mesencephalic trigeminal nucleus; LC, locus coeruleus; and 4V, fourth ventricle). (d) Recorded electrical activity from a single microwire electrode positioned in the BF cortex was discriminated as three ‘unit' waveforms (i–iii) and represented in a scatter plot (PC1 vs PC2; inset). Using our offline criteria, units i–iii were verified as originating from three different single neurons. These neurons were separable in PCA space, though their action potential waveforms overlapped. As such, all three units could be classified as individual neurons.

Figure 2

Peri-stimulus time histograms (PSTHs) illustrate the effects of peri-LC infusions of CRF on VPm thalamic and BF cortical neuronal activity. Neuronal discharge patterns of representative individual neurons are plotted for two cortical neurons (a and b) and two thalamic neurons (c and d) for a 15-min baseline period, 0–15 min following artificial cerebrospinal fluid (aCSF) infusion, as well as 0–15 and 30–45 min post CRF infusion. CRF (300 ng) decreased evoked-discharge of VPm thalamic and BF cortical neurons but increased spontaneous firing rates. VPm thalamic neurons exhibited larger increases in spontaneous activity than that observed in the BF cortex. The abscissae depict time before and after the presentation of whisker pad stimuli (occurring at 0 ms). The ordinates represent the spike counts per time bin (1 ms).

Figure 3

Effects of peri-LC infusions of CRF on spontaneous and stimulus-evoked discharge of VPm thalamic or BF cortical neurons. (a) Spontaneous activity of VPm thalamic neurons is dose-dependently increased 15–30 min following 30 or 300 ng peri-LC CRF infusions. Additionally, neurons of the VPm thalamus exhibit a greater increase in spontaneous activity following CRF administration compared with the BF cortex. (b) Whisker-stimulus evoked discharge of VPm thalamus and BF cortex neurons is suppressed with the highest dose of CRF. A similar degree of suppression is seen in the thalamus and cortex. (c) SNR of sensory-evoked discharge in VPm thalamus and BF cortex is reduced by peri-LC CRF infusions in a dose-dependent manner. The Z-score of the mean evoked-response compared with background was used to calculate the SNR. The VPm thalamus demonstrated a greater suppression of SNR following CRF administration than was observed for the BF cortex. (n=5 animals, neurons=88/55 VPm/BFC; LSD comparison with baseline: ^**p<0.01; LSD comparison with BFC ^††p<0.01; all data presented as mean±SEM).

Figure 4

Time course of CRF effects for VPm thalamic or BF cortical neurons discharge patterns. The modulatory actions of vehicle (aCSF) and the highest dose of CRF (300 ng) were plotted in 15 min intervals for 1 h following peri-LC infusion. (a) The neuromodulatory effects of peri-LC CRF infusions on spontaneous activity peaked within 15 min in the BF cortex, whereas VPm thalamic neurons exhibited the largest increase in spontaneous activity at 15–30 post-infusion. (b) Modulation of whisker-stimulus evoked discharge by peri-LC CRF infusions occurred over a similar time course as changes in spontaneous activity. Maximum suppression of evoked discharge within VPm thalamus and BF cortex occurred between 15–30 post-infusion. (c) SNR calculations indicated that the peak effect occurred 15–30 min following CRF infusion. (n=5 animals, neurons=88/55 VPm/BFC; LSD comparison with baseline: ^*p<0.05, ^**p<0.01; LSD comparison with BFC ^††p<0.01; all data presented as mean±SEM)

Figure 5

Determination of CRF site of action. The effects of peri-LC infusions of CRF were compared with infusions lateral to the LC. (a) × 40 photomicrograph illustrates two needle tracts generated from a peri-LC and lateral infusion site. Bar=1 mm. (b) Spontaneous discharge calculated as a percent of baseline for VPm (bi) and BF cortical (bii) neurons after peri-LC infusions of vehicle, CRF (300 ng), or lateral LC infusions of CRF (300 ng). (c) Lateral infusions of CRF distal to the LC did not effect whisker stimulus-evoked discharge. (d) SNR calculations also demonstrated no change from baseline for lateral infusions of CRF. Although the SNR was slightly lower for BF cortical neurons recorded before and after lateral LC infusions, lateral LC CRF infusions did not significantly alter the responses of these neurons to sensory stimuli. (n=2 animals, neurons=33/23 VPm/BFC; LSD comparison with baseline; all data presented as mean±SEM).